Surgeon Age in Relation to Prognosis After Esophageal Cancer Resection

Objective: It was hypothesized that patient survival improves with increasing surgeon age up to an age where it then decreases. Background: Experience, physical and psychological abilities required for esophagectomy may change with increasing surgeon age. Methods: This population-based cohort study included all patients having undergone esophagectomy for esophageal cancer in Sweden in 1987 to 2010, with follow-up until 2016. Risk-adjusted cumulative sum (RA-CUSUM) analysis was performed to estimate the relation between surgeon age and 90-day mortality, all-cause, and disease-specific 5-year mortality. Change-points in surgeon age identified by the RA-CUSUM were then analyzed in relation to mortality using multivariable Cox regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs), adjusted for age, sex, comorbidity, tumor stage, tumor histology, neoadjuvant therapy, surgeon volume, and calendar year. Results: Among 139 surgeons performing 1761 esophagectomies, RA-CUSUM analysis of 90-day mortality showed change-points at 43 years (downward deflection) and at 56 years (upward deflection). Both all-cause and disease-specific 5-year mortality had corresponding change-points at 52 years and 56 years. Compared with surgeon age 52 to 55 years, surgeon age ≤51 years was associated with increased 90-day mortality (HR = 1.71, 95% CI 1.01–2.90) and 5-year all-cause mortality (HR = 1.21, 95% CI 1.02–1.43), and surgeon age ≥56 years showed increased 90-day mortality (HR = 2.38, 95% CI 1.38–4.13), 5-year all-cause mortality (HR = 1.29, 95% CI 1.08–1.55), and disease-specific 5-year mortality (HR = 1.18, 95% CI 1.01–1.42). Conclusions: Surgeon age ≤51 and ≥56 years may increase short- and long-term mortality after esophagectomy for cancer.

https://ift.tt/2y5AhR9

Immune checkpoint blockade therapy of mesothelioma: a clinical and radiological challenge

Abstract

Treatment of malignant pleural mesothelioma (MPM) represents a highly unmet medical need. Here, we discuss the results and therapeutic potential of first- and second-generation immunomodulatory antibodies targeting distinct immune checkpoints for the treatment of MPM, as well as their prospective therapeutic role in combination strategies. We also discuss the role of appropriate radiological criteria of response for MPM and the potential need of ad hoc criteria of disease evaluation in MPM patients undergoing treatment with immunotherapeutic agents.

https://ift.tt/2Kk4HE9

Cancers, Vol. 10, Pages 215: Role of Minimal (Measurable) Residual Disease Assessment in Older Patients with Acute Myeloid Leukemia

Cancers, Vol. 10, Pages 215: Role of Minimal (Measurable) Residual Disease Assessment in Older Patients with Acute Myeloid Leukemia

Cancers doi: 10.3390/cancers10070215

Authors: Francesco Buccisano Richard Dillon Sylvie D. Freeman Adriano Venditti

Minimal (or measurable) residual (MRD) disease provides a biomarker of response quality for which there is robust validation in the context of modern intensive treatment for younger patients with Acute Myeloid Leukemia (AML). Nevertheless, it remains a relatively unexplored area in older patients with AML. The lack of progress in this field can be attributed to two main reasons. First, physicians have a general reluctance to submitting older adults to intensive chemotherapy due to their frailty and to the unfavourable biological disease profile predicting a poor outcome following conventional chemotherapy. Second, with the increasing use of low-intensity therapies (i.e., hypomethylating agents) differing from conventional drugs in mechanism of action and dynamics of response, there has been concomitant skepticism that these schedules can produce deep hematological responses. Furthermore, age-dependent differences in disease biology also contribute to uncertainty on the prognostic/predictive impact on older adults with certain genetic abnormalities including younger patients validated for MRD monitoring. This review examines the evidence for the role of MRD as a prognosticator in older AML, together with the possible pitfalls of MRD evaluation in older age.

https://ift.tt/2N1dIAf

Three UTHealth Medical Students Invited to Present at Triological Society Meeting

Medical students José Ting, Margaret Engelhardt, and Brandon Esianor, BS, were invited to present the results of their research at...

https://ift.tt/2KoYFP9

Use of brivaracetam in genetic generalized epilepsies and for acute, intravenous treatment of absence status epilepticus

Epilepsia, EarlyView.


https://ift.tt/2N0xjRt

Linalool, citral, eugenol and thymol: control of planktonic and sessile cells of Shigella flexneri

The antimicrobial activity of linalool, citral, eugenol and thymol was determined in growth studies of both planktonic (PC) and biofilm cells (BC) Shigella flexneri. These components were evaluated either in isol...

https://ift.tt/2IolAZj

The dynamics of a healthy and infected red blood cell in flow through constricted channels: A DPD simulation

International Journal for Numerical Methods in Biomedical Engineering, EarlyView.


https://ift.tt/2tvaooU

Relationship between CYP1B1 polymorphisms (c.142C > G, c.355G > T, c.1294C > G) and lung cancer risk in Polish smokers

Future Oncology, Ahead of Print.


https://ift.tt/2Klov6M

The role of clinical and molecular factors in low-grade gliomas: what is their impact on survival?

Future Oncology, Ahead of Print.


https://ift.tt/2K7HWUx

Why are women with obesity more likely to develop breast cancer

Future Oncology, Ahead of Print.


https://ift.tt/2IsXn3Z

Surveillance, Epidemiology, & End Results study of ablation versus partial nephrectomy in cT1A renal cell carcinoma

Future Oncology, Ahead of Print.


https://ift.tt/2Kcvcfl

Novel multidisciplinary approaches in the management of metastatic epidural spinal cord compression

Future Oncology, Ahead of Print.


https://ift.tt/2KnmeIq

Detection of volatile organic compounds in exhaled breath to screen lung cancer: a systematic review

Future Oncology, Ahead of Print.


https://ift.tt/2K8iQ84

Rectal radiation dose-reduction techniques in prostate cancer: a focus on the rectal spacer

Future Oncology, Ahead of Print.


https://ift.tt/2KnsjV9

The role of matricellular proteins and tissue stiffness in breast cancer: a systematic review

Future Oncology, Ahead of Print.


https://ift.tt/2K6O7s1

Letter to the editor 1: Predictors of oesophageal candidiasis in persons with or without HIV infection

Nil

https://ift.tt/2lAk6ST

Child sexual abuse and disclosure in South Western Nigeria: a community based study

Introduction: The true burden of child sexual abuse in Nigeria is not known as most reports are institutional based. This study was designed to determine population level data on the burden and pattern of child sexual abuse among adolescents in South Western Nigeria.
Methods: A community based study among adolescents in SouthWestern Nigeria. Semi- structured interviewer administered questionnaire was used to collect data from respondents selected through a multistage sampling technique. Analysis was with SPSS version 20.
Results: 398 adolescents (314 females and 84 males) aged 10-19 years with a mean age of 15.6 ± 2.0 years participated in the study. Most were single (90.7%), in school (84.2%), and lived with their parents/guardians (89.4%). The prevalence of CSA was 25.7%. Penetrative abuse occurred in 7.5%, and forced abuse in 46.2% of cases. Perpetrators were mostly boyfriends (31.2%) and neighbours (16.1%). Intra-familial abuse occurred in 7.5% of cases. Only 34.4% of cases ever disclosed the abuse.
Conclusion: CSA is common in the community, with perpetrators majorly persons known to the adolescents. A large number of cases are not reported. Efforts should be made to educate children and their parents on various ways to reduce child sexual abuse and its consequences.

Keywords: Adolescent, child, sexual abuse.

https://ift.tt/2yHCmCT

Non- adherence to anti-retroviral medication in Shiraz, 2014: a cross sectional study

Background: Medication adherence is a dynamic and complex behavioral process, which is strongly influenced by personal, social and environmental factors.
Objectives: To determine the prevalence and factors affecting non-adherence to medication among HIV-infected patients.
Methods and materials:
Design: A cross-sectional study.
Setting: Voluntary Counseling and Testing Center (VCT), Shiraz, Fars province, in the South of Iran.
Patients: Among HIV-positive patients who received anti-retroviral therapy, 214 adult patients were selected through convenience sampling. Their medication adherence was checked by interview and counting the pills on visits during two months. Clinical and laboratory data were obtained from the patients' records.
Results: Non-adherence and adherence groups included 30.4% (65) and 69.6% (149) of the patients, respectively. The mean age of patients was 40.80±7.77 years, and ranged from 20 to 65 years. Majority of cases (65%) were male. A significant relationship was found between non-adherence to medications and the variables of transmission method, marital status, housing status, and CD4, but there was no significant relationship with gender.
Conclusion: The prevalence of medication adherence was similar to other regions with limited financial resources. To increase patient's medication adherence, they should be exposed to motivational interventions to promote their drug consumption, social and occupational support.

Keywords: Prevalence, adherence, anti-retroviral medication, HIV.

https://ift.tt/2lAX6TK

Sexuality experiences of secondary school students in Nakuru, Kenya: a cross-sectional study

Background: Adolescence is a phase where one is inquisitive about sex and sexuality. It is but natural to exchange the half-baked feelings and experiences with peers. These days the environment that includes public media has sexually suggestive flavors.
Objective: This study was conducted to find out the sexual experiences of a selected, few school going adolescents.
Methods: A cross-sectional study utilizing stratified sampling to enroll 200 students from secondary schools in Nakuru County, Kenya. A self-administered questionnaire was used to collect data. The data was entered and analyzed in SPSS® version 22. Chi-square test of independence and Fisher's Exact Test were performed to test for associations.
Results: The study found that a large number have had sexual experiences of varying type. It was interesting to learn from the survey that a large number of older adolescents wish that their parents should have talked to them about sexual matters. There is a general conservative outlook that the students had. Although a small percentage had sexual experiences at a very young age, many of them valued ethics and morality.
Conclusion: There is urgency for intervention by the parents and the church in filing the gap in sexual knowledge.

Keywords: Sexuality experiences, secondary school students, Nakuru, Kenya.

https://ift.tt/2tE8Vfz

Congenital genital abnormalities detected during routine circumcision at a South African institution: a retrospective record review

Background: Due to the reduction in HIV transmission through male medical circumcisions (MMC), numerous clinics throughout South Africa offer a voluntary free service to boys from the age of ten years and above. An examination prior to the procedure may detect congenital abnormalities missed after birth.
Objectives: The aim of this study was to measure the incidence of these abnormalities, determine the demographic and clinical characteristics of this group and determine what referral systems, interventions, and follow-up is available to them.
Methods: The study was a descriptive, observational, retrospective analysis of de-identified medical records at a routine MMC service at a Johannesburg clinic in 2015. The participants were male patients between the ages of 10 – 49.
Results: Out of 1548 participants, 91.0% (n=1409) had a normal genital examination while 3.7% (n=57) had an abnormal examination and 5.1% (n=79) had no examination recorded. Thirty five congenital anomalies were detected and only 2 patients (diagnosed with hypospadias) were seen at the urology out-patient's department.
Conclusion: The incidence of congenital genital abnormalities of males presenting for routine circumcision is low. Despite the low incidence the effect on fertility, sexuality, ability to urinate and on psychological wellbeing is significant. Referral services to the urology department should be restructured to improve all outcomes.

Keywords: Congenital genital abnormalities, circumcision, South Africa.

https://ift.tt/2lAX5iE

Peer pressure and home environment as predictors of disruptive and risky sexual behaviours of secondary school adolescents

Background: Not much is understood about the predictive power of home environment and peer pressure on disruptive behaviour and risky sexual behaviour of adolescents.
Objectives: The study investigated the predictive power of home environment and peer pressure on disruptive behaviour and risky sexual behaviour of adolescents in secondary school class two in Enugu State, Nigeria. Four research questions and four null hypotheses guided the study.
Methods: The design was a cross sectional survey of correlational study. The study was carried out in the six Education zones in Enugu State, Nigeria. The population was all the 31,680 senior secondary class two (SS11) adolescents in 285 secondary schools in Enugu State, Nigeria in 2015/2016 academic session. The instruments for data collection were an observation schedule, an interview session and a structured questionnaire of four clusters. To determine the R-squares for each regression model, a multivariate multiple regression model was conducted using "MANOVA" and "MVREG".
Results: This study indicates adolescents who reported their home environments to be stimulated displayed compliant behavior and none or lowered risky sexual behaviour, whilst those with chaotic and unstimulated home environment displayed disruptive behaviours. It was found that adolescents who show a heightened sensitivity to positive peer pressure demonstrated compliant and no or lowered risky sexual behavior whilst, those that are engaged with negative peer pressure strongly exhibit disruptive and risky sexual behaviour.
Conclusion: Unstimulated home environment and negative peer group could consequently interact to predispose these adolescents to disruptive behaviour and risky sexual behaviour.

Keywords: Home, peer group, disruptive, behaviour, adolescents.

https://ift.tt/2tD0OzO

Compliance with epidemic-prone diseases surveillance and response guidelines among health officers at surveillance units in South-West Nigeria

Introduction: Although compliance with surveillance guidelines is crucial to epidemic diseases control, determinants of use of these guidelines in Nigeria are poorly documented. We assess health workers compliance and factors associated with the surveillance and response guidelines for epidemic-prone diseases in South-West Nigeria.
Methods: In a cross-sectional study, 199 disease surveillance and notification officers in Oyo state were interviewed using a questionnaire on knowledge of disease surveillance and performance of surveillance activities. Data were analysed using descriptive statistics, chi-square and multiple logistic regression at P= 0.05.
Results: Most surveillance units submitted disease outbreaks reports (81.48% at the health facility and 100% at the local government level). Timeliness and completeness of weekly reporting were 94% and 95% respectively. a quarter (25.9%) adhered to national case definitions guidelines. About 85.7% did laboratory case confirmation while 2.6% did facility level data analysis. Predictors for six months reporting activity include attending a training on surveillance and reporting (OR=7.92; CI=1.65–37.92), fund adequacy (OR=27.81; CI=7.68–100.60) and knowledge of surveillance dataflow (OR=4.80; CI=1.64–14.10).
Conclusion: In addition to provision of adequate financial and laboratory resources, surveillance activities would benefit from continuous training on surveillance data flow.

Keywords: Epidemic-prone diseases, case definitions guidelines, surveillance and response.

https://ift.tt/2lAX3Hy

Effect of pregnancy on sexual function of couples

Objective: Sexual function is an important part of each human being's personality and in the general couple relationship, with an obvious impact on quality of life and safe sexual performance during pregnancy is important for couples. The objective of this study was to assess effects of pregnancy on sexual function of couples.
Materials: In a prospective cohort study 123 couples were enrolled in the study when women were first diagnosed to be pregnant. During their pre-natal visits, Sexual function of couples was evaluated using the Iranian Version Index of Erectile Function (IIEF) in men and Female Sexual Function Index (FSFI) in women in three trimesters. Statistical analysis was performed.
Results: Indices of sexual function showed significant regressions over time during pregnancy. The greatness of the problem was highest during the third trimester. Female sexual arousal and sexual satisfaction domain scores had the major correlation to IIEF total score. On the other hand, male intercourse satisfaction domain score had the maximum correlation to FSFI total score. A strong correlation between male and female sexual function was observed.
Conclusion: Sexual function is a widespread problem during pregnancy among Iranian couples. Therefore, pregnant women and their husbands need counseling about healthy sexual function in pregnancy.

Keywords: Sexual activity, pregnant woman, husband.

https://ift.tt/2tD0JMw

MicroRNA expression profiling in human acute organophosphorus poisoning and functional analysis of dysregulated miRNAs

Objective: Acute organophosphorus(OP) pesticide poisoning is associated with dysfunctions in multiple organs, especially skeletal muscles, the nervous system and the heart. However, little is known about the specific microRNA (miRNA) changes that control the pathophysiological processes of acute OP poisoning damage. We aimed to explore miRNA expression profiles and gain insight into molecular mechanisms of OP toxic effects.
Methods: MicroRNA expression was analyzed by TaqMan Human MicroRNA Array analysis and subsequent validated with quantitive PCR. The targets of the significantly different miRNAs were predicted with miRNA prediction databases, and pathway analysis of the predicted target genes was performed using bioinformatics resources.
Results: 37 miRNAs were significantly different in the sera of poisoned patients compared to the healthy controls, including 29 miRNAs that were up-regulated and 8 miRNAs that were down-regulated. Functional analysis indicated that many pathways potentially regulated by these miRNAs are involved in skeletal muscle, nervous system and heart disorders.
Conclusion: This study mapped changes in the serum miRNA expression profiles of poisoning patients and predicted functional links between miRNAs and their target genes in the regulation of acute OP poisoning. Our findings are an important resource for further understanding the role of these miRNAs in the regulation of OP-induced injury.

Keywords: MicroRNA, expression profiles, human, acute organophosphorus pesticide poisoning, signaling pathways.

https://ift.tt/2lAX0vm

How do Spondias mombin L (Anacardiaceae) leaves extract increase uterine smooth muscle contractions to facilitate child birth in parturient women?

Background: Spondias mombin L. (Anacardiaceae) leaves were used in Togolese folk to treat dystocia, expel placenta and manage post-partum hemorrhage during child birth.
Objectives: This study aimed to establish how the extract of S. mombin leaves increase uterine smooth muscle contractions relevant to its traditional use to facilitate child birth.
Methods: Tests were performed on uterus muscle strips from Sprague-Dawley rats. Central portion of uterine horns were dissected, cleaned of surrounding fat and loose connective tissue, and cut longitudinally into strips which were placed in the organ bath for isometric tension record in presence of different substances.
Results: S. mombin leaves extract increased uterine spontaneous contractions. This effect was reduced by indomethacin (2 x 10-6 M), yohimbine (2 x 10-6 M) and 2- aminoethoxydiphenyl borate (2-APB) (5 x 10-5 M), but not by atropine (3.45 x 10-8 M) and cholesterol (2.5 mg/ml).
Conclusion: The pharmacological justification for the traditional use of S. mombin leaves to treat dystocia and expel placenta was that its hydro-ethanolic extract induced prostaglandins release, α2-adrenoceptors stimulation, calcium release from internal stores and lifted inhibitory effect of cholesterol on uterine contractions in order to increase uterine smooth muscle contractions.

Keywords: Spondias mombin, uterus, contractions, calcium.

https://ift.tt/2yIo3OD

Neonatal mortality at the neonatal unit: the situation at a teaching hospital in Ghana

Background: The first 28 days of life- the neonatal period is the most vulnerable time for a child's survival. Globally, neonatal mortality has seen a downward trend in recent years. The main objective of this study was to determine the percentage of neonatal mortality and to provide information on factors associated with neonatal mortality at the neonatal unit of a tertiary health facility or teaching hospital.
Methods: Data of neonates admitted to the neonatal in-patient unit of the Komfo Anokye Teaching Hospital (KATH) in Ghana from January 2013 to May 2014 were analyzed. Logistic regression model was performed to assess the association between neonatal mortality and predictors.
Results: A total of 5,195 neonatal admissions were recorded. The overall percentage of neonatal mortality was 20.2%. Infants with very low birth weight, having 5-minute Apgar score lower than 4, newborns with pre-term delivery, being referred from other health facilities, and being diagnosed with respiratory distress and birth asphyxia had a higher percentage of neonatal mortality.
Conclusion: The mortality at the neonatal in-patient unit at the Komfo Anokye Teaching Hospital in Ghana is very high. There is the need for continuous attention and interventions to help reduce the risk of mortality among neonates admitted to the facility.

Keywords: Logistic regression, neonatal mortality, Kumasi.

https://ift.tt/2lyoUbe

Estimation of salivary cortisol level in post-menopausal women with psychosomatic disorders

Background: Stress is an undesirable or health threatening response of the body, which is brought on by deleterious external influences (stressors). Objective measurement of psychosocial stress helps in assessment of pivotal role of stress in precipitation of multitude of health problems and a solution to the same. Salivary biomarkers are suggested to provide a reliable and non-invasive method for the estimation of these general health problems. Salivary cortisol is such biomarker used as tool in the examination of human physiological stress response. Post-menopausal women show an increase in stress levels and hence suffer with multiple health related problems. Hence the present study aimed to estimate salivary cortisol levels in post-menopausal women with clinically diagnosed psychosomatic disorder/disorders of the head and neck region, so as to establish salivary cortisol as a biochemical indicator of stress.
Methods: Thorough intra-oral and extra-oral examination was performed to check for the presence of psychosomatic disorder of head and neck. Unstimulated saliva was collected from 100 post-menopausal women with and 100 without clinically diagnosed psychosomatic disorder/disorders through 'Spit Technique'. Salivary cortisol was estimated using ELISA method.
Results: The results were statistically significant as they showed that the salivary cortisol was in higher levels in post- menopausal women with clinically diagnosed psychosomatic disorder/disorders.
Conclusion: The geriatric patients feel that they have very little skills or resources to deal with the high levels of stress that they are experiencing and hence suffer from lack of self-worth. The results of this study recommend that stress evaluation should be done on a regular basis for all post- menopausal women. For individuals who do not reveal their psychological distress, salivary analysis of cortisol may be used as an aid to diagnose their situation in conjunction with clinical diagnosis.

Keywords: Post-menopausal women, psychosomatic disorder, head and neck, salivary cortisol, biomarker.

https://ift.tt/2tE8DFv

The virtual small cells based on UE positioning: a network densification solution

Next wireless generation mobile networks will be composed of a large number of antennas at the base station (BS), which is known as massive multiple input multiple output (MIMO). Thanks to this technology, the...

https://ift.tt/2MZoirv

An optimized two-level discrete wavelet implementation using residue number system

Using discrete wavelet transform (DWT) in high-speed signal processing applications imposes a high degree of caution to hardware resource availability, latency and power consumption. In this paper, we investig...

https://ift.tt/2KnqiIz

A Case of Cephalic Tetanus in an Elderly Patient with Trismus

We report a case of a 77-year-old woman who presented to the Emergency Room with a three-day history of oral lesions and jaw tightness. Her physical examination was remarkable for the presence of trismus and white ulcers on the visible portion of the tongue. CT head and neck was unremarkable, and she was discharged with empiric treatment for oral candidiasis. She returned two days later with worsening symptoms and subsequently developed tonic-clonic seizures. MRI of the brain and temporomandibular joints were noncontributory. Psychiatry was consulted, and the patient was prescribed olanzapine and mirtazapine for suspected depression with somatization symptoms. She continued to deteriorate despite therapy and developed right lid ptosis and ophthalmoparesis, which led to a presumptive diagnosis of cephalic tetanus. On the 14th day of illness, tetanus immune globulin, metronidazole, and tetanus toxoid vaccine were administered. Despite treatment, the patient died after 24 days of hospitalization. This case illustrates the importance of early recognition of tetanus since successful treatment depends on timely administration of immune globulin.

https://ift.tt/2Mlq5pM

Closed-Loop Insulin Delivery for Glycemic Control in Noncritical Care

The burden of diabetes is increasing worldwide, as is the proportion of patients with diabetes in hospitals. More than one quarter of hospitalized patients in the United States and other developed countries have diabetes. In such patients, the achievement of recommended glycemic targets is…

https://ift.tt/2MZXxmP

Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP

Abstract

Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-β aggregation, deposition of amyloid-β plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer's disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-β aggregation correlates with an unexpected shift in soluble amyloid-β 40/42 ratio. This alteration in amyloid-β isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-β. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer's disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration.

https://ift.tt/2lDoMYd

Phase I and biomarker study of plerixafor and bevacizumab in recurrent high-grade glioma

Purpose: Although anti-angiogenic therapy for high-grade glioma (HGG) is promising, responses are not durable. Correlative clinical studies suggest that the SDF-1α/CXCR4 axis may mediate resistance to VEGFR inhibition. Preclinical data have demonstrated that plerixafor (a reversible CXCR4 inhibitor) could inhibit glioma progression after anti-VEGF pathway inhibition. We conducted a Phase I study to determine the safety of plerixafor and bevacizumab in recurrent HGG. Experimental Design: Part 1 enrolled 23 patients with a 3x3 dose escalation design to a MTD of plerixafor 320µg/kg subcutaneously on days 1-21 and bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle. CSF and plasma samples were obtained for pharmacokinetic analyses. Plasma and cellular biomarkers were evaluated before and after treatment. Part 2 enrolled 3 patients and was a surgical study to determine plerixafor's penetration in tumor tissue. Results: In Part 1, no DLTs were seen at the MTD of plerixafor+bevacizumab. Treatment was well tolerated. After plerixafor 320µg/kg treatment, the average CSF drug concentration was 26.8±19.6ng/mL. Plerixafor concentration in resected tumor tissue from patients pre-treated with plerixafor was 10-12µg/g. Circulating biomarker data indicated that plerixafor + bevacizumab induces rapid and persistent increases in plasma SDF1α and PlGF. PFS correlated with pre-treatment plasma sMET and sVEGFR1, and OS with the change during treatment in CD34+ progenitor/stem cells and CD8-T cells. Conclusions: Plerixafor + bevacizumab was well tolerated in HGG patients. Plerixafor distributed to both the CSF and brain tumor tissue, and treatment was associated with biomarker changes consistent with VEGF and CXCR4 inhibition.

https://ift.tt/2MpGzgy

Loss of E-cadherin enhances IGF1-IGF1R pathway activation and sensitizes breast cancers to anti-IGF1R/InsR inhibitors

Purpose: Insulin-like growth factor 1 (IGF1) signaling regulates breast cancer initiation and progression and associated cancer phenotypes. We previously identified E-cadherin (CDH1) as a repressor of IGF1 signaling and in this study examined how loss of E-cadherin affects IGF1R signaling and response to anti-IGF1R/insulin receptor (InsR) therapies in breast cancer. Experimental Design: Breast cancer cell lines were used to assess how altered E-cadherin levels regulate IGF1R signaling and response to two anti-IGF1R/InsR therapies. In situ proximity ligation assay (PLA) was used to define interaction between IGF1R and E-cadherin. TCGA RNA-seq and RPPA data was used to compare IGF1R/InsR activation in estrogen receptor positive (ER+) invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) tumors. ER+ ILC cell lines and xenograft tumor explant cultures were used to evaluate efficacy to IGF1R pathway inhibition in combination with endocrine therapy. Results: Diminished functional E-cadherin increased both activation of IGF1R signaling and efficacy to anti-IGF1R/InsR therapies. PLA demonstrated a direct endogenous interaction between IGF1R and E-cadherin at points of cell-cell contact. Increased expression of IGF1 ligand and levels of IGF1R/InsR phosphorylation were observed in E-cadherin deficient ER+ILC compared to IDC tumors. IGF1R pathway inhibitors were effective in inhibiting growth in ER+ ILC cell lines and synergized with endocrine therapy and similarly IGF1R/InsR inhibition reduced proliferation in ILC tumor explant culture. Conclusions: We provide evidence that loss of E-cadherin hyperactivates the IGF1R pathway and increases sensitivity to IGF1R/InsR targeted therapy, thus identifying the IGF1R pathway as a potential novel target in E-cadherin deficient breast cancers.

https://ift.tt/2KlCjkY

TERT promoter mutation detection in cell-free tumor-derived DNA in patients with IDH wild-type glioblastomas - a pilot prospective study

Purpose: We conducted a pilot study to assess the feasibility and the potential implications of detecting TERT promoter (TERTp)-mutant cell-free tumor-derived DNA (tDNA) in the cerebrospinal fluid (CSF) and plasma of glioblastoma patients. Experimental Design: Matched CSF and plasma samples were collected in 60 patients with glial tumors. The CSF collection was obtained during surgery, before any surgical manipulation of the tumor. The extracted tDNA and corresponding tumor DNA samples were analyzed for TERTp and isocitrate dehydrogenase (IDH) hotspot mutations. In addition, the variant allele frequency (VAF) of TERTp-mutation in the CSF-tDNA was correlated with patients' outcome. Results: Thirty-eight patients had TERTp-mutant, IDH wild-type glioblastomas. The matched TERTp mutation in the CSF-tDNA was successfully detected with 100% specificity and 92.1% sensitivity (n=35/38). In contrast, the sensitivity in the plasma-tDNA was far lower (7.9%). We concordantly observed a longer overall survival of patients with low VAF in the CSF-tDNA when compared to patients with high VAF, irrespective of using the lower quartile VAF (11.45%) [14.0 mo. (95%CI 10.3-17.6) vs. 8.6 mo. (95%CI 4.1-13.2), p=0.035], the lower third VAF (13%) [15.4 mo. (95%CI 11.6-19.2) vs. 8.3 mo. (95%CI 2.3-14.4), p=0.008] or the median VAF (20.3%) [14.0 mo. (95%CI 9.2-18.7) vs. 8.6 mo. (95%CI 7.5-9.8), p=0.062] to dichotomize the patients. Conclusions: This pilot study highlights the value of CSF-tDNA for an accurate and reliable detection of TERTp mutations. Furthermore, our findings suggest that high TERTp-mutation VAF levels in the CSF-tDNA may represent a suitable predictor of poor survival in glioblastoma patients.

https://ift.tt/2Itb96D

Inhibition of BET bromodomain proteins with GS-5829 and GS-626510 in Uterine Serous Carcinoma, a biologically aggressive variant of Endometrial Cancer

Purpose: Uterine-serous-carcinoma (USC) is a rare and aggressive variant of endometrial cancer. Whole-exome-sequencing (WES) studies have recently reported c-Myc gene amplification in large number of USC suggesting c-Myc as a potential therapeutic target. We investigated the activity of novel BET bromodomain inhibitors (GS-5829 and GS-626510, Gilead-Science-Inc.) and JQ1 against primary USC-cultures and USC-xenografts. Experimental Design: We evaluated c-Myc expression by qRT-PCR in a total of 45 USC including fresh-frozen-tumor-tissues and primary USC-cell-lines. We also performed immunohistochemistry (IHC) and Western-Blot experiments in 8 USC tumors. USC cultures were evaluated for sensitivity to GS-5829, GS-626510 and JQ1 in-vitro using proliferation, viability and apoptosis-assays. Finally, the in-vivo activity of GS-5829, GS-626510 and JQ1 was studied in USC-ARK1 and USC-ARK2 mouse-xenografts. Results: Fresh-frozen USC and primary USC cell-lines overexpressed c-Myc when compared to normal tissues (p =0.0009 and =0.0083, respectively). High c-Myc expression was found in 7 of 8 of primary USC cell lines tested by qRT-PCR and 5 of 8 tested by IHC. In-vitro experiments demonstrated high sensitivity of USC cell-lines to the exposure to GS-5829, GS-626510 and JQ1 with BET-inhibitors causing a dose-dependent decrease in the phosphorylated levels of c-Myc and a dose-dependent increase in caspase activation (apoptosis). In comparative in-vivo experiments GS-5829 and/or GS-626510 were found more effective than JQ1 at the concentrations/doses used in decreasing tumor-growth in both USC-ARK1 and USC-ARK2 mouse-xenograft-models. Conclusions: GS-5829 and GS-626510 may represent novel, highly effective therapeutics agents against recurrent/chemotherapy resistant USC overexpressing c-Myc. Clinical studies with GS-5829 in USC-patients harboring chemotherapy-resistant disease are warranted.

https://ift.tt/2Kly2Oo

Two weeks' notice from allogeneic sources

A novel pipeline for neoantigen-specific T cell receptor (TCR) identification has been validated in ovarian cancer, making use of HLA-matched allogeneic healthy donor T cells. This workflow allows for the identification of tumor-specific TCRs two weeks after antigen-specific stimulation and eliminates problematic patient-to-patient variation in the selection of neoantigen-specific TCRs.

https://ift.tt/2MlMu6A

The combination of the PARP inhibitor olaparib and the Wee1 inhibitor AZD1775 as a new therapeutic option for small cell lung cancer

Purpose:Introduced in 1987, platinum-based chemotherapy remains standard of care for small cell lung cancer, a most aggressive, recalcitrant tumor. Prominent barriers to progress are paucity of tumor tissue to identify drug targets and patient relevant models to interrogate novel therapies. Following our development of circulating tumour cell patient-derived explants (CDX) as models that faithfully mirror patient disease, here we exploit CDX to examine new therapeutic options for small cell lung cancer. Experimental Design: We investigated the efficacy of the PARP inhibitor olaparib alone or in combination with the Wee1 kinase inhibitor AZD1775 in ten phenotypically distinct SCLC CDX in vivo and/or ex vivo. These CDX represent chemosensitive and chemorefractory disease including the first reported paired CDX generated longitudinally before treatment and upon disease progression. Results:There was a heterogeneous depth and duration of response to olaparib/AZD1775 which diminished when tested at disease progression. However, efficacy of this combination consistently exceeded that of cisplatin/etoposide with cures in one CDX model. Genomic and protein analyses revealed defects in homologous recombination repair and oncogenes that induce replication stress (such as MYC family members), predisposed CDX to combined olaparib/AZD1775 sensitivity though universal predictors of response were not noted. Conclusions:These preclinical data provide a strong rationale to trial this combination in the clinic informed by prevalent, readily accessed circulating tumor cell based biomarkers. New therapies will be evaluated in SCLC patients after first line chemotherapy and our data suggest that the combination of olaparib/AZD1775 should be used as early as possible and prior to disease relapse.

https://ift.tt/2K7xbS9

UTHealth Medical Students Make Presentations at International SENTAC Meeting

Nine posters were presented by medical students and residents from the McGovern Medical School Department of Otorhinolaryngology-Head and Neck Surgery...

https://ift.tt/2lycn7G

Parents Urged to Ask Playdates If There Is a Gun in the Home

MONDAY, June 25, 2018 -- The American Academy of Pediatrics (AAP) is urging parents to ask a simple question before sending their children over to play at someone's house: "Is there an unlocked gun in your house?" The ASK Day Campaign, led by the...

https://ift.tt/2tHXT98

Direct-Acting Antivirals Effective for Hepatitis C in Seniors

MONDAY, June 25, 2018 -- For older patients with hepatitis C virus (HCV), direct-acting antiviral (DAA) therapy is effective, according to a study published online May 25 in the Journal of the American Geriatrics Society. Chiara Mazzarelli, M.D.,...

https://ift.tt/2lCR5Wl

Percentage of Teens Trying to Lose Weight Decreasing

MONDAY, June 25, 2018 -- From 1988-1994 to 2009-2014 there was an increase in the prevalence of overweight and obesity among U.S. adolescents and a decrease in the percentage who tried to lose weight, according to a research letter published online...

https://ift.tt/2tHXS54

Efavirenz Doesn't Up Depression, Suicidal Ideation in HIV-Infected

MONDAY, June 25, 2018 -- For persons living with HIV (PLHIV) in Uganda, use of efavirenz is not associated with increased risk of depression or suicidal ideation, according to a study published online June 26 in the Annals of Internal...

https://ift.tt/2lCR4Sh

AMA: Docs Declare Drug Shortages Public Health Emergency

MONDAY, June 25, 2018 -- At the annual meeting of the American Medical Association (AMA), physicians adopted policy declaring drug shortages an urgent public health crisis. Many of the drugs currently in shortage are required for patient care in all...

https://ift.tt/2yJm2BD

Human immunodeficiency virus associated pulmonary conditions leading to hospital admission and the pulmonary rehabilitation services received by patients at two central hospitals in Harare

Use of highly active antiretroviral therapy has led to marked reductions in the incidence of HIV-associated opportunistic infections but has had comparatively less impact on the incidence of some pulmonary dis...

https://ift.tt/2Khq0Gi

Differential expression of cytokines and receptor expression during anoxic growth

Cell density in tumor cell three dimensional (3D) cultures affects secretome expression of components. A microenvironment characteristic shared by high-density 3D cell culture and in vivo tumor masses is poor ...

https://ift.tt/2IrFgM1

Maternal depression does not affect complementary feeding indicators or stunting status of young children (6–23 months) in Northern Ghana

Maternal depression may affect child feeding practice which is an important determinant of child nutritional status. The objective of this study was to explore the association between maternal depression and W...

https://ift.tt/2K8k2bJ

Molecular identification of Bartonella bacilliformis in ticks collected from two species of wild mammals in Madre de Dios: Peru

To study the presence of Bartonella bacilliformis in ticks collected from two wild mammals in Madre de Dios, Peru.

https://ift.tt/2IrC2bk

Closed-Loop Insulin Delivery for Glycemic Control in Noncritical Care

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2MpoC1T

Temporal Small Arterial Inflammation is Common in Patients with Giant Cell Arteritis

Giant cell arteritis (GCA) primarily involves medium-to-large arteries. Small vessel inflammation is a recognized phenomenon occurring in association with GCA. However, its significance is poorly elucidated. Histologic sections and medical records of105 temporal artery specimens were retrospectively reviewed between 2008 and 2017 to examine associated clinical manifestations and laboratory data including ANA and p-ANCA titers. Immunohistochemical staining for CD4 and CD8 was performed in select cases to assess the nature of the inflammatory response.

https://ift.tt/2tCaafe

Co-expression of CDX2 and CK20 in hepatocellular carcinoma, an exceedingly rare coincidence with potential diagnostic pitfall

(See Fig. 1.)

https://ift.tt/2tuWdjH

Clinicopathological and prognostic significance of SHP2 and Hook1 expression in patients with thyroid carcinoma

Some thyroid carcinomas (TCs) have a violent biological behavior and poor prognosis, and lacking of effective molecular markers is still the main obstacle for clinical stratified diagnosis and treatment of TC. The aim of the study was to discover the clinicopathological and prognostic implications of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) and Hook microtubule tethering protein 1(Hook1) expression in TC. The expression of SHP2 and Hook1was detected by immunohistochemistry on tissue microarrays from 313 primary TC who underwent surgery during January 2006 and January 2010 in Zhejiang Cancer Hospital.

https://ift.tt/2tATlBl

DE605 General Examination Camera

The DE605 General Examination Camera is a special purpose, ultra HD digital video camera combined with a high magnification lens and multiple ultra-bright LEDs.

This cutting-edge, digital, polarizing general examination camera is ideal for healthcare professionals and telemedicine deployments where close-up skin inspections or general examinations are essential. Whether you're viewing a questionable mole, a patient's throat, or a subject 15ft away, the DE605 can easily focus on distant and up-close targets. On contact the viewing area is 20mm x 25mm – Perfect for dermoscopy!

The DE605 was designed for telemedicine as it enables remote care providers to see close-up live images of the patient. The DE605 uses standard webcam drivers, which means integration is easy – Just plug the general exam camera into an available USB port and switch the live feed.

With its many uses and applications, the DE605 General Exam Camera is a versatile, easy to use tool and is easy to acquire at a very affordable price. Please contact us for more information.

For Technical Specifications Click Here
[See image gallery at fireflyglobal.com]

Features

• Ultra HD Resolution
• Variable Viewing Distance
  • Torso
  • Portrait
  • Oral/Skin
• Easily integrates with telemedicine solutions
• Built in polarizer for dermoscopy
• Records pictures and video
• 16 LEDs with Controllable Brightness
• Observes and records in real time
• Built-in snapshot button

Uses

• Telemedicine
• Inter-oral Examinations
• Dermatological Examinations
• Micro and Macro focus options
• Patient education
• Electronic Medical Records (EMR)

What's Included

• DE605 General Examination Camera
• FireflyPro Software CD
• USB Cable
• User Manual on CD

Technical Details
Sensor Resolution	True 5 Megapixels (2592 x 1944)
Magnification	Native Optical: 15x – 50x Digital: 15x – 150x
Lens Assembly	3-Layer Glass, 650nm cutoff Integrated Polarizer with variable settings
Video	Format: MJPG, YUY2 Frame rate: Up to 30 FPS
Video/Image Properties	Color: Hue, Saturation Exposure: Brightness, Contrast Image: Sharpness, Gamma
Video/Image Files	JPG / BMP / AVI
Lighting	16 Ultra-Bright LEDs 4 Brightness Settings
Interface	USB2.0
Dimensions	19.5cm length 5cm diameter (nose cone) 3.5cm diameter (body) 180cm cable
Software	Scalable Window, Zoom, Freeze, Selectable Resolution, Image Recording, Video Recording
Operating Systems	Windows 7, 8.1, 10 Mac OS-X 10.4 or higher
Warranty	1 Year Limited Hardware Warranty

For more information contact sales@fireflyglobal.com

https://ift.tt/2lA2YMO

Water/ethanol extract of Cucumis sativus L. fruit attenuates lipopolysaccharide-induced inflammatory response in endothelial cells

It is widely accepted the key role of endothelium in the onset of many chronic and acute vascular and cardiovascular diseases.

https://ift.tt/2yFjZyL

Coconut water vinegar ameliorates recovery of acetaminophen induced liver damage in mice

Coconut water has been commonly consumed as a beverage for its multiple health benefits while vinegar has been used as common seasoning and a traditional Chinese medicine. The present study investigates the po...

https://ift.tt/2lwLctO

Antimicrobial misuse in pediatric urinary tract infections: recurrences and renal scarring

In children, urinary tract infection (UTI) is one of a common bacterial infection. This study was conducted to detect the uropathogen, antimicrobial susceptibility, pathogen associated with recurrences and ren...

https://ift.tt/2KlhLsM

Population-Based Validation of a Clinical Prediction Model for Congenital Diaphragmatic Hernias

To examine the external validity of a well-known congenital diaphragmatic hernia (CDH) clinical prediction model using a population-based cohort.

https://ift.tt/2yE4ZkI

Delayed Cord Clamping in Infants with Suspected Intrauterine Growth Restriction

We evaluated a subset of infants with suspected intrauterine growth restriction or birth weights small for gestational age enrolled in a study of delayed cord clamping for preterm infants. Compared with immediate clamping, delayed cord clamping was associated with no apparent harm and less suspected necrotizing enterocolitis.

https://ift.tt/2MYZhgo

Respiratory Compliance in Late Preterm Infants (340/7-346/7 Weeks) after Antenatal Steroid Therapy

To compare respiratory compliance in late preterm infants (340/7-346/7 weeks) who received antenatal steroids vs matched late preterm infants who did not receive antenatal steroids.

https://ift.tt/2tuqT4Q

The Effect of Noninvasive High-Frequency Oscillatory Ventilation on Desaturations and Bradycardia in Very Preterm Infants: A Randomized Crossover Trial

Noninvasive high-frequency oscillatory ventilation compared with nasal continuous positive airway pressure significantly reduced the number of desaturations and bradycardia in preterm infants. However, noninvasive high-frequency oscillatory ventilation was associated with increased oxygen requirements and higher heart rates.

https://ift.tt/2tEuhsS

Wandering Liver, Wondering Doctors!

A 3-year-old girl was evaluated in the emergency department for severe abdominal pain and vomiting. Her past medical history was unremarkable, and she had normal growth. On physical examination, she had diffuse abdominal pain with a soft abdomen. Joint hyperlaxity and high arched palate were observed. Abdominal radiograph and ultrasound showed a left-sided liver without signs of intussusception or obstruction. Because of the persistence of abdominal pain, an abdominal ultrasound repeated 24 hours later, identified the liver on the right side.

https://ift.tt/2yGVml7

Deep Palmar and Plantar Creases in Costello Syndrome

A male was born at 39 weeks of gestation, weighing 3670 g. Prenatal ultrasound scan showed severe polyhydramnios, requiring amniodrainage. A normal 46XY karyotype was obtained by amniocentesis. On examination, he had macrocephaly, with coarse facial features (broad anterior fontanelle, prominent forehead, bulbous nose, wide mouth), rhizomelic shortening of limbs, and ulnar deviation of the hands, with deep palmar and plantar creases (Figure, A and B). He developed respiratory distress syndrome, which required noninvasive mechanical ventilation.

https://ift.tt/2tsyLnm

In Silico Trial of MR-Guided Mid-Treatment Adaptive Planning for Hypofractionated Stereotactic Radiotherapy in Centrally Located Thoracic Tumors

In this in silico trial, central thorax tumor response to hypofractionated stereotactic radiotherapy (HSRT) was defined using prospective daily MRI. We then investigated whether tumor response could be used advantageously to reduce dose to organs-at-risk while preserving target coverage. We found that mid-treatment adaptive planning based on observed significant tumor response improved organ-at-risk sparing and target coverage. Our findings suggest online adaptive planning using MRI-guided radiation could improve the therapeutic index of central thoracic radiotherapy.

https://ift.tt/2IsL5sj

Changes in brain metastasis during radiosurgical planning

The time between planning MRI and radiosurgical treatment of brain metastases and tumor resection cavities is highly variable between centers. This prospective study performed a standardized planning MRI and a repeat verification MRI 24 hours prior to radiosurgery. Any change in management, including re-planning based on MRI-2 was recorded. Measurable changes occurred in brain metastases over a short amount of time with a change in management required in around 50% of patients and lesions.

https://ift.tt/2KkTbrV

Closed-Loop Insulin Delivery for Glycemic Control in Noncritical Care

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2MpoC1T

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/2Is75ng

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

Defining, Estimating, and Communicating Overdiagnosis in Cancer Screening

The toll of inadequate health care is well-substantiated, but recognition is mounting that "too much" is also possible. Overdiagnosis represents one harm of too much medicine, but the concept can be confusing: It is often conflated with related harms (such as overtreatment, misclassification, false-positive results, and overdetection) and is difficult to measure because it cannot be directly observed. Because the U.S. Preventive Services Task Force (USPSTF) issues screening recommendations aimed largely at healthy persons, it has a particular interest in understanding harms related to screening, especially but not limited to overdiagnosis. In support of the USPSTF, the authors summarize the knowledge and provide guidance on defining, estimating, and communicating overdiagnosis in cancer screening. To improve consistency, thinking, and reporting about overdiagnosis, they suggest a specific definition. The authors articulate how variation in estimates of overdiagnosis can arise, identify approaches to estimating overdiagnosis, and describe best practices for communicating the potential for harm due to overdiagnosis.

https://ift.tt/2KmOScz

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/2KnzL5V

Percutaneous Ablation Versus Partial and Radical Nephrectomy for T1a Renal Cancer A Population-Based Analysis

Background:

Stage T1a renal cell carcinoma (RCC) (tumors <4 cm) is usually curable. Nephron-sparing partial nephrectomy (PN) has replaced radical nephrectomy (RN) as the standard of care for these tumors. Radical nephrectomy remains the first alternative treatment option, whereas percutaneous ablation (PA), a newer, nonsurgical treatment, is recommended less strongly because of the relative paucity of comparative PA data.

Objective:

To compare PA, PN, and RN outcomes.

Design:

Observational cohort analysis using inverse probability of treatment–weighted propensity scores.

Setting:

Population-based SEER (Surveillance, Epidemiology, and End Results) cancer registry data linked to Medicare claims.

Patients:

Persons aged 66 years or older who received treatment for T1a RCC between 2006 and 2011.

Interventions:

PA versus PN and RN.

Measurements:

RCC-specific and overall survival, 30- and 365-day postintervention complications.

Results:

4310 patients were followed for a median of 52 months for overall survival and 42 months for RCC-specific survival. After PA versus PN, the 5-year RCC-specific survival rate was 95% (95% CI, 93% to 98%) versus 98% (CI, 96% to 99%); after PA versus RN, 96% (CI, 94% to 98%) versus 95% (CI, 93% to 96%). After PA versus PN, the 5-year overall survival rate was 77% (CI, 74% to 81%) versus 86% (CI, 84% to 88%); after PA versus RN, 74% (CI, 71% to 78%) versus 75% (CI, 73% to 77%). Cumulative rates of renal insufficiency 31 to 365 days after PA, PN, and RN were 11% (CI, 8% to 14%), 9% (CI, 8% to 10%), and 18% (CI, 17% to 20%), respectively. Rates of nonurologic complications within 30 days after PA, PN, and RN were 6% (CI, 4% to 9%), 29% (CI, 27% to 30%), and 30% (CI, 28% to 32%), respectively. Ten percent of patients in the PN group had intraoperative conversion to RN. Seven percent of patients in the PA group received additional PA within 1 year of treatment.

Limitations:

Analysis of observational data may have been affected by residual confounding by provider or from selection bias toward younger, healthier patients in the PN group. Findings from this older study population are probably less applicable to younger patients. Use of SEER–Medicare linked files prevented analysis of patients who received treatment after 2011, possibly reducing generalizability to the newest PA, PN, and RN techniques.

Conclusion:

For well-selected older adults with T1a RCC, PA may result in oncologic outcomes similar to those of RN, but with less long-term renal insufficiency and markedly fewer periprocedural complications. Compared with PN, PA may be associated with slightly shorter RCC-specific survival but fewer periprocedural complications.

Primary Funding Source:

Association of University Radiologists GE Radiology Research Academic Fellowship and Society of Interventional Radiology Foundation.

https://ift.tt/2IsmsMt

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/2KawUOr

Depression and Suicidal Ideation Among HIV-Infected Adults Receiving Efavirenz Versus Nevirapine in Uganda A Prospective Cohort Study

Background:

Evidence regarding potential adverse neuropsychiatric effects of efavirenz is conflicting, and data from sub-Saharan Africa, where 70% of persons living with HIV (PLHIV) reside and efavirenz is used as first-line therapy, are limited.

Objective:

To estimate associations between efavirenz use and depression and suicidal ideation among PLHIV in Uganda.

Design:

Prospective observational cohort study. (ClinicalTrials.gov: NCT01596322)

Setting:

Mbarara, Uganda.

Participants:

Adult PLHIV enrolled at the start of antiretroviral therapy (ART) and observed every 3 to 4 months from 2005 to 2015.

Measurements:

The exposure of interest was time-varying efavirenz use, defined as use during the 7 days and in 60 or more of the 90 days before a study visit, compared with nevirapine use. Self-reported outcomes were depression, defined as a mean score greater than 1.75 on the Hopkins Symptom Checklist depression subscale, and suicidal ideation. Multivariable-adjusted generalized estimating equations (GEE) logistic regression, Cox proportional hazards regression, and marginal structural models were fit to estimate the association between efavirenz use and the risk for depression and suicidal ideation.

Results:

694 participants (median age, 33 years; median pretreatment CD4⁺ count, 1.8 × 10⁹ cells/L) contributed 1200 person-years of observation (460 person-years receiving efavirenz). No baseline differences in depression or suicidal ideation were found between patients ever exposed to efavirenz and those never exposed to efavirenz and receiving nevirapine (P > 0.80 for both). Of 305 participants ever-exposed to efavirenz, 61 (20.0%) and 19 (6.2%) had depression and suicidal ideation, respectively, on at least 1 follow-up visit, compared with 125 (32.1%) and 47 (12.1%) of the 389 who received nevirapine. In adjusted GEE models, efavirenz use was associated with decreased odds of depression compared with nevirapine use (adjusted odds ratio, 0.62 [95% CI, 0.40 to 0.96]) and was not significantly associated with suicidal ideation (adjusted odds ratio, 0.61 [CI, 0.30 to 1.25]). Time-to-event and marginal structural models yielded similar estimates.

Limitation:

Nonrandom assignment to treatment and substantial differences between the efavirenz and nevirapine groups.

Conclusion:

No evidence was found that use of efavirenz in first-line ART increased the risk for depression or suicidal ideation compared with nevirapine use among PLHIV in Uganda.

Primary Funding Source:

National Institutes of Health.

https://ift.tt/2Kn7BrA

ESPACOMP Medication Adherence Reporting Guideline (EMERGE)

Research on assessing or managing medication adherence applies approaches from observational, interventional, and implementation science that spans many disciplines and demands coherent conceptualization, valid methods, appropriate analyses, and complete and accurate reporting. To ensure such reporting, the European Society for Patient Adherence, COMpliance, and Persistence (ESPACOMP) Medication Adherence Reporting Guideline (EMERGE) recommends standard reporting approaches based on an accepted taxonomy.This guideline is derived from a literature review, a reactive Delphi study with 26 medication adherence experts from many countries and disciplines, and feedback from ESPACOMP members. It is designed to supplement existing guidelines for health research reporting and is structured around 4 minimum reporting criteria and 17 items reflecting best reporting practice. By enhancing and harmonizing research reporting, EMERGE aims to advance research and, ultimately, patient outcomes.

https://ift.tt/2KkRXtL

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/2KleObz

When Height Carries Weight: Communicating Hidden Object Properties for Joint Action

Cognitive Science, EarlyView.


https://ift.tt/2lvVOJE

Ion‐Migration Inhibition by the Cation–π Interaction in Perovskite Materials for Efficient and Stable Perovskite Solar Cells

Advanced Materials, EarlyView.


https://ift.tt/2K8k9UC

Organic Photovoltaics over Three Decades

Advanced Materials, EarlyView.


https://ift.tt/2Mn2Bk1

Zero Linear Compressibility in Nondense Borates with a “Lu‐Ban Stool”‐Like Structure

Advanced Materials, EarlyView.


https://ift.tt/2K7DIMI

Combinatorial Synthesis of Macromolecular Arrays by Microchannel Cantilever Spotting (µCS)

Advanced Materials, EarlyView.


https://ift.tt/2IqBlin

Fabrication of Millimeter‐Scale, Single‐Crystal One‐Third‐Hydrogenated Graphene with Anisotropic Electronic Properties

Advanced Materials, EarlyView.


https://ift.tt/2K7DIwc

A Silica‐Aerogel‐Reinforced Composite Polymer Electrolyte with High Ionic Conductivity and High Modulus

Advanced Materials, EarlyView.


https://ift.tt/2MmGUR9

Device‐Level Photonic Memories and Logic Applications Using Phase‐Change Materials

Advanced Materials, EarlyView.


https://ift.tt/2Mmzc9G

Highly Branched VS4 Nanodendrites with 1D Atomic‐Chain Structure as a Promising Cathode Material for Long‐Cycling Magnesium Batteries

Advanced Materials, EarlyView.


https://ift.tt/2KajtOv

Atomic Cobalt Covalently Engineered Interlayers for Superior Lithium‐Ion Storage

Advanced Materials, EarlyView.


https://ift.tt/2Mi8xL6

Interlayer‐Spacing‐Regulated VOPO4 Nanosheets with Fast Kinetics for High‐Capacity and Durable Rechargeable Magnesium Batteries

Advanced Materials, EarlyView.


https://ift.tt/2Kkejii

Enlarged CoO Covalency in Octahedral Sites Leading to Highly Efficient Spinel Oxides for Oxygen Evolution Reaction

Advanced Materials, EarlyView.


https://ift.tt/2IrGPt1

Tough Hydrogels with Fast, Strong, and Reversible Underwater Adhesion Based on a Multiscale Design

Advanced Materials, EarlyView.


https://ift.tt/2K9cbdN

Lanthanide Contraction as a Design Factor for High‐Performance Half‐Heusler Thermoelectric Materials

Advanced Materials, EarlyView.


https://ift.tt/2Mi8kYk

Perceptions of future health and cancer risk in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study

Cancer, EarlyView.


https://ift.tt/2yJVwZ2

A multiple treatment comparison meta‐analysis of monoamine oxidase type B inhibitors for Parkinson's disease

British Journal of Clinical Pharmacology, EarlyView.


https://ift.tt/2K8MY3i

The Orotomide Olorofim is Efficacious in an Experimental Model of Central Nervous System Coccidioidomycosis [PublishAheadOfPrint]

Olorofim (formerly F901318) is an advanced analog of the orotomide class that inhibits fungal pyrimidine biosynthesis. We evaluated the in vitro and in vivo activity of olorofim against Coccidioides species. In vitro activity was assessed against 59 clinical Coccidioides isolates. Central nervous system infection was established in mice via intracranial inoculation with C. immitis arthroconidia. Oral therapy began 48 hours post-inoculation and consisted of vehicle control, olorofim daily doses of 20 mg/kg (6.67 mg/kg TID or 10 mg/kg BID), and 40 mg/kg (13.3 mg/kg TID or 20 mg/kg BID), or fluconazole (25 mg/kg BID). Treatment continued for 7 and 14 days in the fungal burden and survival arms, respectively. Fungal burden was assessed by colony-forming unit counts in brains. Olorofim demonstrated potent in vitro activity (MIC range ≤ 0.008 - 0.06 μg/ml). Survival was significantly enhanced in mice treated with olorofim. Reductions in brain tissue fungal burden were also observed on day 9 in the olorofim groups. Improvements in survival and reductions in fungal burden also occurred with fluconazole. More frequent dosing of olorofim was associated with enhanced survival and greater reductions in fungal burden. In the olorofim 13.3 mg/kg TID group, fungal burden remained low on day 30, 15 days after treatment stopped, and was undetectable in 7 of 10 mice. In contrast, elevated fungal burden rebounded in all other groups after therapy stopped. Olorofim was highly active in vitro and in vivo against Coccidioides. These results demonstrate that olorofim may have a role in the treatment of coccidioidomycosis.

https://ift.tt/2K7MZEu

Screening and characterization of multidrug-resistant Gram-negative bacteria from a remote African area, Sao Tome and Principe [PublishAheadOfPrint]

Occurrence of resistance to last-resort antibiotics was evaluated among Enterobacteriaceae isolates recovered from hospitalized children in a remote African archipelago, São Tomé and Príncipe, where there is limited access to those antibiotics. Fifty patients were screened for colonization by carbapenem-, pan-aminoglycoside-, or polymyxin-resistant Enterobacteriaceae. A total of 36 isolates (including 30 Escherichia coli and 4 Klebsiella pneumoniae) were recovered from 23 patients, including 26 isolates harboring the bla_OXA-181 carbapenemase gene, a single isolate harboring the 16S rRNA methylase gene rmtB encoding pan-resistance to aminoglycosides, and 8 isolates co-harboring both genes. A single isolate possessed the plasmid-borne colistin resistance gene mcr-1. A high clonal relationship was found for OXA-181-producing E. coli (4 clones), and conversely three out of the four OXA-181-producing K. pneumoniae isolates were clonally unrelated. This study overall showed a high prevalence of resistance to last-resort antibiotics in this country where no epidemiological data was previously available.

https://ift.tt/2IsdTBj

Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia [PublishAheadOfPrint]

Background: Azithromycin is extensively used in children acquired with community-acquired pneumonia (CAP). Currently, the intravenous azithromycin was used off-label in children partly due to lacking of pharmacokinetic data. Our objective was to evaluate the population pharmacokinetics (PPK) and optimize dose strategy in order to improve treatment in this distinctive population.

Methods: This was a prospective, multi-center, open-labeled pharmacokinetic study. Blood samples were collected from hospitalized pediatric patients and concentrations were determined by LC-MS/MS. PPK analysis was conducted using NONMEM software.

Results: The pharmacokinetic data from 95 pediatric patients (age range 2.1 – 11.7 years) were available for analysis. The PPK was best fitted by two-compartment model with linear elimination. Covariate analysis verified body weight and alanine aminotransferase (ALT) had significant effect on azithromycin pharmacokinetics, yielding a 24% decrease of clearance in patients with ALT>40. Monte Carlo simulation showed that for children with normal liver function, a loading dose strategy (a loading dose of 15mg/kg followed by maintenance doses of 10 mg/kg) would achieve the ratio of the area under free drug plasma concentration-time curve over 24 hours (fAUC) to MIC₉₀ (fAUC/MIC) target of 3 h in 53.2% hypothetical patients, using normative MIC susceptibility breakpoint of 2 mg/L. For children with ALT>40, the proposed dose needed to decrease by 15% to achieve comparable exposure. The corresponding risk of overdose for the recommended dosing regimen was less than 5.8%.

Conclusion: The PPK of azithromycin was evaluated in CAP children and an optimal dosing regimen was constructed based on developmental pharmacokinetic-pharmacodynamic modeling and simulation.

https://ift.tt/2Kk15lv

Acquisition of beta-lactamase by Neisseria meningitidis through possible horizontal gene transfer [PublishAheadOfPrint]

We report the detection in France of a beta-lactamase producing invasive meningococcal isolate. Whole genome sequencing of the isolate revealed ROB-1 type beta-lactamase gene that is frequently encountered in Haemophilus influenzae suggesting horizontal transfer between isolates of these bacterial species. Beta-lactamases are exceptional in meningococci with no reports from more than two decades. This report is worrying as the expansion of such isolates may jeopardize the effective treatment against invasive meningococcal disease.

https://ift.tt/2MmdVgl

Quantification of Cefepime, Meropenem, Piperacillin and Tazobactam in Human Plasma using a Sensitive and Robust LC-MS/MS Method- Part II. Stability Evaluation [PublishAheadOfPrint]

Although the stability of β-lactam antibiotics is a known issue, none of the previously reported bioanalytical methods had an adequate evaluation on their stability. In the current study, the stability of cefepime, meropenem, piperacillin, and tazobactam under various conditions was comprehensively evaluated. The evaluated parameters include stock solution stability, short-term stability, long-term stability, freeze-thaw stability, processed sample stability and whole blood stability. When stored at -20 °C, the stock solution of meropenem in methanol is stable for up to 3 weeks, and the stock solutions of cefepime, piperacillin, and tazobactam are stable for up to 6 weeks. All four antibiotics were stable in human plasma for up to 3 months when stored at -80 °C and stable in whole blood for up to 4 hours at room temperature. Short-term stability results indicated that all four β-lactams are stable at room temperature for 2 hours, but substantial degradation was observed when their plasma samples were stored at room temperature for 24 hours, with the degradation of cefepime, meropenem, piperacillin and tazobactam being 30.1 %, 75.6 %, 49.0 % and 37.7 %, respectively. As the stability information is method-independent, our stability results can be used as a reference by other research groups that work with these antibiotics.

https://ift.tt/2K6SNxX

TEM-184: a novel TEM-derived ESBL with enhanced activity against aztreonam [PublishAheadOfPrint]

TEM-184, a novel TEM-derived ESBL, was isolated from an Escherichia coli ST354 clinical strain. Compared to TEM-1, TEM-184 contains the following mutations: Q6K, E104K, I127V, R164S and M182T. Kinetic analysis of this enzyme revealed extended-spectrum activity in particular against aztreonam. TEM-184 was also susceptible to inhibitors including clavulanic acid, tazobactam and avibactam.

https://ift.tt/2Mosn7E

Quantification of Cefepime, Meropenem, Piperacillin and Tazobactam in Human Plasma using a Sensitive and Robust LC-MS/MS Method- Part I. Assay Development and Validation [PublishAheadOfPrint]

The highly variable pharmacokinetics of β-lactam antibiotics and β-lactamase inhibitors poses a significant challenge to clinicians in ensuring appropriate antibiotic doses in critically ill patients. Therefore, routine monitoring of their plasma concentrations is important for individualization of antimicrobial therapy. Accordingly, a simple and robust analytical method for the simultaneous determination of multiple β-lactam antibiotics and β-lactamase inhibitors is highly desirable to ensure quick decisions on dose adjustments. In this study, a sensitive, simple and robust method for the simultaneous quantification of cefepime, meropenem, piperacillin and tazobactam in human plasma was developed and rigorously validated according to the FDA guidance. Sample extraction was accomplished by simple protein precipitation. Chromatographic separation of analytes was achieved using a step-wise gradient elution. Analytes were monitored using MS/MS with a turbo ion spray source in positive multiple reaction monitoring mode. The calibration curve ranged from 0.5-150 μg/mL for cefepime, 0.1-150 μg/mL for meropenem and piperacillin, and 0.25-150 μg/mL for tazobactam. The inter- and intra-day precision and accuracy, sensitivity, selectivity, dilution integrity, matrix effect, extraction recovery and hemolysis effect were investigated for all four analytes and the results met the acceptance criteria. Compared with other reported methods, our method is more robust because of the combination of following features: a) simple sample extraction procedure, b) short sample run time, c) wide dynamic range, and d) small plasma sample volume needed. Since our method already covers β-lactams and a β-lactamase inhibitor with high heterogeneity of physico-chemical properties, further antibiotic candidates could be easily incorporated in this multi-analyte method.

https://ift.tt/2K5vftv

Variability of daptomycin minimum inhibitory concentrations for Enterococcus faecium when measured by reference broth microdilution and gradient diffusion tests [PublishAheadOfPrint]

Daptomycin has become a mainstay therapy for the treatment of serious vancomycin-resistant Enterococcus faecium infections. However, concern exists that current testing methods do not accurately predict clinical success of daptomycin therapy. We evaluated a collection of 40 isolates of E. faecium across 3 centers by reference broth microdilution (BMD), and two gradient strips, to determine the precision of daptomycin MICs by these methods and the correlation of daptomycin MIC testing with mutations in the liaFSR system, one of the primary daptomycin resistance mechanisms among the enterococci. Daptomycin MICs spanned 3 log₂ dilutions by BMD for 60.0% of isolates, 17.5% spanned 4 dilutions, 2.5% spanned 5 dilutions, and 20.0% spanned 6 or more dilutions. Fifteen isolates had MICs interpreted as susceptible by some tests, and nonsusceptible by others. Neither BMD not gradient diffusion tests could reliably differentiate isolates with or without mutations in liaFSR, resulting in a 59.8% very major error rate compared to genotype by BMD, 63.5% by Etest and 68.5% by MIC Test Strip. Imprecision in daptomycin MIC determination for E. faecium make establishment of a revised breakpoint challenging. Clinicians should be aware of this testing variability when making treatment decisions for patients with serious infections caused by this organism.

https://ift.tt/2Mo1Uao

Ceftaroline resistance by clone-specific polymorphism in penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus [PublishAheadOfPrint]

A total of 281 non-duplicated Staphylococcus aureus blood isolates were collected from January to May 2017 from eight hospitals in South Korea to investigate the epidemiological traits of ceftaroline resistance in methicillin-resistant S. aureus (MRSA). Cefoxitin-disk diffusion tests and mecA gene PCR revealed that 56.6% (159/281) of S. aureus was MRSA and mostly belonged to ST5 (50.3%, 80/281) and ST72 (41.5%, 66/281). Of the MRSA isolates, 44.0% (70/159) was non-susceptible to ceftaroline (MIC ≥2 mg/L), whereas all of the methicillin-susceptible S. aureus isolates were susceptible to the drug. Eight amino acid substitutions in penicillin-binding protein 2a (PBP2a), including four (L357I, E447K, I563T, and S649A) in penicillin-binding domain (PBD) and four (N104K, V117I, N146K, and A228V) in non-PBD (nPBD) of PBP2a, were associated with ceftaroline resistance. The accumulation of substitutions in PBP2a resulted in the elevation of ceftaroline MICs: one substitution at 1-2 mg/L, two or three substitutions at 2-4 mg/L, and five substitutions at 4 or 16 mg/L. Ceftaroline resistance in MRSA might be the result of clone-specific PBP2a polymorphism, along with substitutions both in PBD and in nPBD, and the elevated ceftaroline MICs were associated with the substitution sites and accumulation of substitutions.

https://ift.tt/2K8qwax

Reversal of chloroquine resistance of Plasmodium vivax in Aotus monkeys [PublishAheadOfPrint]

Chloroquine resistant (CQR) vivax malaria has emerged as a threat to the malaria elimination agenda. The objective of this study was to assess if a combination of chloroquine (CQ) and prochlorperazine was able to reverse CQ resistance of the Plasmodium vivax AMRU-1 strain from Papua New Guinea in infected Aotus monkeys. For this purpose, in two independent experimental drug efficacy trials, a total of eighteen Aotus monkeys infected with blood obtained from donor animals, were randomly assigned into treatment and control groups and administered CQ at 10 mg/kg or prochlorperazine at 20 mg/kg orally for five consecutive days alone or in combination. Reversal of CQR was achieved in animals that received the drug combination, whereas neither drug alone produced cures. This same drug combination reverses CQR in P. falciparum and could be an alternative for treatment in humans with chloroquine resistance P. vivax infections.

https://ift.tt/2MneEhz

Combination of amino acid substitutions leading to CTX-M-15-mediated resistance to the ceftazidime-avibactam combination [PublishAheadOfPrint]

Single amino-acid substitutions in the -loop of KPC β-lactamases are known to lead to resistance to the ceftazidime-avibactam combination. Here, we investigate this mechanism of resistance in CTX-M enzymes, which are the most widely spread extended-spectrum β-lactamases worldwide. Nine single amino acid polymorphisms were identified in the -loop of the 172 CTX-M sequences present in the Lahey database. The corresponding modifications were introduced in CTX-M-15 by site-directed mutagenesis. None of the nine substitutions was associated with ceftazidime-avibactam resistance in Escherichia coli TOP10. However, two substitutions led to 4-fold (P¹⁶⁷S) and 16-fold (L¹⁶⁹Q) increases in the MIC of ceftazidime. We determined whether these substitutions favor the in vitro selection of mutants resistant to ceftazidime-avibactam. The selection provided mutants for the L¹⁶⁹Q substitution but not for the P¹⁶⁷S substitution or for the parental enzyme CTX-M-15. Resistance to the drug combination (MIC of ceftazidime = 16 μg/ml in the presence of 4 μg/ml of avibactam) resulted from the acquisition of the S¹³⁰G substitution by CTX-M-15 L¹⁶⁹Q. Purified CTX-M-15 with the two substitutions, L¹⁶⁹Q and S¹³⁰G, was only partially inhibited by avibactam at concentrations as high as 50,000 μM but retained ceftazidime hydrolysis activity with partially compensatory decreases in k_cat and K_m. These results indicate that emergence of resistance to the ceftazidime-avibactam combination requires more than one mutation in most CTX-M-encoding genes. Acquisition of resistance could be restricted to rare variants harboring predisposing polymorphisms such as Q at position 169 detected in a single naturally-occurring CTX-M enzyme (CTX-M-93).

https://ift.tt/2KcGosE

Genistein and Ascorbic Acid reduce oxidative stress-derived DNA damage induced by antileishmanial meglumine antimoniate [PublishAheadOfPrint]

Meglumine antimoniate (Glucantime) is an antimonial pentavalent used to treat leishmaniasis, despite its acknowledged toxic effects, such as its ability to cause oxidative damage to lipids and proteins. Recently, our group demonstrated that meglumine antimoniate causes oxidative stress-derived DNA damage. Acknowledging that antioxidants modulate reactive oxygen species, we evaluated the capacity of genistein and ascorbic acid for preventing genotoxicity caused by meglumine antimoniate. For that, mice (n=5/group) received genistein (via gavage) in doses of 5, 10 and 20mg/kg for three consecutive days. After this period, they were treated with 810mg/kg meglumine antimoniate via intraperitoneal (i.p.). Furthermore, mice (n=5/group) received, simultaneously, ascorbic acid (i.p.) in doses of 30, 60 and 120mg/kg and 810mg/kg meglumine antimoniate. We also conducted post- and pre-treatment assays, in which animals received ascorbic acid (60mg/kg) 24 hours prior to or after receiving meglumine antimoniate. Genomic instability and mutagenicity were analyzed through conventional Comet assay and enzymatic assay using Formamidepyrimidine-DNA-glycosylase (Fpg) enzyme, as well as the Micronucleus Test, respectively. Meglumine antimoniate induced an increase in the DNA damage after digestion with Fpg, reinforcing its mutagenic potential by oxidizing DNA bases, which was prevented by genistein. Similarly, ascorbic acid proved itself capable of reducing mutagenic effects in simultaneous treatment, as well as in post-treatment. Therefore, our results demonstrate that both compounds are efficient in preventing mutations in mammalian cells treated with meglumine antimoniate.

https://ift.tt/2IuQmzA

Validating a 14-drug microtitre plate containing bedaquiline and delamanid for large-scale research susceptibility testing of Mycobacterium tuberculosis [PublishAheadOfPrint]

UKMYC5 is a 96-well microtitre plate designed by the Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC) to enable the measurement of minimum inhibitory concentrations (MICs) of 14 different anti-TB compounds for >30,000 clinical tuberculosis isolates. Unlike the MYCOTB plate, on which UKMYC5 is based, the plate included two new (bedaquiline and delamanid) and two repurposed (clofazimine and linezolid) compounds. UKMYC5 plates were tested by seven laboratories on four continents using a panel of 19 external quality assessment (EQA) strains, including H37Rv. To assess the optimal combination of reading method and incubation time, MICs were measured from each plate by two readers using three methods (mirrored-box, microscope and Vizion™ Digital viewing system) after 7, 10, 14 and 21 days incubation. In addition, all EQA strains were whole-genome sequenced and phenotypically characterized by 7H10/7H11 agar proportion method (APM) and MGIT960. We conclude that the UKMYC5 plate is optimally read using the Vizion™ system after 14 days incubation, achieving an inter-reader agreement of 97.9% and intra- and inter-laboratory reproducibility of 95.6% and 93.1%, respectively. The mirrored-box had similar reproducibility. Strains classified as resistant by APM, MGIT960 or the presence of mutations known to confer resistance consistently record elevated MICs compared with those strains classified as susceptible. Finally, the UKMYC5 plate records intermediate MICs for one strain which the APM measured MICs close the applied critical concentration, providing early evidence that the UKMYC5 plate can quantitatively measure the magnitude of resistance to anti-TB compounds due to specific genetic variation.

https://ift.tt/2KbSDFB

UCT943, a next generation Plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of malaria [PublishAheadOfPrint]

The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite lifecycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activity than MMV048 and was more potent against resistant P. falciparum and P. vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in P. berghei and humanized P. falciparum NOD-scid IL-2R^null mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vitro intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next generation Plasmodium PI4K inhibitor, the combined preclinical data suggest that UCT943 has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent and block the transmission of malaria.

https://ift.tt/2Mo1iS8

Molecular analysis of resistance and detection of non-wild type strains using ECV values of Etest for amphotericin B and echinocandins for bloodstream Candida infections from a tertiary hospital in Qatar. [PublishAheadOfPrint]

A total number of 301 Candida bloodstream isolates were evaluated from 289 patients collected over five years at a tertiary hospital in Qatar. Out of all Candida infections, 53% were diagnosed in patients admitted to the ICUs. Steady increases in non-albicans Candida species were reported from 2009 to 2014 (30.2% C. albicans vs. 69.8% for other Candida species). Etest antifungal susceptibility testing was performed on all recovered clinical isolates to determine echinocandin (micafungin and anidulafungin) and amphotericin B susceptibilities and assess non-wild type (WT) strains (MICs above the epidemiological cutoff values). DNA sequence analysis was performed on all isolates to assess the presence of FKS mutations, which confer echinocandin resistance in Candida species. A total of 3.9% of isolates (12/301) contained FKS hot spot mutations including heterozygous mutations in FKS1 among strains of C. albicans and C. orthopsilosis. For C. tropicalis, the Etest appeared to overestimate non-WT for micafungin, anidulafungin, and amphotericin B, as 14%, 11%, and 35% of strains were above the ECV. However, no FKS mutations were identified in this species. For all other species, micafungin best reported echinocandin non-WT strains relative to FKS genotype, as anidulafungin tended to overestimate non-wild type. Besides C. tropicalis, few strains were classified as non-WT towards amphotericin B.

https://ift.tt/2KbSoKH

Surveillance of genetic variations associated with antimalarial resistance of Plasmodium falciparum from returned migrant workers in Wuhan, Central China [PublishAheadOfPrint]

Antimalarial drug resistance developed in Plasmodium falciparum has become a problem for malaria control. Evaluation of drug resistance is the first step for effective malaria control. In this study, we investigated the gene mutations of P. falciparum using blood samples from the Chinese returned migrant workers in order to identify drug resistance-associated molecular markers. These workers returned from Africa and Southeast Asia (SEA) during 2011-2016. The polymorphisms in pfcrt, pfmdr1, and k13-propeller genes and the haplotype patterns of Pfcrt and Pfmdr1 were analyzed. The results showed the presence of four haplotypes of Pfcrt codons 72-76, including CVMNK (wild type), SVMNT, and CVIET (mutation type), CV M/I N/E K/T (mixed type), with 50.57%, 1.14%, 25.00%, and 23.30% prevalence, respectively. For Pfmdr1, N86Y (22.28%) and Y184F (60.01%) were the main prevalent mutations. The prevalence of mutation at position 550, 561, 575, and 589 of K13-propeller were 1.09%, 0.54%, 0.54% and 0.54%, respectively. These data suggested that Pfcrt, Pfmdr1, and K13-propeller polymorphisms are the potential markers to assess drug resistance of P. falciparum in China, Africa and SEA.

https://ift.tt/2MjxmGH

Molecular identification and susceptibility testing of molds isolated in a Prospective Surveillance of Triazole Resistance in Spain (FILPOP2 study) [PublishAheadOfPrint]

Antifungal resistance is increasing by the emergence of intrinsically resistant species and by the development of secondary resistance in susceptible species. A previous study performed in Spain revealed levels of azole resistance in molds between 10 to 12.7% but secondary resistance in A. fumigatus was not detected. We used itraconazole supplemented media to select resistant strains. A total of 500 plates supplemented with 2 mg/L of ITZ were sent to 10 Spanish tertiary hospitals, molecular identification and antifungal susceptibility testing were performed. In addition, cyp51A gene was sequenced in those A. fumigatus strains showing azole resistance. A total of 493 isolates were included in the study. Sixteen strains were isolated from patients with an infection classified as proven, 104 as probable and 373 as colonization. Aspergillus was the most frequent genera isolated with 80.3% followed by Scedosporium/Lomentospora (7.9%), Penicillium/Talaromyces (4.5%), Fusarium (2.6 %) and the order Mucorales (1 %). Antifungal resistance was detected in Scedosporium/Lomentospora species, Fusarium, Talaromyces and Mucorales. Three strains of A. fumigatus senso stricto were resistant to azoles, two of them harbored TR₃₄+L98H mechanism of resistance and the other one had no mutations in cyp51A. The level of azole resistance in A. fumigatus remains low but cryptic species represent over 10% of the isolates and have broader but overall higher range of antifungal resistance

https://ift.tt/2K4UfRs

Functional characterization of AbaQ, a novel efflux pump mediating quinolone resistance in Acinetobacter baumannii. [PublishAheadOfPrint]

Acinetobacter baumannii has emerged as an important multidrug-resistant nosocomial pathogen. In previous work, we identified a putative MFS transporter, AU097_RS17040, involved in the pathogenicity of A. baumannii (Pérez-Varela et al., Infect Immun. 2017). In this study, we analyzed the susceptibility to diverse antimicrobial agents of A. baumannii cells defective in this transporter, referred to herein as AbaQ. Our results showed that AbaQ is mainly involved in the extrusion of quinolone-type drugs in A. baumannii.

https://ift.tt/2IrLQ4P

May the Fittest Protein Evolve: Favoring the Plant‐Specific Origin and Expansion of NAC Transcription Factors

BioEssays, EarlyView.


https://ift.tt/2KmEHVw

Cells in the Non‐Uniform Magnetic World: How Cells Respond to High‐Gradient Magnetic Fields

BioEssays, EarlyView.


https://ift.tt/2tsGQsa

Is Xpert MTB/RIF appropriate for diagnosing tuberculous pleurisy with pleural fluid samples? A systematic review

Tuberculous pleurisy (TP) presents a diagnostic problem due to the limitations of traditional diagnostic methods. Different studies with the Xpert MTB/RIF assay have drawn variable conclusions about its values...

https://ift.tt/2tsoWWj

Biochemical and inflammatory modifications after switching to dual antiretroviral therapy in HIV-infected patients in Italy: a multicenter retrospective cohort study from 2007 to 2015

Triple-drug regimens are the gold standard for HIV therapy. Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) reducing regimens are used to decrease drugs toxicity, exposure and costs. Aim of our study wa...

https://ift.tt/2yDQ0qE

Analysis of N-glycans from Raphanus sativus Cultivars Using PNGase H+

We describe a simple and rapid method for the preparation and analysis of N-glycans from different cultivars of radish (Raphanus sativus).

https://ift.tt/2KnUCmb

A Temperature Gradient Assay to Determine Thermal Preferences of Drosophila Larvae

Here, we present a protocol to determine the preferred environmental temperature of Drosophila larvae using a continuous thermal gradient.

https://ift.tt/2Kk0CQo

Plaster which sticks inside the mouth will revolutionize treatment of oral conditions

A new biodegradable patch administers steroids directly to oral ulcers and forms a protective barrier.

https://ift.tt/2yGYI7N

Vertical Mergers Could Be Challenging for Primary Care

MONDAY, June 25, 2018 -- Vertical level mergers, which incorporate not just health care providers, but also insurers, retailers, and pharmacy benefit managers (PBMs), could pose challenges in primary care, according to an article published in...

https://ift.tt/2yIKinI

Stress Echo Safe for ER Triage of Patients With Chest Pain

MONDAY, June 25, 2018 -- For patients presenting to the emergency department with chest pain, a smaller proportion are hospitalized after undergoing stress echocardiography (SE) versus coronary computed tomography angiography (CCTA), according to a...

https://ift.tt/2ttOK4E

Many Childhood CA Survivors Not Concerned About Future Health

MONDAY, June 25, 2018 -- A substantial number of adult childhood cancer survivors are unconcerned about their future health and subsequent cancer risks, according to a study published online June 25 in Cancer. Todd M. Gibson, Ph.D., from St. Jude...

https://ift.tt/2tBlWGI

Aspirin Use Doesn't Cut Cancer Incidence in Older T2DM Patients

MONDAY, June 25, 2018 -- For Japanese patients with type 2 diabetes, low-dose aspirin is not associated with reduced cancer incidence, except in those younger than 65 years, according to a study published online June 16 in Diabetes Care. Sadanori...

https://ift.tt/2N0p47A

U.S. High School Students Report Sport-Linked Concussion

MONDAY, June 25, 2018 -- The prevalence of concussion among U.S. high school students related to playing a sport or being physically active is 15.1 percent per year, according to research published in the June 22 issue of the U.S. Centers for...

https://ift.tt/2yHhM5K

Awake VATS Can Be Safe Option for Some Lung Cancer Patients

MONDAY, June 25, 2018 -- Awake video-assisted thoracoscopic surgery (AVATS) is a safe and feasible technique for patients with poor lung function and lung cancer, according to a study presented recently at the annual meeting of the American...

https://ift.tt/2MWzkxT

Corneal Abnormalities Seen With Down Syndrome

MONDAY, June 25, 2018 -- Patients with Down syndrome (DS) have steeper and thinner corneas and more corneal aberrations than patients without DS, according to a study published online June 21 in JAMA Ophthalmology. Jorge L. Alio, M.D., Ph.D., from...

https://ift.tt/2twNsF8

Coverage Policies Compared for Back Pain Medications

MONDAY, June 25, 2018 -- There are opportunities for recalibrating the role of opioids in pain care, including expanding access to opioid alternatives through coverage and reimbursement policies, according to a study published online June 22 in JAMA...

https://ift.tt/2MY3tN7

Poison Control Center Data Detail Peds Exposure to Buprenorphine

MONDAY, June 25, 2018 -- Pediatric exposure to buprenorphine can result in serious adverse outcomes, especially among children aged younger than 6 years, according to a study published online June 25 in Pediatrics. Sara Post, from The Research...

https://ift.tt/2yHhyeU

Increased Adiposity Tied to Lower Premenopausal Breast CA Risk

MONDAY, June 25, 2018 -- Across body mass index (BMI) distribution, increased BMI is associated with reduced risk of premenopausal breast cancer, according to a study published online June 21 in JAMA Oncology. Minouk J. Schoemaker, Ph.D., from The...

https://ift.tt/2tsdU3l

Facile Protocol for the Synthesis of Self-assembling Polyamine-based Peptide Amphiphiles (PPAs) and Related Biomaterials

The synthesis of polyamine-based peptide amphiphiles (PPAs) is a significant challenge due to the presence of multiple amine nitrogens, which requires judicious use of protecting groups to mask these reactive functionalities. In this paper, we describe a facile method for the preparation of these new class of self-assembling molecules.

https://ift.tt/2tB5Cpe

Ligand-Mediated Nucleation and Growth of Palladium Metal Nanoparticles

The main goal of this work is to elucidate the role of capping agents in regulating the size of palladium nanoparticles by combining in situ small angle x-ray scattering (SAXS) and ligand-based kinetic modeling.

https://ift.tt/2tqxzRA

A Murine Pancreatic Islet Cell-based Screening for Diabetogenic Environmental Chemicals

Here we present a protocol to isolate mouse pancreatic islet cells for screening the ROS inductions by the xenobiotics in order to identify the potential diabetogenic xenobiotic chemicals.

https://ift.tt/2tuuMGK

Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons

Abstract

Transactivating DNA-binding protein-43 (TDP-43) deposits represent a typical finding in almost all ALS patients, more than half of FTLD patients and patients with several other neurodegenerative disorders. It appears that perturbation of nucleo-cytoplasmic transport is an important event in these conditions but the mechanistic role and the fate of TDP-43 during neuronal degeneration remain elusive. We have developed an experimental system for visualising the perturbed nucleocytoplasmic transport of neuronal TDP-43 at the single-cell level in vivo using zebrafish spinal cord. This approach enabled us to image TDP-43-expressing motor neurons before and after experimental initiation of cell death. We report the formation of mobile TDP-43 deposits within degenerating motor neurons, which are normally phagocytosed by microglia. However, when microglial cells were depleted, injury-induced motor neuron degeneration follows a characteristic process that includes TDP-43 redistribution into the cytoplasm, axon and extracellular space. This is the first demonstration of perturbed TDP-43 nucleocytoplasmic transport in vivo, and suggests that impairment in microglial phagocytosis of dying neurons may contribute towards the formation of pathological TDP-43 presentations in ALS and FTLD.

https://ift.tt/2tCY6Ku

Surface property alterations and osteoblast attachment to contaminated titanium surfaces after different surface treatments: An in vitro study

Clinical Implant Dentistry and Related Research, EarlyView.


https://ift.tt/2lzrk9K

Antibiotics in early life: dysbiosis and the damage done

Abstract

Antibiotics are the most common type of medication prescribed to children, including infants, in the Western world. While use of antibiotics has transformed previously lethal infections into relatively minor diseases, antibiotic treatments can have adverse effects, as well. It has been shown in children, adults and animal models that antibiotics dramatically alter the gut microbial composition. Since the gut microbiota plays crucial roles in immunity, metabolism, and endocrinology, the effects of antibiotics on the microbiota may lead to further health complications. In this review, we present an overview of the effects of antibiotics on the microbiome in children, and correlate them to long lasting complications of obesity, behavior, allergies, autoimmunity and other diseases.

https://ift.tt/2InTrS8

Biotechnology of Extremely Thermophilic Archaea

Abstract

Although the extremely thermophilic archaea (T_opt ≥ 70°C) may be the most primitive extant forms of life, they have been studied to a limited extent relative to mesophilic microorganisms. Many of these organisms have unique biochemical and physiological characteristics with important biotechnological implications. These include methanogens that generate methane, fermentative anaerobes that produce hydrogen gas with high efficiency, and acidophiles that can mobilize base, precious and strategic metals from mineral ores. Extremely thermophilic archaea also have been a valuable source of thermoactive, thermostable biocatalysts, but their use as cellular systems has been limited because of the general lack of facile genetics tools. This situation has changed recently, however, thereby providing an important avenue for understanding their metabolic and physiological details and also opening up opportunities for metabolic engineering efforts. Along these lines, extreme thermophilic archaea have recently been engineered to produce a variety of alcohols and industrial chemicals, in some cases incorporating CO₂ into the final product. There are barriers and challenges to them reaching their full potential as industrial microorganisms but, if these can be overcome, a new dimension for biotechnology will be forthcoming that strategically exploits biology at high temperatures.

https://ift.tt/2KmPGRZ

Cellular Targeting and Segregation of Bacterial Chemosensory Systems

Abstract

The bacterial cytoplasm is not a homogeneous solution of macromolecules, but rather a highly organized and compartmentalized space where the clustering and segregation of macromolecular complexes in certain cell regions confers functional efficiency. Bacterial chemoreceptors represent a versatile model system to study the subcellular localization of macromolecules, as they are present in almost all motile bacterial and archaeal species, where they tend to form highly ordered arrays that occupy distinct positions in cells. The positioning of chemoreceptor clusters, as well as their segregation mechanism on cell division, varies from species to species and probably depends on cells size, environment and speed of movement. In this review we summarize the current understanding of the architecture and the segregation mechanisms of chemoreceptors in a limited number of bacterial model systems and suggest that the pattern of chemoreceptor distribution is coupled to behavioral life-style of that species.

https://ift.tt/2MlOQ5a

Measuring and comparing extinction events: Reconsidering diversity crises and concepts

Synopsis

To understand our present diversity crisis, it is natural to look to past crises for parallels and indicators. This is difficult because the present crisis is unlike the "Big Five" of the past: it is mostly terrestrial (with an increasing marine component), involves widespread habitat destruction and alteration of climate, and is largely anthropogenic, with confounding effects of differences in loss of diversity among continents and the difficulty of separating anthropogenic extinctions from natural Pleistocene and post-Pleistocene extinctions. In contrast, the "Big Five" crises of the geologic record are mainly marine (in the first two, no land vertebrates existed), and because marine taxa outnumber terrestrial taxa by a margin of about 25:1, global analyses of diversity crises have tended to lump together all phyla and environments. As a result, terrestrial evidence has been "swamped" statistically by the marine data. Both synchroneity and causality of terrestrial and marine events have usually been assumed, but without decisive data. Terrestrial vertebrate faunas do not seem to have been suddenly and catastrophically affected at the ends of the Permian, the Triassic, and the Cretaceous; rather, the pattern generally seems to be of steady turnover and replacement of groups and sometimes of slow decline.Here I suggest a revision of the concept of "mass extinction," which has no definitional limits on the application of the term with respect to duration, geography, ecology, or taxa affected. Unusual drops in taxonomic diversity have traditionally focused on increases in extinction rates, with scarce consideration of origination rates and their interplay with extinction rates. Analyses of hypothesized diversity crises should be operationally and situationally defined and statistically normalized through the histories of taxa and biotas, and should explicitly include both origination and extinction rates. The term "mass extinctions" would be usefully replaced by "diversity crises." These parameters require not absolute numerical (or percentage) limits but situational ones.

https://ift.tt/2lwVCcX

New on NCI Websites for June 2018

NCI periodically provides updates on new websites and other online content of interest to the cancer community. See selected content that has been added as of June 2018.

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Effect and Mechanism of ShiZhiFang on Uric Acid Metabolism in Hyperuricemic Rats

Objective. To explore the effect and mechanism of ShiZhiFang on uric acid metabolism. Methods. 40 rats were divided into normal group, model group, ShiZhiFang group, and benzbromarone group. The hyperuricemic rat model was induced by yeast gavage at 15 g/kg and potassium oxonate intraperitoneal injection at 600 mg/kg for two weeks. During the next two weeks, ShiZhiFang group rats were given ShiZhiFang by gavage, and benzbromarone group rats were given benzbromarone by gavage. The serum uric acid, creatinine, blood urea nitrogen, XOD activity, urinary uric acid, urinary β2-MG, and histopathological changes were observed in the rats of each group after treatment. Results. The hyperuricemic model was established successfully and did not show the increase of serum creatinine and blood urea nitrogen. Compared with the model group, the serum uric acid, serum XOD activity, and urinary β2-MG were significantly decreased (), and 24 h urinary uric acid excretion was significantly decreased () in ShiZhiFang group, whereas the two treatment groups were of no statistical significant in above indicators (); renal histopathology showed that the lesions in two treatment groups were reduced compared to the model groups. The gene and protein expression of uric acid anion transporters rOAT1 and rOAT3 in the kidney was significantly higher than that in model group (). Conclusion. The model is suitable for the study of primary hyperuricemia. The mechanisms of ShiZhiFang on uric acid metabolism in hyperuricemic rats may be involved in reducing the activity of serum XOD and promoting the transcription and expression of rOAT1 and rOAT3 in the kidney.

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