Abnormal effector and regulatory T cell subsets in paediatric-onset multiple sclerosis

Abstract

Elucidation of distinct T-cell subsets involved in multiple sclerosis immune-pathophysiology continues to be of considerable interest since an ultimate goal is to more selectively target the aberrant immune response operating in individual patients. While abnormalities of both effector (Teff) and regulatory (Treg) T cells have been reported in patients with multiple sclerosis, prior studies have mostly assessed average abnormalities in either limb of the immune response, rather than both at the same time, which limits the ability to evaluate the balance between effectors and regulators operating in the same patient. Assessing both phenotypic and functional responses of Teffs and Tregs has also proven important. In studies of adults with multiple sclerosis, in whom biological disease onset likely started many years prior to the immune assessments, an added challenge for any reported abnormality is whether the abnormality indeed contributes to the disease (and hence of interest to target therapeutically) or merely develops consequent to inflammatory injury (in which case efforts to develop targeted therapies are unlikely to be beneficial). Paediatric-onset multiple sclerosis, though rare, offers a unique window into early disease mechanisms. Here, we carried out a comprehensive integrated study, simultaneously assessing phenotype and functional responses of both effector and regulatory T cells in the same children with multiple sclerosis, monophasic inflammatory CNS disorders, and healthy controls, recruited as part of the multicentre prospective Canadian Pediatric Demyelinating Disease Study (CPDDS). Stringent standard operating procedures were developed and uniformly applied to procure, process and subsequently analyse peripheral blood cells using rigorously applied multi-parametric flow cytometry panels and miniaturized functional assays validated for use with cryopreserved cells. We found abnormally increased frequencies and exaggerated pro-inflammatory responses of CD8⁺CD161^highTCR-Vα7.2⁺ MAIT T cells and CD4⁺CCR2⁺CCR5⁺ Teffs in paediatric-onset multiple sclerosis, compared to both control groups. CD4⁺CD25^hiCD127^lowFOXP3⁺ Tregs of children with multiple sclerosis exhibited deficient suppressive capacity, including diminished capacity to suppress disease-implicated Teffs. In turn, the implicated Teffs of multiple sclerosis patients were relatively resistant to suppression by normal Tregs. An abnormal Teff/Treg ratio at the individual child level best distinguished multiple sclerosis children from controls. We implicate abnormalities in both frequencies and functional responses of distinct pro-inflammatory CD4 and CD8 T cell subsets, as well as Treg function, in paediatric-onset multiple sclerosis, and suggest that mechanisms contributing to early multiple sclerosis development differ across individuals, reflecting an excess abnormality in either Teff or Treg limbs of the T cell response, or a combination of lesser abnormalities in both limbs.

http://bit.ly/2GmATFp

Entorhinal cortex tau, amyloid-β, cortical thickness and memory performance in non-demented subjects

Abstract

As more biomarkers for Alzheimer's disease and age-related brain conditions become available, more sophisticated analytic approaches are needed to take full advantage of the information they convey. Most work has been done using categorical approaches but the joint relationships of tau PET, amyloid PET and cortical thickness in their continuous distributions to cognition have been under-explored. We evaluated non-demented subjects over age 50 years in the Mayo Clinic Study of Aging, 2037 of whom had undergone 3 T MRI scan, 985 amyloid PET scan with ¹¹C-Pittsburgh compound B (PIB) and MRI, and 577 PIB-PET, ¹⁸F-AV1451 flortaucipir PET and MRI. Participants received a nine-test cognitive battery. Three test scores (logical memory delayed recall, visual reproduction delayed recall and auditory verbal learning test delayed recall) were used to generate a memory composite z-score. We used Gradient Boosting Machine models to analyse the relationship between regional cortical thickness, flortaucipir PET signal, PIB-PET signal and memory z-scores. Age, education, sex and number of test exposures were included in the model as covariates. In this population-based study of non-demented subjects, most of the associations between biomarkers and memory z-scores accrued after 70 years of age. Entorhinal cortex exhibited the strongest associations between biomarkers and memory z-scores. Other temporal regions showed similar but attenuated associations, and non-temporal regions had negligible associations between memory z-scores and biomarkers. Entorhinal flortaucipir PET signal, PIB-PET signal and entorhinal cortical thickness were independently and additively associated with declining memory z-scores. In contrast to global PIB-PET signal where only very high amyloid-β levels were associated low memory z-scores, entorhinal flortaucipir PET signal just above background levels was associated with low memory z-scores. The lowest memory z-scores occurred with the confluence of elevated entorhinal flortaucipir PET signal and lower entorhinal cortical thickness.

http://bit.ly/2Ik0QqC

Abnormal visuo-vestibular interactions in vestibular migraine: a cross sectional study

Abstract

Vestibular migraine is among the commonest causes of episodic vertigo. Chronically, patients with vestibular migraine develop abnormal responsiveness to both vestibular and visual stimuli characterized by heightened self-motion sensitivity and visually-induced dizziness. Yet, the neural mechanisms mediating such symptoms remain unknown. We postulate that such symptoms are attributable to impaired visuo-vestibular cortical interactions, which in turn disrupts normal vestibular function. To assess this, we investigated whether prolonged, full-field visual motion exposure, which has been previously shown to modulate visual cortical excitability in both healthy individuals and avestibular patients, could disrupt vestibular ocular reflex and vestibular-perceptual thresholds of self-motion during rotations. Our findings reveal that vestibular migraine patients exhibited abnormally elevated reflexive and perceptual vestibular thresholds at baseline. Following visual motion exposure, both reflex and perceptual thresholds were significantly further increased in vestibular migraine patients relative to healthy controls, migraineurs without vestibular symptoms and patients with episodic vertigo due to a peripheral inner-ear disorder. Our results provide support for the notion of altered visuo-vestibular cortical interactions in vestibular migraine, as evidenced by vestibular threshold elevation following visual motion exposure.

http://bit.ly/2GmB1on

Epidemiology of Pneumococcal Carriage among HIV-Infected Individuals in the Conjugate Vaccine Era: A Study in Southern Ghana

Carriage of pneumococcus is considered as the precursor for development of pneumococcal disease. In sub-Saharan Africa, very little research has been done on the pneumococcus in relation to people with HIV infection in the era of pneumococcal conjugate vaccines. This study investigated pneumococcal carriage among HIV/AIDS patients in southern Ghana to determine the prevalence, risk factors, serotypes and antibiotic resistance of the organism. This was a cross sectional study involving 245 HIV/AIDS patients recruited from Korle Bu Teaching Hospital and Princess Marie Louis Hospital in Accra from November 2016 to March 2017. Epidemiological data on demographic, household and clinical features of the study participants were collected. Nasopharyngeal (NP) swabs were also collected from the study participants and cultured for Streptococcus pneumoniae; the isolates were serotyped by latex agglutination and Quellung reaction. Antimicrobial disc susceptibility was performed on the isolates, and antibiotics tested included tetracycline, erythromycin, cotrimoxazole, levofloxacin, oxacillin and ceftriaxone. Prevalence of pneumococcal carriage among the study participants was 11% (95% CI: 7.4 to 15.6); carriage among children and adults was 25% (95% CI: 14% to 38.9%) and 7.3% (95% CI: 4% to 11.9%) respectively. School attendance (p=0.001) and history of pneumococcal disease in the past year (p=0.001) were significantly associated with pneumococcal carriage. The most prevalent pneumococcal serotypes carried by the study participants were 19A (15.4%) and 23F (15.4%). Serotype coverage of the various pneumococcal vaccines were PCV10 (23.1%), PCV13 (42.3%) and PPV23 (50%). The prevalence of pneumococcal multidrug resistance was 18.5%. In conclusion, pneumococcal carriage among HIV-infected children was three-fold higher compared to carriage among HIV-infected adults. Pneumococcal carriage among both HIV-infected children and adults in the study area tends to be characterized by a predominance of non-vaccine serotypes and a considerable level of multidrug resistance.

http://bit.ly/2RVxkao

Risk Factors for Sudden Unexpected Death in Epilepsy (SUDEP) and Their Mitigation

Abstract

Purpose of review

People with epilepsy have an increased risk of mortality when compared to the general population. Sudden unexpected death in epilepsy (SUDEP) is the most common cause of epilepsy-related death in children and adults. The purpose of this review is to discuss SUDEP, with an emphasis on SUDEP risk factors, their mitigation and prevention.

Recent findings

SUDEP affects approximately 1 in 1000 people with epilepsy each year. Recent studies suggest that the incidence in children is similar to that of adults. The most important risk factor for SUDEP is the presence and frequency of generalized tonic-clonic seizures. The presence of nocturnal supervision may decrease risk along with the use of nocturnal listening devices. Underlying genetic influences, both cardiac and epilepsy-related may further alter risk. Risk mitigation strategies include reducing seizure frequency, optimizing therapy, and the use of nocturnal supervision/seizure detection devices.

Summary

Risk factors for SUDEP are well established; however, pediatric specific risk factors have not been identified. Current prevention strategies are focused on reduction of risk factors and the possible role of seizure detection devices. More research is needed to better understand the varied underlying pathological mechanisms and develop targeted prevention strategies. Further understanding the genetic factors that influence SUDEP risk may potentially aid in understanding the underlying pathophysiology of SUDEP.

http://bit.ly/2N3VgHQ

Stereotactic Radiosurgery for Multiple Brain Metastases

Abstract

Purpose of review

To give an overview on the current evidence for stereotactic radiosurgery of brain metastases with a special focus on multiple brain metastases.

Recent findings

While the use of stereotactic radiosurgery in patients with limited brain metastases has been clearly defined, its role in patients with multiple lesions (> 4) is still a matter of controversy. Whole-brain radiation therapy (WBRT) has been the standard treatment approach for patients with multiple brain lesions and is still the most commonly used treatment approach worldwide. Although distant brain failure is improved by WBRT, the overall survival is not readily impacted. As WBRT is associated with significant neurocognitive decline compared to stereotactic radiosurgery (SRS), SRS has been explored and increasingly utilized for selected patients with multiple brain metastases. Recent clinical data indicated the feasibility of stereotactic radiosurgery to multiple brain metastases with a similar survival in patients with more than 4 brain metastases versus patients with a maximum of 4 brain metastases. Also, neurocognitive function and quality of life was maintained after stereotactic radiosurgery which is essential in a palliative setting.

Summary

The application of stereotactic radiosurgery with Gamma Knife, Cyberknife, or LINAC-based equipment has emerged as an effective and widely available treatment option for patients with limited brain metastases. Although not formally proven in prospective studies, SRS may also be considered as a safe and effective treatment option in selected patients with multiple brain metastases. Especially in patients with a favorable prognosis, survival over several years is observed also in the setting of multiple BM. For these patients, avoidance of the neurocognitive damage of WBRT is desirable, and SRS is often a more appropriate treatment in the current multimodality treatment of BM in which systemic treatment is often the cornerstone of the treatment. For patients with an intermediate (3–12 months) and poor prognosis (< 3 months), the application of WBRT becomes more and more controversial, because of its acute side effects, such as hair loss and fatigue and, thereby, detrimental effect on quality of life. For these patients, best supportive care, primary systemic treatment, and even SRS may be preferred over WBRT on an individualized patient basis.

http://bit.ly/2SMOLhQ

Real-world data on discordance between estrogen, progesterone, and HER2 receptor expression on diagnostic tumor biopsy versus tumor resection material

Abstract

Purpose

The estrogen (ER), progesterone (PR), and HER2 status are essential in guiding treatment decisions in breast cancer patients. In daily life, the ER/PR/HER2 status is expected to be commonly tested twice, i.e., at diagnosis using material from tumor needle biopsies, and after tumor resection using full tumor tissue material. This study explored the discordance of ER/PR/HER2 between tumor needle biopsies and full tumor resection material using real-world patient-level data from Dutch breast cancer patients.

Methods

Pathology reports of 11,054 breast cancer patients were derived from PALGA (Dutch Pathology Registry). Discordance was calculated for multiple combinations of the ER/PR/HER2 receptor status. The influence of patient and tumor characteristics on the probability of having discordant test results was analyzed using multiple logistic regression models (separately for ER, PR and HER2).

Results

For 1279 patients (14.4%), at least one of the receptors (ER/PR/HER2) was determined on both biopsy and tumor tissue material. The majority had concordant test results for ER (n = 916; 94.8%), PR (n = 1170; 86.7%), and HER2 (n = 881; 98.1%). Patients having an ER- and HER2-positive but PR-negative biopsy classification, BR grade III, and < 10% tumor tissue remaining after neoadjuvant therapy (NAT) have the highest probability of ER discordant test results (OR 4.991; p = 83.31%). The probability of discordance in PR is based on different sets of patient and tumor characteristics. Potential cost savings from omitting multiple tests if concordance can be perfectly predicted can be up to €205,000 yearly.

Conclusions

Double testing of ER/PR/HER2 is less common than expected. Discordance in ER/PR/HER2 test results between tumor needle biopsy taken at the time of diagnosis and tumor resection material is very low, especially in patients not receiving any form of neoadjuvant therapy. These results imply that a substantial number of tests can potentially be omitted in specific subgroups of breast cancer patients.

http://bit.ly/2E8DhNy

Mapping of modifiable barriers and facilitators of medication adherence in bipolar disorder to the Theoretical Domains Framework: a systematic review protocol

Introduction

People with bipolar disorder require long-term treatment but it is estimated that 40% of these people do not adhere to prescribed medication regimens. Non-adherence increases the risk of relapse, hospitalisation and suicide. Some evidence syntheses report barriers to mental health treatment adherence but rarely delineate between modifiable and non-modifiable barriers. They also fail to distinguish between the patients' perspective and that of other stakeholders such as clinicians despite of their different understanding and priorities about adherence. Facilitators of adherence, which are also important for informing adherence intervention design, are also lacking from syntheses and few syntheses focus on medications for bipolar disorder.

This systematic review aims to identify modifiable barriers and facilitators (determinants) of medication adherence in bipolar disorder. We also plan to report determinants of medication adherence from perspectives of patients, carers, healthcare professionals and other third parties. A unique feature of this systematic review in the context of mental health is the use of the Theoretical Domains Framework (TDF) to organise the literature identified determinants of medication adherence.

Methods and analysis

The protocol adheres to Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols and ENhancing Transparency in REporting the synthesis of Qualitative research (ENTREQ) guidelines. This review will include both qualitative and quantitative primary studies exploring determinants of medication adherence in bipolar disorder. We will search the following databases using a preplanned strategy: CINAHL, Cochrane Library (CENTRAL), Embase, LiLACS, Medline, PsychINFO, PubMed without date restrictions. We will report the quality of included studies. We will use framework synthesis using the TDF as an a priori 'framework'. We will map the literature identified modifiable determinants to the domains of TDF.

Ethics and dissemination

Ethical approval is not required as primary data will not be collected. The results will be disseminated through a peer-reviewed publication.

PROSPERO registration number

CRD42018096306.

http://bit.ly/2tjn8yx

Intraoperative evoked potential monitoring for detecting cerebral injury during adult aneurysm clipping surgery: a systematic review and meta-analysis of diagnostic test accuracy

Objectives

We aim to evaluate the diagnostic test accuracy (DTA) of intraoperative evoked potential (EP) monitoring to detect cerebral injury during clipping of cerebral aneurysms.

Design

Systematic review.

Data sources

Major electronic databases including MEDLINE, EMBASE, LILACS.

Eligibility criteria

We included studies that reported the DTA of intraoperative EP monitoring during intracranial aneurysm clipping procedures in adult patients.

Data extraction and synthesis

After quality assessment, we performed a meta-analysis using the bivariate random effects model, and calculated the possible range of DTA point estimates using a new best-case/worst-case scenario approach to quantify the impact of rescue intervention on DTA.

Results

A total of 35 studies involving 4011 patients were included. The quality of the primary studies was modest and the heterogeneity across studies was high. The pooled sensitivity and specificity for predicting postoperative neurological deficits for the somatosensory evoked potential (SSEP) monitoring was 59% (95% CI: 39% to 76%; I²: 76%) and 86% (95% CI: 77% to 92%; I²: 94%), for motor evoked potential (MEP) monitoring was 81% (95% CI: 58% to 93%; I²: 54%) and 90% (95% CI: 86% to 93%; I²: 81%), and for combined SSEP and MEP monitoring was 92% (95% CI: 62% to 100%) and 88% (95% CI: 83% to 93%). The best-case/worst-case range for the pooled point estimates for sensitivity and specificity for SSEP was 50%–63% and 81%–100%, and for MEP was 59%–74% and 93%–100%, and for combined SSEP and MEP was 89%–94% and 83%–100%.

Conclusions

Due to the modest quality and high heterogeneity of the existing primary studies, it is not possible to confidently support or refute the diagnostic value of EP monitoring in cerebral aneurysm clipping surgery. However, combined SSEP and MEP appears to provide the best DTA for predicting postoperative stroke. Contrary to popular assertion, the modest sensitivity of SSEP monitoring is not explained by the use of rescue intervention.

PROSPERO registration number

CRD42015016884.

http://bit.ly/2GDnDeJ

Staff experiences of enhanced recovery after surgery: systematic review of qualitative studies

Objectives

To conduct a systematic review of qualitative studies which explore health professionals' experiences of and perspectives on the enhanced recovery after surgery (ERAS) pathway.

Design

Systematic review of qualitative literature using a qualitative content analysis. Literature includes the experiences and views of a wide range of multidisciplinary team and allied health professional staff, to incorporate a diverse range of clinical and professional perspectives.

Data sources

PsycINFO, Medline, CINAHL and PubMed were searched in May 2017.

Eligibility criteria for selecting studies

The searches included relevant qualitative studies across a range of healthcare contexts. We included studies published from 2000 to 2017, as an appropriate time frame to capture evidence about ERAS after implementation in the late 1990s. Only studies published in the English language were included, and we included studies that explicitly stated that they used qualitative approaches.

Data extraction and synthesis

Literature searches were conducted by the first author and checked by the second author: both contributed to the extraction and analysis of data. Studies identified as relevant were assessed for eligibility using the Critical Appraisal Skills Programme guidance.

Results

Eight studies were included in the review, including studies in six countries and in four surgical specialties. Included studies focus on health professionals' experiences of ERAS before, during and after implementation in colorectal surgery, gastrointestinal surgery, abdominal hysterectomy and orthopaedics. Five main themes emerged in the analysis: communication and collaboration, resistance to change, role and significance of protocol-based care, and knowledge and expectations. Professionals described the importance of effective multidisciplinary team collaboration and communication, providing thorough education to staff and patients, and appointing a dedicated champion as means to implement and integrate ERAS pathways successfully. Evidence-based guidelines were thought to be useful for improvements to patient care by standardising practices and reducing treatment variations, but were thought to be too open to interpretation at local levels. Setting and managing 'realistic' expectations of staff was seen as a priority. Staff attitudes towards ERAS tend to become more favourable over time, as practices become successfully 'normalised'. Strengths of the review are that it includes a wide range of different studies, a variety of clinical populations, diversity of methodological approaches and local contexts. Its limitation is the inclusion of a small number of studies, although these represent six countries and four surgical specialties, and so our findings are likely to be transferable.

Conclusions

Staff feel positive about the implementation of ERAS, but find the process is complex and challenging. Challenges can be addressed by ensuring that multidisciplinary teams understand ERAS principles and guidelines, and communicate well with one another and with patients. Provision of comprehensive, coherent and locally relevant information to health professionals is helpful. Identifying and recruiting local ERAS champions is likely to improve the implementation and delivery of ERAS pathways.

PROSPERO registration number

CRD42017059952

http://bit.ly/2tjn41L

Brain natriuretic peptide to predict successful liberation from mechanical ventilation in critically ill patients: protocol for a systematic review and meta-analysis

Introduction

Predicting successful liberation from mechanical ventilation (MV) among critically ill patients receiving MV can be challenging. The current parameters used to predict successful extubation have shown variable predictive value. Brain natriuretic peptide (BNP) has been proposed as a novel biomarker to help guide decision-making in readiness for liberation of MV following a spontaneous breathing trial (SBT). Current evidence on the predictive ability of BNP has been uncertain, and BNP has not been integrated into clinical practice guidelines.

Methods and analysis

We will perform a systematic review and meta-analysis to evaluate the value of BNP during SBT to predict success of liberation from MV. A search strategy will be developed in collaboration with a research librarian, and electronic databases (MEDLINE, EMBASE, Cochrane Library, Web of Science) and additional sources will be searched. Search themes will include: (1) BNP and (2) weaning, extubation and/or liberation from MV. Citation screening, selection, quality assessment and data abstraction will be performed in duplicate. The primary outcome will be liberation from MV; secondary outcomes will include time to reintubation, mortality, MV duration, total and postextubation intensive care unit (ICU) stay, hospitalisation duration, tracheostomy rate, ICU-acquired weakness rate and ventilator-free days. Primary statistical analysis will include predictive value of BNP by receiver operating characteristic curve, sensitivity/specificity and likelihood ratios for combination of BNP and SBT parameters for failure of liberation from MV. Secondary statistical analysis will be performed on individual and combinations of extracted metrics.

Ethics and dissemination

Our review will add knowledge by mapping the current body of evidence on the value of BNP testing for prediction of successful liberation from MV, and describe knowledge gaps and research priorities. Our findings will be disseminated through peer-reviewed publication, presentation at a scientific congress, through regional/national organisations and social media. Research ethics approval is not required.

PROSPERO registration number

CRD42018087474.

http://bit.ly/2GFydlj

Support for smoke-free policy among Malaysian adults: findings from a population-based study

Objective

Public opinion and support can be powerful mandates for smoke-free policy. However, the scarcity of evidence on public opinion among Malaysians necessitates further investigation. Therefore, this study aimed to determine the level of support for smoke-free policy at various public domains and its associated factors among Malaysian adults.

Design

Data were derived from the Global Adult Tobacco Survey, Malaysia (GATS-M). GATS-M is a nationwide study that employed a multistage, proportionate-to-size sampling strategy to select a representative sample of 5112 Malaysian adults aged 15 years and above. Multiple logistic regression was used to identify factors associated with support for smoke-free policy in selected public domains that is, workplaces, restaurants, bars, hotels, casinos, karaoke centres, public transport terminals and shopping centres.

Results

The level of support for enactment of a smoke-free policy at selected public domains varied from 37.8% to 94.4%, with the highest support was for gazetted smoke-free domains, namely, shopping centres (94.4%, 95% CI: 93.2% to 95.3%) and public transport terminals (85.2%, 95% CI: 83.3% to 86.9%). Multiple logistic regression revealed that non-smokers were more likely to support smoke-free policy at all domains. In addition, respondents who worked in workplaces with total or partial smoking restrictions were more likely to support a smoke-free policy ((total restriction adjusted OR (AOR): 14.94 (6.44 to 34.64); partial restriction AOR: 2.96 (1.138 to 6.35); non-restriction was applied as a reference).

Conclusion

A majority of the Malaysian adult population supported the smoke-free policy, especially at gazetted smoke-free domains. Therefore, expansion of a total smoking ban to workplaces, restaurants, bars, hotels, casinos and karaoke centres is strongly recommended to reduce exposure to secondhand smoke and to denormalise smoking behaviour.

http://bit.ly/2GFZl3C

Multimorbidity, eHealth and implications for equity: a cross-sectional survey of patient perspectives on eHealth

Objective

There is increasing awareness of the burden of medical care experienced by those with multimorbidity. There is also increasing interest and activity in engaging patients with chronic disease in technology-based health-related activities ('eHealth') in family practice. Little is known about patients' access to, and interest in eHealth, in particular those with a higher burden of care associated with multimorbidity. We examined access and attitudes towards eHealth among patients attending family medicine clinics with a focus on older adults and those with polypharmacy as a marker for multimorbidity.

Design

Cross-sectional survey of consecutive adult patients attending consultations with family physicians in the McMaster University Sentinel and Information Collaboration practice-based research network. We used univariate and multivariate analyses for quantitative data, and thematic analysis for free text responses.

Setting

Primary care clinics.

Participants

693 patients participated (response rate 70%). Inclusion criteria: Attending primary care clinic. Exclusions: Too ill to complete survey, cannot speak English.

Results

The majority of participants reported access to the internet at home, although this decreased with age. Participants 70 years and older were less comfortable using the internet compared with participants under 70. Univariate analyses showed age, multimorbidity, home internet access, comfort using the internet, privacy concerns and self-rated health all predicted significantly less interest in eHealth. In the multivariate analysis, home internet access and multimorbidity were significant predictors of disinterest in eHealth. Privacy and loss of relational connection were themes in the qualitative analysis.

Conclusion

There is a significant negative association between multimorbidity and interest in eHealth. This is independent of age, computer use and comfort with using the internet. These findings have important implications, particularly the potential to further increase health inequity.

http://bit.ly/2tlvRQS

Atypical presentation of IgG4 sclerosing cholangitis

IgG₄ sclerosing cholangitis (ISC) is a rare disease which usually presents in patients in their 60's or above. Patients often present with obstructive jaundice as the first symptom, especially when associated with autoimmune pancreatitis. We report the case of a 20-year-old man who presented with acute abdominal pain, which was subsequently diagnosed as ISC in addition to autoimmune pancreatitis following magnetic resonance cholangiopancreatography (MRCP). The patient was thus treated with steroids.

http://bit.ly/2SNUJ26

Child with unusual combination of sickle cell disease and autosomal recessive agammaglobulinemia associated with a novel CD79a gene mutation

This article describes a novel mutation in CD79a gene identified in a child with sickle cell disease (SCD), who was diagnosed with autosomal recessive agammaglobulinaemia in the context of prolonged febrile syndrome. The association of a primary immunodeficiency with SCD in the same child was unexpected.

http://bit.ly/2N42BHh

Intermediate uveitis in a child with phosphatase and tensin homolog gene mutation and Bannayan-Riley-Ruvalcaba syndrome

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a congenital disorder characterised by macrocephaly, multiple hamartomas, lipomas, and pigmented macules of the glans penis. Intermediate uveitis is characterised by chronic inflammatory cells aggregates on the pars plana (snowbanks) and within the vitreous cavity (snowballs). We describe what we believe to be the first case of intermediate uveitis associated with BRRS. Early examination under anaesthesia should be considered in the management of young children diagnosed with this syndrome in order to provide appropriate ocular evaluation, treatment and follow-up. Further research is needed to establish a better understanding of the ophthalmic manifestations of this syndrome.

http://bit.ly/2N20Eew

Cutaneous angiosarcoma with lymphoedema: the Stewart-Treves syndrome

http://bit.ly/2SNUAM6

Outcome of a giant coronary artery mycotic pseudoaneurysm secondary to non-typhoid Salmonella managed without surgical intervention

A 48-year-old woman with a history of AIDS, a recent coronary artery bypass graft operation and prior bacteraemia with non-typhoid Salmonella presented with non-exertional chest pain and elevated troponins. The cardiac catheterisation and coronary CT angiography revealed a 9 cm pseudoaneurysm arising from the proximal left anterior descending artery. The blood cultures confirmed non-typhoid Salmonella. Emergent surgery was initially deferred due to her complex anatomy. Moreover, the hospital course was complicated by Epstein-Barr virus meningitis and an associated decline in the patient's mentation. Consequently, the mycotic pseudoaneurysm was medically managed with antibiotics and strict blood pressure goals. The natural history of giant mycotic coronary artery pseudoaneurysm formation and progression is appreciated through this first reported medically managed case. The follow-up coronary CT angiography at 3 months showed evidence of pseudoaneurysm leakage into surrounding tissue. The patient expired at 5 months from an unknown cause.

http://bit.ly/2N1iNJk

Isolated superior petrosal sinus dural arteriovenous fistula treated with selective sinus packing using a quadriaxial catheter system

A 67-year-old patient presented with a headache, vertigo and nausea, followed by a disturbance of consciousness. CT and MRI showed venous ectasia at the left cerebellopontine angle and extensive oedema in the left cerebellum. Angiography demonstrated a dural arteriovenous fistula that appeared at the left superior petrosal sinus–cavernous sinus) junction. After the evaluation of the shunt point, occluded areas were recanalised via the femoral vein with a quadriaxial catheter system using a 6-Fr guiding sheath, 6-Fr guiding catheter, 4.2-Fr catheter and microcatheter. Selective coil embolisation was performed, resulting in shunt removal.

http://bit.ly/2SL56Ub

Progress in Focused Ultrasound for Glioblastomas

Focused ultrasound researchers worldwide are making unprecedented progress in addressing the unmet need of providing life-extending treatment for patients with deadly brain tumors – glioblastoma multiforme (GBM).

http://bit.ly/2GnsGAz

Infographic: 10 apps every paramedic should have

Stay up to speed on the latest mobile technology to help you do your job

http://bit.ly/2SPVxmU

The Thioredoxin-Like Family of Selenoproteins: Implications in Aging and Age-Related Degeneration

Abstract

The thioredoxin-like (Rdx) family proteins contain four selenoproteins (selenoprotein H, SELENOH; selenoprotein T, SELENOT; selenoprotein V, SELENOV; selenoprotein W, SELENOW) and a nonselenoprotein Rdx12. They share a CxxU or a CxxC (C, cysteine; x, any amino acid; U, selenocysteine) motif and a stretch of eGxFEI(V) sequence. From the evolutionary perspective, SELENOW and SELENOV are clustered together and SELENOH and SELENOT are in another branch. Selenoproteins in the Rdx family exhibit tissue- and organelle-specific distribution and are differentially influenced in response to selenium deficiency. While SELENOH is nucleus-exclusive, SELENOT resides mainly in endoplasmic reticulum and SELENOW in cytosol. SELENOV is expressed essentially only in the testes with unknown cellular localization. SELENOH and SELENOW are more sensitive than SELENOT and SELENOV to selenium deficiency. While physiological functions of the Rdx family of selenoproteins are not fully understand, results from animal models demonstrated that (1) brain-specific SELENOT knockout mice are susceptible to 1-methyl-4-phenylpyridinium-induced Parkinson's disease in association with redox imbalance and (2) adult zebrafishes with heterozygous SELENOH knockout are prone to dimethylbenzanthracene-induced tumorigenesis together with increased DNA damage and oxidative stress. Further animal and human studies are needed to fully understand physiological roles of the Rdx family of selenoproteins in redox regulation, genome maintenance, aging, and age-related degeneration.

http://bit.ly/2thgqsL

The Impact of Trace Minerals on Bone Metabolism

Abstract

Bone is a metabolically active tissue that responds to alterations in dietary intake and nutritional status. It is ~ 35% protein, mostly collagen which provides an organic scaffolding for bone mineral. The mineral is the remaining ~ 65% of bone tissue and composed mostly of calcium and phosphate in a form that is structurally similar to mineral within the apatite group. The skeletal tissue is constantly undergoing turnover through resorption by osteoclasts coupled with formation by osteoblasts. In this regard, the overall bone balance is determined by the relative contribution of each of these processes. In addition to macro minerals such as calcium, phosphorus, and magnesium which have well-known roles in bone health, trace elements such as boron, iron, zinc, copper, and selenium also impact bone metabolism. Effects of trace elements on skeletal metabolism and tissue properties may be indirect through regulation of macro mineral metabolism, or direct by affecting osteoblast or osteoclast proliferation or activity, or finally through incorporation into the bone mineral matrix. This review focuses on the skeletal impact of the following trace elements: boron, iron, zinc, copper, and selenium, and overviews the state of the evidence for each of these minerals.

http://bit.ly/2GDan9Z

Systematic Review of the Effects of Chromium(III) on Chickens

Abstract

Chromium supplementation has been proposed to have beneficial effects in farm animals, particularly when under stress. The last two decades, in particular, have seen an emphasis on examining the effects of supplemental chromium on a variety of variables in chicks and chickens. Thus, given the recent approval of a Cr(III) compound for use in chicken feed in the United States and the recent surge in papers on the use of Cr in chicken feed, the need for a systematic review of studies utilizing chickens is extremely urgent and timely. With the exception of studies on cold-stressed laying hens, the results of studies of Cr supplementation of chickens, whether broilers or laying hens, were found to be too inconsistent for any firm conclusions to be drawn other than that Cr supplementation generally leads to accumulation of Cr in tissues. Few potential trends in terms or beneficial or deleterious effects from Cr supplementation were found regardless of strain of chicken, Cr source, Cr dose, duration of supplementation, or variable examined. Hence, in summary, no recommendation for the use of Cr as a supplement for the diet of chickens can be made at this time.

http://bit.ly/2tmaleB

Nutritional Effects of Zinc on Metabolic Syndrome and Type 2 Diabetes: Mechanisms and Main Findings in Human Studies

Abstract

Zinc (Zn) plays crucial roles in mammalian metabolism. There is increasing interest about the potential beneficial effects of Zn on the prevention or treatment of non-communicable diseases. This review critically analyzes the information related to the role of Zn on the metabolic syndrome (MetS) as well as type 2 diabetes (T2D), and summarizes the biological basis of these potential effects of Zn. There are several mechanisms by which Zn may help to prevent the development or progression of MetS and T2D, respectively. Zn is involved in both insulin secretion and action in peripheral tissues. Specifically, Zn has insulin-mimetic properties that increase the activity of the insulin signaling pathway. Zn modulates long-chain polyunsaturated fatty acids levels through its action on the absorption of essential fatty acids in the intestine and its subsequent desaturation. Zn is also involved in both the assembly of chylomicrons and lipoproteins as well as their clearance, and thus, plays a role in lipolysis regulation. Finally, Zn has been found to play a role in redox metabolism, and in turn, on blood pressure. The evidence related to the association between Zn status and occurrence of MetS is inconsistent. Although there are several studies reporting an inverse relationship between Zn status or dietary Zn intake and MetS prevalence, others found a direct relationship between Zn status and MetS prevalence. Intervention studies also provide confusing information about this issue, making it hard to reach firm conclusions. Zn as part of the treatment for patients with T2D has been shown to have positive responses in terms of glucose control outcomes, but only among those with Zn deficiency.

http://bit.ly/2VolA3a

Iodine Nutrition During Pregnancy: Past, Present, and Future

Abstract

Iodine is a trace element that is important for the synthesis of thyroid hormones. During pregnancy, iodine requirements are increased by approximately 50% because of physiological changes. Adequate iodine status in pregnancy is crucial for maternal health and fetal growth. The World Health Organization (WHO) recommends a daily intake of 250 μg iodine for pregnant women to maintain adequate iodine status. Severe iodine deficiency during pregnancy can result in a series of detrimental effects on maternal and fetal health including hypothyroidism, goiter, stillbirth, abortion, increased neonatal mortality, neurological damage, and intellectual impairment. Correction of severe iodine deficiency can reduce the risk of adverse impacts. However, the influences of mild-to-moderate maternal iodine deficiency on fetal neural development and cognitive function are less clear. The safety and efficacy of iodine supplementation in mildly-to-moderately iodine-deficient women also remain uncertain. In addition, excess iodine during pregnancy carries a risk of adverse effects, and the recommended safe upper limits of iodine intake are controversial. Effective iodine supplementation should be implemented, and routine monitoring is necessary to guarantee adequate iodine status.

http://bit.ly/2GFF2n1

A Review of Iodine Status of Women of Reproductive Age in the USA

Abstract

Iodine, an essential micronutrient, is required to produce thyroid hormones. Iodine deficiency disorders (IDD) comprise a range of adverse maternal and fetal outcomes, with the most significant irreversible effect resulting from neurodevelopmental deficits in fetal brain caused by deficient iodine status during early pregnancy. The objective of this scoping review was to summarize the studies that assessed iodine status of women of reproductive age in the USA. A systematic review of literature using the PRISMA Extension for Scoping Reviews (PRISMA-ScR) statement was conducted. PubMed, Medline, CINAHL, EMBASE, EBSCOHost, Cochrane, ERIC, Google Scholar, and Web of Science databases were searched, 1652 records were identified. One thousand six hundred forty-one records that did not satisfy the inclusion/exclusion criteria and quality review were excluded, and 11 peer-reviewed articles were determined to be eligible for this scoping review. Despite the USA being considered iodine sufficient for the general population, the US dietary iodine intakes have decreased drastically since the 1970s, with iodine deficiency reemerging in vulnerable groups such as women of reproductive age. Although data to conduct a scoping review of iodine status among women of reproductive age in the USA was scarce, majority of the articles reviewed demonstrate emergent iodine deficiency in this population of women of reproductive age, indicating alarm for a public health concern needing immediate attention.

http://bit.ly/2Tzf5sn

Copper and Zinc Nutritional Issues for Agricultural Animal Production

Abstract

Livestock have presented unique requirements and toxicity issues depending on the species for the various concentrations of Cu and Zn and their interactions with other nutrients especially Fe, Se, Mo, and S. Soil concentrations of these elements and their availability to crops influence the health of the crop and the amount found in vegetative tissues and seeds. Hence, many livestock issues are a result of the soils in the area where production is occurring (Loneragan et al. 1981). While water can provide minerals to animals, the amount consumed and availability are highly variable. Many discoveries about Cu were a result of low Cu concentrations and its availability due to interactions with other nutrients in the soils. Anemia, bone disorders, cardiovascular abnormalities, defective wool and hair, and infertility are signs/symptoms of Cu deficiency. Toxicity due to excess Cu is more likely to occur in sheep than other farm species. Swine are tolerant of high concentrations of dietary Cu, and it is often used as a growth stimulant in production. There are many species and physiological stages where the animal's Cu requirement is not known. Grazing animals can exhibit Zn deficiency when soils and forages contain limited concentrations of Zn. Pastures have been observed to be Zn-deficient in many parts of the world. However, non-ruminant animals usually receive adequate Zn when fed corn and soybean meal diets if there is not excessive Ca and Fe in their diets, but this is not true for rapidly growing young animals. Characteristics of a Zn deficiency include loss of appetite, reduced growth and reproduction, and impaired health of bone and skin tissues.

http://bit.ly/2Rwmyvb

Vanadium in Biological Action: Chemical, Pharmacological Aspects, and Metabolic Implications in Diabetes Mellitus

Abstract

Vanadium compounds have been primarily investigated as potential therapeutic agents for the treatment of various major health issues, including cancer, atherosclerosis, and diabetes. The translation of vanadium-based compounds into clinical trials and ultimately into disease treatments remains hampered by the absence of a basic pharmacological and metabolic comprehension of such compounds. In this review, we examine the development of vanadium-containing compounds in biological systems regarding the role of the physiological environment, dosage, intracellular interactions, metabolic transformations, modulation of signaling pathways, toxicology, and transport and tissue distribution as well as therapeutic implications. From our point of view, the toxicological and pharmacological aspects in animal models and humans are not understood completely, and thus, we introduced them in a physiological environment and dosage context. Different transport proteins in blood plasma and mechanistic transport determinants are discussed. Furthermore, an overview of different vanadium species and the role of physiological factors (i.e., pH, redox conditions, concentration, and so on) are considered. Mechanistic specifications about different signaling pathways are discussed, particularly the phosphatases and kinases that are modulated dynamically by vanadium compounds because until now, the focus only has been on protein tyrosine phosphatase 1B as a vanadium target. Particular emphasis is laid on the therapeutic ability of vanadium-based compounds and their role for the treatment of diabetes mellitus, specifically on that of vanadate- and polioxovanadate-containing compounds. We aim at shedding light on the prevailing gaps between primary scientific data and information from animal models and human studies.

http://bit.ly/2thFJuR

Iron, Zinc, and Physical Performance

Abstract

Iron and zinc are nutritionally essential trace elements that function through incorporation into proteins and enzymes; many of these proteins and enzymes affect physical performance. Poor iron status (iron deficiency and iron deficiency anemia) is prevalent in both developed and developing nations. Zinc deficiency has been reported in clinical and population studies, although the incidence is difficult to quantify due to the lack of a reliable zinc status indicator. The objective of this manuscript is to review the relationship between iron and zinc status and physical performance. In sum, numerous reports indicate diminished physical performance in individuals with poor iron and/or zinc status, whereas, in individuals with adequate status, evidence supporting a beneficial role of iron or zinc at levels beyond the recommended dietary allowance for optimizing physical performance is lacking.

http://bit.ly/2GBCs1q

Editorial

http://bit.ly/2tkSapY

Boric Acid Activation of eIF2α and Nrf2 Is PERK Dependent: a Mechanism that Explains How Boron Prevents DNA Damage and Enhances Antioxidant Status

Abstract

Boron is abundant in vegetables, nuts, legumes, and fruit and intake is associated with reduced risk of cancer and DNA damage and increased antioxidant status. Blood boric acid (BA) levels are approximately 10 μM BA in men at the mean US boron intake. Treatment of DU-145 human prostate cancer cells with 10 μM BA stimulates phosphorylation of elongation initiation factor 2α (eIF2α) at Ser51 leading to activation of the eIF2α/ATF4 pathway which activates the DNA damage-inducible protein GADD34. In the present study, we used MEF WT and MEF PERK (±) cells to test the hypothesis that BA-activated eIF2α phosphorylation requires protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activates Nrf2 and the antioxidant response element (ARE). BA (10 μM) increased phosphorylation of eIF2α Ser51 in MEF WT cells at 1 h, but not in MEF Perk −/− cells exposed for as long as 6 h. GCN2 kinase-dependent phosphorylation of eIF2α Ser51 was activated in MEF PERK −/− cells by amino acid starvation. Nrf2 phosphorylation is PERK dependent and when activated is translocated from the cytoplasm to the nucleus where it acts as a transcription factor for ARE. DU-145 cells were treated with 10 μM BA and Nrf2 measured by immunofluorescence. Cytoplasmic Nrf2 was translocated to the nucleus at 1.5–2 h in DU-145 and MEF WT cells, but not MEF PERK −/− cells. Real-time PCR was used to measure mRNA levels of three ARE genes (HMOX-1, NQO1, and GCLC). Treatment with 10 μM BA increased the mRNA levels of all three genes at 1–4 h in DU-145 cells and HMOX1 and GCLC in MEF WT cells. These results extend the known boric acid signaling pathway to ARE-regulated genes. The BA signaling pathway can be expressed using the schematic [BA + cADPR → cADPR-BA → [[ER]_i Ca²⁺↓] → 3 pathways: PERK/eIF2αP → pathways ATF4 and Nrf2; and [[ER]_i Ca²⁺↓] → ER stress → ATF6 pathway. This signaling pathway provides a framework that links many of the molecular changes that underpin the biological effects of boron intake.

http://bit.ly/2GD0AAQ

Hair Mineral and Trace Element Content in Children with Down’s Syndrome

Abstract

The objective of the present study was to assess the level of minerals and trace elements in 40 children with Down's syndrome and 40 controls aged 1–2 years old. Hair mineral and trace element analysis was performed using inductively coupled plasma mass spectrometry. The obtained data demonstrate that hair levels of Mg, P, I, Cr, Si, Zn, and Pb in Down's syndrome patients exceeded the respective control values by 36, 36, 93, 57, 45, 28, and 54%, whereas hair mercury was more than twofold lower in children with Down's syndrome. The observed difference in the levels of trace elements was age-dependent. In particular, in 1-year-olds, major differences were observed for essential elements (Cr, Si, Zn), whereas in 2-year-olds—for toxic elements (Hg, Pb). At the same time, hair P levels in Down's syndrome patients were 14 and 35% higher at the age of 1 and 2 years in comparison to the respective controls. Multiple regression analysis demonstrated that a model incorporating all elements, being characterized by a significant group difference, accounted for 42.5% of status variability. At the same time, only hair phosphorus was significantly interrelated with Down's syndrome status (β = 0.478; p < 0.001). Principal component analysis (PCA) used As, Ca, Cr, Fe, Hg, I, Mg, P, Pb, Se, Si, Sn, and Zn as predictors, with the resulting R² = 0.559. The OPLS-DA models also separated between Down's and health control groups. Therefore, 1–2-year-old patients with Down's syndrome are characterized by significant alterations of mineral and trace element status.

http://bit.ly/2GJKvth

The Problematic Use of Dietary Reference Intakes to Assess Magnesium Status and Clinical Importance

Abstract

Determination of the public health concern about magnesium (Mg) in health and disease has been confounded by the lack of a practical measure of status. This has resulted in a lack of consistency in associating Mg deficiency with specific pathological conditions. Some attempts at associating Mg with a chronic disease have used the Dietary Reference Intakes (DRIs) as a status assessment measure. Use of current DRIs for Mg is problematic because recent evidence suggests that they should be updated and based on body weight. An evidence-based suggested Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA) for a 70-kg individual is 175 and 250 mg/day, respectively. However, numerous dietary and physiological factors can affect the need for Mg and thus affect the use of the current or suggested new DRIs to assess Mg status. Calcium intakes above normal requirements can decrease Mg balance and exacerbate signs of Mg deficiency. Mg deficiency apparently occurs often in obesity because of increased need to counteract the inflammatory stress induced by adipose tissue dysfunction. Deficiency in anti-oxidant nutrients such as vitamin E and selenium can exacerbate a response to low dietary Mg indicated by increased oxidative stress which can lead to chronic disease. Dietary modifiers of Mg absorption and excretion affect balance and thus the need for Mg. Factors decreasing Mg balance include low dietary protein and non-fermentable fiber, while factors that can increase balance include fructose and fermentable fiber and fructose-containing oligosaccharides. Use of the DRIs to assess the Mg status of a population or group needs to consider their physiological characteristics and dietary habits and be aware that the DRIs may need updating. The DRIs only can be considered a component of a toolbox that presently includes serum Mg concentration and the daily urinary Mg excretion to assess the Mg status of an individual.

http://bit.ly/2tltkWE

A Brief Overview from the Physiological and Detrimental Roles of Zinc Homeostasis via Zinc Transporters in the Heart

Abstract

Zinc (mostly as free/labile Zn²⁺) is an essential structural constituent of many proteins, including enzymes in cellular signaling pathways via functioning as an important signaling molecule in mammalian cells. In cardiomyocytes at resting condition, intracellular labile Zn²⁺ concentration ([Zn²⁺]_i) is in the nanomolar range, whereas it can increase dramatically under pathological conditions, including hyperglycemia, but the mechanisms that affect its subcellular redistribution is not clear. Therefore, overall, very little is known about the precise mechanisms controlling the intracellular distribution of labile Zn²⁺, particularly via Zn²⁺ transporters during cardiac function under both physiological and pathophysiological conditions. Literature data demonstrated that [Zn²⁺]_i homeostasis in mammalian cells is primarily coordinated by Zn²⁺ transporters classified as ZnTs (SLC30A) and ZIPs (SLC39A). To identify the molecular mechanisms of diverse functions of labile Zn²⁺ in the heart, the recent studies focused on the discovery of subcellular localization of these Zn²⁺ transporters in parallel to the discovery of novel physiological functions of [Zn²⁺]_i in cardiomyocytes. The present review summarizes the current understanding of the role of [Zn²⁺]_i changes in cardiomyocytes under pathological conditions, and under high [Zn²⁺]_i and how Zn²⁺ transporters are important for its subcellular redistribution. The emerging importance and the promise of some Zn²⁺ transporters for targeted cardiac therapy against pathological stimuli are also provided. Taken together, the review clearly outlines cellular control of cytosolic Zn²⁺ signaling by Zn²⁺ transporters, the role of Zn²⁺ transporters in heart function under hyperglycemia, the role of Zn²⁺ under increased oxidative stress and ER stress, and their roles in cancer are discussed.

http://bit.ly/2GBFV02

Boron, Chromium, Manganese, and Nickel in Agricultural Animal Production

Abstract

This paper provides an overview of research that has been conducted with manganese (Mn), chromium (Cr), nickel (Ni), and boron (B) in poultry, swine, and ruminants. Manganese is an essential trace mineral that functions as an enzyme component and enzyme activator. A deficiency of Mn results in a variety of bone abnormalities, and Mn deficiency signs have been observed under practical conditions in poultry and cattle. Chromium can potentiate the action of insulin, but whether Cr is an essential trace mineral is controversial. Insulin sensitivity has been enhanced by Cr in cattle, swine, and broilers. Responses to Cr supplementation have been variable. Production responses to Cr supplementation have been most consistent in animals exposed to various stressors (heat, cold, weaning, etc). The legality of supplementing Cr to animal diets varies among countries, Cr sources, and animal species. A specific biochemical function for Ni and B has not been identified in mammals. Signs of Ni deficiency have been produced experimentally in a number of animal species. Nickel may affect rumen microbial fermentation in ruminants, as Ni is a component of bacterial urease and cofactor F₄₃₀ in methanogenic bacteria. There is little evidence that dietary Ni limits animal production under practical conditions. Beneficial effects of B supplementation on growth and bone strength have been seen in poultry and swine, but results have been variable.

http://bit.ly/2tjQI78

Investigating the Essentiality and Requirements of Iron from the Ancient to the Present

Abstract

This review discusses the development of studies that evaluated the essentiality and requirements of iron from the ancient to the present. The therapeutic effects of iron compounds were recognized by the ancient Greeks and Romans. The earliest recognition of the essentiality of iron was stated by Paracelsus, a distinguished physician alchemist, in the sixteenth century. Iron was included in the earliest nutritional standard prepared for the Royal Army by E. A. Parkes, the first professor of hygiene. The League of Nations Health Organisation determined average iron requirements based on literature review. In the first US Recommended Dietary Allowances (RDA), the RDA of iron was determined from the results of iron balance studies. In the current Dietary Reference Intakes, iron requirements were determined based on the factorial method with the aid of Monte Carlo simulation for combining basal and menstrual iron losses. Population data analysis is a recently developed alternative that does not use the pre-estimated iron absorption rate and requires the prevalence of inadequacy instead. Population data analysis uses the convolution integral for combining basal and menstrual iron losses to ensure the required accuracy. This review also provides new estimates of hair and nail iron losses.

http://bit.ly/2GBfZBz

Improved Magnesium Levels in Morbidly Obese Diabetic and Non-diabetic Patients After Modest Weight Loss

Abstract

Serum magnesium (Mg) is reported to be reduced in individuals with obesity, hypertension, and diabetes mellitus and has been suggested as a marker for metabolic syndrome. We have studied changes in serum Mg concentrations in a group of obese patients (n = 92) with and without diabetes mellitus after weight loss induced by dieting and bariatric surgery. At inclusion, 11% (10/92) of the population had severe Mg deficiency (< 0.75 mmol/L) and median serum Mg was lower in diabetic (n = 20) compared to non-diabetic (n = 72) patients (p = 0.002). A weight loss of 10 kg after 8 weeks of lifestyle interventions was accompanied by increased serum Mg of about 5% in both diabetic and non-diabetic patients. Serum Mg remained stable thereafter in the non-diabetic patients, while it continued to increase in the diabetic patients after bariatric surgery. Six months after bariatric surgery, there was no significant difference in serum Mg concentration between the groups (p = 0.08). The optimal range of circulating Mg concentration is not known, but as even small increments in serum Mg are reported to lower the risk of cardiovascular and ischemic heart disease, our results are interesting in a public health perspective.

http://bit.ly/2tltkG8

Small Molecule Modifiers of In Vitro Manganese Transport Alter Toxicity In Vivo

Abstract

Manganese (Mn) is essential for several species and daily requirements are commonly met by an adequate diet. Mn overload may cause motor and psychiatric disturbances and may arise from an impaired or not fully developed excretion system, transporter malfunction and/or exposure to excessive levels of Mn. Therefore, deciphering processes regulating neuronal Mn homeostasis is essential to understand the mechanisms of Mn neurotoxicity. In the present study, we selected two small molecules (with opposing effects on Mn transport) from a previous high throughput screen of 40,167 to test their effects on Mn toxicity parameters in vivo using Caenorhabditis elegans. We pre-exposed worms to VU0063088 and VU0026921 for 30 min followed by co-exposure for 1 h with Mn and evaluated Mn accumulation, dopaminergic (DAergic) degeneration and worm survival. Control worms were exposed to vehicle (DMSO) and saline only. In pdat-1::GFP worms, with GFP labeled DAergic neurons, we observed a decrease of Mn-induced DAergic degeneration in the presence of both small molecules. This effect was also observed in an smf-2 knockout strain. SMF-2 is a regulator of Mn transport in the worms and this strain accumulates higher Mn levels. We did not observe improved survival in the presence of small molecules. Our results suggest that both VU0063088 and VU0026921 may modulate Mn levels in the worms through a mechanism that does not require SMF-2 and induce protection against Mn neurotoxicity.

http://bit.ly/2GE8UAq

Recent success and limitations of immune checkpoint inhibitors for cancer: a lesson from melanoma

Abstract

Several researches have been carried over the last few decades to understand of how cancer evades the immune system and thus to identify therapies that could directly act on patient's immune system in the way of restore or induce a response to cancer. As a consequence, "cancer immunotherapy" is conquering predominantly the modern scenario of the fight against cancer. The recent clinical success of immune checkpoint inhibitors (ICIs) has created an entire new class of anti-cancer drugs and restored interest in the field of immuno-oncology, leading to regulatory approvals of several agents for the treatment of a variety of malignancies. The first to be approved in 2011 was the anti-CTLA-4 antibody ipilimumab for the treatment of unresectable or metastatic melanoma. Subsequently, the anti-PD-1s, nivolumab and pembrolizumab, received regulatory approvals for the treatment of melanoma and several other cancers. More recently, three anti-PD-L1 antibodies have received approval: atezolizumab and durvalumab for locally advanced or metastatic urothelial carcinoma and metastatic non-small cell lung cancer (NSCLC) and avelumab for the treatment of locally advanced or metastatic urothelial carcinoma and metastatic Merkel cell carcinoma. This review, starting from the results of melanoma trials, highlights in turn different ICIs and data for different indications in several malignancies are included under each drug class.

http://bit.ly/2SKodO7

Two rare cases of endosalpingiosis in the axillary sentinel lymph nodes: evaluation of immunohistochemical staining and one-step nucleic acid amplification (OSNA) assay in patients with breast cancer

Abstract

Benign inclusions, such as endosalpingiosis, in an axillary sentinel lymph node (SLN) can be misdiagnosed as metastatic breast carcinoma. However, endosalpingiosis is rare in lymph nodes above the diaphragm. Among 792 patients with breast carcinoma who underwent sentinel lymph node biopsy at our center, 2 patients have experienced benign glandular inclusions in 3 SLNs, and all of these glandular inclusions were lined with columnar and ciliated epithelial cells. Immunohistochemistry revealed that the epithelial cells were positive for Müllerian markers (e.g., PAX8 and WT-1) and negative for mammary markers (e.g., mammaglobin, GCDFP-15, and GATA3), which confirm the diagnosis of endosalpingiosis. The epithelial cells were positive for CK19 but the one-step nucleic acid amplification assay revealed negative results for the axillary SLNs. Although endosalpingiosis is rare in axillary SLNs, care is needed to identify these rare cases and avoid unnecessary axillary lymph node dissection, overstaging, and overtreatment.

http://bit.ly/2N3kPbT

T-type Cav3.1 channels mediate progression and chemotherapeutic resistance in glioblastoma

T-type Ca2+ channels (TTCC) have been identified as key regulators of cancer cell cycle and survival. In vivo studies in glioblastoma (GBM) murine xenografts have shown that drugs able to block TTCC in vitro (such as tetralol derivatives mibefradil/NNC-55-096, or different 3,4-dihydroquinazolines) slow tumor progression. However, currently available TTCC pharmacological blockers have limited selectivity for TTCC, and are unable to distinguish between TTCC isoforms. Here we analyzed the expression of TTCC transcripts in human GBM cells and show a prevalence of Cav3.1 mRNAs. Infection of GBM cells with lentiviral particles carrying shRNA against Cav3.1 resulted in GBM cell death by apoptosis. We generated a murine GBM xenograft via subcutaneous injection of U87-MG GBM cells and found that tumor size was reduced when Cav3.1 expression was silenced. Furthermore, we developed an in vitro model of temozolomide-resistant GBM that showed increased expression of Cav3.1 accompanied by activation of macroautophagy. We confirmed a positive correlation between Cav3.1 and autophagic markers in both GBM cultures and biopsies. Of note, Cav3.1 knockdown resulted in transcriptional downregulation of p62/SQSTM1 and deficient autophagy. Together, these data identify Cav3.1 channels as potential targets for slowing GBM progression and recurrence based on their role in regulating autophagy.

http://bit.ly/2DySRjX

Acidification of tumor at stromal boundaries drives transcriptome alterations associated with aggressive phenotypes

Acidosis is a fundamental feature of the tumor microenvironment that directly regulates tumor cell invasion by affecting immune cell function, clonal cell evolution, and drug resistance. Despite the important association of tumor microenvironment acidosis with tumor cell invasion, relatively little is known regarding which areas within a tumor are acidic and how acidosis influences gene expression to promote invasion. Here we injected a labeled pH-responsive peptide to mark acidic regions within tumors. Surprisingly, acidic regions were not restricted to hypoxic areas and overlapped with highly proliferative, invasive regions at the tumor-stroma interface, which were marked by increased expression of matrix metalloproteinases and degradation of the basement membrane. RNA-seq analysis of cells exposed to low pH conditions revealed a general rewiring of the transcriptome that involved RNA splicing and enriched for targets of RNA binding proteins with specificity for AU-rich motifs. Alternative splicing of Mena and CD44, which play important isoform-specific roles in metastasis and drug resistance, respectively, was sensitive to histone acetylation status. Strikingly, this program of alternative splicing was reversed in vitro and in vivo through neutralization experiments that mitigated acidic conditions. These findings highlight a previously underappreciated role for localized acidification of tumor microenvironment in the expression of an alternative splicing-dependent tumor invasion program.

http://bit.ly/2SvCyi7

MDM2 and MDM4 are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors

Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that respond poorly to current therapies. In this study, we screened several MRT cell lines with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries to identify potential drug targets specific for these cancers. We discovered MDM2 and MDM4, the canonical negative regulators of p53, as significant vulnerabilities. Using two compounds currently in clinical development, idasanutlin (MDM2-specific) and ATSP-7041 (MDM2/4-dual), we show that MRT cells were more sensitive than other p53 wild-type cancer cell lines to inhibition of MDM2 alone as well as dual inhibition of MDM2/4. These compounds caused significant upregulation of the p53 pathway in MRT cells, and sensitivity was ablated by CRISPR-Cas9-mediated inactivation of TP53. We show that loss of SMARCB1, a subunit of the SWI/SNF (BAF) complex mutated in nearly all MRT, sensitized cells to MDM2 and MDM2/4 inhibition by enhancing p53-mediated apoptosis. Both MDM2 and MDM2/4 inhibition slowed MRT xenograft growth in vivo, with a five-day idasanutlin pulse causing marked regression of all xenografts including durable complete responses in 50% of mice. Together, these studies identify a genetic connection between mutations in the SWI/SNF chromatin-remodeling complex and the tumor suppressor gene p53 and provide preclinical evidence to support the targeting of MDM2 and MDM4 in this often-fatal pediatric cancer.

http://bit.ly/2DwuZ0s

QTL Underlying Circadian Clock Parameters Under Seasonally Variable Field Settings in Arabidopsis thaliana

The circadian clock facilitates coordination of the internal rhythms of an organism to daily environmental conditions, such as the light-dark cycle of one day. Circadian period length (the duration of one endogenous cycle) and phase (the timing of peak activity) exhibit quantitative variation in natural populations. Here, we measured circadian period and phase in June, July and September in three Arabidopsis thaliana recombinant inbred line populations. Circadian period and phase were estimated from bioluminescence of a genetic construct between a native circadian clock gene (COLD CIRCADIAN RHYTHM RNA BINDING 2) and the reporter gene (LUCIFERASE) after lines were entrained under field settings. Using a Bayesian mapping approach, we estimated the median number and effect size of genomic regions (Quantitative Trait Loci, QTL) underlying circadian parameters and the degree to which these regions overlap across months of the growing season. We also tested for QTL associations between the circadian clock and plant morphology. The genetic architecture of circadian phase was largely independent across months, as evidenced by the fact that QTL determining phase values in one month of the growing season were different from those determining phase in a second month. QTL for circadian parameters were shared with both cauline and rosette branching in at least one mapping population. The results provide the first insights into the QTL architecture of the clock under field settings, and suggest that the circadian clock is highly responsive to changing environments and that selection can act on clock phase in a nuanced manner.

http://bit.ly/2N3W0N1

Early Administration of Antibiotics for Suspected Sepsis

These two cases encapsulate a common dilemma for clinicians who are trying to implement the recommendation of the Surviving Sepsis Campaign to administer broad-spectrum antibiotics within 1 hour after a patient's presentation with possible sepsis. Both patients meet Surviving Sepsis Campaign…

http://bit.ly/2Iby63m

Cutaneous Malakoplakia

Figure 1.

http://bit.ly/2IiGdeO

Omadacycline for Acute Bacterial Skin and Skin-Structure Infections

The incidence and severity of skin and skin-structure infections have increased, and such infections impose a substantial burden on the health care system. Gram-positive bacteria, especially Staphylococcus aureus, are the most frequent cause of infection, accounting for almost 45% of pathogens.…

http://bit.ly/2GrfDOG

The Devil Is in the Details

Foreword. In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information by sharing relevant background and reasoning with the reader (regular type). The authors' commentary follows. Stage. A 75-year-old woman…

http://bit.ly/2Gml3dV

Omadacycline for Community-Acquired Bacterial Pneumonia

Community-acquired pneumonia is the most common infection leading to hospitalization and death in all age groups, especially the elderly. The economic effect is substantial, with annual costs in excess of $17 billion in the United States and €10 billion in Europe. For pathogens such as…

http://bit.ly/2UXCPaB

Omadacycline — The Newest Tetracycline

Omadacycline was the second antibiotic of the tetracycline class to be approved by the Food and Drug Administration (FDA) in 2018. Results of two phase 3, double-blind, randomized clinical trials of the drug, one involving acute bacterial skin and skin-structure infections and the other…

http://bit.ly/2E701O0

Molecular Signatures Predict Problematic Lung Lesions [News in Brief]

Carcinoma in situ lesions destined to become tumors have molecular characteristics distinct from those that will regress.

http://bit.ly/2SMqTLg

E-cigarettes Best Other Cessation Tools [News in Brief]

People using the devices more likely to quit smoking than those using nicotine-replacement therapies—but also more likely to keep using them.

http://bit.ly/2RXB1fV

Secretome profiling of heterotypic spheroids suggests a role of fibroblasts in HIF-1 pathway modulation and colorectal cancer photodynamic resistance

Abstract

Purpose

Previous analyses of the tumor microenvironment (TME) have resulted in a concept that tumor progression may depend on interactions between cancer cells and its surrounding stroma. An important aspect of these interactions is the ability of cancer cells to modulate stroma behavior, and vice versa, through the action of a variety of soluble mediators. Here, we aimed to identify soluble factors present in the TME of colorectal cancer cells that may affect relevant pathways through secretome profiling.

Methods

To partially recapitulate the TME and its architecture, we co-cultured colorectal cancer cells (SW480, TC) with stromal fibroblasts (MRC-5, F) as 3D-spheroids. Subsequent characterization of both homotypic (TC) and heterotypic (TC + F) spheroid secretomes was performed using label-free liquid chromatography-mass spectrometry (LC-MS).

Results

Through bioinformatic analysis using the NCI-Pathway Interaction Database (NCI-PID) we found that the HIF-1 signaling pathway was most highly enriched among the proteins whose secretion was enhanced in the heterotypic spheroids. Previously, we found that HIF-1 may be associated with resistance of colorectal cancer cells to photodynamic therapy (PDT), an antitumor therapy that combines photosensitizing agents, O₂ and light to create a harmful photochemical reaction. Here, we found that the presence of fibroblasts considerably diminished the sensitivity of colorectal cancer cells to photodynamic activity. Although the biological significance of the HIF-1 pathway of secretomes was decreased after photosensitization, this decrease was partially reversed in heterotypic 3D-spheroids. HIF-1 pathway modulation by both PDT and stromal fibroblasts was confirmed through expression assessment of the HIF-target VEGF, as well as through HIF transcriptional activity assessment.

Conclusion

Collectively, our results delineate a potential mechanism by which stromal fibroblasts may enhance colorectal cancer cell survival and photodynamic treatment resistance via HIF-1 pathway modulation.

http://bit.ly/2tmZelC

Protective effects of ethyl gallate on H 2 O 2 -induced mitochondrial dysfunction in PC12 cells

Abstract

Oxidative stress has been suggested to play an important role in neuronal injury. Ethyl gallate (EG) is the ethyl ester of gallic acid which has been acknowledged as an antioxidant. We previously demonstrated that EG effectively inhibited H₂O₂-induced cytotoxicity and decreased the ROS levels in PC12 cells, while the relevant mechanisms of action of this compound remain largely uncharacterized. The present study was carried out in an attempt to clarify the underlying mechanisms of EG against H₂O₂-induced neurotoxicity in PC12 cells. EG pretreatment attenuated H₂O₂-induced mitochondrial dysfunction as indicated by the decreased caspase-9/−3 activation, PARP cleavage, mitochondrial membrane potential (MMP) depletion, Bax/Bcl-2 ratio, cytochrome c release and ROS overproduction. Furthermore, EG treatment resulted in nuclear translocation of Nrf2 along with increased expression of ARE-dependent cytoprotective genes, such as γ-GCS and NQO1, which indicated EG as an Nrf2 pathway activator. Silencing of Nrf2 signaling by siRNA abrogated the protective effects offered by EG on H₂O₂-induced PC12 cells injury, which suggested the important role of Nrf2 pathway in the protection of EG against oxidative stress induced PC12 cell apoptosis. These results taken together indicated that EG protects PC12 cells against H₂O₂-induced cell mitochondrial dysfunction possibly through activation of Nrf2 pathway. EG might be a potential candidate for further preclinical study aimed at the prevention and treatment of neurodegenerative diseases.

http://bit.ly/2I6rseD

Mutation spectrum of PAH gene in phenylketonuria patients in Northwest China: identification of twenty novel variants

Abstract

This study was performed to analyze the mutational spectrum of the phenylalanine hydroxylase (PAH) gene in phenylketonuria (PKU) patients in Northwest China, to identify mutational hot spots, and to determine the correlation between variants and clinical phenotypes of PKU. A large cohort of 475 PKU families in Northwest China was enrolled to analyze PAH gene variants using Sanger sequencing, Multiplex ligation-dependent probe amplification (MLPA), and gap-PCR. Bioinformatics software was used to predict the pathogenicity of novel variants and analyze the correlations between PAH gene variants and phenotypes of PKU patients. A total of 895 variants were detected in the 950 alleles of 475 patients with PKU (detection rate: 94.21%), 20 of which were novel variants. Other 108, previously known variants, were also identified, with the three most frequent variants being p.Arg243Gln (14.00%), c.611A > G (5.58%), and p.Tyr356* (4.95%). Seven different large deletion/duplication variants were identified by the MLPA method, including the large deletion c.-4163_-406del3758 with high frequency. A correlation analysis between patient phenotype and gene variant frequency showed that p.Arg53His and p.Gln419Arg were correlated with mild hyperphenylalaninemia (MHP). In conclusion, the mutational spectrum underlying PKU in Northwest China was established for the first time. Functional analysis of 20 novel PAH gene variants enriched the PAH gene mutational spectrum. Correlation analysis between variants frequencies in compound heterozygous patients and phenotype severity is helpful for phenotypic prediction.

http://bit.ly/2Gmxgz3

Influence of screw to joint distance on articular subsidence in tibial‐plateau fractures

In the operative fixation of tibial‐plateau fractures with displaced osteochondral fragments, decreased screw to joint distance is associated with decreased articular subsidence at time of union. The screw to joint distance is a simple measure which may help guide intra‐operative screw placement.

Background

Tibial‐plateau fractures with depressed osteochondral fragments have a high incidence of articular subsidence post reduction. Locking plates aim to prevent this via 'raft' screws below the subchondral bone. However, differences in plate design and patient anatomy result in variability of screw position in relation to the fragments they are designed to support. We evaluate the effect of screw placement and articular subsidence with this fracture pattern.

Methods

A retrospective cohort study of operatively treated tibial‐plateau fractures with free osteochondral fragments was performed to determine if screw placement was correlated with articular subsidence. Primary outcome was the relationship between screw to joint distance and articular subsidence. Secondary outcomes were whether bicortical fixation, presence of bone graft, fracture characteristics and patient age was correlated with articular subsidence.

Results

Sixty‐eight of 309 tibial‐plateau fractures had depressed osteochondral fragments (22%). The average thickness of these fragments was 10.2 mm. Fractures with raft screws placed closer to the joint than the thickness of the osteochondral fragment were less likely to subside (1.8 versus 3.4 mm; P = 0.02). The proportion of fractures with no radiographic subsidence was also greater in this cohort versus fractures with distal screw placement (33% versus 8%; P = 0.02). Articular comminution (P = 0.04) and female patients aged over 65 years (P = 0.03) were associated with increased articular subsidence.

Conclusion

Fractures fixed with screws closer to the joint than the thickness of the osteochondral fragment were correlated with less articular subsidence. The 'screw‐joint distance' may help guide screw placement intra‐operatively.

http://bit.ly/2GmvrlH

Safety of laparoscopic appendicectomy during pregnancy: a systematic review and meta‐analysis

Laparoscopic appendicectomy is a common surgical approach including in women who are pregnant. However, level III evidence found that laparoscopic approach had a lower preterm labour but higher foetal loss

Background

Acute appendicitis is the most common non‐obstetric surgical presentation during pregnancy. There were concerns that laparoscopic appendicectomy increases the risk of foetal loss compared to an open approach. Therefore, with recent advances in perioperative care, it is likely the risk has changed. Here, we performed an updated meta‐analysis assessing the safety of laparoscopic appendicectomy in pregnant women.

Methods

A meta‐analysis was performed according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. A search was undertaken between 2000 and 2017 on Ovid Medline and Embase. The primary outcome measures were foetal loss and preterm delivery, whereas secondary outcome measures were operative time and hospital length of stay. A random‐effect model was performed to pool odds ratio (OR) and standardized mean difference (SMD).

Results

Seventeen observational studies were included, with 1886 patients in the laparoscopic and 4261 patients in the open group. Comparing laparoscopic versus open appendicectomy, there were 54 (5.96%) and 136 (3.73%) foetal losses, respectively. However, preterm delivery was much higher in the open approach (8.99%) compared to laparoscopic approach (2.84%). Pooled OR for foetal loss was 1.84 (95% confidence interval (CI) 1.31–2.58, P < 0.001), whereas OR for preterm delivery was 0.39 (95% CI 0.27–0.55, P < 0.001). There was no significant difference between both approaches for operative time (SMD −0.07; 95% CI −0.43 to 0.30, P = 0.71) or hospital length of stay (SMD −0.34; 95% CI −0.83 to 0.16, P = 0.18).

Conclusion

In a pooled analysis of level III evidence, laparoscopic appendicectomy posed a higher risk of foetal loss but lower risk of preterm delivery. Caution and informed consent are crucial when offering a laparoscopic approach.

http://bit.ly/2I50BzI

External fixation of unstable pelvic fractures: a systematic review and meta‐analysis

A descriptive meta‐analysis of pelvic external fixation to establish optimal fixation techniques and management of unstable pelvic fractures is provided. Outcomes of interest included fracture re‐displacement, complications, functional outcome scores, time to mobilization and removal of the external fixation device.

Background

Unstable pelvic fractures are typically caused by high‐impact trauma. Early stabilization is required to prevent further neurological or visceral injury, haemorrhage, reduce pain, infection and long‐term deformity and disability. The aim was to review the optimal external fixation techniques and management for unstable pelvic fractures.

Methods

A total of 28 studies were identified from the initial database search. Seventeen studies met our inclusion criteria – eight prospective cohorts, four retrospective cohorts and five in vitro studies. This equated to 539 patients and 38 cadaveric (in vitro) models.

Results

Type B and double vertical fractures have less re‐displacement (43.7% and 68.2% <5 mm, respectively) than Type C fractures (55.7% >15 mm) regardless of pin placement. Greater than 50% experience a complication with the most common being pin site infection (36%) and a trend towards increased infection with increasing pins was seen. Most can be managed with antibiotics alone (93%). A minimum time of 6–8 weeks in frame was required for definitive management of all fractures.

Conclusion

This review supports the use of supra‐acetabular pins over iliac crest pins to decrease re‐displacement, the least number of pins for the shortest amount of time and the largest size pin where possible. Type B fractures will generally have a better outcome than Type C fractures. Definitive management in a frame should be at least 8 weeks. Further studies directly comparing iliac crest and supra‐acetabular pin placement are recommended.

http://bit.ly/2Gmvn5r

The Devil Is in the Details

Foreword. In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information by sharing relevant background and reasoning with the reader (regular type). The authors' commentary follows. Stage. A 75-year-old woman…

http://bit.ly/2Gml3dV

Do not open Pandora's box!

http://bit.ly/2SzXJ2U

Health Care Spending Per Person Increased to $5,641 in 2017

TUESDAY, Feb. 12, 2019 -- In 2017, health care spending per person reached $5,641, according to the Health Care Cost Institute (HCCI) annual Health Care Cost and Utilization Report. Researchers from the HCCI examined medical and prescription drug...

http://bit.ly/2DAJy2V

USPSTF Recommends Counseling to Prevent Perinatal Depression

TUESDAY, Feb. 12, 2019 -- The U.S. Preventive Services Task Force (USPSTF) recommends that clinicians provide or refer counseling interventions for pregnant or postpartum women at increased risk for perinatal depression. This recommendation forms...

http://bit.ly/2StzKSJ

CDC: Student Tobacco Use Increased From 2017 to 2018

TUESDAY, Feb. 12, 2019 -- From 2017 to 2018, there was an increase in any tobacco use, especially electronic cigarette use, for high school and middle school students, according to research published online Feb. 11 in the U.S. Centers for Disease...

http://bit.ly/2DDTKHY

Larger Physician Bonus May Improve Care in Chronic Disease

TUESDAY, Feb. 12, 2019 -- Increased bonus size for physicians caring for patients with chronic disease is associated with improvements in care quality, according to a study published online Feb. 8 in JAMA Network Open. Amol S. Navathe, M.D., Ph.D.,...

http://bit.ly/2SvuEVW

Point of Care Ultrasound Handbook – RUSH Chapter

A free chapter from a POC ultrasound book

EMCrit Project by Guest Author.

http://bit.ly/2N1fEJL

Organ Donation and Drug Intoxication–Related Deaths in the United States

To the Editor: The drug-overdose epidemic has led to an increase in the number of organ donors dying from drug intoxication; this pattern is confined to the United States and has not been observed in Europe. Geographic disparity in the rates of death from drug intoxication in the United States led…

http://bit.ly/2GFcCd1

Organ Donation and Drug Intoxication–Related Deaths in the United States

To the Editor: The drug-overdose epidemic has led to an increase in the number of organ donors dying from drug intoxication; this pattern is confined to the United States and has not been observed in Europe. Geographic disparity in the rates of death from drug intoxication in the United States led…

http://bit.ly/2GFcCd1

Early Administration of Antibiotics for Suspected Sepsis

These two cases encapsulate a common dilemma for clinicians who are trying to implement the recommendation of the Surviving Sepsis Campaign to administer broad-spectrum antibiotics within 1 hour after a patient's presentation with possible sepsis. Both patients meet Surviving Sepsis Campaign…

http://bit.ly/2Iby63m

Organ Donation and Drug Intoxication–Related Deaths in the United States

To the Editor: The drug-overdose epidemic has led to an increase in the number of organ donors dying from drug intoxication; this pattern is confined to the United States and has not been observed in Europe. Geographic disparity in the rates of death from drug intoxication in the United States led…

http://bit.ly/2GFcCd1

A Step toward Protecting Payments for Primary Care

Even as the U.S. health care system increasingly adopts alternative payment models such as accountable care organizations, the traditional fee-for-service system continues to be the most commonly used method of physician payment. Moreover, although alternative payment models often involve budgets…

http://bit.ly/2I90anX

Risk Compensation and Clinical Decision Making — The Case of HIV Preexposure Prophylaxis

Imagine a daily pill that prevents an unwanted consequence of sexual intercourse. Does it give users a "license for promiscuity"? Will its widespread availability lead to "sexual anarchy"? These questions were posed more than a half-century ago about oral contraceptive pills, which enabled…

http://bit.ly/2IjEvJM

The Devil Is in the Details

Foreword. In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information by sharing relevant background and reasoning with the reader (regular type). The authors' commentary follows. Stage. A 75-year-old woman…

http://bit.ly/2Gml3dV

Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors

Factor Xa inhibitors have a favorable benefit–risk profile for the treatment and prevention of thrombotic events but may cause or worsen acute major bleeding, with substantial morbidity and mortality. Acute major bleeding episodes that are associated with the use of factor Xa inhibitors may be…

http://bit.ly/2RV6pvm

Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria

Acute hepatic porphyrias are rare, serious, and life-threatening genetic diseases caused by mutations in hepatic heme biosynthesis enzymes. The neurotoxic heme intermediates delta aminolevulinic acid (ALA) and porphobilinogen (PBG) accumulate in patients with acute hepatic porphyrias, leading to…

http://bit.ly/2I6Oe6l

Effects of Habitat Types on Macroinvertebrates Assemblages Structure: Case Study of Sun Island Bund Wetland

Sun Island Bund Wetland (SIBW) is a river floodplain wetland located at the south part of Heilongjiang Province in Northeast China. An investigation of the influence of habitat type on macroinvertebrates assemblages structure was conducted in July 2016. Nine (9) sampling sites were selected based on sediment type, water condition, and aquatic vegetation type. Macroinvertebrates attributes including density, biomass, and four diversity indices (Simpson diversity index, Margalef richness index, Shannon-Weiner index, and Pielou evenness index) were assessed. A total of 53 taxa were collected during the study period, with the highest density dominated being from aquatic insects and gastropods. Bellamya purificata and Exopalaemon annandalei were the most dominant among all the species. The results showed that the assemblages structure of macroinvertebrates in different habitats was significantly different. Also, the results with PCA showed that the higher values of invertebrates density, biomass, diversity indices, and species richness had a greater association with the habitat types of silt-humus sediment, closed lentic area, and submerged-flouting-emergent vegetation.

http://bit.ly/2GFacer

Safety and Efficacy of Triple Antithrombotic Therapy with Dabigatran versus Vitamin K Antagonist in Atrial Fibrillation Patients: A Pilot Study

Background. Combination of dual antiplatelet (DAPT) and oral anticoagulation therapy is required to decrease cardioembolic stroke and stent thrombosis risk in patients with atrial fibrillation (AF) and acute coronary syndrome (ACS). We compared the safety and efficacy of dabigatran etexilate with vitamin K antagonist (VKA), in combination with DAPT (aspirin plus clopidogrel) treatment in AF patients who underwent percutaneous coronary intervention (PCI) with stenting for ACS. Methods. Consecutive nonvalvular AF patients who received twice-daily dabigatran 110 mg (n = 389) or VKA (n = 510) and DAPT were included. Primary endpoints were major bleeding (safety) and the composite of ischemic stroke, systemic embolism, and myocardial infarction (efficacy). The secondary efficacy endpoint was hospitalization for cardiovascular disease. Results. After propensity score matching, comparative treatment groups comprised 175 dabigatran recipients and 175 VKA recipients. The cumulative incidence of major bleeding was lower in the dabigatran group (2.3%) compared with the VKA group (10.3%) with a hazard ratio (HR) of 4.81 [95% confidence interval (CI) 1.6–14.2, p

http://bit.ly/2tgc19I

Analgesia during Labor and Vaginal Birth among Women with Severe Maternal Morbidity: Secondary Analysis from the WHO Multicountry Survey on Maternal and Newborn Health

Aim. To evaluate the use of analgesia for vaginal birth, in women with and without severe maternal morbidity (SMM) and to describe sociodemographic, clinical, and obstetric characteristics and maternal and perinatal outcomes associated with labor analgesia. Methods. Secondary analysis of the WHO Multicountry Survey on Maternal and Newborn Health (WHO-MCS), a global cross-sectional study performed between May 2010 and December 2011 in 29 countries. Women who delivered vaginally and had an SMM were included in this analysis and were then divided into two groups: those who received and those who did not receive analgesia for labor/delivery. We further compared maternal characteristics and maternal and perinatal outcomes between these two groups. Results. From 314,623 women originally included in WHO-MCS, 9,788 developed SMM and delivered vaginally, 601 (6.1%) with analgesia and 9,187 (93.9%) without analgesia. Women with SMM were more likely to receive analgesia than those who did not experience SMM. Global distribution of SMM was similar; however, the use of analgesia was less prevalent in Africa. Higher maternal education, previous cesarean section, and nulliparity were factors associated with analgesia use. Analgesia was not an independent factor associated with an increase of severe maternal outcome (Maternal Near Miss + Maternal Death). Conclusions. The overall use of analgesia for vaginal delivery is low but women with SMM are more likely to receive analgesia during labor. Social conditions are closely linked with the likelihood of having analgesia during delivery and such a procedure is not associated with increased adverse maternal outcomes. Expanding the availability of analgesia in different levels of care should be a concern worldwide.

http://bit.ly/2GECVQv

How to achieve operational uniformity with consolidated communication centers

Striking the balance between agency independence and operational synergy through conflict resolution, funding and governance

http://bit.ly/2N9e60p

Risk Compensation and Clinical Decision Making — The Case of HIV Preexposure Prophylaxis

Imagine a daily pill that prevents an unwanted consequence of sexual intercourse. Does it give users a "license for promiscuity"? Will its widespread availability lead to "sexual anarchy"? These questions were posed more than a half-century ago about oral contraceptive pills, which enabled…

http://bit.ly/2IjEvJM

Oral and Genital Ulcers in Behçet’s Disease

Figure 1.

http://bit.ly/2Gml8hJ

Early Administration of Antibiotics for Suspected Sepsis

These two cases encapsulate a common dilemma for clinicians who are trying to implement the recommendation of the Surviving Sepsis Campaign to administer broad-spectrum antibiotics within 1 hour after a patient's presentation with possible sepsis. Both patients meet Surviving Sepsis Campaign…

http://bit.ly/2Iby63m

The Devil Is in the Details

Foreword. In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information by sharing relevant background and reasoning with the reader (regular type). The authors' commentary follows. Stage. A 75-year-old woman…

http://bit.ly/2Gml3dV

A Step toward Protecting Payments for Primary Care

Even as the U.S. health care system increasingly adopts alternative payment models such as accountable care organizations, the traditional fee-for-service system continues to be the most commonly used method of physician payment. Moreover, although alternative payment models often involve budgets…

http://bit.ly/2I90anX

Depression in the Primary Care Setting

Foreword. This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations. Stage. A 45-year-old…

http://bit.ly/2GnFmaI

Heart and Sole — Of Metatarsals, Meaning, and Medicine

One Sunday a few months ago, I was walking in Central Park and my ankle rolled out of my shoe. I slammed my foot down to regain my balance and felt a shooting pain. A minute later, my father called, as he does every Sunday. He's a physician-scientist, and we typically talk about what we're working…

http://bit.ly/2I8P2Yh

Organoids — Preclinical Models of Human Disease

An organoid is a three-dimensional construct composed of multiple cell types that originates from stem cells by means of self-organization and is capable of simulating the architecture and functionality of native organs. Organoids permit in vivo and in vitro investigation and represent one of the…

http://bit.ly/2GnFh6U

Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria

Acute hepatic porphyrias are rare, serious, and life-threatening genetic diseases caused by mutations in hepatic heme biosynthesis enzymes. The neurotoxic heme intermediates delta aminolevulinic acid (ALA) and porphobilinogen (PBG) accumulate in patients with acute hepatic porphyrias, leading to…

http://bit.ly/2I6Oe6l

Does eradication of Helicobacter pylori cause inflammatory bowel disease?

http://bit.ly/2SPzeO8

Metachronous Neoplasias Arise in a Higher Proportion of Colon Segments From Which Large Polyps Were Previously Removed, and Can be Used to Estimate Incomplete Resection of 10–20 mm Colorectal Polyps

Incomplete resection of polyps could be an important cause of post-colonoscopy colorectal cancer. However, it is difficult to study progression of incompletely removed polyps or their clinical importance. We aimed to estimate incomplete polyp resection using risk of metachronous neoplasia per colon segment.

http://bit.ly/2N4RZYB

Timing Isn’t Everything for Diagnostic Colonoscopy After Positive Results From a Fecal Immunohistochemical Test

http://bit.ly/2SPyuIQ

Unreformed nutritional epidemiology: a lamp post in the dark forest

http://bit.ly/2DxOjKB

Outcomes With Overlapping Surgery at a Large Academic Medical Center

Objective: The aim of the study was to evaluate the efficiency and safety of overlapping surgery (OS) at a training institution by comparing it with nonoverlapping surgery (NO) with respect to operative time, mortality, readmissions, and complications. Background: OS is the practice of an attending physician providing supervision to 2 surgeries that are scheduled at overlapping times. Recent media and government attention have raised concerns about this practice and the need for informed patient consent. Methods: A population-based, retrospective, cohort study was conducted using data on operative procedures from January 1, 2014 to December 31, 2015 at a large tertiary academic center. Patients who had undergone surgery by attending surgeons who performed ≥10% of their cases overlapping were selected. Thirty-day mortality, readmission within 30 days, and 7 patient safety indicators (PSIs) were recorded. Results: A total of 26,260 cases met our criteria for analysis for surgical time and 15,106 cases for outcomes. OS patients had an average case length of 2.18 hours compared with 1.64 hours among NO patients (P

http://bit.ly/2WRnfPl