Cancers, Vol. 10, Pages 277: The Impact of Mesothelin in the Ovarian Cancer Tumor Microenvironment

Cancers, Vol. 10, Pages 277: The Impact of Mesothelin in the Ovarian Cancer Tumor Microenvironment

Cancers doi: 10.3390/cancers10090277

Authors: Tyvette S. Hilliard

Ovarian cancer is the deadliest gynecological disease among U.S. women. Poor 5-year survival rates (<30%) are due to presentation of most women at diagnosis with advanced stage disease with widely disseminated intraperitoneal metastasis. However, when diagnosed before metastatic propagation the overall 5-year survival rate is >90%. Metastasizing tumor cells grow rapidly and aggressively attach to the mesothelium of all organs within the peritoneal cavity, including the parietal peritoneum and the omentum, producing secondary lesions. In this review, the involvement of mesothelin (MSLN) in the tumor microenvironment is discussed. MSLN, a 40kDa glycoprotein that is overexpressed in many cancers including ovarian and mesotheliomas is suggested to play a role in cell survival, proliferation, tumor progression, and adherence. However, the biological function of MSLN is not fully understood as MSLN knockout mice do not present with an abnormal phenotype. Conversely, MSLN has been shown to bind to the ovarian cancer antigen, CA-125, and thought to play a role in the peritoneal diffusion of ovarian tumor cells. Although the cancer-specific expression of MSLN makes it a potential therapeutic target, more studies are needed to validate the role of MSLN in tumor metastasis.

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Genetic alterations of 9p24 in lymphomas and their impact for cancer (immuno-)therapy

Abstract

Chromosome 9 harbors several relevant oncogenes related to hematolymphoid malignancies and one specific region, 9p24, has come into the focus of attention in the last years as it contains recurrently mutant genes of therapeutic interest. The most prominent genes of this locus are programmed death ligands 1 and 2 (PDL1/PDL2), with the amplification of PDL1 being a hallmark of both classical Hodgkin and primary mediastinal B cell lymphoma, and Janus kinase 2 (JAK2), which is point-mutated in myeloproliferative neoplasms and other myeloid malignancies, and rearranged in PCM1-JAK2-positive myeloid/lymphoid neoplasms with eosinophila. Finally, this locus contains the lysine (K)-specific demethylase 4C (KDM4C/JMJD2C), which is also relevant for oncogenesis. Activation of these genes is effectuated, as exemplified, by multiple mechanisms, which is rather unique to oncogenes, since they are usually affected by just one type of mutation, and points towards the central role of these genes in tumor initiation and growth. Amplifications and, less frequently, translocations are the most common findings for PDL1/PDL2 and JAK2 in lymphomas. In this review, we describe the role of genes located on chromosome 9p24 and their derived proteins in diverse subtypes of lymphomas, with a special focus on PDL1 and PDL2, which are becoming a central target of immunotherapy, not only in classical Hodgkin lymphoma but also in various types of solid cancers. We also elucidate the role of the surgical pathologists in this setting — concerning what they can contribute — both diagnostically and predictively.

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Computational Investigation of Ripple Dynamics in Biofilms in Flowing Systems

Biofilms are collections of microorganisms that aggregate using a self-produced matrix of extracellular polymeric substance (EPS). It has been broadly demonstrated that many microbial infections in the body, including dental plaque, involve biofilms. While studying experimental models of biofilms relevant to mechanical removal of oral biofilms, distinct ripple patterns have been observed. In this paper, we describe a multiphase model used to approximate the dynamics of the biofilm removal process.

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Effects of bioengineered scaffold loaded with neurotrophins and locomotor training in restoring H-reflex responses after spinal cord injury

Abstract

The combinational effects of a bioengineered scaffold loaded with neurotrophins and rehabilitation training on spasticity observed after spinal cord injury (SCI) has not been studied. We used an animal model of moderate contusion injury at T9/T10 that received bioengineered scaffold poly N-isopropylacrylamide-g-poly ethylene glycol (PNIPAAm-g-PEG) loaded with BDNF/NT3 followed by body weight supported treadmill training (BWSTT) and assessed the efficacy of the combinational bioengineered approaches in treating spasticity. Five animal groups were included: Group 1: Sham, Group 2: Injury (SCI), Group 3: SCI + BWSTT (BWSTT), Group 4: SCI + PNIPAAm-g-PEG loaded with BDNF/NT3 (Transplant), and Group 5: SCI + PNIPAAm-g-PEG loaded with BDNF/NT3 + BWSTT (Combinational). Results indicate no significant changes in the BBB scores of animals among various groups, however, a significant restoration in the rate depression property of H-reflex was observed in both BWSTT and Combinational animals. Transplant group reported no improvement in the rate depression property of H-reflex and were similar to SCI only group. Histological findings report restoration of the chloride cotransporter (KCC2) labeling in both BWSTT and Combinational animals and down-regulation of KCC2 in both SCI and Transplant only animals. Findings from this study confirm that rehabilitation training is critical in restoring H-reflex responses and transplantation therapies alone cannot restore these responses after SCI. Also, although no significant difference was observed between the BWSTT and Combinational animals, comparable improvements in the two groups does open new pathways to exploring unique tissue-engineering approaches with promising clinical application for individuals with SCI.

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Bowel perforation in chronic idiopathic megarectum and megacolon

Description 

A 24-year-old man with autism spectrum disorder presented to accident and emergency complaining of a 1-week history of abdominal pain and diarrhoea. He had a history of chronic constipation with multiple previous admissions stretching 4 years back. On examination, he had a tender, distended abdomen with quiet bowel sounds. His CT scan on admission (figure 1) showed a dilated (up to 18 cm) rectum and sigmoid colon filled with faeces. The patient was managed conservatively with oral laxatives and regular enemas. However, the patient refused the enemas and was maintained on oral laxatives. Two days later, the patient complained of worsening abdominal pain. On examination, he had a peritonitic abdomen and reduced consciousness level. Biochemical investigations revealed worsening renal function and that the patient was now acidotic. A chest X-ray revealed free air beneath the diaphragm. A repeat CT scan (figures 2 and 3

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Hypermucoviscous Klebsiella pneumoniae liver abscess requiring liver resection

Description 

A 41-year-old healthy woman from China presented to her local hospital with a 4-day history of fevers, malaise and epigastric pain. On examination, she had localised right upper quadrant abdominal pain on palpation. Laboratory investigations showed leukocytosis (13.8x10⁹/L), thrombocytopaenia (82x10⁹/L) and elevated alanine transaminase (184 U/L). An abdominal CT scan revealed a 10x8x9 cm multiloculated collection within the right liver lobe, with a second nodular septated collection under the left subcapsular region (figure 1). Her blood cultures returned positive for Klebsiella pneumoniae, resistant to ampicillin and susceptible to cefazolin, ciprofloxacin and meropenem. She was admitted to hospital and started on ceftriaxone.

Figure 1

Abdominal CT showing large multiloculated liver abscesses in segments 2/3 of the left liver lobe (white arrow) and segments 6/7 of the right liver lobe (black arrow).

Diagnostic and therapeutic ultrasound-guided 10F drains were inserted into both abscesses...

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Paediatric parapharyngeal ganglioneuroma

A 17-year-old man initially presented to his primary care physician with throat pain for 1 week and was started on amoxicillin. After four additional days of ongoing pain and difficulty swallowing with decreased oral intake, he presented to the emergency department. Exam showed fullness to the right posterior oropharynx and palpable mass in the right neck without stridor. Initial imaging was soft tissue neck CT with contrast, which showed cystic 8 cm mass in the parapharyngeal space. Patient additionally underwent MRI, which showed an 8.6 cm mass in the right posterior oropharynx with obliteration of the vallecula. Differential diagnosis included abscess; therefore, ear, nose, and throat (ENT) specialist was consulted for possible drainage. Intraoperatively, there was no abscess; alternatively a biopsy was obtained, which was identified by pathology as a ganglioneuroma. Patient was referred to paediatric ENT specialist, underwent extensive resection confirming diagnosis of ganglioneuroma and did well postoperatively.

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Euglycaemic diabetic ketoacidosis in bariatric surgery patients with type 2 diabetes taking canagliflozin

A 52-year-old type 2 diabetic man previously on canagliflozin developed severe anion gap metabolic acidosis and markedly elevated beta-hydroxybutyrate on postoperative day (POD) 2 status post laparoscopic Roux-en-Y gastric bypass. An insulin drip and aggressive intravenous fluid repletion were initiated, and electrolytes were monitored and repleted. His anion gap closed, and he was discharged on POD 4. This euglycaemic diabetic ketoacidosis prolonged his hospital stay by 2 days.

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Asymptomatic dysphagia causing recurrent aspiration pneumonia

52-year-old male patient with known bipolar disorder and innate cerebral palsy causing widespread spasticity problems. Treated for 2 years with antidepressants and electroconvulsive therapy. He repeatedly presented with—and was treated for—pneumonia resulting in more than 20 episodes of hospital admission. He underwent numerous examinations until a diagnosis of dysphagia was established using video fluoroscopic swallowing examination (modified barium swallow). Eventually, as all other treatment regimens had proven effortless, percutaneous gastrostomy feeding tube was inserted and intensive training with a specialised occupational therapist was started. This treatment regimen caused the recurrent episodes of pneumonia to vanish. It is important to acknowledge that otherwise silent dysphagia may cause recurrent pneumonia.

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Trisomy 5 as the sole chromosomal anomaly in acute lymphoblastic leukaemia

Trisomy 5 as the sole cytogenetic aberration in acute lymphoblastic leukaemia (ALL) is exceedingly rare. As such, its prognostic and therapeutic relevance remains unknown. We report a case of an 18-year-old young man who was diagnosed with B cell ALL with trisomy 5 as the sole chromosomal abnormality. He was treated with chemotherapy and went into complete remission. On the 14th month of treatment, he relapsed with central nervous system involvement characterised by leukaemic infiltration of the optic nerve and facial palsy. He subsequently underwent reinduction chemotherapy with aggressive intrathecal chemotherapy followed by posterior globe and whole brain radiation therapy. He is currently on his 26th month of treatment, in second remission, with complete resolution of leukaemic infiltrative optic neuropathy and facial paralysis. As more cases of this nature are reported, we will be able to determine the relevance of this distinct cytogenetic entity.

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Colobronchial fistula: a rare cause of non-resolving pneumonia in Crohns disease

We discuss the case of a 44-year-old man with a refractory left lower lobe pneumonia progressing to a pulmonary abscess caused by a colobronchial fistula, a rare complication of underlying Crohn's disease. The patient presented with weight loss and signs of a pulmonary consolidation, which responded incompletely to the targeted antibiotic treatment. The causative colobronchial fistula was demonstrated by CT-guided puncture and retrograde injection of contrast medium. After fistula excision, the patient recovered rapidly with a weight gain of 4 kg within a few weeks.

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Charcot osteoarthropathy of the knee secondary to neurosyphilis: a rare condition managed by a challenging arthrodesis

The Charcot joint or neuropathic osteoarthropathy was first described as an arthritic sequela of neurosyphilis (tabes dorsalis). It results in significant joint destruction and instability. Nowadays, it is a very rare condition and represents a considerable challenge to the orthopaedic surgeon. The authors describe the case of a patient diagnosed with neurosyphilis who was requested an orthopaedic consultation for an enlarged and unstable knee. The diagnosis of Charcot knee was made and based on the clinical and radiographical findings combined with the patient's medical history. Knee arthrodesis was the surgical treatment chosen to preserve the limb and only succeeded at second attempt. At 4 years of follow-up, it proved to be an effective surgical treatment. In this article, we focus on the importance of early recognition of joint changes in these patients in order to prevent irreversible joint loss.

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Quadruple torsion of the fallopian tube in an 18-year-old virgin: a rare twist

In this report, we describe an 18-year-old nulliparous virgo, with no medical history, who presented herself at the emergency department with symptoms of lower abdominal pain and nausea with vomiting. On examination, an echogenic unilocular cyst with possible relation to the right ovary was found. The working diagnosis was an ovarian torsion. She underwent a diagnostic laparoscopy which revealed a quadruple torsion of the fallopian tube with hydrosalpinx. Detorsion of the tube was performed, and the tube was drained using diathermic incision. After the surgery, the patient recovered rapidly. Ultrasonic evaluation 38 days later showed an echogenic area measuring 2x3 cm suspected for persistent hydrosalpinx. Because of the asymptomatic postoperative period, the patient was treated conservatively, and no further treatment was performed.

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Non-cutaneous AIDS-associated Kaposis sarcoma presenting as recurrent rectal abscesses

Kaposi's sarcoma is a fatal disease that typically presents with cutaneous manifestations in immunocompromised individuals. There are a small number of documented cases where patients diagnosed with this disease present without cutaneous lesions. We present a 35-year-old man with recurrent rectal abscesses and fistula-in-ano, which required multiple drainage procedures. Further investigation revealed a diagnosis of HIV-AIDS, and biopsy of a rectal mass confirmed the diagnosis of visceral Kaposi's sarcoma, despite the absence of cutaneous involvement. Workup revealed hepatic metastasis and a second pulmonary primary malignancy. The patient denied chemotherapy or further intervention and was subsequently lost to follow-up. Prompt diagnosis of Kaposi's sarcoma and initiation of treatment is vital to decrease disease progression. A high index of suspicion should be present in immunocompromised patients, and clinicians must recognise atypical presentations in order to improve long-term survival.

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Primary amelanotic malignant melanoma of cervix masquerading as squamous cell carcinoma presenting with extensive metastases

Amelanotic melanoma of cervix is a rare and aggressive neoplasm and only few cases have been reported in the literature. We report a rare case of an amelanotic melanoma of the uterine cervix with extensive metastases and multiple subcutaneous nodules. Due to the unusual site and amelanotic nature of the lesion, chances of misdiagnosis are high and immunohistochemical markers for melanoma help establish the diagnosis. The possibility of metastasis from a primary malignant melanoma of the skin needs to be ruled out. The present case was initially misdiagnosed and treated on the regimen for squamous cell carcinoma, but progressed despite chemotherapy. After a thorough re-evaluation and applying extensive panel of immunohistochemistry, the diagnosis of an amelanotic malignant melanoma of uterine cervix was established.

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Internal iliac artery transposition for vascular reconstruction in a patient with life-threatening iatrogenic common iliac artery injury

Major vascular injury during surgery is life threatening and can be a nightmare for any surgeon.

We share our experience of a 42-year-old woman where right common iliac artery and both common iliac veins were accidentally injured during lumbar discectomy leading to haemorrhagic shock. Patient was resuscitated and explored. A 4 cm segment of right common iliac artery was found lacerated along with perforations of both iliac veins. Proximal segment of internal iliac artery was mobilised quickly and vascular continuity was restored by end-to-end anastomosis of this segment to the proximal segment of common iliac artery after excising the damaged segment. Iliac veins were repaired primarily. Patient made an uneventful recovery. We share this technique as it was found expeditious and effective and may benefit surgeons working in this field.

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Fever in a returning traveller: visceral leishmaniasis triggering haemophagocytic lymphohistiocytosis

We present the case of a 23-year-old student admitted with fever, night sweats and splenomegaly. These non-specific signs and symptoms posed a diagnostic challenge which was further complicated by a history of recent foreign travel. The range of potential diagnoses required a variety of investigations in order to reach the final diagnosis. The incidental finding of an incompetent bicuspid aortic valve and an inflamed gallbladder further clouded the diagnostic process. Despite treatment with broad spectrum antibiotics, the patient continued to deteriorate. Serological testing finally provided a diagnosis of visceral leishmaniasis. The patient subsequently developed haemophagocytic lymphohistiocytosis, a life-threatening immune hyperactivity state that very rarely complicates leishmaniasis infection. With the use of amphotericin B and high-dose steroids, the patient made an excellent recovery.

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Progressive supranuclear palsy responding to intravenous thiamine: superimposed Wernickes encephalopathy?

Progressive supranuclear palsy (PSP) may be a risk factor for thiamine deficiency. The classic symptoms of PSP (postural instability, supranuclear vertical gaze palsy and dementia) overlap with the clinical triad of Wernicke's encephalopathy (cognitive impairment, gait problems and ocular abnormality). Therefore, superimposed thiamine deficiency in patients with PSP may aggravate the pre-existing symptoms of PSP. Here, we are reporting a 64-year-old woman having supranuclear ocular palsy, gait instability and dementia for the past 2–3 years. The patient fulfilled the diagnostic criteria of PSP. In parallel, she fulfilled the Caine's criteria of Wernicke's encephalopathy. Her serum thiamine level was low. Supplementation of thiamine led to marked improvement in the symptoms which had been present for many years. These symptoms were originally presumed to be due to PSP. This case highlights the needs to identify superimposed thiamine deficiency in patients with PSP.

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Multiple renal calculi due to hypercalcaemia induced by over-the-counter vitamin D intoxication

Renal stone disease is a common and painful condition. Even though it is rarely fatal, patients describe it as the worst pain in their life. While dietary calcium may decrease the risk of stone formation, patients on supplemental calcium are at higher risk. Moreover, patients with diabetes are more prone to develop renal calculi. Hypervitaminosis D is a rare cause of hypercalcaemia. This is a case of an elderly diabetic man who developed multiple calcium oxalate renal stones due to hypercalcaemia following calcium–vitamin D supplementation.

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Misplaced Foley catheter in ureter in a female with neurogenic bladder: a rare complication report

Accidental placement of Foley catheter in ureter is a rare phenomenon. It is more common in females with neurogenic bladder who have hypocontractile bladder or there can be iatrogenic placement during surgical procedures. We describe a case of a female suffering from upper motor neuronal lesion due to trauma at T8 level (American Spinal Injury grade A) following which she developed neurogenic bladder. A Foley catheter was unintentionally placed in the ureter and subsequently removed through a novel technique of percutaneous ultrasound-guided balloon puncture. It is not only imperative to diagnose and manage such an aberrant Foley catheter placement but also more importantly proper steps must be taken to prevent such a complication from occurring in these patients.

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Mediastinal metastasectomy from a primary germ cell testicular tumour resulting in occult thoracic duct injury and chylothorax

A 22-year-old man underwent mediastinal metastasectomy for a testicular germ cell tumour via median sternotomy. Intraoperatively, the tumour was massive, measuring 88 mm in anterior-posterior (AP) diameter. It was densely adherent to the trachea and aggressive debulking resulted in tracheal injury. Therefore, the patient was kept nil by mouth for 3 days postoperatively and was discharged uneventfully. He represented only 2 days later with a large right-sided chylothorax. His chylothorax was managed conservatively with insertion of an intercostal catheter (ICC) and a low-fat diet. Over the course of 9 days, the ICC drained approximately 5 L of fluid. His admission was further complicated by severe gastroparesis requiring feeding Nasojejunal (NJ) tube placement. The delayed feeding in this case resulted in late detection of the occult thoracic duct injury. This case illustrates that conservative and multidisciplinary management of a postoperative chylothorax from a suspected thoracic duct injury achieves favourable outcomes avoiding further surgical intervention.

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Malignant proliferating trichilemmal tumour

Proliferating trichilemmal tumours are benign but locally aggressive skin neoplasms arising from hair follicles. Rarely, they can become malignant and must be appropriately managed to prevent recurrence and metastasis. One must have a low threshold for diagnosing this rare neoplasm.

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Tracking a painful episode after a joint replacement using patient-reported outcome measures (PROMs)

Patient-reported outcome measures (PROMs) are an important tool in measuring the benefit of a surgery for patients and for clinicians. The results of such assessment tools can be used to monitor patient progress or initiate intervention. The scores also provide a reproducible evaluation of functional recovery and well-being after surgery. We report the case of a 68-year-old woman who underwent left unicondylar knee replacement in November 2011 followed by right unicondylar knee replacement in April 2012. Prospective, web-based electronic PROMs were used preoperatively and every 6–12 months postoperatively to monitor the improvement in pain and function symptoms. These outcome measures were beneficial in helping to monitor an episode of new pain in her left knee, without requiring invasive or extensive investigation.

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Delirium and topographical disorientation associated with glioblastoma multiforme tumour progression into the isthmus of the cingulate gyrus

Since there is no cure for glioblastoma multiforme (GBM), the goal of treatment becomes prolonging the survival through cytoreduction while minimising neurological deficits. In this case report, laser interstitial thermal therapy (LITT) was used once the tumour progressed into the isthmus of the cingulate gyrus. One year after temporal lobectomy, disorders of memory, emotion, personality and navigation, likely related to limbic system involvement along with hallucinations and fluctuating cognition occurred as the tumour progressed. After ablation of the posterior cingulum, worsening of topographical disorientation was observed.

Per literature review, delirium has been noted in patients with strokes involving the right-sided temporo-parieto-occipital junction, and topographical disorientation has been associated with lesions of the right posterior cingulum. Alternative causes of these deficits were ruled out, leaving structural changes as the primary explanation. This is the first report of the neurological deficits associated with tumour progression and vasogenic oedema in this region.

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A preliminary epidemiological study of pinworm infection in Thaklong Municipal Early Childhood Development Center and Rangsit Babies’ Home, Pathum Thani, Thailand

We investigated the prevalence and risk factors for Enterobius vermicularis in children at the Thaklong Municipal Early Childhood Development Center (TMECDC), and the Rangsit Babies' Home (RBH) in Pathum Thani, T...

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Colostrum avoidance and associated factors among mothers having children less than 2 years of age in Aksum town, Tigray, Ethiopia: a cross-sectional study 2017

To assess colostrum avoidance practices and associated factors among mothers of children aged less than two in Aksum town, Tigray, Ethiopia, 2017.

https://ift.tt/2N4tvhy

Multidrug-resistant bacterial isolates from patients suspected of nosocomial infections at the University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia

As the hospital environment favors the circulation of drug resistant bacteria, continuous surveillance of antibiotic resistant patterns is an important approach for a better patient management. This study is t...

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Poor glycemic control impacts heart rate variability in patients with type 2 diabetes mellitus: a cross sectional study

We aimed to determine and compare HRV parameters in poorly and well controlled type 2 diabetes. 54 normotensive type 2 diabetes patients without clinical signs of CAN were enrolled; 29 poorly controlled (HbA1c...

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The dental infections in patients undergoing preoperative dental examination before surgical treatment of saccular intracranial aneurysm

Dental bacterial DNA and bacterial-driven inflammation markers have previously been detected in intracranial aneurysm tissue samples. This study aimed (i) to assess the possible presence of dental infectious f...

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CD200 expression is a feature of solid pseudopapillary neoplasms of the pancreas

Abstract

CD200 has been recently indicated as a robust marker of well-differentiated neuroendocrine neoplasms. Here, we evaluate its role in differential diagnosis of solid pancreatic neoplasms. We immunostained for CD200 22 solid pseudopapillary neoplasms (SPNs), 8 acinar carcinomas (ACs), 2 pancreatoblastomas (PBs), 138 neuroendocrine tumors (PanNETs), and 48 ductal adenocarcinomas. All SPNs showed strong cytoplasmic and membranous staining for CD200, while only one case of AC had focal positivity. The two PBs showed focal CD200 positivity, mainly located in squamoid nests. The vast majority of PanNETs (96%) showed strong cytoplasmic and membranous staining for CD200, whereas all PDACs were negative. As both PanNETs and SPNs express CD200, it has no role in the differential diagnosis between these two entities.

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Microneedles Improve the Immunogenicity of DNA Vaccines

Human Gene Therapy, Ahead of Print.


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Reproductive and gynecological complication risks among thyroid cancer survivors

Abstract

Purpose

Thyroid cancer is the most rapidly increasing cancer in the USA, affects a young, mostly female population, and has high survival. The aim of this study was to determine if there is an increased risk of reproductive system adverse events or pregnancy complications among women diagnosed with thyroid cancer under the age of 50.

Methods

Up to five female cancer-free individuals were matched to each female thyroid cancer survivor diagnosed before the age of 50 based on birth year, birth state, and follow-up time, within the Utah Population Database. Medical records were used to identify disease diagnoses stratified over three time periods: 0–1, > 1–5, and > 5–10 years after cancer diagnosis. Cox proportional hazards models were used to estimate hazard ratios (HR) with adjustment on matching factors, race, BMI, and Charlson Comorbidity Index.

Results

There were 1832 thyroid cancer survivors and 7921 matched individuals. Thyroid cancer survivors had higher rates of having multiple health conditions associated with the gynecological system (15.4% vs. 9.4%) and pregnancy (14.3% vs 9.5%) > 1–5 years after cancer diagnosis. Increased risks persisted > 5–10 years after cancer diagnosis for menopausal disorders (HR = 1.78, 99% CI = 1.37, 2.33) and complications related to pregnancy (HR = 2.13, 99% CI = 1.14, 3.98). Stratified analyses showed these risks remained increased across different treatment types.

Conclusions

There were significant risk increases in reproductive system and pregnancy complications among female thyroid cancer survivors within this study.

Implications for Cancer Survivors

Although radiation has been linked to reproductive risks in previous studies, we found risks were increased in patients regardless of treatment.

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The effect of diabetes mellitus on the pharmacokinetics and pharmacodynamics of tuberculosis treatment [Clinical Therapeutics]

Background: Diabetes mellitus (DM) and tuberculosis (TB) are two common diseases with increasing geographic overlap and clinical interactions. The effect of DM and hemoglobin A1c (HbA1c) values on the pharmacokinetics and pharmacodynamics of anti-TB drugs remains poorly-characterized.

Methods: Newly-diagnosed TB patients with and without DM starting fixed-dose, thrice-weekly treatment underwent sampling for PK assessments (pre-dose, 0.5, 2, 6 hours post-dose) during intensive and continuation phases of treatment. The effect of DM and HbA1c on the maximum concentration (C_max) of rifampin, isoniazid, and pyrazinamide and the association between drug concentrations and microbiologic and clinical outcomes were assessed.

Results: Of 243 patients, 101 had DM. Univariate analysis showed significant reductions in C_max of pyrazinamide and isoniazid (but not rifampicin) with DM or increasing HbA1c. After adjusting for age, sex, and weight, DM was associated only with reduced pyrazinamide concentrations [adjusted GMR: 0.74, p=.032]. In adjusted Cox models, female gender (aHR=1.75, p=0.001), lower Xpert smear grade (aHR=1.40, p<0.001) and pyrazinamide C_max (aHR=0.99, p=0.006) were independent predictors of sputum culture conversion to negative. Higher isoniazid or rifampicin concentrations were associated with faster time to culture conversion in patients with DM only. Pyrazinamide C_max above the therapeutic target was associated with higher unfavorable outcomes (treatment failure, relapse, death) [OR: 1.92, p=.041].

Conclusion: DM and higher HbA1c increased the risk of not achieving therapeutic targets for pyrazinamide (but not rifampicin or isoniazid). Higher pyrazinamide concentrations, though, were associated with worse microbiologic and clinical outcomes. DM status also appeared to influence PK-PD relationships for isoniazid and rifampicin.

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Characterizing the Effects of Glutathione as an Immunoadjuvant in the Treatment of Tuberculosis [Experimental Therapeutics]

Mycobacterium tuberculosis (M. tb) is the etiological agent that is responsible for causing tuberculosis (TB), which continues to affect millions of people worldwide, with an ever-increasing resistance to antibiotics. We tested the synergistic effects of N-acetyl cysteine (NAC, the precursor molecule for the synthesis of glutathione) and individual first-line antibiotics typically given for the treatment of TB such as Isoniazid (INH), Rifampicin (RIF), Ethambutol (EMB) and Pyrazinamide (PZA) to improve the ability of macrophages to control intracellular M. tb infection. Glutathione (GSH), a pleiotropic antioxidant molecule has been previously shown to display both antimycobacterial and immune-enhancing effects. Our results indicate that there was not only an increase in beneficial immunomodulatory effects, but a greater reduction in the intracellular viability of M. tb when macrophages were treated with the combination of antibiotics (INH/RIF/EMB or PZA) and NAC.

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Biolog phenotype microarray: a tool for the identification of multidrug resistance efflux pumps inducers [Mechanisms of Resistance]

Multidrug resistance efflux pumps frequently present low levels of basal expression. However, antibiotic resistant mutants that overexpress these resistance determinants are selected during infection. In addition, increased expression of efflux pumps can be induced by environmental signals/cues, which can lead to situations of transient antibiotic resistance. Herein, we have applied a novel high-throughput methodology in order to identify inducers able of triggering the expression of the Stenotrophomonas maltophilia SmeVWX and SmeYZ efflux pumps. To that goal, bioreporters in which the expression of the yellow fluorescent protein (YFP) is linked to the activity of either smeVWX or smeYZ promoters were developed and used for the screening of potential inducers of the expression of these efflux pumps using Biolog phenotype microarrays. YFP production was measured by flow cytometry and the levels of expression of smeV and smeY in the presence of a set of selected compounds were also determined by real-time RT-PCR. The expression of smeVWX was induced by iodoacetate, clioquinol and selenite, while boric acid, erythromycin, chloramphenicol and lincomycin triggered smeYZ expression. The susceptibility to antibiotics that are known substrates of the efflux pumps decreased in the presence of the inducers. However, the analyzed multidrug efflux systems did not contribute to S. maltophilia resistance to the studied inducers. To sum up, the use of fluorescent bioreporters in combination with Biolog plates is a valuable tool for identifying inducers of the expression of bacterial multidrug efflux pumps, and likely of other bacterial systems whose expression is regulated in response to signals/cues.

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Deletion of one 23S rDNA (rrl) copy contributes to the development of resistance to linezolid in Staphylococcus warneri [Letters]

Staphylococcus warneri, one of the emerging coagulase negative staphylococci, could be responsible for bone and joint infections (1-3), where linezolid (LZD) seems to be a good alternative treatment (4, 5)....

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Short-Term Peripheral Venous Catheter-Related Bloodstream Infections: Evidence for Increasing Prevalence of Gram-Negative Microorganisms from a 25-Year Prospective Observational Study [Epidemiology and Surveillance]

Aim of this study was to describe the etiology and outcome of short-term peripheral venous catheter (PVC)-related blood-stream infections (PVCRBSI) in a 25-year period (1992-2016) and to identify predictive factors of gram-negative PVCRBSI.

This was a prospective observational study including all episodes of PVCRBSI. A multivariate logistic regression model adjusted for calendar year was built to explore factors associated with gram-negative etiology.

Over the study period, 711 episodes of PVCRBSI were identified. Incidence rate of PVCRBSI increased from 0.06 to 0.13 episodes/1000patient-days. Gram-negative etiology was demonstrated in 162 (22.8%) episodes. There was a significant increase in the proportion of gram-negative etiology (22.6% in 1992-1996 versus 33.2% in 2012-2016). Independent predictive factors of gram-negative PVCRBSI were being in the hospital for more than 7 days with a catheter in situ for more than 3 days (aOR 1.80, 95%CI 1.20-2.69), surgery in the previous month (aOR 2.39, 95%CI 1.40-4.09), and antimicrobial treatment with beta-lactams (aOR 1.80, 95%CI 1.16-2.78).

In conclusion, we reported an increase in the prevalence of gram-negative PVCRBSI over the last 25 years. Factors associated with gram-negative etiology were being in the hospital for more than 7 days with a catheter in situ for more than 3 days, having undergone surgery and having received antimicrobial treatment with beta-lactams.

https://ift.tt/2nVprFa

Identifying vancomycin as an effective antibiotic for killing Borrelia burgdorferi [Experimental Therapeutics]

Borrelia burgdorferi is the causative agent of Lyme borreliosis. Antibiotic therapy of early acute infection is effective for most patients, but 10-20% go on to develop Post-Treatment Lyme Disease Syndrome. The nature of PTLDS remains unknown, but currently approved antibiotics for treatment of Lyme disease do not appear to impact these symptoms after they have developed. We reason that minimizing the time the pathogen interacts with the host will diminish the probability of developing PTLDS, irrespective of its nature. This calls for an efficient eradication of the pathogen during acute infection. In search of a superior killing antibiotic, we examined approved antibiotics for their ability to kill B. burgdorferi. Vancomycin proved more effective in killing the pathogen in vitro than ceftriaxone, the standard of care for disseminated B. burgdorferi infection. Both compounds were also the most effective in killing stationary phase cells. This is surprising, given that inhibitors of cell wall biosynthesis are known to only kill growing bacteria. We found that peptidoglycan synthesis continues in stationary cells of B. burgdorferi, explaining this paradox. A combination of vancomycin and gemifloxacin sterilized a stationary phase culture of B. burgdorferi. Examination of the action of antibiotics in immune-deficient SCID mice showed that doxycycline, a standard of care for uncomplicated acute infection, did not clear the pathogen. By contrast, both ceftriaxone and vancomycin cleared the infection. A trial examining early use of more potent antibiotics on development of PTLDS may be warranted.

https://ift.tt/2OOprlZ

An optimized background regimen for treatment of active tuberculosis with the next-generation benzothiazinone Macozinone (PBTZ169) [Susceptibility]

The efficacy of the standardized four-drug regimen (comprising isoniazid, rifampicin, pyrazinamide and ethambutol) for the treatment of tuberculosis (TB) is menaced by the emergence of multidrug (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. Intensive efforts have been made to develop new antibiotics or to repurpose old drugs and several of these are currently being evaluated in clinical trials for their anti-tubercular activity. Among the new candidate drugs is macozinone (MCZ), the piperazine-containing benzothiazinone, PBTZ169, which is currently being evaluated in phase I/II clinical trials.

Here, we determined the in vitro and in vivo activity of MCZ in combination with a range of anti-TB drugs in order to design a new regimen against active TB. Two-drug combinations with MCZ were tested against M. tuberculosis using checkerboard and CFU enumeration after drug exposure assays. MCZ was observed to have no interactions with all first- and second-line anti-TB drugs. At the MIC of each drug, MCZ with either bedaquiline (BDQ), clofazimine (CLO), delamanid (DMD) or sutezolid (STZ) reduced the bacterial burden by two logs compared to the drugs alone, indicating synergism. MCZ also displays synergism with clomiphene (CLM), a potential inhibitor of the undecaprenyl pyrophosphate synthase (UppS) in mycobacteria. For all the other drugs tested in combination with MCZ, no synergistic activity was observed. Neither antagonism nor increased cytotoxicity were found for most combinations, suggesting that MCZ could be added to different TB regimens without any significant adverse effects.

https://ift.tt/2nW1kGK

Voriconazole resistance in clinical and environmental isolates of Aspergillus flavus - frequency and investigation into the role of multidrug efflux pumps. [Mechanisms of Resistance]

The magnitude of azole resistance in Aspergillus flavus and the underlying mechanism is obscure. We evaluated the frequency of azole resistance in a collection of clinical (n=121) and environmental isolates (n=68) of A. flavus by broth microdilution method. Six (5%) clinical isolates displayed voriconazole minimum inhibitory concentration (MIC) greater than the epidemiological cut-off value. Two of these isolates with non-wild-type MIC were isolated from same patient and were genetically distinct, which was confirmed by amplified length polymorphism. Mutations associated with azole resistance were not present in the lanosterol 14-α demethylase coding genes (cyp51A, cyp51B and cyp51C). Basal and voriconazole-induced expression of cyp51A homologs and various efflux pump genes was analyzed in three each of non-wild type and wild-type isolates. All the efflux pump genes screened showed low basal expression irrespective of the azole susceptibility of the isolate. However, the non-wild type isolates demonstrated heterogeneous overexpression of many efflux pumps and the target enzyme coding genes in response to induction with voriconazole (1μg/mL). The most distinctive observation was approximately 8-9 fold voriconazole-induced overexpression of an ortholog of Candida albicans ABC multidrug efflux transporter, Cdr1 in two non-wildtype isolates as compared to the reference strain A. flavus ATCC204304 and other wild type strains. Although the dominant marker of azole resistance in A. flavus is still elusive, the current study proposes the possible role of multidrug efflux pumps, especially Cdr1B overexpression in contributing azole resistance in A. flavus.

https://ift.tt/2OObvbA

In Vitro Susceptibility Testing of a Novel Benzimidazole, SPR719, Against Nontuberculous Mycobacteria [Susceptibility]

Nontuberculous mycobacteria (NTM) infections are increasing globally. Mycobacterium avium complex (MAC) and M. abscessus are the most frequently encountered NTM among clinical laboratories, and treatment options are extremely limited. In this study, the in vitro potency of a novel benzimidazole, SPR719, the microbiologically active form of the orally available prodrug SPR720, was tested against several species of NTM.

MICs were performed on 161 isolates of NTM of 13 taxa (seven species, three subspecies and three groups/complexes) in cation adjusted Mueller Hinton Broth as described and recommended by the Clinical and Laboratory Standards Institute (CLSI M24-A2). Comparator antimicrobials included amikacin, cefoxitin, ciprofloxacin, clarithromycin, doxycycline, imipenem, linezolid, minocycline, moxifloxacin, tigecycline, and trimethoprim/sulfamethoxazole (TMP/SMX) for the rapidly growing species (RGM); amikacin and clarithromycin for the MAC; amikacin, ciprofloxacin, clarithromycin, doxycycline, linezolid, moxifloxacin, rifabutin, rifampin and TMP/SMX for the other slowly growing NTM. SPR719 was found to be potent against multiple clinical strains of NTM with an MIC₅₀ range of 0.25 – 4 μg/mL for several species of NTM. These findings support the further advancement of SPR720 for the treatment of NTM disease.

https://ift.tt/2nW1jTc

Plasma and Intrapulmonary Concentrations of ETX2514 and Sulbactam following Intravenous Administration of ETX2514SUL to Healthy Adult Subjects [Pharmacology]

ETX2514 is a novel β-lactamase inhibitor that broadly inhibits Ambler class A, C and D β-lactamases. ETX2514 combined with sulbactam (SUL) in vitro restores sulbactam activity against Acinetobacter baumannii. ETX2514/sulbactam (ETX2514SUL) is under development for the treatment of A. baumannii infections. The objective of this study was to determine and compare plasma, epithelial lining fluid (ELF) and alveolar macrophages (AM) concentrations following intravenous (i.v.) ETX2514 and sulbactam. Plasma, ELF, and AM concentrations of ETX2514 and sulbactam were measured by LC-MS/MS in 30 healthy adult subjects following repeated dosing (ETX2514 [1 g] and sulbactam [1 g] q6h, as a 3-hour i.v. infusion, for a total of 3 doses). A bronchoalveolar lavage (BAL) was performed once in each subject at either 1, 2.5, 3.25, 4 or 6 h after the start of the last infusion. Penetration ratios were calculated from AUC_0–6 values for total plasma and ELF using mean and median concentrations at the BAL sampling times. Respective ELF AUC_0-6, based on mean and median concentrations, were 40.1 and 39.4 mg·h/liter for ETX2514 and 34.7 and 34.5 mg·h/liter for sulbactam. Respective penetration ratios of ELF to total/unbound plasma concentrations, based on mean/median AUC_0-6, of ETX2514 were 0.36/0.40 and 0.35/0.39, whereas these same ratio values were 0.5/0.81 and 0.50/0.80 for sulbactam. ETX2514 and sulbactam concentrations in AM were measurable and fairly constant throughout the dosing interval (median values of 1.31 and 1.01 mg/liter, respectively). These data support further study of ETX2514SUL for treatment of pneumonia caused by multidrug-resistant A. baumanni.

https://ift.tt/2OPF3FO

Contributions of yap1 mutation and subsequent atrF upregulation to voriconazole resistance in Aspergillus flavus [PublishAheadOfPrint]

Aspergillus flavus is the second most significant pathogen that causes invasive aspergillosis; however, its emergence risks and mechanisms of voriconazole (VRC) resistance have not yet been elucidated in detail. Here, we demonstrate that repeated exposure of A. flavus to sub-inhibitory concentrations of VRC in vitro causes the emergence of a VRC-resistant mutant with a novel resistance mechanism. The VRC-resistant mutant shows a MIC of 16 μg/mL for VRC, and of 0.5 μg/mL for itraconazole (ITC). Whole-genome sequencing analysis showed that the mutant possesses a point mutation in yap1, which encodes a bZIP transcription factor working as the master regulator of oxidative stress response, but no mutations in the cyp51 genes. This point mutation in yap1 caused substitution of Leu558 to Trp (Yap1^Leu558Trp) in the putative nuclear export sequence in the carboxy-terminal cysteine-rich domain of Yap1. This Yap1^Leu558Trp substitution was confirmed as being responsible for the VRC-resistant phenotype, but not for ITC, by the revertant to Yap1^wild-type with homologous gene replacement. Furthermore, Yap1^Leu558Trp caused marked upregulation of the atrF ATP-binding cassette transporter, and the deletion of atrF restored susceptibility to VRC in A. flavus. These findings provide new insights into VRC-resistance mechanisms via a transcriptional factor mutation that is independent of the cyp51 gene mutation in A. flavus.

https://ift.tt/2nRbgRM

Carbapenem resistance caused by high-level expression of OXA-663 {beta}-lactamase in an OmpK36-deficient Klebsiella pneumoniae clinical isolate [PublishAheadOfPrint]

Carbapenem resistance is mainly mediated by carbapenemases or extended-spectrum β-lactamases (ESBL) plus loss of porins. However, we have identified a Klebsiella pneumoniae clinical isolate that contains neither carbapenemases nor ESBLs. Instead, we found that high-level expression of a novel bla_OXA-10-derived β-lactamase gene, bla_OXA-663, in conjunction with OmpK36 deficiency results in high-level carbapenem resistance. This finding demonstrates the combinatorial complexity of factors including β-lactamase activity, its expression levels, and porin activity that yield carbapenem resistance.

https://ift.tt/2LdYdDj

Crystal structures of full-length lanosterol 14{alpha}-demethylases of prominent fungal pathogens Candida albicans and Candida glabrata provide tools for antifungal discovery [PublishAheadOfPrint]

Targeting lanosterol 14α-demethylase (LDM) with azole drugs provides prophylaxis and treatments for superficial and disseminated fungal infections but cure rates are not optimal for immune compromised patients and individuals with co-morbidities. The efficacy of azole drugs has also been reduced due to the emergence of drug resistant fungal pathogens. We have addressed the need to improve the potency, spectrum and specificity for azoles by expressing in Saccharomyces cerevisiae functional, recombinant, hexahistidine-tagged, full-length Candida albicans LDM (CaLDM6xHis) and Candida glabrata LDM (CgLDM6xHis) and determining their X-ray crystal structures. The crystal structures of CaLDM6xHis, CgLDM6xHis and ScLDM6xHis have the same fold and bind itraconazole in near identical conformations. The catalytic domains of the full-length LDMs have the same fold as the CaLDM6xHis catalytic domain in complex with posaconazole, with minor structural differences within the ligand binding pocket. Our structures give insight into the LDM reaction mechanism and phenotypes of single site CaLDM mutations. This study provides a practical basis for the structure-directed discovery of novel antifungals that target LDMs of fungal pathogens.

https://ift.tt/2nUjQzh

Heterologous expression of full-length lanosterol 14{alpha}-demethylases of prominent fungal pathogens Candida albicans and Candida glabrata provides tools for antifungal discovery [PublishAheadOfPrint]

Targeting lanosterol 14α-demethylase (LDM) with azole drugs provides prophylaxis and treatments for superficial and disseminated fungal infections but cure rates are modest for immune compromised patients and individuals with co-morbidities. The efficacy of azole drugs has also been reduced due to the emergence of drug resistant fungal pathogens. We have addressed these problems by expressing in Saccharomyces cerevisiae functional, hexahistidine-tagged, full-length Candida albicans LDM (CaLDM6xHis) and Candida glabrata LDM (CgLDM6xHis) for drug discovery purposes and determining their X-ray crystal structures. In comparison with S. cerevisiae overexpressing LDM6xHis (ScLDM6xHis), the reduced susceptibility of CgLDM6xHis to all azole drugs tested correlated with its level of overexpression. In contrast, the reduced susceptibility to short- (fluconazole, voriconazole) but not medium- (VT-1161) or long-tailed azoles (itraconazole and posaconazole) indicates CaLDM6xHis works best when co-expressed with its cognate NADPH-cytochrome P450 reductase (CaNcp1A) rather than the host reductase (ScNcp1). Overexpression of LDM or Ncp1 modified the ergosterol content of yeast and affected growth inhibition by the polyene antibiotic amphotericin B. Affinity-purified recombinant Candida LDMs bind carbon monoxide and show tight type II binding of a range of azole drugs including itraconazole, posaconazole, fluconazole, and voriconazole. This study provides a practical basis for the phenotypic-, biochemical- and structure-directed discovery of novel antifungals that target LDMs of fungal pathogens.

https://ift.tt/2OTBnTv

Functional Interactions Between rsks-1/S6K, glp-1/Notch, and Regulators of Caenorhabditis elegans Fertility and Germline Stem Cell Maintenance

The proper accumulation and maintenance of stem cells is critical for organ development and homeostasis. The Notch signaling pathway maintains stem cells in diverse organisms and organ systems. In Caenorhabditis elegans, GLP-1/Notch activity prevents germline stem cell (GSC) differentiation. Other signaling mechanisms also influence the maintenance of GSCs, including the highly-conserved TOR substrate ribosomal protein S6 kinase. Although C. elegans bearing either a null mutation in rsks-1/S6K or a reduction-of-function (rf) mutation in glp-1/Notch produce half the normal number of adult germline progenitors, virtually all these single mutant animals are fertile. However, glp-1(rf) rsks-1(null) double mutant animals are all sterile, and in about half of their gonads, all GSCs differentiate, a distinctive phenotype associated with a significant reduction or loss of GLP-1 signaling. How rsks-1/S6K promotes GSC fate is unknown. Here, we determine that rsks-1/S6K acts germline-autonomously to maintain GSCs, and that it does not act through Cyclin-E or MAP kinase in this role. We found that interfering with translation also enhances glp-1(rf), but that regulation through rsks-1 cannot fully account for this effect. In a genome-scale RNAi screen for genes that act similarly to rsks-1/S6K, we identified 56 RNAi enhancers of glp-1/Notch sterility, many of which were previously not known to interact functionally with Notch. Further investigation revealed six candidates that, by genetic criteria, act linearly with rsks-1/S6K. These include genes encoding translation-related proteins, cacn-1/Cactin, an RNA exosome component and a Hedgehog-related ligand. We found that additional Hedgehog-related ligands may share functional relationships with glp-1/Notch and rsks-1/S6K in maintaining germline progenitors.

https://ift.tt/2w0c7DZ

A Novel Mutation in brain tumor Causes Both Neural Over-Proliferation and Neurodegeneration in Adult Drosophila

A screen for neuroprotective genes in Drosophila melanogaster led to the identification of a mutation that causes extreme, progressive loss of adult brain neuropil in conjunction with massive brain overgrowth. We mapped the mutation to the brain tumor (brat) locus, which encodes a tripartite motif-NCL-1, HT2A, and LIN-41 (TRIM-NHL) RNA-binding protein with established roles limiting stem cell proliferation in developing brain and ovary. However, a neuroprotective role for bratin the adult Drosophila brain has not been described previously. The new allele, brat^cheesehead (brat^chs), carries a mutation in the coiled-coil domain of the TRIM motif, and is temperature-sensitive. We demonstrate that mRNA and protein levels of neural stem cell genes are increased in heads of adult brat^chs mutants and that the over-proliferation phenotype initiates prior to adult eclosion. We also report that disruption of an uncharacterized gene coding for a presumptive prolyl-4-hydroxylase strongly enhances the over-proliferation and neurodegeneration phenotypes. Together, our results reveal an unexpected role for brat that could be relevant to human cancer and neurodegenerative diseases.

https://ift.tt/2LcfGf8

Identification of Candidate Genes Controlling Black Seed Coat and Pod Tip Color in Cowpea (Vigna unguiculata [L.] Walp)

Seed coat color is an important part of consumer preferences for cowpea (Vigna unguiculata [L.] Walp). Color has been studied in numerous crop species and has often been linked to loci controlling the anthocyanin biosynthesis pathway. This study makes use of available resources, including mapping populations, a reference genome, and a high-density single nucleotide polymorphism genotyping platform, to map the black seed coat and purple pod tip color traits, with the gene symbol Bl, in cowpea. Several gene models encoding MYB domain protein 113 were identified as candidate genes. MYB domain proteins have been shown in other species to control expression of genes encoding enzymes for the final steps in the anthocyanin biosynthesis pathway. PCR analysis indicated that a presence/absence variation of one or more MYB113 genes may control the presence or absence of black pigment. A PCR marker has been developed for the MYB113 gene Vigun05g039500, a candidate gene for black seed coat color in cowpea.

https://ift.tt/2nTKBUh

A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT)

Abstract

Background

In order to facilitate implementation of precision medicine in clinical management of cancer, there is a need to harmonise and standardise the reporting and interpretation of clinically relevant genomics data.

Methods

The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) launched a collaborative project to propose a classification system for molecular aberrations based on the evidence available supporting their value as clinical targets. A group of experts from several institutions was assembled to review available evidence, reach a consensus on grading criteria and present a classification system. This was then reviewed, amended and finally approved by the ESMO TR and PM WG and the ESMO leadership.

Results

This first version of the ESMO Scale of Clinical Actionability for molecular Targets (ESCAT) defines six levels of clinical evidence for molecular targets according to the implications for patient management: tier I, targets ready for implementation in routine clinical decisions; tier II, investigational targets that likely define a patient population that benefits from a targeted drug but additional data are needed; tier III, clinical benefit previously demonstrated in other tumour types or for similar molecular targets; tier IV, preclinical evidence of actionability; tier V, evidence supporting co-targeting approaches; and tier X, lack of evidence for actionability.

Conclusions

The ESCAT defines clinical evidence-based criteria to prioritise genomic alterations as markers to select patients for targeted therapies. This classification system aims to offer a common language for all the relevant stakeholders in cancer medicine and drug development.

https://ift.tt/2ORBuyY

Targeting Myddosome Signaling in Waldenström's Macroglobulinemia with the Interleukin-1 Receptor-associated Kinase 1/4 Inhibitor R191

Purpose: Waldenström's macroglobulinemia is an incurable lymphoproliferative disorder driven by an L265P mutation in the Myeloid differentiation primary response gene 88 (MYD88), which activates downstream Nuclear factor kappa-B (NF-kB) signaling through the Myddosome. As this pathway depends in part on activity of Interleukin-1 receptor-associated kinases (IRAK)-1 and -4, we sought to evaluate the potential of the IRAK1/4 inhibitor R191 in pre-clinical models. Experimental design:Patient-derived cell lines and primary samples were used in both in vitro and in vivo experiments to model Waldenström's macroglobulinemia and its response to IRAK1/4 inhibitors. Results: R191 induced a dose- and time-dependent reduction in viability of BCWM.1 and MWCL-1 Waldenström's cell lines, and suppressed activation of IRAK1/4. This was associated with cell cycle arrest at G₀/G₁, reduced levels of Cyclin-dependent kinases 4 and 6, and induction of apoptosis in cell lines and primary patient samples. Further downstream, R191 exposure led to reduced activation of NF-kB, and of Protein kinase B/Akt/mammalian target of rapamycin signaling, while expression of a constitutively active Akt mutant induced R191 resistance. Gene expression profiling and gene set enrichment analysis revealed a signature consistent with inhibition of c-Myc and activation of the endoplasmic reticulum stress response. In both subcutaneous and systemic murine models of Waldenström's, R191 showed anti-tumor activity. Finally, the activity of R191 was enhanced when it was combined with novel chemotherapeutics such as bortezomib, afuresertib, and ibrutinib. Conclusion:Taken together, these data support the translation of R191 as an approach to target IRAK1/4 to the clinic for Waldenström's macroglobulinemia patients.

https://ift.tt/2MsTcfm

Physicians Rate Communication During Visit Lower Than Patients

MONDAY, Aug. 20, 2018 -- There is a lack of correlation between physician scores and those of others for physician-patient communication, according to a study published in the July/August issue of the Annals of Family Medicine. Jenni Burt, Ph.D.,...

https://ift.tt/2Bsn9Hg

Wildfire Smoke Causing Poor Air Quality in U.S. Pacific Northwest

MONDAY, Aug. 20, 2018 -- Smoke from wildfires will cause poor air quality in parts of the U.S. Pacific Northwest this week, officials warn. Air quality alerts are in effect for much of Washington state through Wednesday, according to the National...

https://ift.tt/2MGYqU2

Experts Offer Tips for Provider Appeal of Denied Medical Claims

MONDAY, Aug.20, 2018 -- Knowing payer policies and regulatory requirements is critical to appealing denials, according to an article published in Medical Economics. Michael Strong, a bill review technical specialist at SFM Mutual Insurance Co. in...

https://ift.tt/2Bsn726

NYU Becomes First Medical School to Cover All Tuition

MONDAY, Aug. 20, 2018 -- The NYU School of Medicine has announced that it is offering full-tuition scholarships to all current and future students in its M.D. degree program, regardless of need or merit. The scholarship is intended to address the...

https://ift.tt/2MGozCz

Odds of Death Up With Exposure to Pregabalin, Opioids

MONDAY, Aug. 20, 2018 -- Concomitant exposure to pregabalin and opioids is associated with increased odds of opioid-related death, according to a research letter published online Aug. 21 in the Annals of Internal Medicine. Tara Gomes, Ph.D., from...

https://ift.tt/2Bsn6v4

Towards BCI-actuated smart wheelchair system

Electroencephalogram-based brain–computer interfaces (BCIs) represent novel human machine interactive technology that allows people to communicate and interact with the external world without relying on their ...

https://ift.tt/2MHegya

Ultrasonic image analysis of longitudinal strain in uremic patients with preserved left ventricular ejection fraction

Patients with uremia have high cardiovascular disease morbidity and mortality despite having normal left ventricular ejection fraction (LVEF). Longitudinal strain (LS) can be associated with subtle changes in ...

https://ift.tt/2BuKNmJ

The clinical prognostic significance of hs-cTnT elevation in patients with acute ischemic stroke

Cardiac autonomic dysfunction caused by ischemic stroke might lead to an adverse outcome. Elevated high sensitivity cardiac troponin (hs-cTnT) is a marker of cardiac disease, it can elevate in acute stroke pat...

https://ift.tt/2nRJKDF

Estimated lifetime survival benefit of tumor treating fields and temozolomide for newly diagnosed glioblastoma patients

CNS Oncology, Ahead of Print.


https://ift.tt/2OMo9Yw

A prospective surveillance study for multidrug-resistant bacteria colonization in hospitalized patients at a Thai University Hospital

Colonization with multidrug-resistant (MDR) bacteria is a major risk factor for developing subsequent MDR infections.

https://ift.tt/2OSk0m5

Incident HIV infection has fallen rapidly in men who have sex with men in Melbourne, Australia (2013–2017) but not in the newly-arrived Asian-born

We examined differences in incident HIV infection between newly-arrived Asian-born and other men who have sex with men (MSM) after the introduction of universal HIV treatment guidelines in 2015 and pre-exposur...

https://ift.tt/2La24RL

Determination of hepatitis B, C and D prevalence among urban and Amerindian populations from the Eastern Brazilian Amazon: a cross sectional study

This study was conducted to determine the prevalence of HBV, HCV, and HDV in urban populations and Amerindians living in the state of Tocantins (Eastern Amazon).

https://ift.tt/2LfvoWO

Improving the quality and acceptance of colonoscopy preparation by reinforced patient education with short message service: results from a randomized, multicenter study (PERICLES-II)

Sufficient bowel preparation is crucial for successful screening and surveillance colonoscopy. However, the rates of inadequate preparation are still high. We investigated the effects of reinforcing patient education and guidance using short message service (SMS).

https://ift.tt/2vZQR19

Evaluation of adenomas per colonoscopy and adenomas per positive participant as new quality parameters in screening colonoscopy

The primary aim of this study was to evaluate adenomas per positive participant (APP) and adenomas per colonoscopy (APC) as new quality parameters in screening colonoscopy. Furthermore, we wanted to assess if these parameters differ depending on the setting or profession.

https://ift.tt/2ONJxNd

Duodenal and Rectal Mucosa Inflammation in Patients With Non-celiac Wheat Sensitivity

Studies of non-celiac gluten or wheat sensitivity (NCGWS) have increased but there are no biomarkers of this disorder. We aimed to evaluate histologic features of colon and rectal tissues from patients with NCGWS.

https://ift.tt/2Bv5vmm

Cost-effectiveness of Transplanting HCV-Infected Livers into Uninfected Recipients with Preemptive Antiviral Therapy

Guidelines do not recommend transplanting hepatitis C virus (HCV)-infected livers into HCV-uninfected recipients. Direct-acting antivirals (DAAs) can be used to treat donor-derived HCV infection. However the added cost of DAA therapy is a barrier. We evaluated the cost effectiveness of transplanting HCV-positive livers into HCV-negative patients with preemptive DAA therapy.

https://ift.tt/2w1w9Ox

Underwater endoscopic mucosal resection of a large jejunal polyp by single-balloon enteroscopy in a patient with Peutz-Jeghers syndrome

https://ift.tt/2vWGc7G

Epidemiology of Inflammatory Bowel Disease in the Republic of San Marino: the “EPIMICI − San Marino” Study

The burden of Crohn's disease (CD) and ulcerative colitis (UC) has never been estimated in the Republic of San Marino, the third smallest Nation of the World.

https://ift.tt/2wkHh8K

Chronic use of statins and risk of post-ERCP acute pancreatitis (STARK): Study protocol for an international multicenter prospective cohort study

Acute pancreatitis (AP) is the most common complication after endoscopic retrograde cholangiopancreatography (ERCP). Statins have been traditionally associated to an increased risk of AP, however, recent evidence suggests that statins may have a protective role against this disease.

https://ift.tt/2Mo8ger

Allogeneic mesenchymal stromal cells for refractory luminal Crohn’s disease: A phase I–II study

Crohn's disease (CD) is a complex chronic relapsing disease involving abnormal systemic and mucosal immune responses against intraluminal antigens, favoured by microbial factors and alteration of the mucosal barrier. A key role in its pathogenesis is played by the imbalance between proinflammatory T helper (Th)1/Th17 cells and regulatory T lymphocytes (Treg), resulting in activation of macrophages and B cells, and recruitment of circulating leukocytes into the gut. Mesenchymal stromal cells (MSCs) exert potent immunomodulatory effects and exhibit interesting properties for tissue repair [1].

https://ift.tt/2wewzAp

Prognostic stratification of resected pancreatic ductal adenocarcinoma: past, present, and future

Pancreatic ductal adenocarcinoma (PDAC) is the digestive cancer with the poorest prognosis, with a 5-year overall survival rate of 7%. Complete surgical resection followed by adjuvant chemotherapy is the only treatment with curative intent. However, many patients with an apparently localized disease who may undergo primary tumor resection already have micro-metastatic disease and will promptly develop metastases. Considering the significant rate of morbidity and mortality upon pancreatic surgery, the pre-operative identification of patients with an aggressive disease is therefore a major clinical issue.

https://ift.tt/2vYBgiD

Effective cholangioscopic management of a patient with type IV Mirizzi syndrome

Mirizzi syndrome (MS), a complication of gallstones in which the common hepatic duct (CHD) is obstructed by extrinsic compression from the cystic duct or gallbladder, is classified into four types, according to the degree of cholecysto-biliary fistulization.

https://ift.tt/2LdrdLr

The Importance of Reporting Biases in Patient Care: Can We Trust the Evidence From Either Individual Studies or Systematic Reviews?

Dechartres and colleagues' examination of the association between publication characteristics and treatment effect estimates suggests that reporting biases are threatening our understanding of the truth in clinical evidence. The editorialists discuss the findings and propose strategies to increase the certainty that the body of evidence on which we base health-related decision making is correct.

https://ift.tt/2nQDzjg

Association Between Publication Characteristics and Treatment Effect Estimates A Meta-epidemiologic Study

Background:

Evidence about the effect on meta-analysis results of including unpublished trials or those published in languages other than English is unclear or discordant.

Purpose:

To compare treatment effects between published and unpublished randomized controlled trials (RCTs) and between trials published in English and other languages using a meta-epidemiologic approach.

Data Sources:

Cochrane reviews published between March 2011 and January 2017 and trial references cited in the reviews.

Study Selection:

RCTs included in meta-analyses of 3 or more trials with a binary efficacy outcome.

Data Extraction:

Trial characteristics were extracted by original review authors. A single reviewer assessed publication status and language, with quality assurance by another investigator.

Data Synthesis:

Among 5659 RCTs included in 698 meta-analyses, 5303 (93.7%) were published in journal articles and 356 (6.3%) were unpublished. Of journal articles, 92.6% (4910 of 5303) were published in English and 7.4% (393 of 5303) in another language. Treatment effects were larger in published than unpublished trials (combined ratio of odds ratios [ROR] for 174 meta-analyses, 0.90 [95% CI, 0.82 to 0.98]; I² = 19.3%; τ² = 0.0492). Treatment effects were also larger for trials published in a language other than English than in English (combined ROR for 147 meta-analyses, 0.86 [CI, 0.78 to 0.95]; I² = 0%; τ² = 0.0000).

Limitation:

Reliance on the primary reference cited by review authors as the record of interest.

Conclusion:

In meta-analyses, treatment effects were larger in published than unpublished trials and, for published trials, in those published in a language other than English than in English.

Primary Funding Source:

Cochrane France.

https://ift.tt/2nV2RwE

Data Are Needed on the Potential Adverse Effects of Marijuana Use in Pregnancy

Marijuana use during pregnancy is increasing, and its adverse effect on mothers and babies remains unclear. In a cohort of pregnant women in the Kaiser Permanente Northern California health system who were universally screened for prenatal substance use by self-report and urine toxicology, the authors examined the co-use of marijuana with other substances of potential misuse.

https://ift.tt/2ORimRG

Clinical–Community Partnerships to Reduce Food Insecurity Among High-Need, High-Cost Medicaid Patients

Limited or uncertain access to adequate food is associated with adverse health consequences. Although federal programs, such as the Supplemental Nutrition Assistance Program, aim to improve access to healthy food for low-income Americans, the current benefits are inadequate for many. In this essay, the authors propose cross-sector partnerships between clinical programs and community-based organizations as a promising approach for addressing food insecurity in the United States.

https://ift.tt/2nVbh7c

Ending the HIV Epidemic in the United States: Closing the Implementation Gaps

In 2014, the Joint United Nations Programme on HIV/AIDS challenged all countries to diagnose 90% of HIV infections within their borders, provide effective antiretroviral therapy to 90% of diagnosed persons, and achieve viral suppression in 90% of treated patients. As of 2015, only 51% of people living with HIV in the United States had achieved viral suppression. In this issue, Nance and colleagues bring us closer to understanding the viral suppression gap. The editorialists discuss the findings and strategies to close this gap.

https://ift.tt/2OSUZqR

Combined Gabapentinoid and Opioid Use: The Consequences of Shifting Prescribing Trends

Gomes and colleagues explore the trends and consequences of the recent and striking increase in prescribing of gabapentinoids, particularly in combination with opioids. The editorialists discuss these findings and the need to carefully investigate the consequences of combined use of all central nervous system–active drugs.

https://ift.tt/2MBAyRS

HIV Viral Suppression Trends Over Time Among HIV-Infected Patients Receiving Care in the United States, 1997 to 2015 A Cohort Study

Background:

Because HIV viral suppression is essential for optimal outcomes and prevention efforts, understanding trends and predictors is imperative to inform public health policy.

Objective:

To evaluate viral suppression trends in people living with HIV (PLWH), including the relationship of associated factors, such as demographic characteristics and integrase strand transfer inhibitor (ISTI) use.

Design:

Longitudinal observational cohort study.

Setting:

8 HIV clinics across the United States.

Participants:

PLWH receiving clinical care.

Measurements:

To understand trends in viral suppression (≤400 copies/mL), annual viral suppression rates from 1997 to 2015 were determined. Analyses were repeated with tests limited to 1 random test per person per year and using inverse probability of censoring weights to address loss to follow-up. Joint longitudinal and survival models and linear mixed models of PLWH receiving antiretroviral therapy (ART) were used to examine associations between viral suppression or continuous viral load (VL) levels and demographic factors, substance use, adherence, and ISTI use.

Results:

Viral suppression increased from 32% in 1997 to 86% in 2015 on the basis of all tests among 31 930 PLWH. In adjusted analyses, being older (odds ratio [OR], 0.76 per decade [95% CI, 0.74 to 0.78]) and using an ISTI-based regimen (OR, 0.54 [CI, 0.51 to 0.57]) were associated with lower odds of having a detectable VL, and black race was associated with higher odds (OR, 1.68 [CI, 1.57 to 1.80]) (P < 0.001 for each). Similar patterns were seen with continuous VL levels; when analyses were limited to 2010 to 2015; and with adjustment for adherence, substance use, or depression.

Limitation:

Results are limited to PLWH receiving clinical care.

Conclusion:

HIV viral suppression rates have improved dramatically across the United States, which is likely partially attributable to improved ART, including ISTI-based regimens. However, disparities among younger and black PLWH merit attention.

Primary Funding Source:

National Institutes of Health.

https://ift.tt/2ORcuI1

Treatment Approach and Outcomes in Infants with Localized Rhabdomyosarcoma: A Report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group

Infants (≤ 24 months old) enrolled on Children's Oncology Group ARST0331 and ARST0531 protocols were permitted to undergo individualized local therapy. This retrospective review assesses the treatment approach and outcomes for these infants. While local control, event-free survival, and overall survival did not differ from older children on these protocols, individualized therapy was associated with a lower 5-year event-free survival and double the rate of local failure compared to protocol-specified therapy.

https://ift.tt/2LflpAO

Cycling Related Traumatic Brain Injury Requiring Intensive Care: Association with Non-Helmet Wearing in Young People

Publication date: Available online 20 August 2018

Source: Injury

Author(s): Laura Carone, Rohan Ardley, Patrick Davies

Abstract

Introduction

Traumatic injury is the leading cause of death in children after infancy. Almost 25% of all cyclists killed in the UK are children, and two thirds of these will die because of their head injuries. We compared the population of young people wearing helmets whilst cycling, to those admitted with serious post cycling head injuries to our paediatric critical care unit.

Method

All children aged 0-18 years admitted to our intensive care following a bicycle accident between the years January 2011-June 2018 were identified and information on the mechanism of injury, and both immediate and long term clinical data were collected. For comparison data, helmet wearing on a random morning was observed from six schools. All pupils arriving at school by bicycle were observed. Data collected included the school year and sex of the child, and whether each child was wearing a helmet or not.

Results

Of 28 cases, 22 were admitted due to head injuries. None wore a helmet. 23/133 school pupils wore a helmet. The intensive care population were significantly less likely to be wearing helmets than the general population (p = 0.044, Fisher's exact test). A Chi-Square test for helmet wearing by school year showed a reduction in helmet wearing with increasing school year with a p value of 0.0026. There was no association between helmet wearing and abdominal injury.

Conclusion

Young people admitted to a Critical Care Unit with cycling related head trauma are statistically significantly less likely to wear a helmet than the general, age matched cycling population. Helmet wearing decreases as children get older. Outcomes were mixed, but in the head trauma group only 3/18 recovered with no neurological deficit

https://ift.tt/2w0NRlh

Early vs deferred endovenous ablation reduced time to ulcer healing in venous leg ulcers with varicose veins

https://ift.tt/2w0m5p8

Transplanting Hepatitis C Virus–Infected Versus Uninfected Kidneys Into Hepatitis C Virus–Infected Recipients A Cost-Effectiveness Analysis

Background:

Direct-acting antiviral agents are now available to treat chronic hepatitis C virus (HCV) infection in patients with end-stage renal disease (ESRD).

Objective:

To examine whether it is more cost-effective to transplant HCV-infected or HCV-uninfected kidneys into HCV-infected patients.

Design:

Markov state-transition decision model.

Data Sources:

MEDLINE searches and bibliographies from relevant English-language articles.

Target Population:

HCV-infected patients with ESRD receiving hemodialysis in the United States.

Time Horizon:

Lifetime.

Perspective:

Health care system.

Intervention:

Transplant of an HCV-infected kidney followed by HCV treatment versus transplant of an HCV-uninfected kidney preceded by HCV treatment.

Outcome Measures:

Effectiveness, measured in quality-adjusted life-years (QALYs), and costs, measured in 2017 U.S. dollars.

Results of Base-Case Analysis:

Transplant of an HCV-infected kidney followed by HCV treatment was more effective and less costly than transplant of an HCV-uninfected kidney preceded by HCV treatment, largely because of longer wait times for uninfected kidneys. A typical 57.8-year-old patient receiving hemodialysis would gain an average of 0.50 QALY at a lifetime cost savings of $41 591.

Results of Sensitivity Analysis:

Transplant of an HCV-infected kidney followed by HCV treatment continued to be preferred in sensitivity analyses of many model parameters. Transplant of an HCV-uninfected kidney preceded by HCV treatment was not preferred unless the additional wait time for an uninfected kidney was less than 161 days.

Limitation:

The study did not consider the benefit of decreased HCV transmission from treating HCV-infected patients.

Conclusion:

Transplanting HCV-infected kidneys into HCV-infected patients increased quality-adjusted life expectancy and reduced costs compared with transplanting HCV-uninfected kidneys into HCV-infected patients.

Primary Funding Source:

Merck Sharp & Dohme and the National Center for Advancing Translational Sciences.

https://ift.tt/2NE04Uk

Benefits and Harms of Cranial Electrical Stimulation

https://ift.tt/2w1bIkL

Hypertensive Disorders of Pregnancy and Maternal Cardiovascular Disease Risk Factor Development An Observational Cohort Study

Background:

Women with a history of hypertensive disorders of pregnancy (HDP) are nearly twice as likely to develop cardiovascular disease (CVD) as those who are normotensive during pregnancy. However, the emergence of CVD risk factors after HDP is less well-understood.

Objective:

To identify associations between HDP and maternal CVD risk factors and chart the trajectory of risk factor development after pregnancy.

Design:

Observational cohort study.

Setting:

United States.

Participants:

58 671 parous NHS II (Nurses' Health Study II) participants who did not have CVD or risk factors of interest at baseline.

Measurements:

Women were followed for self-reported physician diagnosis of chronic hypertension and hypercholesterolemia and confirmed type 2 diabetes mellitus (T2DM) from their first birth through 2013; mean follow-up ranged from 25 to 32 years across these end points. Multivariable Cox proportional hazards models estimated hazard ratios (HRs) and 95% CIs, with adjustment for prepregnancy confounders.

Results:

Compared with women who were normotensive during pregnancy, those with gestational hypertension (2.9%) or preeclampsia (6.3%) in their first pregnancy had increased rates of chronic hypertension (HRs, 2.8 [95% CI, 2.6 to 3.0] and 2.2 [CI, 2.1 to 2.3], respectively), T2DM (HRs, 1.7 [CI, 1.4 to 1.9] and 1.8 [CI, 1.6 to 1.9], respectively), and hypercholesterolemia (HRs, 1.4 [CI, 1.3 to 1.5] and 1.3 [CI, 1.3 to 1.4], respectively). Although these women were more likely to develop CVD risk factors throughout follow-up, the relative risk for chronic hypertension was strongest within 5 years after their first birth. Recurrence of HDP further elevated risks for all end points.

Limitation:

Participants self-reported HDP.

Conclusion:

Women with HDP in their first pregnancy had increased rates of chronic hypertension, T2DM, and hypercholesterolemia that persisted for several decades. These women may benefit from lifestyle intervention and early screening to reduce lifetime risk for CVD.

Primary Funding Source:

National Institutes of Health.

https://ift.tt/2tZ7JDA

Annals for Educators - 21 August 2018

https://ift.tt/2vWoHnO

When Tissue Is No Longer the Issue: Tissue-Agnostic Cancer Therapy Comes of Age

Matching unique features of cancer types with effective therapies is a cornerstone of precision medicine. Clinical success has been seen in inhibiting specific molecular alterations that drive the growth of cancer cells and targeting molecules whose elevated expression is confined to cancer cells. In addition, cancer cells can have vulnerabilities induced by somatic mutations they carry; attacks on these vulnerabilities range from specific molecular alterations pointing to direct drug strategies to harnessing immune recognition of genetically altered epitopes produced by the cancer cells. Recent advances have found that the success of biomarker-driven cancer therapy may be relevant across sites of origin. For example, cancer types that show DNA mismatch repair deficiency, such as colon, biliary, and endometrial cancer, are more sensitive to immune checkpoint inhibition. Several large, ongoing clinical trials with a "basket" design are combining tumor tissue genomics with potential off-the-shelf therapies in drug development, and more tissue-agnostic biomarker therapies are reaching the bedside.

https://ift.tt/2mWSCri

Guideline: USPSTF recommends exercise and multifactorial interventions for fall prevention in older adults

https://ift.tt/2nUNe8w

Harms Reporting in Randomized Controlled Trials of Interventions Aimed at Modifying Microbiota A Systematic Review

Background:

Probiotics, prebiotics, and synbiotics are used increasingly, although the safety and potential harms of these interventions are poorly understood.

Purpose:

To examine how harms-related information is reported in publications of randomized controlled trials (RCTs) of probiotics, prebiotics, and synbiotics.

Data Sources:

Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and Web of Science (without language restrictions) from 1 January 2015 to 20 March 2018.

Study Selection:

RCTs assessing the safety or efficacy of at least 1 intervention involving probiotics, prebiotics, or synbiotics alone or in combination with another intervention compared with any control (such as a placebo or an antibiotic) for any clinical condition.

Data Extraction:

4 reviewers independently assessed study characteristics, the reporting of harms, and the presentation of safety results.

Data Synthesis:

Of 384 trials conducted in healthy volunteers (n = 136) or patients with any of several medical conditions (n = 248), 339 (88%) were published in specialty journals. Trials most often evaluated probiotics (n = 265 [69%]). Studies in persons with medical conditions enrolled outpatients (n = 195) and high-risk patients (n = 53). No harms-related data were reported for 106 trials (28%), safety results were not reported for 142 (37%), and the number of serious adverse events (SAEs) per study group was not given for 309 (80%). Of 242 studies mentioning harms-related results, 37% (n = 89) used only generic statements to describe AEs and 16% (n = 38) used inadequate metrics. Overall, 375 trials (98%) did not give a definition for AEs or SAEs, the number of participant withdrawals due to harms, or the number of AEs and SAEs per study group with denominators.

Limitation:

Journal publication processes may have affected the completeness of reporting; only English-language publications were examined.

Conclusion:

Harms reporting in published reports of RCTs assessing probiotics, prebiotics, and synbiotics often is lacking or inadequate. We cannot broadly conclude that these interventions are safe without reporting safety data.

Primary Funding Source:

No specific funding.

https://ift.tt/2NkGCuI

In gluteal tendinopathy, education + exercise improved outcomes vs corticosteroid injection or wait strategy

https://ift.tt/2w6fDwX

Brief Commentary: The Glycemic Target Guideline Controversy: Same Evidence, Different Perspectives, and a Proposal for Common Ground

This commentary was selected for publication from among several submitted in response to a call for readers' perspectives on treatment targets for type 2 diabetes.

https://ift.tt/2Lc3ISB

Kidney Transplants for Patients With Hepatitis C Virus Infection

https://ift.tt/2L3ucXx

Brief Commentary: Glycemic Targets for Older Adults With Type 2 Diabetes

This commentary was selected for publication from among several submitted in response to a call for readers' perspectives on treatment targets for type 2 diabetes.

https://ift.tt/2K6vDru

Prevention of Diabetes With Mediterranean Diets

https://ift.tt/2MFHxJr

Brief Commentary: Social Determinants of Health and Treatment Targets for Type 2 Diabetes

This commentary was selected for publication from among several submitted in response to a call for readers' perspectives on treatment targets for type 2 diabetes.

https://ift.tt/2LaQ1DJ

In symptomatic COPD, once-daily triple vs dual therapy reduced moderate or severe exacerbations at 1 year

https://ift.tt/2vYuoSn

Brief Commentary: Confusing Treatment Guidelines for Patients With Type 2 Diabetes

This commentary was selected for publication from among several submitted in response to a call for readers' perspectives on treatment targets for type 2 diabetes.

https://ift.tt/2MFMIJh

Tenecteplase before thrombectomy for ischemic stroke improved reperfusion compared with alteplase

https://ift.tt/2nRjxoL

Brief Commentary: Laboratory Accuracy of Hemoglobin A 1c Ranges and Treatment Targets for Patients With Type 2 Diabetes

This commentary was selected for publication from among several submitted in response to a call for readers' perspectives on treatment targets for type 2 diabetes.

https://ift.tt/2BvKvfm

Correction to ACP Journal Club: Guideline—The AHA/ASAmade 217 recommendations for early management of acute ischemic stroke in adults

https://ift.tt/2w0UKTv

Initial validation of the Danish version of the Fear of Cancer Recurrence Inventory (FCRI) in colorectal cancer patients

Abstract

Purpose

The Fear of Cancer Recurrence Inventory (FCRI) is a multidimensional measure for fear of cancer recurrence (FCR). The aim of this study was to assess the psychometric properties of the translated Danish version of the FCRI in a population of colorectal cancer patients.

Methods

The English version of the FCRI was forward–backward translated into Danish and pilot tested in a gynaecological cancer population. The psychometric properties of the FCRI were assessed in terms of responsiveness, test–retest reliability and discriminative and convergent validity in a population of colorectal cancer patients by asking them to complete questionnaires at three time points during follow-up. Clinical FCR was defined as ≥ 16 at the FCRI short form.

Results

The participation rate was 57%. A low association was found between higher scores on the FCRI and younger age (r = − 0.29, p = 0.02). A moderate correlation was found between the FCRI score and a measure for worry traits (r = 0.49, p < 0.001). Mean difference in total FCRI score was statistically significant between 'pre-scan' and 'postscan' (p < 0.001), thus indicating that the FCRI was responsive to change. The FCRI score showed good test–retest reliability (intraclass correlation = 0.84).

Conclusion

The Danish version of the FCRI is a reliable and responsive measure for FCR in colorectal cancer patients and shows acceptable discriminative and convergent validity.

Implications for Cancer Survivors

A valid measure for FCR is crucial in order to identify patients with a need for special attention or interventions for high levels of FCR and to improve future research into FCR among cancer survivors.

https://ift.tt/2Btxz9z

Postoperative adjuvant and very early salvage radiotherapy after prostatectomy in high-risk prostate cancer patients can improve specific and overall survival

Abstract

Purpose

Adjuvant radiotherapy (ART) for biochemical relapse (BR) after radical prostatectomy (RP) showed increased disease-free survival (DFS) in three previous randomized trials. Retrospective phase II trials evaluated if early salvage RT (ESRT) is equivalent to ART. Our study aims to compare ART and ESRT to salvage RT.

Materials and methods

We compared RP plus ART and ESRT versus SRT. Indication for RT was made by PSA determination after RP: ART when PSA ≤ 0.2 ng/ml, ESRT when PSA ≤ 0.3 after PSA rise from 0.0 to SRT PSA ≥ 0.3. The cause of death of each patients was analyzed, DFS, cause-specific survival (CSS) overall survival (OS) and metastasis-free survival (MFS) in relation to RT intention.

Results

Between 1993 and 2008, 204 patients with a median age of 65 years (44–75) were treated. The median follow-up was 160 months (28.1–273.3). At diagnosis, 89.7% had localized clinical stages and 90.2% had Gleason (G) ≤ 7. The median PSA was 10 (range 4–101). The postoperative G was ≥ 7 in 66.2%; 56.4% had ≥ 2 positive margins; 29.4% received ART, 20% ESRT and 59.3% SRT. The DFS for ART, ESRT and SRT was 74, 56 and 39% with significant differences between the three groups (p < 0.001). ART + ESRT were combined versus SRT; for the DFS, the significant differences (p < 0.001) remained 67% versus 39%. Positive margins, pT3 and pre-RT PSA were significant factors on multivariate analysis. The CSS in the ART + ESRT group was 92 vs. 78% in the SRT group (p < 0.05). OS was 69% in ART + ESRT vs. 57% in SRT (p < 0.05). MFS was 82.7% in ART + ESRT vs. 67.4% in SRT.

Conclusions

In this study the ART + ESRT presented benefits versus SRT in DFS, CSS, OS and MFS.

https://ift.tt/2MnnYGu

IL-10 inducible CD8 + regulatory T-cells are enriched in patients with multiple myeloma and impact the generation of antigen-specific T-cells

Abstract

Tumor-mediated immunosuppression via regulatory T-cells is a key player among the various immune-escape mechanisms in multiple myeloma. We analyzed the generation, distribution, function and immunophenotype of CD8⁺CD28⁻ regulatory T-cells in patients with multiple myeloma. Functionality of CD8⁺CD28⁻ T-cells was assessed by immunological assays using ex vivo generated antigen-specific T-cells from patients with plasma cell dyscrasias and healthy donors. Detailed analysis of distribution, immunophenotype and cytotoxic potential of CD8⁺CD28⁻ T-cells was performed by flow cytometry and ELISA. We found that the amount of CD8⁺CD28⁻ T-cells was directly correlated with the suppression of antigen-specific T-cell responses in patients with plasma cell dyscrasia. Analyzing the CD8⁺CD28⁻ T-cells in detail, increased numbers of these cells were observed in the bone marrow (i.e., tumor microenvironment) of patients with plasma cell dyscrasia. Furthermore, we identified the expression of lymphocyte function-associated antigen 1 (LFA-1) as a marker of immunosuppression and defined the CD8⁺CD28⁻CD57⁺LFA-1^high population as the relevant immunosuppressive compartment. These regulatory T-cells act as immunosuppressors via soluble factors and incubation with IL-10 augmented their immunosuppressive capacity. The immunosuppressive regulatory network of IL-10 and the CD8⁺CD28⁻CD57⁺LFA-1^high regulatory T-cells show unique characteristics and contribute to the tumor immune escape mechanism in patients with multiple myeloma.

https://ift.tt/2L7Miqh

A phase I trial of topotecan plus tivantinib in patients with advanced solid tumors

Abstract

Purpose

Tyrosine kinase inhibitors (TKI) that target MET signaling have shown promise in various types of cancer, including lung cancer. Combination strategies have been proposed and developed to increase their therapeutic index. Based on preclinical synergy between inhibition of MET and topoisomerase I, a phase I study was designed to explore the combination of topotecan with the MET TKI tivantinib.

Methods

Eligible patients with advanced solid malignancies for which there was no known effective treatment received topotecan at doses of 1.0–1.5 mg/m²/day for five consecutive days in 21-day cycles with continuous, oral tivantinib given at escalating doses of 120–360 mg orally twice daily. Pharmacokinetic analyses of tivantinib were included. Circulating tumor cells (CTC) were collected serially to identify peripheral changes in MET phosphorylation.

Results

The trial included 18 patients, 17 of whom received treatment. At the planned doses, the combination of topotecan and tivantinib was not tolerable due to thrombocytopenia and neutropenia. The addition of G-CSF to attenuate neutropenia did not improve tolerability. Greater tivantinib exposure, assessed through pharmacokinetic analysis, was associated with greater toxicity. No responses were seen. MET phosphorylation was feasible in CTC, but no changes were seen with therapy.

Conclusions

The combination of topotecan and oral tivantinib was not tolerable in this patient population.

https://ift.tt/2L9xaJf

Multicentre analysis of PET SUV using vendor-neutral software: the Japanese Harmonization Technology (J-Hart) study

Abstract

Background

Recent developments in hardware and software for PET technologies have resulted in wide variations in basic performance. Multicentre studies require a standard imaging protocol and SUV harmonization to reduce inter- and intra-scanner variability in the SUV. The Japanese standardised uptake value (SUV) Harmonization Technology (J-Hart) study aimed to determine the applicability of vendor-neutral software on the SUV derived from positron emission tomography (PET) images. The effects of SUV harmonization were evaluated based on the reproducibility of several scanners and the repeatability of an individual scanner.

Images were acquired from 12 PET scanners at nine institutions. PET images were acquired over a period of 30 min from a National Electrical Manufacturers Association (NEMA) International Electrotechnical Commission (IEC) body phantom containing six spheres of different diameters and an ¹⁸F solution with a background activity of 2.65 kBq/mL and a sphere-to-background ratio of 4. The images were reconstructed to determine parameters for harmonization and to evaluate reproducibility. PET images with 2-min acquisition × 15 contiguous frames were reconstructed to evaluate repeatability. Various Gaussian filters (GFs) with full-width at half maximum (FWHM) values ranging from 1 to 15 mm in 1-mm increments were also applied using vendor-neutral software. The SUV_max of spheres was compared with the reference range proposed by the Japanese Society of Nuclear Medicine (JSNM) and the digital reference object (DRO) of the NEMA phantom. The coefficient of variation (CV) of the SUV_max determined using 12 PET scanners (CV_repro) was measured to evaluate reproducibility. The CV of the SUV_max determined from 15 frames (CV_repeat) per PET scanner was measured to determine repeatability.

Results

Three PET scanners did not require an additional GF for harmonization, whereas the other nine required additional FWHM values of GF ranging from 5 to 9 mm. The pre- and post-harmonization CV_repro of six spheres were (means ± SD) 9.45% ± 4.69% (range, 3.83–15.3%) and 6.05% ± 3.61% (range, 2.30–10.7%), respectively. Harmonization significantly improved reproducibility of PET SUV_max (P = 0.0055). The pre- and post-harmonization CV_repeat of nine scanners were (means ± SD) 6.59% ± 1.29% (range, 5.00–8.98%) and 4.88% ± 1.64% (range, 2.65–6.72%), respectively. Harmonization also significantly improved the repeatability of PET SUV_max (P < 0.0001).

Conclusions

Harmonizing SUV using vendor-neutral software produced SUV_max for 12 scanners that fell within the JSNM reference range of a NEMA body phantom and improved SUV_max reproducibility and repeatability.

https://ift.tt/2OQuh1U

A phase I dose-escalation trial of stereotactic ablative body radiotherapy for non-spine bone and lymph node metastases (DESTROY-trial)

Abstract

Background

In an oligometastatic setting, metastasis-directed treatment could render patients disease free, possibly for a protracted interval. Stereotactic ablative radiotherapy (SABR) is one of the treatment modalities that can be offered to these patients. In addition, the radiobiological qualities of SABR are promising for the use in perceived radioresistant tumours. There is also emerging evidence that SABR can stimulate the immune response, and a specific therapeutic window may exist for the optimal use of radiotherapy as an immune adjuvant. However, when SABR is considered for non-spine bone or lymph node metastases, the optimal fractionation schedule is not yet known.

Methods

The DESTROY-trial is a non-randomized prospective phase I trial determining a regimen of choice for patients with non-spine bone and lymph node metastases. A total of 90 patients will be included in three different treatment regimens. They will be offered stereotactic ablative radiotherapy in 5, 3 or 1 fractions. Dose-limiting toxicity will be recorded as primary endpoint. Acute and late toxicity, local response and local recurrence, and progression-free survival are secondary endpoints. Liquid biopsies will be collected throughout the course of this study from the second fractionation schedule on.

Discussion

Despite its almost universal use in (oligo-)metastatic patients, the level of evidence supporting radical local treatment in general, and stereotactic radiotherapy in particular, is low. This prospective phase I trial will evaluate different SABR regimens for metastases and the differences in immune-stimulatory effects.

Trial registration

The Ethics committee of the GZA Hospitals (B099201732915) approved this study on 05/07/2017. Amendment for translational research was approved on 06/02/2018. Trial registered on Clinicaltrials.gov (NCT03486431) on 03/04/2018 – Retrospectively registered.

https://ift.tt/2w0V5pl

Modifying Baculovirus Expression Vectors to Produce Secreted Plant Proteins in Insect Cells

Here, we present the protocols for utilizing the insect cell and baculovirus protein expression system to produce large quantities of plant secreted proteins for protein crystallization. A baculovirus expression vector has been modified with either GP67 or insect hemolin signal peptide for plant protein secretion expression in insect cells.

https://ift.tt/2OSAVVz

IL-10 inducible CD8 + regulatory T-cells are enriched in patients with multiple myeloma and impact the generation of antigen-specific T-cells

Abstract

Tumor-mediated immunosuppression via regulatory T-cells is a key player among the various immune-escape mechanisms in multiple myeloma. We analyzed the generation, distribution, function and immunophenotype of CD8⁺CD28⁻ regulatory T-cells in patients with multiple myeloma. Functionality of CD8⁺CD28⁻ T-cells was assessed by immunological assays using ex vivo generated antigen-specific T-cells from patients with plasma cell dyscrasias and healthy donors. Detailed analysis of distribution, immunophenotype and cytotoxic potential of CD8⁺CD28⁻ T-cells was performed by flow cytometry and ELISA. We found that the amount of CD8⁺CD28⁻ T-cells was directly correlated with the suppression of antigen-specific T-cell responses in patients with plasma cell dyscrasia. Analyzing the CD8⁺CD28⁻ T-cells in detail, increased numbers of these cells were observed in the bone marrow (i.e., tumor microenvironment) of patients with plasma cell dyscrasia. Furthermore, we identified the expression of lymphocyte function-associated antigen 1 (LFA-1) as a marker of immunosuppression and defined the CD8⁺CD28⁻CD57⁺LFA-1^high population as the relevant immunosuppressive compartment. These regulatory T-cells act as immunosuppressors via soluble factors and incubation with IL-10 augmented their immunosuppressive capacity. The immunosuppressive regulatory network of IL-10 and the CD8⁺CD28⁻CD57⁺LFA-1^high regulatory T-cells show unique characteristics and contribute to the tumor immune escape mechanism in patients with multiple myeloma.

https://ift.tt/2L7Miqh

Why your EMS agency needs near-miss reporting

Near-miss reporting can help build a culture of safety in your agency and improve the EMS profession as a whole

https://ift.tt/2KXf8d9

Digital Polymerase Chain Reaction Assay for the Genetic Variation in a Sporadic Familial Adenomatous Polyposis Patient Using the Chip-in-a-tube Format

Digital polymerase chain reaction (PCR) is a useful tool for the high-sensitivity detection of single nucleotide variants and DNA copy number variants. Here, we demonstrate key considerations for measuring rare variants in the human genome using digital PCR with the chip-in-a-tube format.

https://ift.tt/2PpngGI

Covalent Immobilization of Proteins for the Single Molecule Force Spectroscopy

This protocol describes the covalent immobilization of proteins with a heterobifunctional silane coupling agent to silicon-oxide surfaces designed for the atomic force microscopy based single molecule force spectroscopy which is exemplified by the interaction of RrgA (pilus-1 tip adhesin of S. pneumoniae) with fibronectin.

https://ift.tt/2N3gLrg

Trabectedin arrests a doxorubicin-resistant PDGFRA-activated liposarcoma patient-derived orthotopic xenograft (PDOX) nude mouse model

Abstract

Background

Pleomorphic liposarcoma (PLPS) is a rare, heterogeneous and an aggressive variant of liposarcoma. Therefore, individualized therapy is urgently needed. Our recent reports suggest that trabectedin (TRAB) is effective against several patient-derived orthotopic xenograft (PDOX) mouse models. Here, we compared the efficacy of first-line therapy, doxorubicin (DOX), and TRAB in a platelet-derived growth factor receptor-α (PDGFRA)-amplified PLPS.

Methods

We used a fresh sample of PLPS tumor derived from a 68-year-old male patient diagnosed with a recurrent PLPS. Subcutaneous implantation of tumor tissue was performed in a nude mouse. After three weeks of implantation, tumor tissues were isolated and cut into small pieces. To match the patient a PDGFRA-amplified PLPS PDOX was created in the biceps femoris of nude mice. Mice were randomized into three groups: Group 1 (G1), control (untreated); Group 2 (G2), DOX-treated; Group 3 (G3), TRAB-treated. Measurement was done twice a week for tumor width, length, and mouse body weight.

Results

The PLPS PDOX showed resistance towards DOX. However, TRAB could arrest the PLPS (p < 0.05 compared to control; p < 0.05 compared to DOX) without any significant changes in body-weight.

Conclusions

The data presented here suggest that for the individual patient the PLPS PDOX model could specifically distinguish both effective and ineffective drugs. This is especially crucial for PLPS because effective first-line therapy is harder to establish if it is not individualized.

https://ift.tt/2MxJpEf

Combination Antihypertensive Therapy with Perindopril and Indapamide in Patients with Essential Hypertension: Effect on Endothelial and Cognitive Markers of Vascular Improvement

Abstract

Introduction

The objective of this study was to assess the impact of a single-pill combination (SPC) of perindopril/indapamide (PER/IND) at full doses (10/2.5 mg) on endothelial and cognitive function as a clinical intermediate marker of vascular improvement.

Methods

This open-label, uncontrolled, observational study enrolled 30 patients (20 females and 10 males) with grade II–III uncontrolled arterial hypertension (SBP/DBP ≥ 160/100 mmHg) and no evidence of cerebrovascular disease. All patients underwent assessment of macro- and microvascular endothelial function parameters at baseline and after 12 months of treatment with SPC PER/IND using photoplethysmography and video capillaroscopy. Cognitive function was assessed using the Montreal Cognitive Assessment scale (MoCA).

Results

All patients (mean age 60.06 ± 10.19 years) were at high risk for cardiovascular events: mean body mass index (BMI) 31.2 ± 3.9 kg/m², 33% diagnosed with coronary artery disease angina class I, 30% with impaired glucose tolerance, and 7% with type 2 diabetes. Impaired endothelial function was observed at the both micro- and macrovascular levels. Endothelial function parameters improved after 12-month treatment with SPC PER/IND with an increase in occlusion index from 1.4 to 1.8 (P < 0.00005) and phase shift from 5.0 to 10.8 (P < 0.00001); all values achieved levels in the normal range. Resting capillary network density (CND) increased from 44.8 to 52 cap/mm² (P < 0.00007), and CND after a venous occlusion test increased from 55 to 61 cap/mm² (P < 0.006). Signs of cognitive impairment were present at baseline with a mean MoCA score of 23 (normal cognitive function score ≥ 26), but improved after 12-month treatment with a mean MoCA score of 27 (P< 0.0001). Treatment was well tolerated.

Conclusion

SPC PER/IND at full doses for 12 months improves endothelial function, structural and functional parameters of the microcirculation, as well as cognitive function in patients with arterial hypertension at high cardiovascular risk.

Funding

Les Laboratoires Servier.

https://ift.tt/2LbNsB4