Checkpoint kinase 2 controls insulin secretion and glucose homeostasis.

After the discovery of insulin, a century ago, extensive work has been done to unravel the molecular network regulating insulin secretion. Here we performed a chemical screen and identified AZD7762, a compound that potentiates glucose-stimulated insulin secretion (GSIS) of a human ß cell line, healthy and type 2 diabetic (T2D) human islets and primary cynomolgus macaque islets. In vivo studies in diabetic mouse models and cynomolgus macaques demonstrated that AZD7762 enhances GSIS and improves glucose tolerance. Furthermore, genetic manipulation confirmed that ablation of CHEK2 in human ß cells results in increased insulin secretion. Consistently, high-fat-diet-fed Chk2-/- mice show elevated insulin secretion and improved glucose clearance. Finally, untargeted metabolic profiling demonstrated the key role of the CHEK2-PP2A-PLK1-G6PD-PPP pathway in insulin secretion. This study successfully identifies a previously unknown insulin secretion regulating pathway that is conserved across rodents, cynomolgus macaques and human ß cells in both healthy and T2D conditions.

Utility of Direct Specimen Sequencing in Addition to Conventional Testing in Management of Infections in an Urban Referral Health Center.

BACKGROUND: Direct specimen sequencing (DSS) offers the promise of enhanced pathogen detection and disease diagnosis. METHODS: A single healthcare network, retrospective chart review over a 3-year period was completed for all cases in which DSS was submitted, in addition to conventional testing (CT) for workup of an infectious disease. We sought to compare results (concordance and discordance) from these 2 techniques in order to evaluate any additional yield from DSS over CT. Additionally, we calculated mean turnaround time (TAT) and average cost for obtaining DSS on all specimens. RESULTS: A total of 23 patients' specimens were sent for DSS. DSS and CT concordance occurred in 91% (21/23) of cases. DSS testing was able to identify specific pathogens in 17.4% (4/23) of patients, out of which 4% (1/23) were discordant. The respective mean TAT and total cost per specimen for DSS were 6 days and $821.52 (range $573-$1590), respectively. CONCLUSIONS: In our limited cohort of patients, there was significant concordance between the 2 testing modalities primarily due to negative tests. DSS did not provide significant additional yield in the infectious diagnosis in our cohort compared to CT. Short TAT may provide advantage in the detection of fastidious organisms, but high cost remains a limitation. Larger sample size may reveal a clinically meaningful difference.

Unmet needs for hypertension diagnosis among older adults in Myanmar: secondary analysis of a multistage sampling study.

BACKGROUND: Hypertension is a major cause of morbidity among older adults. We investigated older adults' access to health services in Myanmar by focusing on unmet needs in diagnosing hypertension. This study aims to identify factors associated with the unmet needs for hypertension diagnosis in the study areas of Myanmar. METHODS: This is a secondary data analysis of the survey which is a cross-sectional study conducted with older adults (aged ≥ 60 years) in the Yangon and Bago regions of Myanmar. Objective indicators of health were collected, including blood pressure, height and weight. The diagnosis of hypertension was considered an unmet need when a participant's blood pressure measurement met the diagnostic criteria for hypertension but the disease had not yet been diagnosed. Bivariate and multivariate analyses using logistic regression were performed to identify factors associated with the unmet need for hypertension diagnosis. Factors related to lifestyle habits and medical-seeking behaviour were selected and put into the multivariate model. RESULTS: Data from 1200 people, 600 from each of the two regions, were analysed. Altogether 483 (40.3%) participants were male, 530 (44.2%) were aged ≥ 70 years, and 857 were diagnosed with hypertension based on their measured blood pressure or diagnostic history, or both, which is a 71.4% prevalence of hypertension. Moreover, 240 (20.0%) participants had never been diagnosed with hypertension. In the multivariate analysis, these unmet needs for hypertension diagnosis were significantly associated with male sex (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.05-2.05), residence in the Bago region (OR 1.64, 95% CI 1.09-2.45) and better self-rated health (OR 1.70, 95% CI 1.24-2.33), but not with education, category on the wealth index or living arrangement. CONCLUSIONS: There are barriers to accessing health services for hypertension diagnosis, as evidenced by the regional disparities found in this study, and charitable clinics may decrease the financial barrier to this diagnosis.

Scedosporium apiospermum mediastinitis in an orthotopic heart transplant recipient.

Scedosporiosis is an opportunistic mycosis that may cause disseminated disease in transplant recipients. This article reports a case of recurrent Scedosporium apiospermum mediastinitis without pneumonia in an orthotopic heart transplant recipient, with durable control achieved by long-term antifungal therapy and serial debridement. This case highlights the importance of an opportunistic scedosporium infection in immunocompromised hosts, given the challenges in microbiological identification and limited treatment options.

Brain abscess associated with Mycoplasma faucium - The initial presentation of pulmonary arteriovenous malformation.

Brain abscesses represent a pathology with significant morbidity and mortality. An underlying predisposing condition may not be apparent or identifiable in some instances. We present a patient with cerebral abscess who was found to have, previously undiagnosed, pulmonary arteriovenous malformations (PAVMs). PAVMs are rare pulmonary vascular anomalies resulting in intrapulmonary right to left shunt. These have been implicated in the development of brain abscesses. Conventional cultures from the lesion were non-revealing; hence, sample was sent for next-generation sequencing (NGS) which revealed multiple organisms, with predominance of Mycoplasma faucium, a bacterium initially felt to be a commensal of the oropharynx, but recently implicated as a human pathogen. This case, along with other documented associations between brain abscesses and pulmonary AVMs, highlights that brain abscess could be an initial clinical presentation in asymptomatic PAVMs. Additionally, novel testing such as NGS should be utilized in select settings where microbiological diagnosis can be elusive. This will help institute pathogen-directed specific antimicrobial therapy for favorable clinical outcomes.

Staphylococcus aureus native mitral valve endocarditis associated with bed bug bites - A case report and review of the literature.

Staphylococcus aureus is a leading cause of community acquired bacteremia and infective endocarditis. S. aureus is a part of the normal skin flora in approximately one third of the human population. Infective endocarditis due to S. aureus can cause several complications and is associated with increased mortality. A 48-year-old female with no significant medical history presented with S. aureus bacteremia and native mitral valve endocarditis. Multiple cutaneous skin lesions were identified, which she reported were due to recent bed bug bites. No source of infection was found except for the skin lesions. Her hospital course was complicated by pulmonary and cerebral septic emboli, left pleural empyema, and acute renal injury. We suspected the bed bug skin bites were the most likely source of bacteremia. Bed bugs carry many human pathogens but have not been shown to be a competent vector. We did not find any literature on endocarditis associated with bed bug bites; thus, our case will be a novel finding.

Axillary lymphadenopathy in a liver transplant recipient: Initial manifestation of disseminated cryptococcosis.

Immunocompromised patients, especially organ transplant recipients, are at risk for opportunistic infections. Cryptococcus, a ubiquitous environmental fungus, can cause potentially fatal infection in such hosts. While it can involve any organ in the human body, respiratory and central nervous systems are commonly affected. We present a case of disseminated cryptococcal infection in a liver transplant recipient in whom the initial presentation was bilateral axillary lymphadenopathy, a relatively rare clinical manifestation. Rapid diagnosis and targeted antimicrobial therapy are paramount for favorable clinical outcomes, particularly in this patient population.

Voriconazole-associated periostitis: Pathophysiology, risk factors, clinical manifestations, diagnosis, and management.

Voriconazole use has been associated with osteoarticular pain and periostitis, likely due to high fluoride content in the drug formulation. This phenomenon has been described primarily with high dosage or prolonged course of voriconazole therapy in immunocompromised and transplant patient populations. Patients typically present with diffuse bony pains associated with elevated serum alkaline phosphatase and plasma fluoride levels in conjunction with radiographic findings suggestive of periostitis. We provide a comprehensive review of the literature to highlight salient characteristics commonly associated with voriconazole-induced periostitis.

Ceftaroline-related acute eosinophilic pneumonia.

Ceftaroline fosamil is a novel 5th generation broad-spectrum oxyimino-cephalosporin with activity against Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), Streptococcus pneumoniae, Haemophilus influenzae, and Gram-negative bacteria. It has been approved by the United States Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. There have been reported cases of successful treatment of MRSA bacteremia with this agent. Common adverse drug reactions from ceftaroline include skin rash, hives, neutropenia, thrombocytopenia, and anemia. Acute eosinophilic pneumonia is a rare untoward drug reaction associated with it. We report a case of fever and acute hypoxic respiratory failure with bilateral interstitial pulmonary infiltrates while on ceftaroline therapy for sternal osteomyelitis and ascending aortic graft infection secondary to MRSA. Laboratory studies revealed peripheral blood eosinophilia (>3000 cells/mm3). After exclusion of infectious, autoimmune, and other extrinsic allergic causes of pneumonia, ceftaroline-related acute eosinophilic pneumonia was suspected. Ceftaroline was discontinued and a therapeutic trial of high-dose steroid was initiated. Significant improvement of clinical symptoms and hypoxia was achieved after 24 h of steroid therapy. There was no recurrence of clinical symptoms after completing steroid course, which supported our suspicion of acute eosinophilic pneumonia from ceftaroline. Radiographic improvement of pulmonary infiltrates occurred 4 weeks later with complete resolution at 3 months from the initial event. The current case adds to this rarely reported adverse effect from this relatively newer antimicrobial agent. Increased awareness, early recognition, discontinuation of medication, and steroid therapy are key in favorable clinical outcome and recovery.

SARS-CoV-2 infection induces beta cell transdifferentiation.

Recent clinical data have suggested a correlation between coronavirus disease 2019 (COVID-19) and diabetes. Here, we describe the detection of SARS-CoV-2 viral antigen in pancreatic beta cells in autopsy samples from individuals with COVID-19. Single-cell RNA sequencing and immunostaining from ex vivo infections confirmed that multiple types of pancreatic islet cells were susceptible to SARS-CoV-2, eliciting a cellular stress response and the induction of chemokines. Upon SARS-CoV-2 infection, beta cells showed a lower expression of insulin and a higher expression of alpha and acinar cell markers, including glucagon and trypsin1, respectively, suggesting cellular transdifferentiation. Trajectory analysis indicated that SARS-CoV-2 induced eIF2-pathway-mediated beta cell transdifferentiation, a phenotype that could be reversed with trans-integrated stress response inhibitor (trans-ISRIB). Altogether, this study demonstrates an example of SARS-CoV-2 infection causing cell fate change, which provides further insight into the pathomechanisms of COVID-19.

Guillain-Barré syndrome following the first dose of SARS-CoV-2 vaccine: A temporal occurrence, not a causal association.

Safety monitoring is of paramount importance for vaccines authorized for emergent use (EUA) by the US Food and Drug Administration (FDA) against SARS-CoV-2. Mass immunization is an essential tool to end the current pandemic, but vaccine surveillance is necessary to identify any potentially associated harms. At the same time, probability of temporal bias should be borne in mind before making conclusions about causality between the vaccine and an attributable undesired effect. We report a case of Guillain-Barré syndrome after the first dose of SARS-CoV-2 vaccine and believe this is a temporal, rather than causal association.

A Great Masquerader: Nasal Type, Extranodal Natural Killer/T-cell Lymphoma Presenting as Recalcitrant Bacterial Sinusitis and Periorbital Cellulitis.

Nasal extranodal natural killer/T-cell lymphoma (ENKL) is a rare clinical entity. It may, however, masquerade as a commonly encountered disease, such as sinusitis. A high index of clinical suspicion of nasal ENKL should be raised when there is inadequate clinical response despite appropriate therapeutic intervention of sinusitis. Biopsy would be warranted and crucial in those instances to make an accurate and timely diagnosis.

A Bayesian phase 2 model based adaptive design to optimise antivenom dosing: Application to a dose-finding trial for a novel Russell's viper antivenom in Myanmar.

For most antivenoms there is little information from clinical studies to infer the relationship between dose and efficacy or dose and toxicity. Antivenom dose-finding studies usually recruit too few patients (e.g. fewer than 20) relative to clinically significant event rates (e.g. 5%). Model based adaptive dose-finding studies make efficient use of accrued patient data by using information across dosing levels, and converge rapidly to the contextually defined 'optimal dose'. Adequate sample sizes for adaptive dose-finding trials can be determined by simulation. We propose a model based, Bayesian phase 2 type, adaptive clinical trial design for the characterisation of optimal initial antivenom doses in contexts where both efficacy and toxicity are measured as binary endpoints. This design is illustrated in the context of dose-finding for Daboia siamensis (Eastern Russell's viper) envenoming in Myanmar. The design formalises the optimal initial dose of antivenom as the dose closest to that giving a pre-specified desired efficacy, but resulting in less than a pre-specified maximum toxicity. For Daboia siamensis envenoming, efficacy is defined as the restoration of blood coagulability within six hours, and toxicity is defined as anaphylaxis. Comprehensive simulation studies compared the expected behaviour of the model based design to a simpler rule based design (a modified '3+3' design). The model based design can identify an optimal dose after fewer patients relative to the rule based design. Open source code for the simulations is made available in order to determine adequate sample sizes for future adaptive snakebite trials. Antivenom dose-finding trials would benefit from using standard model based adaptive designs. Dose-finding trials where rare events (e.g. 5% occurrence) are of clinical importance necessitate larger sample sizes than current practice. We will apply the model based design to determine a safe and efficacious dose for a novel lyophilised antivenom to treat Daboia siamensis envenoming in Myanmar.

Pott's puffy tumor caused by Actinomyces naeslundii.

Pott's puffy tumor is characterized by forehead swelling from subperiosteal abscess and frontal bone osteomyelitis. It is encountered mainly in children; rarely in adults. When it does occur in the latter population, the most common risk factors include head trauma, sinusitis, or cocaine abuse. Generally, the organisms thought to be involved include streptococci, staphylococci and oral anaerobic flora. We present a case of a 53 year old female who presented with forehead swelling of 3 month duration after a dental procedure, found to be secondary to Actinomyces naeslundii. Actinomyces is a very rare etiology of this disease and has been reported only twice earlier in the literature. We present an uncommon infectious disease along with summary of clinical characteristics of this entity in the adult population.

COVID-19: Diagnostic Testing and Challenges.

Coronavirus disease-2019 (COVID-19) was declared a pandemic by the World Health Organization on March 11, 2020. Following this, there has been a rapid development in policies and strategies to contain and mitigate the pandemic. One of such strategies involves the development and utilization of testing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative organism of COVID-19. In this article, we explore the diagnostic modalities for COVID-19 based on the available information to date.

The use of single-pill combinations as first-line treatment for hypertension: translating guidelines into clinical practice.

: The 2008 European Society of Cardiology/European Society of Hypertension guidelines recommend the first-line prescription of two antihypertensive drugs in single-pill combinations (SPCs), also known as fixed-dose combinations, for the treatment of most patients with hypertension. This recommendation is based on a large amount of data, which shows that first-line treatment with SPCs supports reaching blood pressure targets rapidly and reducing cardiovascular outcome risk while keeping the therapeutic strategies as simple as possible and fostering adherence and persistence. As this approach constitutes a big shift from the stepped-care approaches that have been dominant for many years, practicing physicians have expressed concerns about using SPCs as first-line agents. In this review, we will discuss the barriers to the uptake of this recommendation. We will also offer suggestions to reduce the impact of these barriers and address specific concerns that have been raised.