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Beta-catenin (CTNNB1) is commonly mutated in hepatocellular carcinoma (HCC). CTNNB1-mutated HCC has important clinical correlates, such as being immune cold and less likely to respond to immune checkpoint inhibitor therapies. It remains unclear, however, if they are a morphologically homogenous group of tumors. To better understand the association between the morphology, CTNNB1 mutations, and other molecular features, a detailed study of 338 The Cancer Genome Atlas cases was performed. A characteristic histological morphology was strongly associated with CTNNB1 mutations but was present in only 58% of CTNNB1-mutated HCCs. Tumors with APC mutations tended to have the classic morphology; those with AXIN mutations did not. Pseudoglands are a key feature of the classic morphology, and they were associated with CTNNB1 mutations, male gender, specific CTNNB1 mutation site, and lack of TP53 mutations. Differential gene expression analysis stratified by the presence/absence of pseudoglands identified 60 differentially expressed genes (FDR

Outcomes and costs of coronavirus disease (COVID-19) contact tracing are limited. During March-May 2020, we constructed transmission chains from 184 index cases and 1,499 contacts in Salt Lake County, Utah, USA, to assess outcomes and estimate staff time and salaries. We estimated 1,102 staff hours and $29,234 spent investigating index cases and contacts. Among contacts, 374 (25%) had COVID-19; secondary case detection rate was ≈31% among first-generation contacts, ≈16% among second- and third-generation contacts, and ≈12% among fourth-, fifth-, and sixth-generation contacts. At initial interview, 51% (187/370) of contacts were COVID-19-positive; 35% (98/277) became positive during 14-day quarantine. Median time from symptom onset to investigation was 7 days for index cases and 4 days for first-generation contacts. Contact tracing reduced the number of cases between contact generations and time between symptom onset and investigation but required substantial resources. Our findings can help jurisdictions allocate resources for contact tracing.

Prostate-specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68 Ga-PSMA-11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68 Ga-PSMA-11 PET was prospectively performed in patients with treatment-naive HCC on a digital PET scanner using cyclotron-produced 68 Ga. Uptake was graded qualitatively and semi-quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor-associated neovasculature. Higher tumor grade was associated with PSMA expression (P = 0.012) but there was no association with tumor size (P = 0.14), fibrosis (P = 0.35), cirrhosis (P = 0.74), hepatitis B virus (P = 0.31), or hepatitis C virus (P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10-5 ) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = -0.753; P = 1.58 × 10-6 ). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68 Ga-PSMA-11 standardized uptake value: SUVmax (median [range] 9.2 [4.9-28.4]), SUVmean 4.7 (2.4-12.7), and tumor-to-liver background ratio 2 (1.1-11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on 68 Ga-PSMA-11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.

PURPOSE Cholangiocarcinomas (CCA) are a group of heterogeneous tumors arising from the biliary epithelia. Significant sequencing efforts have provided further insights into the molecular mechanisms of this disease including fibroblast growth factor receptor ( FGFR) alterations, which occurs in approximately 15%-20% of intrahepatic CCAs. Herein, we describe the FGFR inhibitor (FGFRi)-associated treatment toxicity and cancer-specific outcomes from a multicenter single-institution cohort. METHODS This is a retrospective study of patients with CCA and known FGFR alterations treated with FGFRi. We describe the toxicity and efficacy in patients treated at Mayo Clinic between January 2010 and December 2020. RESULTS Our group identified 61 patients with advanced or metastatic CCA, 19 males (31%) and 42 females (69%), harboring FGFR alterations who received FGFRi. The most common grade 1 or higher adverse events for all patients included fatigue (92%), AST elevations (78%), anemia (80%), decreased platelet count (63%), and hyperphosphatemia (74%). Median progression-free survival on FGFRi was 5.8 months for all patients (95% CI, 4.9 to 9.0). Females had significantly longer progression-free survival at 6.9 months (95% CI, 5.2 to 11.8) on FGFRi compared with males at 4.9 months (95% CI, 2.8 to not estimable; P = .038). CONCLUSION FGFRi are well tolerated with clinical efficacy. With the recent approval of FGFRi by the US Food and Drug Administration and ongoing clinical trials for new FGFRi, understanding outcomes and toxicity associated with these medications is important for precision oncology.

Summary Background & aims Survivors of critical illness requiring prolonged mechanical ventilation (PMV) are predisposed to malnutrition, muscle wasting, and weakness. There is a lack of data regarding nutrition adequacy among these patients, and although nitrogen balance has been studied as a marker of adequate protein intake in healthy individuals and acutely critically ill patients, it has not been well studied in critically ill patients with PMV. The purpose of this study was to determine if patients requiring PMV admitted to a long-term acute care hospital (LTACH) achieved registered dietitian (RD) recommended goals for energy and protein intake and if the recommendations were adequate to avoid negative nitrogen balance. Methods Using a retrospective, cohort study design, patients requiring PMV who had orders for 24-h urine collections for urea nitrogen (24hrUUN) were included. Energy and protein intake was calculated from chart documentation of dietary intake for the 24-h period during which patients underwent a 24hrUUN. Nitrogen intake was estimated from protein intake. Dietary intake was compared to RD-recommendations to determine the percentage of RD-recommendations achieved. Nitrogen balance was calculated as nitrogen intake minus nitrogen loss, with negative balance categorized as less than −1. Results Subjects (n = 16) were 38% male and 75% African American (mean age 61.5 ± 3.2 years; mean BMI 27.5 ± 2.5 kg/m2). Duration of LTACH hospitalization was 26.5 (6–221) days. Mean energy and protein intake was 21.7 ± 2.9 kcal/kg/d and 1.1 ± 0.1 g/kg/d, respectively, which corresponded to 86% of both RD energy and protein recommendations. Ten patients achieved a positive nitrogen balance (mean 0.9 ± 1.1 g). In addition, there was a positive linear relationship between protein intake and nitrogen balance (r = 0.59, p = 0.016). Conclusion Survivors of critical illness requiring PMV achieved a high percentage of RD-recommended protein and calories, and prevented a negative nitrogen balance in a majority of patients. Increasing protein intake can prevent a negative nitrogen balance. Future studies should evaluate whether these patients are able to maintain a steady state of nitrogen intake and excretion over time and how this affects time to and/or success of weaning.

Background Biliary tract cancers (BTC) are rare, chemo resistant and are associated with a poor prognosis. Preclinical and early clinical work had demonstrated interesting anti-tumor activity from targeting fibroblast growth factor receptor (FGFR) pathway. We hypothesized that ponatinib, a multi-targeted tyrosine kinase inhibitor with activity against FGFR, would be active in BTC patients with FGFR alterations. Methods This was a multi-center, single institution pilot study of ponatinib in patients with advanced, refractory BTC with FGFR alterations. The primary end point was overall response rate, with secondary points of overall survival (OS), progression-free survival (PFS) and Health Related Quality of Life (HRQoL) assessment. Results Twelve patients were enrolled prior to early termination of the trial. Partial responses were observed in 1 from 12 patients. Median PFS was 2.4 months and median OS was 15.7 months. All observed toxicities were manageable and reversible. Toxicities were mild, with lymphopenia (75%), rash (63%) and fatigue (50%) being the most frequent. No significant detriment in global QoL was observed. Conclusions Ponatinib as a single agent in FGFR altered BTC is tolerable with limited clinical activity. This is the first report of prospective assessment of FGFR inhibition in BTC using ponatinib, and the first study to report its effect on HRQoL. Further development of ponatinib will involve correlative studies to better refine patient selection, focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy, and studies to better understand mechanisms of treatment resistance.

Recent studies of the human microbiome have offered new insights into how the microbiome can impact cancer development and treatment. Specifically, in pancreatic ductal adenocarcinoma (PDAC), the microbiota has been shown to modulate PDAC risk, contribute to tumorigenesis, impact the tumor microenvironment, and alter treatment response. These findings provide rationale for further investigations into leveraging the microbiome to develop new strategies to diagnose and treat PDAC patients. There is growing evidence that microbiome analyses have the potential to become easily performed, non-invasive diagnostic, prognostic, and predictive biomarkers in pancreatic cancer. More excitingly, there is now emerging interest in developing interventions based on the modulation of microbiota. Fecal microbiota transplantation, probiotics, dietary changes, and antibiotics are all potential strategies to augment the efficacy of current therapeutics and reduce toxicities. While there are still challenges to overcome, this is a rapidly growing field that holds promise for translation into clinical practice and provides a new approach to improving patient outcomes.

Azole-resistant environmental Aspergillus fumigatus presents a threat to public health but the extent of this threat in Southeast Asia is poorly described. We conducted environmental surveillance in the Mekong Delta region of Vietnam, collecting air and ground samples across key land-use types, and determined antifungal susceptibilities of Aspergillus section Fumigati (ASF) isolates and azole concentrations in soils. Of 119 ASF isolates, 55% were resistant (or non-wild type) to itraconazole, 65% to posaconazole and 50% to voriconazole. Azole resistance was more frequent in A. fumigatus sensu stricto isolates (95%) than other ASF species (32%). Resistant isolates and agricultural azole residues were overrepresented in samples from cultivated land. cyp51A gene sequence analysis showed 38/56 resistant A. fumigatus sensu stricto isolates carried known resistance mutations, with TR34 /L98H most frequent (34/38).

Background With the restructuring of primary care into patient-centered medical homes (PCMH), researchers have described role transformations that accompany the formation of core primary care teamlets (eg, primary care provider, registered nurse care manager, licensed practical nurse, medical support assistant). However, few studies offer insight into how primary care teamlets, once established, integrate additional extended team members, and the factors that influence the quality of their integration. Methods We examine the process of integrating Clinical Pharmacy Specialists (CPS) into primary care teams in the Veterans Health Administration (VHA). We conducted semi-structured interviews with CPS (n = 6) and clinical team members (n = 16) and performed a thematic analysis of interview transcripts. Results We characterize 2 ways CPS are integrated into primary care teamlets: in consultative roles and collaborative roles. CPS may be limited to consultative roles by team members' misconceptions about their competencies (ie, if CPS are perceived to handle only medication-related issues like refills) and by primary care providers' opinions about distributing responsibilities for patient care. Over time, teams may correct misconceptions and integrate the CPS in a more collaborative role (ie, CPS helps manage disease states with comprehensive medication management). Conclusions CPS integrated into collaborative roles may have more opportunities to optimize their contributions to primary care, underscoring the importance of clarifying roles as part of adequately integrating advanced practitioners in interprofessional teams.

Background and purpose Paclitaxel, a widely used anti-cancer drug, is frequently associated with prolonged and severe peripheral neuropathies (PIPN), associated with neuroinflammation. Currently, PIPN effective treatments are lacking. Peroxisome Proliferator-Activated Receptor-α (PPAR-⍺) can modulate inflammatory responses. Thus, the use of PPAR-⍺ agonists, such as fibrates (fenofibrate and choline-fenofibrate), currently used in dyslipidemia treatment, could represent an interesting therapeutic approach in PIPN. Experimental approach Our studies tested the efficacy of fenofibrate (150 mg/kg, daily, i.p.) and choline fenofibrate (60 mg/kg daily, p.o.) in reversing and preventing the development of PIPN (paclitaxel: 8 mg/kg, i.p., every other day for 4 days) in male and female C57BL/6J mice. Mechanical and cold hypersensitivity, conditioned place preference, sensory nerve action potential (SNAP), as well as the expression of PPAR-⍺, TNF-⍺, IL-1β and IL-6 mRNA were evaluated. Key results While fenofibrate treatment partially reversed and prevented the development of mechanical hypersensitivity, this was completely reversed and prevented by choline-fenofibrate. Both fibrates were able to completely reverse and prevent cold hypersensitivity induced by paclitaxel. The reduction of SNAP amplitude induced by paclitaxel was also reversed by both fenofibrate and choline-fenofibrate. Our results indicate that suppression of paclitaxel-induced hypersensitivity by fibrates involves the regulation of PPAR-⍺ expression and decrease neuroinflammation in DRG. Finally, the co-treatment of Paclitaxel and fenofibric acid (fibrates active metabolite) was tested on different cancer cell lines, no decrease in the antitumoral effect of paclitaxel was observed. Conclusions and implications Taken together, our results show for the first time the therapeutic potential (prevention and reversal) of fibrates in PIPN and opens to a potential pharmacological repurposing of these drugs.

Purpose Strategies for deploying clinical pharmacists to increase access to buprenorphine in inpatient, outpatient and transitional care, and community practice settings are described. Summary Access to medications for opioid use disorder (MOUD) is essential, but patients face many barriers when pursuing treatment and MOUD. The coronavirus disease 2019 (COVID-19) pandemic has compounded the opioid crisis and worsened outcomes by introducing new barriers to MOUD access. Many strategies to ensure continued access to MOUD have been described, but the role of leveraging pharmacists during the opioid/COVID-19 syndemic to improve medication access and outcomes remains underappreciated. Pharmacists, while both qualified and capable of liberalizing access to all forms of MOUD, may have the strongest impact by increasing access to buprenorphine. Herein, we present progressive strategies to maintain and extend buprenorphine access for patients with OUD through deployment of clinical pharmacists, particularly in the context of the COVID-19 pandemic, during which access may be further restricted. Conclusion Leveraging pharmacists to extend access to MOUD, particularly buprenorphine, remains an underutilized strategy that should be implemented, particularly during the concurrent COVID-19 global pandemic.

Objective: Pulse wave analysis estimates arterial wave reflections relating to left ventricular dysfunction and cardiovascular event risk in adults. Forward and backward waves (Pf and Pb) may improve risk stratification for cardiovascular events. Data in youth are lacking. We hypothesized that a significant difference in wave reflections would be identified in young subjects with adverse cardiovascular risk factors. Approach and Results: Vital signs and labs were obtained in 551 patients aged 10 to 24 years who were lean (L=199), obese (O=173), or had type 2 diabetes (T=179). Wave separation was performed. Differences in cardiovascular risk factors and wave reflections were assessed using ANOVA. General linear models were constructed to elucidate independent predictors of wave reflections. O and T subjects had an adverse cardiovascular risk profile versus L. O and T subjects had higher Pf and Pb versus L ( P ≤0.05). When adjusted for adiposity and other cardiovascular risk factors, reflection magnitude increased from L to O to T with higher T versus L values ( P ≤0.05) and near-significant O versus L values ( P =0.06). Adiposity and blood pressure were major determinants of wave reflections. Pb influenced log left ventricular mass index, log E/e′, and log composite carotid intima-media thickness. Conclusions: Adolescents and young adults with obesity and type 2 diabetes have altered forward and backward wave reflections versus lean controls related to adiposity, BP, and insulin levels. These parameters may help risk stratify patients with adverse cardiovascular risk factors.

Contextual processing (or context processing; CP) is an integral component of cognition. CP allows people to manage their thoughts and actions by adjusting to surroundings. CP involves the formation of an internal representation of context in relation to the environment, maintenance of this information over a period of time, and the updating of mental representations to reflect changes in the environment. Each of these functions can be affected by aging and associated conditions. Here, we introduced contextual processing research and summarized the literature studying the impact of normal aging and neurodegeneration-related cognitive decline on CP. Through searching the PubMed, PsycINFO, and Google Scholar databases, 23 studies were retrieved that focused on the impact of aging, mild cogniitve impairment (MCI), Alzheimer’s disease (AD), and Parkinson’s disease (PD) on CP. Results indicated that CP is particularly vulnerable to aging and neurodegeneration. Older adults had a delayed onset and reduced amplitude of electrophysiological response to information detection, comparison, and execution. MCI patients demonstrated clear signs of impaired CP compared to normal aging. The only study on AD suggested a decreased proactive control in AD participants in maintaining contextual information, but seemingly intact reactive control. Studies on PD restricted to non-demented older participants, who showed limited ability to use contextual information in cognitive and motor processes, exhibiting impaired reactive control but more or less intact proactive control. These data suggest that the decline in CP with age is further impacted by accelerated aging and neurodegeneration, providing insights for improving intervention strategies. This review highlights the need for increased attention to research this important but understudied field.

Background: Pediatric salivary gland-type neoplasms (SGTNs) pose a significant diagnostic problem due to histo-morphological heterogeneity. Previous reports have shown that Mucin 4 (MUC4) expression is associated with adult mucoepidermoid carcinoma (MEC). We hypothesize that MUC4 is also a sensitive marker for distinguishing MEC from other SGTNs in the pediatric population. Objective: To evaluate MUC4 expression in pediatric SGTNs. Methods: A retrospective review of 74 SGTNs diagnosed between 1993–2015 at Children’s Hospital Los Angeles, Boston Children’s Hospital, and Rhode Island Hospital was performed. H&E sections of 31 MECs were compared to 3 adenoid cystic carcinomas (AdCCs), 6 acinic cell carcinomas (AcCCs), 30 pleomorphic adenomas (PAs), 3 mammary analogue secretory carcinomas (MASCs), and one sialoblastoma (SB). Samples underwent immunohistochemical staining for MUC4, with expression score criteria: 0% positivity = 0, 1-10% = +, 11-50% = ++, 51-90% = +++, >90% = ++++. Results: All MECs were MUC4-positive, with 25 (80.65%) having an expression score ≥ +++. AdCCs and PAs demonstrated no to minimal MUC4-positivity. Subsets of AcCCs and MASCs were unexpectedly MUC4-positive. As a novel marker for pediatric MEC, MUC4’s sensitivity = 100%, specificity = 79.41%, positive predictive value = 75.86%, and negative predictive value = 100%. Conclusion: MUC4 is a sensitive marker for pediatric MEC

Global HIV program stakeholders, including the US President's Emergency Plan for AIDS Relief (PEPFAR), are undertaking efforts to ensure that eligible people living with HIV (PLHIV) receiving antiretroviral treatment (ART) receive a course of TB preventive treatment (TPT). In PEPFAR programming, this effort may require providing TPT not only to newly diagnosed PLHIV as part of HIV care initiation, but also to treatment-experienced PLHIV stable on ART who may not have been previously offered TPT. TPT scale-up is occurring at the same time as a trend to provide more person-centered HIV care through differentiated service delivery (DSD). In DSD, PLHIV stable on ART may receive less frequent clinical follow-up or receive care outside the traditional clinic-based model. The misalignment between traditional delivery of TPT and care delivery in innovative DSD may require adaptations to TPT delivery practices for PLHIV. Adaptations include components of planning and operationalization of TPT in DSD, such as determination of TPT eligibility and TPT initiation, and clinical management of PLHIV while on TPT. A key adaptation is alignment of timing and location for TPT and ART prescribing, monitoring, and dispensing. Conceptual examples of TPT delivery in DSD may help program managers operationalize TPT in HIV care.Les parties prenantes du programme mondial VIH, notamment le plan américain PEPFAR (US President’s Emergency Plan for AIDS Relief), entreprennent des efforts afin de s’assurer que les personnes vivant avec le VIH (PLVIH), éligibles, recevant un traitement antirétroviral (TAR), reçoivent également un traitement préventif TB (TPT). Dans la programmation PEPFAR, cet effort pourrait nécessiter de fournir le TPT non seulement aux PLVIH nouvellement diagnostiquées dans le cadre de l’initiation de la prise en charge du VIH, mais également aux PLVIH stables déjà traités par TAR à qui on n’aurait pas encore offert le TPT. L’expansion du TPT survient au même moment comme une tendance à offrir une prise en charge du VIH davantage centrée sur la personne à travers une prestation de services différenciée (DSD). Dans la DSD, les PLVIH stables sous TAR bénéficient d’un suivi clinique moins fréquent ou sont soignés hors du modèle traditionnel en structures de santé. Le décalage entre la prestation traditionnelle du TPT et la prestation de soins dans des DSD innovantes peut nécessiter des adaptations aux pratiques de prestation du TPT pour les PLVIH. Ces adaptations incluent des éléments de planification et d’opérationnalisation du TPT dans la DSD, comme la détermination de l’éligibilité au TPT et sa mise en route et la prise en charge clinique des PLVIH sous TPT. Une adaptation majeure est l’alignement en termes de temps et de lieu pour la prescription, le suivi et la délivrance du TPT et du TAR. Des exemples conceptuels de délivrance du TPT dans la DSD aideraient les gestionnaires de programme à rendre opérationnel le TPT au sein de la prise en charge du VIH.Los interesados directos del Programa Mundial del VIH, incluido el Plan de Emergencia del Presidente (de los Estados Unidos) para el Alivio del Sida (PEPFAR), emprenden ahora esfuerzos encaminados a garantizar que las personas con infección por el VIH (PLVIH), que siguen un tratamiento antirretrovírico (TAR) y que reúnen las condiciones, reciban un ciclo de tratamiento preventivo de la TB (TPT). En la programación del PEPFAR esta iniciativa puede necesitar la provisión de TPT no solo a las personas con un diagnóstico reciente de infección por el VIH, como parte del inicio de la atención del VIH, sino también a las PLVIH, con experiencia de tratamiento y que se encuentran estables recibiendo el TAR, a quienes tal vez no se haya propuesto antes el TPT. La ampliación del TPT ocurre de manera simultánea con la tendencia a ofrecer una atención del VIH más centrada en la persona mediante la prestación diferenciada de servicios (DSD). En la DSD, las PLVIH, estables con el TAR, pueden tener encuentros de seguimiento clínico menos frecuentes o recibir atención por fuera del modelo tradicional en los consultorios. La discordancia entre la provisión tradicional del TPT y la prestación de atención en el marco innovador de la DSD exige adaptaciones de las prácticas de prestación del TPT a las PLVIH. Las adaptaciones incluyen componentes de planeación y puesta en práctica del TPT en la DSD, como la determinación de los criterios para recibir el TPT, el inicio del mismo y el manejo clínico de las PLVIH mientras reciben el TPT. Una adaptación primordial es la coordinación del ritmo y el lugar de prescripción, supervisión y suministro del TPT y el TAR. La presentación de ejemplos teóricos de provisión del TPT en el marco de la DSD puede ayudar a los gerentes de programas a poner en práctica el TPT en la atención del VIH.

Reports suggest that children aged ≥10 years can efficiently transmit SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19) (1,2). However, limited data are available on SARS-CoV-2 transmission from young children, particularly in child care settings (3). To better understand transmission from young children, contact tracing data collected from three COVID-19 outbreaks in child care facilities in Salt Lake County, Utah, during April 1-July 10, 2020, were retrospectively reviewed to explore attack rates and transmission patterns. A total of 184 persons, including 110 (60%) children had a known epidemiologic link to one of these three facilities. Among these persons, 31 confirmed COVID-19 cases occurred; 13 (42%) in children. Among pediatric patients with facility-associated confirmed COVID-19, all had mild or no symptoms. Twelve children acquired COVID-19 in child care facilities. Transmission was documented from these children to at least 12 (26%) of 46 nonfacility contacts (confirmed or probable cases). One parent was hospitalized. Transmission was observed from two of three children with confirmed, asymptomatic COVID-19. Detailed contact tracing data show that children can play a role in transmission from child care settings to household contacts. Having SARS-CoV-2 testing available, timely results, and testing of contacts of persons with COVID-19 in child care settings regardless of symptoms can help prevent transmission. CDC guidance for child care programs recommends the use of face masks, particularly among staff members, especially when children are too young to wear masks, along with hand hygiene, frequent cleaning and disinfecting of high-touch surfaces, and staying home when ill to reduce SARS-CoV-2 transmission (4).

The small GTPase KRAS is localized at the plasma membrane where it functions as a molecular switch, coupling extracellular growth factor stimulation to intracellular signaling networks. In this process, KRAS recruits effectors, such as RAF kinase, to the plasma membrane where they are activated by a series of complex molecular steps. Defining the membrane-bound state of KRAS is fundamental to understanding the activation of RAF kinase and in evaluating novel therapeutic opportunities for the inhibition of oncogenic KRAS-mediated signaling. We combined multiple biophysical measurements and computational methodologies to generate a consensus model for authentically processed, membrane-anchored KRAS. In contrast to the two membrane-proximal conformations previously reported, we identify a third significantly populated state using a combination of neutron reflectivity, fast photochemical oxidation of proteins (FPOP), and NMR. In this highly populated state, which we refer to as “membrane-distal” and estimate to comprise ∼90% of the ensemble, the G-domain does not directly contact the membrane but is tethered via its C-terminal hypervariable region and carboxymethylated farnesyl moiety, as shown by FPOP. Subsequent interaction of the RAF1 RAS binding domain with KRAS does not significantly change G-domain configurations on the membrane but affects their relative populations. Overall, our results are consistent with a directional fly-casting mechanism for KRAS, in which the membrane-distal state of the G-domain can effectively recruit RAF kinase from the cytoplasm for activation at the membrane.

BACKGROUND: Protein supplementation and mobility-based rehabilitation programs (MRP) individually improve functional outcomes in survivors of critical illness. We hypothesized that combining MRP therapy with high protein supplementation is associated with greater weaning success from prolonged mechanical ventilation (PMV) and increased discharge home in this population. METHODS: We conducted a retrospective analysis assessing the effects of an MRP on a cohort of survivors of critical illness. All received usual care (UC) rehabilitation. The MRP group received 3 additional MRP sessions each week for a maximum of 8 weeks. Subjects were prescribed nutrition and classified as receiving high protein (HPRO) or low protein (LPRO), based on a recommended 1.0 g/kg/d, and then the subjects were categorized into 4 groups: MRP+HPRO, MRP+LPRO, UC+HPRO, and UC+LPRO. RESULTS: A total of 32 subjects were enrolled. The MRP+HPRO group had greater weaning success (90% vs 38%, P = .045) and a higher rate of discharge home (70% vs 13%, P = .037) compared to UC+LPRO group. The MRP+HPRO group had a higher, nonsignificant rate of discharge home compared to the MRP+LPRO (70% vs 20%, P = .10). CONCLUSIONS: Combining high protein with mobility-based rehabilitation was associated with increased rates of discharge home and ventilator weaning success in survivors of critical illness. Further studies are needed to evaluate the role of combined exercise and nutrition interventions in this population.

Background The evidence base for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is nascent. We sought to characterize SARS-CoV-2 transmission within US households and estimate the household secondary infection rate (SIR) to inform strategies to reduce transmission. Methods We recruited patients with laboratory-confirmed SARS-CoV-2 infection and their household contacts in Utah and Wisconsin during 22 March 2020–25 April 2020. We interviewed patients and all household contacts to obtain demographics and medical histories. At the initial household visit, 14 days later, and when a household contact became newly symptomatic, we collected respiratory swabs from patients and household contacts for testing by SARS-CoV-2 real-time reverse-transcription polymerase chain reaction (rRT-PCR) and sera for SARS-CoV-2 antibodies testing by enzyme-linked immunosorbent assay (ELISA). We estimated SIR and odds ratios (ORs) to assess risk factors for secondary infection, defined by a positive rRT-PCR or ELISA test. Results Thirty-two (55%) of 58 households secondary infection among household contacts. The SIR was 29% (n = 55/188; 95% confidence interval [CI], 23%–36%) overall, 42% among children (aged Conclusions We found substantial evidence of secondary infections among household contacts. People with COVID-19, particularly those with immunocompromising conditions or those with household contacts with diabetes, should take care to promptly self-isolate to prevent household transmission.

Purpose of review Hypertension is a common finding in children, and increases the risk for future cardiovascular events. This review focuses on recent advances in pediatric hypertension research including changes in hypertension guidelines, epidemiology, predictors of hypertension, blood pressure (BP) measurement, effects on target organs, and treatment of hypertension. Recent findings Changes in the 2017 hypertension guidelines by the American Academy of Pediatrics (AAP) have resulted in increased prevalence of elevated BP and hypertension in the United States, and there is no international consensus on these changes. Despite rising pediatric overweight and obesity in China, hypertension prevalence is stable, suggesting multifactorial effects on childhood BP. Maternal diabetes and exposure to particulate matter are associated with higher childhood BP, and body size in infancy and early childhood is a determinant of adult high BP. Children with elevated BP have evidence of target organ damage with altered retinal vasculature and pulse wave velocity parameters compared to normotensive patients. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be the best antihypertensive medications for the pediatric population even for African-American patients. Summary Research continues to illuminate contributors to pediatric hypertension and demonstrates opportunities for further study on the effects of hypertension and its management in children.

BACKGROUND: Survivors of prolonged ICU admissions are bedridden and immobilized for an extended period of time. These patients often are discharged to long-term acute care hospitals (LTACHs) for continued medical care and rehabilitation. Early ambulation has been associated with improved functional outcomes and lower readmission rates in hospitalized patients. The aim of this study was to determine the association between ambulatory status and discharge disposition in survivors of prolonged ICU stays who were admitted to an LTACH. METHODS: We performed a retrospective cohort study of 285 survivors of prolonged ICU stays who were admitted to a university-affiliated LTACH facility from 2010 to 2013. Outcomes of interest included comparing the relationship between ambulatory status and disposition status (ie, home vs acute rehabilitation facility, nursing home, readmission to an ICU, or death). RESULTS: The mean age of our cohort was 59.0 ± 15.3 y, with 129 (45%) males, 148 (52%) African-American, 123 (43%) white, and 14 (5%) of subjects other races. Most of these subjects were transferred from a medical ICU (68%). The median ICU and LTACH lengths of stay were 25.5 (13–38.8) d and 34.0 (14–64) d, respectively. Thirty-eight (13.3%) subjects were discharged home, 25 (8.7%) to an acute rehabilitation facility, 70 (24.6%) to a nursing home, 139 (48.8%) were readmitted to an ICU, and 13 (4.6%) died. Of 285 total subjects, 74 (26%) ambulated during physical therapy, while 211 (74%) subjects never ambulated. Of those who ambulated, 24 (32.4%) went home, whereas 14 of 211 (6.6%) subjects who did not ambulate went home (P < .001). CONCLUSIONS: The ability to ambulate was associated with a greater likelihood of being discharged home in survivors of prolonged ICU stays who were admitted to an LTACH. These results suggest that mobility training for survivors of prolonged ICU stays in LTACH facilities should be strongly emphasized to improve their likelihood of being discharged home.

Repeated alcohol exposure leads to changes in gene expression that are thought to underlie the transition from moderate to excessive drinking. However, the mechanisms by which these changes are mobilized to a maladaptive response that leads to alcohol dependence are not well understood. One mechanism could involve the recruitment of transcriptional co-regulators that bind and modulate the activity of several transcription factors. Our results indicate that the transcriptional regulator LMO4 is one such candidate regulator. Lmo4-deficient mice (Lmo4gt/+) consumed significantly more and showed enhanced preference for alcohol in a 24-hour intermittent access procedure. shRNA-mediated knockdown of Lmo4 in the nucleus accumbens (NAc) enhanced alcohol consumption whereas knockdown in the basolateral amygdala (BLA) decreased alcohol consumption and reduced conditioned place preference to alcohol. To ascertain the molecular mechanisms that underlie these contrasting phenotypes, we carried out unbiased transcriptome profiling of these two brain regions in wild type and Lmo4gt/+ mice. Our results revealed that the transcriptional targets of LMO4 are vastly different between the two brain regions, which may explain the divergent phenotypes observed upon Lmo4 knockdown. Bioinformatic analyses revealed that Oprk1 and genes related to the extracellular matrix (ECM) are important transcriptional targets of LMO4 in the BLA. Chromatin immunoprecipitation (ChIP) revealed that LMO4 bound Oprk1 promoter elements. Consistent with these results, disruption of the ECM or infusion of NorBNI, a selective kappa opioid receptor (KOR) antagonist, in the BLA reduced alcohol consumption. Hence our results indicate that an LMO4-regulated transcriptional network regulates alcohol consumption in the BLA.

1-Methyl-3-sulfo-1H-imidazol-3-ium chloride ([Msim]Cl) catalyzed the condensation of β-naphthol with aromatic aldehydes under microwave irradiation. This method is efficient to synthesize dibenzoxanthene derivatives in excellent yields, and the catalyst can be reused up to three times without significant loss of activity.

Recurrent seizures, which define epilepsy, are transient abnormalities in the electrical activity of the brain. The mechanistic basis of seizure initiation, and the contribution of defined neuronal subtypes to seizure pathophysiology, remains poorly understood. We performedin vivotwo-photon calcium imaging in neocortex during temperature-induced seizures in male and female Dravet syndrome (Scn1a+/−) mice, a neurodevelopmental disorder with prominent temperature-sensitive epilepsy. Mean activity of both putative principal cells and parvalbumin-positive interneurons (PV-INs) was higher inScn1a+/− relative to wild-type controls during quiet wakefulness at baseline and at elevated core body temperature. However, wild-type PV-INs showed a progressive synchronization in response to temperature elevation that was absent in PV-INs fromScn1a+/− mice. Hence, PV-IN activity remains intact interictally inScn1a+/− mice, yet exhibits decreased synchrony immediately before seizure onset. We suggest that impaired PV-IN synchronization may contribute to the transition to the ictal state during temperature-induced seizures in Dravet syndrome.SIGNIFICANCE STATEMENTEpilepsy is a common neurological disorder defined by recurrent, unprovoked seizures. However, basic mechanisms of seizure initiation and propagation remain poorly understood. We performedin vivotwo-photon calcium imaging in an experimental model of Dravet syndrome (Scn1a+/− mice)—a severe neurodevelopmental disorder defined by temperature-sensitive, treatment-resistant epilepsy—and record activity of putative excitatory neurons and parvalbumin-positive GABAergic neocortical interneurons (PV-INs) during naturalistic seizures induced by increased core body temperature. PV-IN activity was higher inScn1a+/− relative to wild-type controls during quiet wakefulness. However, wild-type PV-INs showed progressive synchronization in response to temperature elevation that was absent in PV-INs fromScn1a+/− mice before seizure onset. Hence, impaired PV-IN synchronization may contribute to transition to seizure in Dravet syndrome.

Summary Background Nutrients, such as glutamine (GLN), have been shown to effect levels of a family of protective proteins termed heat shock proteins (HSPs) in experimental and clinical critical illness. HSPs are believed to serve as extracellular inflammatory messengers and intracellular cytoprotective molecules. Extracellular HSP70 (eHSP70) has been termed a chaperokine due to ability to modulate the immune response. Altered levels of eHSP70 are associated with various disease states. Larger clinical trial data on GLN effect on eHSP expression and eHSP70's association with inflammatory mediators and clinical outcomes in critical illness are limited. Objective Explore effect of longitudinal change in serum eHSP70, eHSP27 and inflammatory cytokine levels on clinical outcomes such as pneumonia and mortality in adult surgical intensive care unit (SICU) patients. Further, evaluate effect of parenteral nutrition (PN) supplemented with GLN (GLN-PN) versus GLN-free, standard PN (STD-PN) on serum eHSP70 and eHSP27 concentrations. Methods Secondary observational analysis of a multicenter clinical trial in 150 adults after cardiac, vascular, or gastrointestinal surgery requiring PN support and SICU care conducted at five academic medical centers. Patients received isocaloric, isonitrogenous PN, with or without GLN dipeptide. Serum eHSP70 and eHSP27, interleukin-6 (IL-6), and 8 (IL-8) concentrations were analyzed in patient serum at baseline (prior to study PN) and over 28 days of follow up. Results eHSP70 declined over time in survivors during 28 days follow-up, but non-survivors had significantly higher eHSP70 concentrations compared to survivors. In patients developing pneumonia, eHSP70, eHSP27, IL-8, and IL-6 were significantly elevated. Adjusted relative risk for hospital mortality was reduced 75% (RR = 0.25, p = 0.001) for SICU patients with a faster decline in eHSP70. The area under the receiver operating characteristic curve was 0.85 (95% CI: 0.76 to 0.94) for the final model suggesting excellent discrimination between SICU survivors and non-survivors. GLN-PN did not alter eHSP70 or eHSP27 serum concentrations over time compared to STD-PN. Conclusion Our results suggest that serum HSP70 concentration may be an important marker for severity of illness and likelihood of recovery in the SICU. GLN-supplemented-PN did not increase eHSP70.

Allele-specific signaling by different KRAS alleles remains poorly understood. The KRASG12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of KRAS mutations: It is rare (∼1%) in lung and colorectal cancers, yet relatively common (∼20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specific properties. We evaluated whether KRASG12R is functionally distinct from the more common KRASG12D- or KRASG12V-mutant proteins (KRASG12D/V). We found that KRASG12D/V but not KRASG12R drives macropinocytosis and that MYC is essential for macropinocytosis in KRASG12D/V- but not KRASG12R-mutant PDAC. Surprisingly, we found that KRASG12R is defective for interaction with a key effector, p110α PI3K (PI3Kα), due to structural perturbations in switch II. Instead, upregulated KRAS-independent PI3Kγ activity was able to support macropinocytosis in KRASG12R-mutant PDAC. Finally, we determined that KRASG12R-mutant PDAC displayed a distinct drug sensitivity profile compared with KRASG12D-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy.Significance:We determined that KRASG12R is impaired in activating a key effector, p110α PI3K. As such, KRASG12R is impaired in driving macropinocytosis. However, overexpression of PI3Kγ in PDAC compensates for this deficiency, providing one basis for the prevalence of this otherwise rare KRAS mutant in pancreatic cancer but not other cancers.See related commentary by Falcomatà et al., p. 23.This article is highlighted in the In This Issue feature, p. 1

Sponges and swabs were evaluated for their ability to recover Candida auris dried 1 hour on steel and plastic surfaces. Culture recovery ranged from 50% recovery (swabs), indicating that cells may enter a viable but nonculturable state.

BackgroundIn contrast with the setting of acute myocardial infarction, there are limited data regarding the impact of diabetes mellitus on clinical outcomes in contemporary cohorts of patients with chronic coronary syndromes. We aimed to investigate the prevalence and prognostic impact of diabetes according to geographical regions and ethnicity.Methods and resultsCLARIFY is an observational registry of patients with chronic coronary syndromes, enrolled across 45 countries in Europe, Asia, America, Middle East, Australia, and Africa in 2009–2010, and followed up yearly for 5 years. Chronic coronary syndromes were defined by ≥1 of the following criteria: prior myocardial infarction, evidence of coronary stenosis >50%, proven symptomatic myocardial ischaemia, or prior revascularization procedure.Among 32 694 patients, 9502 (29%) had diabetes, with a regional prevalence ranging from below 20% in Northern Europe to ∼60% in the Gulf countries. In a multivariable-adjusted Cox proportional hazards model, diabetes was associated with increased risks for the primary outcome (cardiovascular death, myocardial infarction, or stroke) with an adjusted hazard ratio of 1.28 (95% confidence interval 1.18, 1.39) and for all secondary outcomes (all-cause and cardiovascular mortality, myocardial infarction, stroke, heart failure, and coronary revascularization). Differences on outcomes according to geography and ethnicity were modest.ConclusionIn patients with chronic coronary syndromes, diabetes is independently associated with mortality and cardiovascular events, including heart failure, which is not accounted by demographics, prior medical history, left ventricular ejection fraction, or use of secondary prevention medication. This is observed across multiple geographic regions and ethnicities, despite marked disparities in the prevalence of diabetes.ClinicalTrials identifierISRCTN43070564

A 55-year-old male with a past medical history of type 2 diabetes mellitus on metformin presented to the emergency department (ED) due to shortness of breath and three days of lumbar back pain. Workup revealed bilateral obstructing ureteral stones causing bilateral hydronephrosis, acute kidney injury (AKI), and profound anion gap metabolic acidosis due to concomitant metformin-associated lactic acidosis (MALA). In the ED, the patient developed profound shock refractory to fluid resuscitation, requiring initiation of multiple vasopressors, and stress dose steroids. He was transferred to the interventional radiology suite for bilateral percutaneous nephrostomy tubes and only improved once continuous renal replacement therapy was initiated.

The heart has a dynamic mechanical environment contributed by its unique cellular composition and the resultant complex tissue structure. In pathological heart tissue, both the mechanics and cell composition can change and influence each other. As a result, the interplay between the cell phenotype and mechanical stimulation needs to be considered to understand the biophysical cell interactions and organization in healthy and diseased myocardium. In this work, we hypothesized that the overall tissue organization is controlled by varying densities of cardiomyocytes and fibroblasts in the heart. In order to test this hypothesis, we utilized a combination of mechanical strain, co-cultures of different cell types, and inhibitory drugs that block intercellular junction formation. To accomplish this, an image analysis pipeline was developed to automatically measure cell type-specific organization relative to the stretch direction. The results indicated that cardiac cell type-specific densities influence the overall organization of heart tissue such that it is possible to model healthy and fibrotic heart tissue in vitro. This study provides insight into how to mimic the dynamic mechanical environment of the heart in engineered tissue as well as providing valuable information about the process of cardiac remodeling and repair in diseased hearts.

BackgroundNon-pharmaceutical interventions (NPIs) are recommended for COVID-19 mitigation. However, the effectiveness of NPIs in preventing SARS-CoV-2 transmission remains poorly quantified.MethodsWe conducted a test-negative design case-control study enrolling cases (testing positive for SARS-CoV-2) and controls (testing negative) with molecular SARS-CoV-2 diagnostic test results reported to California Department of Public Health between 24 February-26 September, 2021. We used conditional logistic regression to assess predictors of case status among participants who reported contact with an individual known or suspected to have been infected with SARS-CoV-2 (“high-risk exposure”) within ≤14 days of testing.Results643 of 1280 cases (50.2%) and 204 of 1263 controls (16.2%) reported high-risk exposures ≤14 days before testing. Adjusted odds of case status were 2.94-fold (95% confidence interval: 1.66-5.25) higher when high-risk exposures occurred with household members (vs. other contacts), 2.06-fold (1.03-4.21) higher when exposures occurred indoors (vs. not indoors), and 2.58-fold (1.50-4.49) higher when exposures lasted ≥3 hours (vs. shorter durations) among unvaccinated and partially-vaccinated individuals; excess risk associated with such exposures was mitigated among fully-vaccinated individuals. Mask usage by participants or their contacts during high-risk exposures reduced adjusted odds of case status by 48% (8-72%). Adjusted odds of case status were 68% (32-84%) and 77% (59-87%) lower for partially- and fully-vaccinated participants, respectively, than for unvaccinated participants. Benefits of mask usage were greatest when exposures lasted ≥3 hours, occurred indoors, or involved non-household contacts.ConclusionsNPIs reduced the likelihood of SARS-CoV-2 infection following high-risk exposure. Vaccine effectiveness was substantial for partially and fully vaccinated persons.KEY POINTSSARS-CoV-2 infection risk was greatest for unvaccinated participants when exposures to known or suspected cases occurred indoors or lasted ≥3 hours.Face mask usage when participants were exposed to a known or suspect case reduced odds of infection by 48%.

Antipsychotic medications are used in the management of schizophrenia. Antipsychotic medications treat both positive and negative symptoms via the dopamine D2 receptor and serotonin 5-HT2A blockade pathway. Side effects include hyperprolactinemia, prolonged QTc, and neuroleptic malignant syndrome. However, antipsychotic medication-induced hyperthermia potentiating a cerebrovascular accident (CVA) is a rare side effect that is less well known. A 47-year-old male presented to the emergency department (ED) via emergency medical services for altered mental status. He was given naloxone without improvement in mental status. His glucose was 110 mg/dL. Upon presentation to the ED, he was hyperthermic (106.7 degrees Fahrenheit) and tachycardic (heart rate of 160’s beats/minute). Home medications included risperidone and fluphenazine. After the resolution of his hyperthermia, he had a right-sided facial droop concerning a cerebrovascular accident. Magnetic resonance imaging (MRI) of the brain confirmed an early/acute subacute right cerebellar infarction. The patient received optimal treatment; his mental status returned to baseline, and he was discharged home without antipsychotic medications. Patients who are prescribed antipsychotics should be aware of the potentially fatal adverse events that can occur from these medications. Thermoregulation may be impaired in these patients, resulting in significant hyperthermia, in which case antipsychotic medications should be discontinued.

In 1997, Soergel et al 1 published the first set of normative values for ambulatory blood pressure monitoring (ABPM) in children. Since then, the clinical utility of ABPM has increased dramatically, and now, ABPM is accepted as the standard method to confirm the diagnosis of hypertension in children. Despite significant progress in the field of pediatric ABPM, many important questions remain unanswered. One of the most controversial issues is how to define ambulatory hypertension in children. The purpose of this review is to discuss the limitations of the current pediatric ABPM classification scheme and to provide the justification and rationale for a new classification.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) emerged from Wuhan, China, in 2019, causing coronavirus disease 19 (COVID-19) and creating a global pandemic affecting millions of people worldwide. Though COVID-19 primarily affects the pulmonary structures, deleterious effects can also occur in the cardiac system. We present a case of a patient with recurrent pericardial effusions secondary to COVID-19 infection, an unusual cardiovascular manifestation of this disease. A 47-year-old man presented with altered mental status and tested positive for COVID-19. He left against medical advice and later presented two weeks later with pleuritic chest pain associated with shortness of breath. His symptoms were attributed to a moderate- to large-sized pericardial effusion, without evidence of tamponade, as confirmed by echocardiography. The fluid was removed by pericardiocentesis; analysis was negative for malignant cells, inflammatory markers, or microbiologic studies. Reaccumulation of the fluid necessitated placement of a pericardial window, resulting in the resolution of his symptoms. There are limited case reports demonstrating the association of pericardial effusion with COVID-19 infection. The effusion is likely secondary to the inflammatory response leading to capillary leakage, resulting in pericardial fluid traversing the serous pericardium. In addition to other demonstrated cardiovascular effects, COVID-19 appears to be associated with recurrent pericardial effusion. Due to the rise in COVID-19 cases, it is essential to consider pericardial effusion as a rare but potential complication of this virus. The pericardial effusion can be the primary clinical manifestation, recurrent in nature, and potentially result in tamponade physiology.

Dolosigranulum pigrum is positively associated with indicators of health in multiple epidemiological studies of human nasal microbiota. Knowledge of the basic biology of D. pigrum is a prerequisite for evaluating its potential for future therapeutic use; however, such data are very limited. To gain insight into D. pigrum’s chromosomal structure, pangenome, and genomic stability, we compared the genomes of 28 D. pigrum strains that were collected across 20 years. Phylogenomic analysis showed closely related strains circulating over this period and closure of 19 genomes revealed highly conserved chromosomal synteny. Gene clusters involved in the mobilome and in defense against mobile genetic elements (MGEs) were enriched in the accessory genome versus the core genome. A systematic analysis for MGEs identified the first candidate D. pigrum prophage and insertion sequence. A systematic analysis for genetic elements that limit the spread of MGEs, including restriction modification (RM), CRISPR-Cas, and deity-named defense systems, revealed strain-level diversity in host defense systems that localized to specific genomic sites, including one RM system hot spot. Analysis of CRISPR spacers pointed to a wealth of MGEs against which D. pigrum defends itself. These results reveal a role for horizontal gene transfer and mobile genetic elements in strain diversification while highlighting that in D. pigrum this occurs within the context of a highly stable chromosomal organization protected by a variety of defense mechanisms. IMPORTANCE Dolosigranulum pigrum is a candidate beneficial bacterium with potential for future therapeutic use. This is based on its positive associations with characteristics of health in multiple studies of human nasal microbiota across the span of human life. For example, high levels of D. pigrum nasal colonization in adults predicts the absence of Staphylococcus aureus nasal colonization. Also, D. pigrum nasal colonization in young children is associated with healthy control groups in studies of middle ear infections. Our analysis of 28 genomes revealed a remarkable stability of D. pigrum strains colonizing people in the United States across a 20-year span. We subsequently identified factors that can influence this stability, including genomic stability, phage predators, the role of MGEs in strain-level variation, and defenses against MGEs. Finally, these D. pigrum strains also lacked predicted virulence factors. Overall, these findings add additional support to the potential for D. pigrum as a therapeutic bacterium.

Introduction Providing more convenient and patient‐centred options for service delivery is a priority within global HIV programmes. These efforts improve patient satisfaction and retention and free up time for providers to focus on new HIV diagnoses or severe illness. Recently, the coronavirus disease 2019 (COVID‐19) pandemic precipitated expanded eligibility criteria for these differentiated service delivery (DSD) models to decongest clinics and protect patients and healthcare workers. This has resulted in dramatic scale‐up of DSD for antiretroviral therapy, cotrimoxazole and tuberculosis (TB) preventive treatment. While TB treatment among people living with HIV (PLHIV) has traditionally involved frequent, facility‐based management, TB treatment can also be adapted within DSD models. Such adaptations could include electronic tools to ensure appropriate clinical management, treatment support, adherence counselling and adverse event (AE) monitoring. In this commentary, we outline considerations for DSD of TB treatment among PLHIV, building on best practices from global DSD model implementation for HIV service delivery. Discussion In operationalizing TB treatment in DSD models, we consider the following: what activity is being done, when or how often it takes place, where it takes place, by whom and for whom. We discuss considerations for various programme elements including TB screening and diagnosis; medication dispensing; patient education, counselling and support; clinical management and monitoring; and reporting and recording. General approaches include multi‐month dispensing for TB medications during intensive and continuation phases of treatment and standardized virtual adherence and AE monitoring. Lastly, we provide operational examples of TB treatment delivery through DSD models, including a conceptual model and an early implementation experience from Zambia. Conclusions COVID‐19 has catalysed the rapid expansion of differentiated patient‐centred service delivery for PLHIV. Expanding DSD models to include TB treatment can capitalize on existing platforms, while providing high‐quality, routine treatment, follow‐up and patient education and empowerment.

PURPOSE To determine the effect of atropine on pupillary diameter, accommodative amplitude as well as myopia progression. METHODS Medical databases and Cochrane Library were systematically searched for studies from 1980 until June 2020. The primary and secondary outcomes were: a) change in pupillary diameter (PD) and accommodative amplitude (AA) and b) annualized mean change in spherical equivalent and axial length with various concentrations of atropine compared to control. RESULTS Thirteen trials (6 RCTs, 7 observational studies) that studied 9 atropine concentrations (0.01-1.0%) were included. The relation between atropine and change in PD and AA was nonlinear; at < 0.10% atropine, the slope of the curve was steep but the change in PD (+0.7 mm; 95% CI: +0.1 to +1.4) and AA (-1.6D; 95% CI: -3.9 to +0.7) was smaller whereas at ≥0.10% atropine, the slope plateaued but change in PD (+3.2 mm, 95% CI: +2.8 to +3.5) and AA (-10.7D; 95% CI: -12.2 to -9.2) was high.Reduction in myopia progression with atropine at

Background:Biliary tract cancers (BTC) are rare, chemo resistant and are associated with a poor prognosis. Preclinical and early clinical work had demonstrated interesting anti-tumor activity from targeting fibroblast growth factor receptor (FGFR) pathway. We hypothesized that ponatinib, a multi-targeted tyrosine kinase inhibitor with activity against FGFR, would be active in BTC patients with FGFR alterations.Methods:This was a multi-center, single institution pilot study of ponatinib in patients with advanced, refractory BTC with FGFR alterations. The primary end point was overall response rate, with secondary points of overall survival (OS), progression-free survival (PFS) and Health Related Quality of Life (HRQoL) assessment. Results:Twelve patients were enrolled prior to early termination of the trial. Clinical benefit (defined as complete/partial response + stable disease) of 45.5% was observed. All observed toxicities were manageable and reversible. Toxicities were mild, with lymphopenia (75%), rash (63%) and fatigue (50%) being the most frequent. No significant detriment in global QoL was observed.Conclusions:Ponatinib as a single agent in FGFR altered BTC is tolerable with very modest clinical activity. This is the first report of prospective assessment of FGFR inhibition in BTC using ponatinib, and the first study to report its effect on HRQoL. Further development of ponatinib will involve correlative studies to better refine patient selection, focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy, and studies to better understand mechanisms of treatment resistance.

In long-term spaceflight, astronauts will face unique cognitive loads and social challenges which will be complicated by communication delays with Earth. It is important to understand the central nervous system (CNS) effects of deep spaceflight and the associated unavoidable exposure to galactic cosmic radiation (GCR). Rodent studies show single- or simple-particle combination exposure alters CNS endpoints, including hippocampal-dependent behavior. An even better Earth-based simulation of GCR is now available, consisting of a 33-beam (33-GCR) exposure. However, the effect of whole-body 33-GCR exposure on rodent behavior is unknown, and no 33-GCR CNS countermeasures have been tested. Here astronaut-age-equivalent (6mo-old) C57BL/6J male mice were exposed to 33-GCR (75cGy, a Mars mission dose). Pre-/during/post-Sham or 33-GCR exposure, mice received a diet containing a ‘vehicle’ formulation alone or with the antioxidant/anti-inflammatory compound CDDO‐EA as a potential countermeasure. Behavioral testing beginning 4mo post-irradiation suggested radiation and diet did not affect measures of exploration/anxiety-like behaviors (open field, elevated plus maze) or recognition of a novel object. However, in 3-Chamber Social Interaction (3-CSI), CDDO-EA/33-GCR mice failed to spend more time exploring a holder containing a novel mouse vs. a novel object (empty holder), suggesting sociability deficits. Also, Vehicle/33-GCR and CDDO-EA/Sham mice failed to discriminate between a novel stranger vs. familiarized stranger mouse, suggesting blunted preference for social novelty. CDDO-EA given pre-/during/post-irradiation did not attenuate the 33-GCR-induced blunting of preference for social novelty. Future elucidation of the mechanisms underlying 33-GCR-induced blunting of preference for social novelty will improve risk analysis for astronauts which may in-turn improve countermeasures.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged from Wuhan, China in December 2019 and is the strain of coronavirus that causes coronavirus disease 2019 (COVID-19). Approximately one-third of the patients with COVID-19 require intensive care unit (ICU) admission, and almost 30% of the patients develop acute respiratory distress syndrome (ARDS). Extracorporeal membrane oxygenation (ECMO) is used as salvage therapy for severe ARDS. The role of ECMO in the treatment of COVID-19 remains unclear, although there is emerging evidence that this approach may be an effective salvage therapy for severe ARDS. Case Presentation: We present a case of a previously healthy 39-year-old Hispanic male who presented to the hospital with flu-like symptoms, including headache, fatigue, and myalgia for 8 days in late April 2020. He denied dyspnea on exertion. The patient’s symptoms progressed, resulting in pneumonia and acute respiratory distress syndrome (ARDS). The patient was managed with prone positioning, convalescent plasma and veno-venous extracorporeal membrane oxygenation (VV-ECMO) for 35 days. The patient successfully recovered and was able to ambulate independently and was discharged home from an acute care hospital without oxygen supplementation on hospital day 63. Conclusion: We present one of the first few documented cases of ECMO for severe ARDS due to COVID-19. After a prolonged hospital course requiring VV-ECMO, the patient was discharged home from an acute care hospital without oxygen requirement and ambulated independently, likely as a result of daily aggressive mobility-focused rehabilitation.

Acute respiratory distress syndrome (ARDS) is often due to direct lung injury, trauma, surgery, or infection. Making a definitive diagnosis may be difficult initially, as clinical manifestations are nonspecific until the disease progresses. We present a case of human metapneumovirus (hMPV) pulmonary infection precipitating ARDS. A 51-year-old woman presented with one week of pleuritic chest pain, dyspnea, wheezing, subjective fever, and productive cough prior to presentation. Her medical history was significant for human immunodeficiency virus (HIV) with an unknown CD4 count and viral load, pulmonary sarcoidosis, asthma, and being an active smoker. On admission, the patient was dyspneic and using accessory muscles to breathe. She was afebrile and hypotensive. Physical examination revealed bilateral diffuse crackles. Her white blood cell (WBC) count was 7.7 K/mcL. A chest radiograph demonstrated bilateral lung opacifications suggestive of pneumonia, possibly Pneumocystis jiroveci pneumonia (PJP). Broad-spectrum antibiotics, including PJP treatment, corticosteroids, and fluids, were started. The patient received approximately 4 liters of intravenous fluids; yet, she remained hypotensive and required norepinephrine. Chest computed tomography (CT) demonstrated bilateral consolidations. Arterial blood gas (ABG) showed a partial pressure of oxygen (PaO2) of 55 mmHg. The patient was intubated for acute hypoxemic respiratory failure and had a PaO2/fraction of inspired oxygen (FiO2) < 100. Repeat ABG within 12 hours showed a potential of hydrogen (pH) of 7.34, partial pressure of carbon dioxide (pCO2) of 42 mmHg, and a PaO2 of 130 mmHg. Bronchoalveolar lavage revealed only hMPV. The patient was managed supportively and extubated three days later. She was discharged home without oxygen requirement. hMPV causes respiratory infections, most commonly in the extremes of age and immunocompromised patients. The treatment is supportive. Our patient developed acute hypoxemic respiratory failure secondary to an hMPV infection. hMPV pneumonia should be considered as a differential diagnosis in patients with severe respiratory illness and ARDS in order to promote antibiotic stewardship.

Cell-cell interactions underlie diverse physiological processes yet remain challenging to examine with conventional imaging tools. Here we report a novel strategy to illuminate cell proximity using transcriptional activators. We repurposed cumate, a small molecule inducer of gene expression, by caging its key carboxylate group with a nitrile. Nitrilase-expressing activator cells released the cage, liberating cumate for consumption by reporter cells. Reporter cells comprising a cumate-responsive switch expressed a target gene when in close proximity to the activator cells. Overall, this strategy provides a versatile platform to image and potentially manipulate cellular interactions over time.

For the past 2 decades, the earnings gap between genders has narrowed for pharmacists, making it 1 of the smallest for a high-wage profession. Gender bias is reflected in 2 main areas, pay and opportunity. The Department of Veterans Affairs (VA) is the largest integrated health care system in the country, and the authors performed an analysis to see if there was any evidence of gender bias within its pharmacist workforce. The distribution of pharmacists by gender, age, and years of service was examined and whether part-time employment had any impact was also studied. Overall, there is a high degree of gender egalitarianism in terms of pay and opportunity for pharmacists at the VA. The level of step achievement, and thus, pay for men and women, was not associated with gender but rather years of service.

Anti-synthetase syndrome (ASS) is characterized by myositis that is associated with progressive interstitial lung disease (ILD). The prognosis of the disease is affected by the type and degree of pulmonary involvement. We report a rare case of ASS with positive Anti-EJ antibody presenting with a combination of recurrent deep vein thrombosis/pulmonary embolism (DVT/PE) and progressive ILD. This case demonstrates the delayed diagnosis of ASS and the association of thromboembolic disease and ASS. Physicians should have a high index of suspicion for ASS, as early diagnosis and management alters the morbidity and prognosis of patients with ASS. Abbreviations ASS: Anti-synthetase syndrome; Ab: Antibody; Ag: Antigen; ANA: Anti-nuclear antibodies; CK: Creatine kinase; CRP: C-reactive protein; DVT: Deep Vein Thrombosis; ESR: Erythrocyte Sedimentation Rate; ILD: Interstitial lung disease; PE: Pulmonary Embolism; CTA: CT Angiography