Fast, accurate ranking of engineered proteins by target-binding propensity using structure modeling.

Deep-learning-based methods for protein structure prediction have achieved unprecedented accuracy, yet their utility in the engineering of protein-based binders remains constrained due to a gap between the ability to predict the structures of candidate proteins and the ability toprioritize proteins by their potential to bind to a target. To bridge this gap, we introduce Automated Pairwise Peptide-Receptor Analysis for Screening Engineered proteins (APPRAISE), a method for predicting the target-binding propensity of engineered proteins. After generating structural models of engineered proteins competing for binding to a target using an established structure prediction tool such as AlphaFold-Multimer or ESMFold, APPRAISE performs a rapid (under 1 CPU second per model) scoring analysis that takes into account biophysical and geometrical constraints. As proof-of-concept cases, we demonstrate that APPRAISE can accurately classify receptor-dependent vs. receptor-independent adeno-associated viral vectors and diverse classes of engineered proteins such as miniproteins targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike, nanobodies targeting a G-protein-coupled receptor, and peptides that specifically bind to transferrin receptor or programmed death-ligand 1 (PD-L1). APPRAISE is accessible through a web-based notebook interface using Google Colaboratory (https://tiny.cc/APPRAISE). With its accuracy, interpretability, and generalizability, APPRAISE promises to expand the utility of protein structure prediction and accelerate protein engineering for biomedical applications.

Diminished Neuronal ESCRT-0 Function Exacerbates AMPA Receptor Derangement and Accelerates Prion-Induced Neurodegeneration.

Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the multivesicular body (MVB) and are routed for degradation in lysosomes or for release in exosomes, yet how prions impact proteostatic pathways is unclear. We found that prion-affected human and mouse brain showed a marked reduction in Hrs and STAM1 (ESCRT-0), which route ubiquitinated membrane proteins from early endosomes into MVBs. To determine how the reduction in ESCRT-0 impacts prion conversion and cellular toxicity in vivo, we prion-challenged conditional knockout mice (male and female) having Hrs deleted from neurons, astrocytes, or microglia. The neuronal, but not astrocytic or microglial, Hrs-depleted mice showed a shortened survival and an acceleration in synaptic derangements, including an accumulation of ubiquitinated proteins, deregulation of phosphorylated AMPA and metabotropic glutamate receptors, and profoundly altered synaptic structure, all of which occurred later in the prion-infected control mice. Finally, we found that neuronal Hrs (nHrs) depletion increased surface levels of the cellular prion protein, PrPC, which may contribute to the rapidly advancing disease through neurotoxic signaling. Taken together, the reduced Hrs in the prion-affected brain hampers ubiquitinated protein clearance at the synapse, exacerbates postsynaptic glutamate receptor deregulation, and accelerates neurodegeneration.SIGNIFICANCE STATEMENT Prion diseases are rapidly progressive neurodegenerative disorders characterized by prion aggregate spread through the central nervous system. Early disease features include ubiquitinated protein accumulation and synapse loss. Here, we investigate how prion aggregates alter ubiquitinated protein clearance pathways (ESCRT) in mouse and human prion-infected brain, discovering a marked reduction in Hrs. Using a prion-infection mouse model with neuronal Hrs (nHrs) depleted, we show that low neuronal Hrs is detrimental and markedly shortens survival time while accelerating synaptic derangements, including ubiquitinated protein accumulation, indicating that Hrs loss exacerbates prion disease progression. Additionally, Hrs depletion increases the surface distribution of prion protein (PrPC), linked to aggregate-induced neurotoxic signaling, suggesting that Hrs loss in prion disease accelerates disease through enhancing PrPC-mediated neurotoxic signaling.

Arrhythmias in Female Patients: Incidence, Presentation and Management.

There is a growing appreciation for differences in epidemiology, treatment, and outcomes of cardiovascular conditions by sex. Historically, cardiovascular clinical trials have under-represented females, but findings have nonetheless been applied to clinical care in a sex-agnostic manner. Thus, much of the collective knowledge about sex-specific cardiovascular outcomes result from post hoc and secondary analyses. In some cases, these investigations have revealed important sex-based differences with implications for optimizing care for female patients with arrhythmias. This review explores the available evidence related to cardiac arrhythmia care among females, with emphasis on areas in which important sex differences are known or suggested. Considerations related to improving female enrollment in clinical trials as a way to establish more robust clinical evidence for the treatment of females are discussed. Areas of remaining evidence gaps are provided, and recommendations for areas of future research and specific action items are suggested. The overarching goal is to improve appreciation for sex-based differences in cardiac arrhythmia care as 1 component of a comprehensive plan to optimize arrhythmia care for all patients.

Association of patient characteristics and insurance type with anti-obesity medications prescribing and fills.

AIM: To characterize factors associated with the receipt of anti-obesity medication (AOM) prescription and fill. MATERIALS AND METHODS: This retrospective cohort study used electronic health records from 1 January 2015 to 30 June 2023, in a large health system in Ohio and Florida. Adults with a body mass index ≥30 kg/m2 who attended ≥1 weight-management programme or had an initial AOM prescription between 1 July 2015 and 31 December 2022, were included. The main measures were a prescription for an AOM (naltrexone-bupropion, orlistat, phentermine-topiramate, liraglutide 3.0 mg and semaglutide 2.4 mg) and an AOM fill during the study follow-up. RESULTS: We identified 50 678 adults, with a mean body mass index of 38 ± 8 kg/m2 and follow-up of 4.7 ± 2.4 years. Only 8.0% of the cohort had AOM prescriptions and 4.4% had filled prescriptions. In the multivariable analyses, being a man, Black, Hispanic and other race/ethnicity (vs. White), Medicaid, traditional Medicare, Medicare Advantage, self-pay and other insurance types (vs. private insurance) and fourth quartile of the area deprivation index (vs. first quartile) were associated with lower odds of a new prescription. Hispanic ethnicity, being a man, Medicaid, traditional Medicare and Medicare Advantage insurance types, liraglutide and orlistat (vs. naltrexone-buproprion) were associated with lower odds of AOM fill, while phentermine-topiramate was associated with higher odds. Among privately insured individuals, the insurance carrier was associated with both the odds of AOM prescription and fill. CONCLUSIONS: Significant disparities exist in access to AOM both at the prescribing stage and getting the prescription filled based on patient characteristics and insurance type.

Resident worklife and wellness through the late phase of the pandemic: a mixed methods national survey study.

BACKGROUND: System contributors to resident burnout and well-being have been under-studied. We sought to determine factors associated with resident burnout and identify at risk groups. METHODS: We performed a US national survey between July 15 2022 and April 21, 2023 of residents in 36 specialties in 14 institutions, using the validated Mini ReZ survey with three 5 item subscales: 1) supportive workplace, 2) work pace/electronic medical record (EMR) stress, and 3) residency-specific factors (sleep, peer support, recognition by program, interruptions and staff relationships). Multilevel regressions and thematic analysis of 497 comments determined factors related to burnout. RESULTS: Of 1118 respondents (approximate median response rate 32%), 48% were female, 57% White, 21% Asian, 6% LatinX and 4% Black, with 25% PGY 1 s, 25% PGY 2 s, and 22% PGY 3 s. Programs included internal medicine (15.1%) and family medicine (11.3%) among 36 specialties. Burnout (found in 42%) was higher in females (51% vs 30% in males, p = 0.001) and PGY 2's (48% vs 35% in PGY-1 s, p = 0.029). Challenges included chaotic environments (41%) and sleep impairment (32%); favorable aspects included teamwork (94%), peer support (93%), staff support (87%) and program recognition (68%). Worklife subscales were consistently lower in females while PGY-2's reported the least supportive work environments. Worklife challenges relating to burnout included sleep impairment (adjusted Odds Ratio (aOR) 2.82 (95% CIs 1.94, 4.19), absolute risk difference (ARD) in burnout 15.9%), poor work control (aOR 2.25 (1.42, 3.58), ARD 12.2%) and chaos (aOR 1.73 (1.22, 2.47), ARD 7.9%); program recognition was related to lower burnout (aOR 0.520 (0.356, 0.760), ARD 9.3%). These variables explained 55% of burnout variance. Qualitative data confirmed sleep impairment, lack of schedule control, excess EMR and patient volume as stressors. CONCLUSIONS: These data provide a nomenclature and systematic method for addressing well-being during residency. Work conditions for females and PGY 2's may merit attention first.

You Cannot Function in "Overwhelm": Helping Primary Care Navigate the Slow End of the Pandemic.

GOAL: This study was developed to explicate underlying organizational factors contributing to the deterioration of primary care clinicians' mental health during the COVID-19 pandemic. METHODS: Using data from the Larry A. Green Center for the Advancement of Primary Health Care for the Public Good's national survey of primary care clinicians from March 2020 to March 2022, a multidisciplinary team analyzed more than 11,150 open-ended comments. Phase 1 of the analysis happened in real-time as surveys were returned, using deductive and inductive coding. Phase 2 used grounded theory to identify emergent themes. Qualitative findings were triangulated with the survey's quantitative data. PRINCIPAL FINDINGS: The clinicians shifted from feelings of anxiety and uncertainty at the start of the pandemic to isolation, lack of fulfillment, moral injury, and plans to leave the profession. The frequency with which they spoke of depression, burnout, and moral injury was striking. The contributors to this distress included crushing workloads, worsening staff shortages, and insufficient reimbursement. Consequences, both felt and anticipated, included fatigue and demoralization from the inability to manage escalating workloads. Survey findings identified responses that could alleviate the mental health crisis, namely: (1) measuring and customizing workloads based on work capacity; (2) quantifying resources needed to return to sufficient staffing levels; (3) promoting state and federal support for sustainable practice infrastructures with less administrative burden; and (4) creating patient visits of different lengths to rebuild relationships and trust and facilitate more accurate diagnoses. PRACTICAL APPLICATIONS: Attention to clinicians' mental health should be rapidly directed to on-demand, confidential mental health support so they can receive the care they need and not worry about any stigma or loss of license for accepting that help. Interventions that address work-life balance, workload, and resources can improve care, support retention of the critically important primary care workforce, and attract more trainees to primary care careers.

Lessons for tomorrow: The role of relationships and mindfulness in sustaining services during a crisis.

BACKGROUND: The COVID-19 pandemic placed unprecedented demands on hospitals around the globe, making timely crisis response critical for organizational success. One mechanism that has played an effective role in health care service management during large-scale crises is the Hospital Incident Command System. PURPOSE: The aim of this article was to understand the role of HICS in the management of a large academic medical center and its impact on relationships and communication among providers in the delivery of services during a crisis. METHODOLOGY: This mixed methods study was based on meeting observations, document reviews, semistructured interviews, and two measures of team performance within an academic medical center in the Northeast during the COVID-19 pandemic. Descriptive and bivariate analyses were applied, and qualitative data were coded and analyzed for themes. RESULTS: HICS provided a systematic information-sharing and decision-making process that increased communication and coordination among team members. Analyses indicate a correlation between dimensions of relational coordination and organizational mindfulness. Qualitative data revealed the importance of shared meetings and huddles and the evolution of HICS across multiple waves of the crisis. CONCLUSION: HICS facilitated organizational improvements during the crisis response and generated opportunities to maintain specific coordination practices beyond the crisis. The prolonged implementation of HICS during the COVID-19 pandemic created challenges, including the disruption of the routine leadership structure. PRACTICAL IMPLICATIONS: Applying relational coordination and organizational mindfulness frameworks may allow hospitals to leverage communications and relationships within a high-stakes environment to improve service delivery.

Disparities in Pediatric Specialty Referral Scheduling and Completion.

OBJECTIVE: To estimate differences in scheduled and completed specialty referrals by race, ethnicity, language for care, and insurance type. STUDY DESIGN: We studied a retrospective cohort of 38 334 specialty referrals to a large children's hospital between March 2019 and March 2021. We included referrals for patients with primary care clinics within 5 miles of the hospital. We examined whether the odds of and time to scheduled and completed referrals differed by patient sociodemographic characteristics. RESULTS: Of all referrals, 62% were scheduled and 54% were completed. Referral completion rates were lower for patients with Black race (45%), Native Hawaiian/Pacific Islander race (48%), Spanish language (49%), and public insurance (47%). Odds of scheduled and completed referral were lower for Asian (aOR scheduled: 0.94, [95% CI: 0.89, 0.99]; aOR completed: 0.92 [0.87, 0.97]), Black (aOR scheduled: 0.86 [0.79, 0.94]; aOR completed: 0.80 [0.73, 0.87]), and publicly insured patients (aOR scheduled: 0.71 [0.66, 0.75]; aOR completed: 0.70 [0.66, 0.75]). Time to scheduled and completed referral was longer for Black (adjusted hazard ratio [aHR] scheduled: 0.93 [0.88, 0.98]; aHR completed: 0.93 [0.87, 0.99]) and publicly insured patients (aHR scheduled: 0.85 [0.82, 0.88]; aHR completed: 0.84 [0.80, 0.87]) and families with a language other than English (aHR scheduled: 0.66 [0.62, 0.70]; aHR completed: 0.92 [0.86, 0.99]). CONCLUSIONS: Within a geographically homogenous pediatric population, the odds and time to scheduled and completed specialty referrals differed by sociodemographic characteristics, suggesting the effects of discrimination. To improve access equity, health care organizations need clear and consistent referral workflows and more comprehensive metrics for access.

Burnout Among Hospitalists During the Early COVID-19 Pandemic: a National Mixed Methods Survey Study.

BACKGROUND  : Hospitalist physician stress was exacerbated by the pandemic, yet there have been no large scale studies of contributing factors. OBJECTIVE: Assess remediable components of burnout in hospitalists. PARTICIPANTS, STUDY DESIGN AND MEASURES: In this Coping with COVID study, we focused on assessment of stress factors among 1022 hospital-based clinicians surveyed between April to December 2020. We assessed variables previously associated with burnout (anxiety/depression due to COVID-19, work overload, fear of exposure or transmission, mission/purpose, childcare stress and feeling valued) on 4 point Likert scales, with results dichotomized with the top two categories meaning "present"; burnout was assessed with the Mini Z single item measure (top 3 choices = burnout). Quantitative analyses utilized multilevel logistic regression; qualitative analysis used inductive and deductive methods. These data informed a conceptual model. KEY RESULTS: Of 58,408 HCWs (median response rate 32%), 1022 were hospital-based clinicians (906 (89%) physicians; 449 (44%) female; 469 (46%) White); 46% of these hospital-based clinicians reported burnout. Work overload was associated with almost 5 times the odds of burnout (OR 4.9, 95% CIs 3.67, 6.85, p < 0.001), and those with anxiety or depression had 4 times the odds of burnout (OR 4.2, CIs 3.21, 7.12, p < 0.001), while those feeling valued had half the burnout odds (OR 0.43, CIs 0.31, 0.61, p < 0.001). Regression models estimated 42% of burnout variance was explained by these variables. In open-ended comments, leadership support was helpful, with "great leadership" represented by transparency, regular updates, and opportunities to ask questions. CONCLUSIONS: In this national study of hospital medicine, 2 variables were significantly related to burnout (workload and mental health) while two variables (feeling valued and leadership) were likely mitigators. These variables merit further investigation as means of reducing burnout in hospital medicine.

Intrapyloric Botulinum Toxin Injection for Refractory Nausea and Vomiting in Pediatric Patients.

OBJECTIVES: Chronic nausea and vomiting may be associated with gastroparesis or other conditions. Poor mechanistic understanding of symptoms often precludes targeted therapy. Numerous case series suggest that intrapyloric botulinum toxin injection (IPBI) may be beneficial in treating gastroparesis and dyspepsia in children. We hypothesized that nausea, vomiting, and other symptoms, independent of gastroparesis, may improve with IPBI. We sought to identify gastric emptying (GE) and manometric patterns in IPBI responders versus nonresponders. METHODS: Electronic records of 25 pediatric patients who received IPBI for refractory nausea, vomiting, or both were retrospectively reviewed. We assessed symptom improvement post-IPBI and compared symptoms, GE, and antroduodenal manometry (ADM) findings between IPBI responders and nonresponders. RESULTS: At least one major symptom improved in 19 patients (76%) after IPBI. Of 22 patients completing a GE study, 14 had delayed GE with no significant difference between IPBI responders and nonresponders. Of 22 patients who underwent ADM, 18 had normal fasting peristalsis, 5 had postprandial antral hypomotility, 4 had neuropathic findings, and 19 had pylorospasm. IPBI responders, compared to nonresponders, demonstrated higher antral pressures with feeding ( P < 0.0001) and shorter duration of pylorospasm ( P = 0.0036). Antral pressures did not differ significantly with fasting or following motilin agonists. CONCLUSIONS: Our findings suggest that IPBI may have therapeutic benefit in pediatric patients with chronic nausea and/or vomiting, independent of gastroparesis. ADM findings of intact antral peristalsis and elevated antral pressures, in conjunction with efficacy of IPBI, support pyloric non-relaxation as a potential contributor to nausea and/or vomiting in pediatric patients.

Feasibility and acceptability of at-home play kits for middle school physical activity promotion during the COVID-19 pandemic.

BACKGROUND: Schools are central to providing opportunities for youth physical activity (PA), however such opportunities were limited during the COVID-19 pandemic. Identifying feasible, acceptable, and effective approaches for school-based PA promotion amid pandemic-related barriers can inform resource allocation efforts in future circumstances necessitating remote instruction. The aims of this study were to: (1) describe the pragmatic, stakeholder-engaged and theory-informed approach employed to adapt one school's PA promotion efforts to pandemic restrictions, leading to the creation of at-home "play kits" for students, and (2) assess the feasibility, acceptability, and preliminary effectiveness of this intervention. METHODS: Intervention activities occurred in one middle school (enrollment: 847) located in a Federal Opportunity Zone in the Seattle, WA area, with control data from a nearby middle school (enrollment: 640). Students at the intervention school were eligible to receive a play kit during the quarter they were enrolled in physical education (PE) class. Student surveys were completed across the school year (n = 1076), with a primary outcome of days/week that the student engaged in ≥ 60 min of PA. Qualitative interviews (n = 25) were conducted with students, staff, parents, and community partners, and focused on play kit acceptability and feasibility. RESULTS: During remote learning play kits were received by 58% of eligible students. Among students at the intervention school only, students actively enrolled in PE (versus not enrolled) reported significantly more days with ≥ 60 min of PA in the previous week, however the comparison between schools was not statistically significant. In qualitative interviews, most students reported the play kit motivated them to participate in PA, gave them activity ideas, and made virtual PE more enjoyable. Student-reported barriers to using play kits included space (indoors and outdoors), requirements to be quiet at home, necessary but unavailable adult supervision, lack of companions to play outdoors, and inclement weather. CONCLUSIONS: A pre-existing community organization-school partnership lent itself to a rapid response to meet student needs at a time when school staff and resources were highly constrained. The intervention developed through this collaborative response-play kits-has potential to support middle school PA during future pandemics or other conditions that necessitate remote schooling, however modifications to the intervention concept and implementation strategy may be needed to improve reach and effectiveness.

Validating within-limb calibrated algorithm using a smartphone attached infrared thermal camera for detection of arthritis in children.

OBJECTIVES: To determine the impact of physical activity on temperature after within-limb calibration (TAWiC) measures and their reproducibility. To determine if thermal imaging from a smartphone attached thermal camera is comparable to thermal imaging using a handheld thermal camera for detection of arthritis in children. METHODS: Children without symptoms were enrolled to the "asymptomatic exercise cohort", and received infrared imaging, using a standard handheld camera, after initial resting period, after activity, and after second resting period. Children seen in the rheumatology clinic with knee pain were enrolled into the "symptomatic knee pain cohort" and received imaging with both the smartphone-attached and handheld cameras before a routine clinical exam. TAWiC was defined as the temperature differences between joint and ipsilateral mid-tibia as the main readout for arthritis detection. RESULTS: The asymptomatic exercise cohort demonstrated notable changes in absolute and TAWiC temperatures collected by thermal imaging after physical activity, and temperatures did not consistently return to pre-activity levels after a second period of rest. The 95th TAWiC from anterior view were, resting one -0.1 C (0.5), activity -0.7 C (0.5), resting two -0.2 C (0.6) (resting 1 vs resting 2, p-value = 0.13). In the symptomatic knee pain cohort, the smartphone attached and handheld thermal cameras performed similarly in regards to detection of joint inflammation and evaluation of joint temperature using the TAWiC algorithm, with high sensitivity of 80% (55.2-100.0%) and specificity of 84.2% (76.0-92.4%) in the anterior knee view when compared with the gold standard joint exam performed by a pediatric rheumatologist. The mean 95th TAWiC temperature difference between the two cameras was -0.1 C (-0.1 to 0.0) (p = 0.0004). CONCLUSIONS: This study showed continued validity of the TAWiC algorithm across two distinct thermal camera platforms and demonstrates promise for improved accessibility and utility of this technology for arthritis detection.

What do rural young people want from their mental health service.

INTRODUCTION: Rural young people have high rates of mental illness and low rates of help-seeking making it crucial to extend research about service improvement in rural and remote Australia. OBJECTIVE: To describe what rural young people want from their headspace service, and what rural headspace clinicians understand they provide. DESIGN: This study used a qualitative methodology with reflexive thematic analysis to analyse participant interviews and systematically derive common themes. FINDINGS: Thirteen participants were interviewed comprising young people aged 16 to 18 years who had accessed one of three rural headspace services, together with clinicians working in those services. Key themes for both young people and clinicians comprised accessibility, flexibility, engagement, safety, youth-focus, and evidence-based treatment although there were some differences of emphasis amongst themes. There was also an additional theme for young people of awareness, and for clinicians of caring. DISCUSSION: The results supported that what young people were seeking was largely consistent with what headspace clinicians were providing. There were however some specific issues relevant to service provision in a rural context such as increased awareness of services, the need to focus on evidenced based interventions, and better promotion in schools and the local community. Service gaps such as unmet needs for young people with higher risk who might fall outside of agency requirements were also identified. CONCLUSION: Results of this study help inform better service delivery and increased awareness for mental health of young people in rural communities to improve access and outcomes.

Identifying odds of bloodstream infection in repaired silastic central venous catheters in a pediatric population.

Background: Silicone central venous catheters (CVCs) that weaken or rupture are reparable using a commercial repair kit. A literature review exploring bloodstream infections in repaired CVCs identified many findings indicating low or no increased risk of infection. This study aimed to understand pediatric patients' risk of bloodstream infection with repaired Hickman or Broviac catheters. Methods: A matched retrospective case-control study examined central line-associated bloodstream infection (CLABSI) or bacteremia in two separately matched cohorts of patients with silicone-type catheters. Controls were patients with CVCs selected from 2016 to 2019 and were matched to cases based on age group (older or younger than 3 years). Conditional logistic regression models calculated odds ratios (OR), with 95% confidence intervals (CI) representing the odds of a line repair occurring 30 days before an event among cases versus controls. Results: In 61 CLABSI cases and 104 controls, the OR of exposure to a line repair was 0.43; 95% CI, 0.05-3.87, P = 0.45. In comparing 49 bacteremia cases to 109 controls, the OR of exposure to a line repair was 6.69; 95% CI, 0.69-8, P = 0.10. Conclusions: The frequency of CVC repair was relatively low. Associations between repair and infection were not detected in either cohort; however, odds of line repair exposure appeared to be higher in bacteremia cases (a trend not observed in the CLABSI cohort). More extensive studies examining the demographic and clinical characteristics of the CVC repair population will be critical for improving outcomes.

The impact of physician leadership development on behaviour and work-related changes.

In this article, we present findings from a retrospective survey of 117 physician leadership development program graduates at the Sauder School of Business at the University of British Columbia in Vancouver. The survey was designed to assess how the program contributed to graduates' leadership development, specifically in terms of behaviour change and work-related changes. The themes resulting from the analysis of the open-ended questions reflected that the program led to changes in graduates' leadership behaviour and their ability to lead change in their respective organizations. The study highlighted the benefits of investment in training for physician leaders to advance transformation and improvement initiatives in a changing world.

Perceptions of patient disease burden and management approaches in systemic mastocytosis: Results of the TouchStone Healthcare Provider Survey.

BACKGROUND: Systemic mastocytosis (SM) is a rare clonal neoplasm driven by the KIT D816V mutation and has a broad range of debilitating symptoms. In this study, the authors evaluated SM disease perceptions and management strategies among US health care providers (HCPs). METHODS: Hematologist/oncologist (H/O) HCPs and allergist/immunologist (A/I) HCPs who were treating four or more patients with SM completed an online, 51-item TouchStone HCP Survey, which queried provider characteristics, perceptions of disease burden, and current management. Descriptive analyses by specialty and SM subtype were performed. RESULTS: Of 304 HCPs contacted, 111 (37%) met eligibility criteria, including 51% A/I specialists and 49% H/O specialists. On average, the HCPs had 14 years of practice experience and cared for 20 patients with SM. A/I HCPs saw more patients with nonadvanced SM (78%) compared with H/O HCPs, who saw similar proportions of patients with nonadvanced SM (54%) and advanced SM (46%). HCPs reported testing 75% of patients for the KIT D816V mutation and found an estimated prevalence of 47%. On average, HCPs estimated 8 months between symptom onset and SM diagnosis. HCPs reported that 62% of patients with indolent SM felt depressed or discouraged because of symptoms. In terms of treatment goals for SM, both types of specialists prioritized symptom improvement for nonadvanced SM and improved survival for advanced SM while also prioritizing improving patient quality of life. CONCLUSIONS: Both A/I and H/O specialists highlighted unmet needs for patients with SM. The HCPs surveyed reported a lower rate of KIT D816V mutations and a perceived shorter time between symptom onset and SM diagnosis compared with published estimates. LAY SUMMARY: Specialists treating systemic mastocytosis (SM) completed a 51-item questionnaire about their clinical practices and perceptions of disease impact. The study included 111 hematology, oncology, allergy, and immunology physicians. Physicians reported that most patients had nonadvanced disease, yet SM symptoms significantly disrupted their patients' lives. Physicians estimated that SM is diagnosed within months of symptom onset, in contrast with published reports of years' long delays reported by patients with SM. This study identified unmet needs that can inform educational and patient management priorities in this rare disease.

Patient-reported outcomes among patients with systemic mastocytosis in routine clinical practice: Results of the TouchStone SM Patient Survey.

BACKGROUND: Systemic mastocytosis (SM) is a rare clonal neoplasm driven by KIT D816V and other mutations. Data were collected from the patient perspective on disease burden and included an SM-specific symptom assessment tool. METHODS: US adults aged 18 years and older with a self-reported SM diagnosis completed an online TouchStone SM Patient Survey of 100 items, including the 12-item Short-Form Health Survey, the Indolent Systemic Mastocytosis Symptom Assessment Form, and the Work Productivity and Activity Impairment Questionnaire, as well as questions about SM diagnosis, the impact of SM on daily activities, work impairment, and health care use. The results were analyzed using descriptive statistics. RESULTS: Fifty-six individuals completed the survey (89% women; median age, 48 years; mean time since diagnosis, 6.7 years), reporting indolent SM (66%), aggressive SM (9%), smoldering SM (5%), and unknown SM subtype (18%). Over a 1-year recall, respondents reported seeking emergency care for anaphylaxis (30%) and taking three or more prescription medications (52%) for SM. Over one half of patients (54%) reduced their work hours because of SM, and 64% avoided leaving home because of symptoms. A majority of respondents (93%) had experienced ≥10 SM-related symptoms, noting that the most bothersome were anaphylactic episodes (18%), abdominal/stomach pain (16%), diarrhea/loose stools (13%), and fatigue (11%). Whereas an Indolent Systemic Mastocytosis Symptom Assessment Form-derived total symptom score of 28 is used to indicate moderate-to-severe symptoms, the mean total symptom score was 52.7. Mental and physical component summary scores from the 12-item Short-Form Health Survey were below population norms. CONCLUSIONS: Patients who were surveyed reported substantial symptom burden and unmet needs because of SM, as evidenced by seeking emergency care and reporting bothersome symptoms, poor quality of life, and reduced work hours and productivity. LAY SUMMARY: The objective of this research was to understand the burden and unmet needs in the rare disease of systemic mastocytosis (SM) to guide future care. Fifty-six patients completed an online survey containing questions about their diagnosis, medications, health care use, quality of life, and SM symptoms. The results demonstrated that SM is associated with severe and burdensome symptoms, anaphylactic events, emergency department visits, use of multiple medications, reduced ability to work, and poor physical and psychological quality of life. These findings suggest the need for future advances to address unmet needs in patients affected by SM.

Psoriasis rate is increased by the exposure to TNF inhibition in children with JIA.

OBJECTIVE: We aimed to investigate the relationship between tumour necrosis factor inhibitors (TNFi) therapy and the onset of new psoriasis in children with juvenile idiopathic arthritis (JIA) using Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry data. METHODS: De-identified data were obtained from the CARRA Registry. Patients with inflammatory bowel disease or psoriasis documented on or prior to JIA diagnosis date or with incomplete data were excluded. Exposure to TNFi was categorised as: (1) ever use; (2) current use or (3) first use only. Adjusted HRs (aHRs) were calculated between exposed and unexposed groups adjusted for methotrexate exposure, sex, race, family history of psoriasis and initial JIA category. RESULTS: A total of 8225 patients were included with a median follow-up of 3.9 years. Over half of the patients were prescribed TNFi (n=4437, 54%). The aHR of new onset of psoriasis after ever exposure to TNFi was 2.93 (2.15 to 3.98). The incidence rate of psoriasis was the highest in children ever receiving and actively receiving adalimumab. Ever concurrent methotrexate use (HR 0.45, 0.29 to 0.69) was associated with lower risk. CONCLUSION: In a large prospective JIA patient registry, we observed a nearly threefold increased risk of psoriasis after TNFi exposureCite Now.

Comparative Analysis of Bacillus cereus Group Isolates' Resistance Using Disk Diffusion and Broth Microdilution and the Correlation between Antimicrobial Resistance Phenotypes and Genotypes.

Bacillus cereus group isolates (n = 85) were screened for phenotypic resistance to 18 antibiotics using broth microdilution and CLSI M45 Bacillus spp. breakpoints. The susceptibility to 9 out of 18 antibiotics was also tested using disk diffusion method and M100 Staphylococcus spp. breakpoints when available. Overall, a high prevalence of susceptibility to clinically relevant antibiotics was identified using broth microdilution. For most tested antibiotics, a poor correlation was found between zones of inhibition and MICs. Using the broth microdilution results as a reference for comparison, we identified high error rates and low categorical agreement between results produced using disk diffusion and broth microdilution for the seven tested antibiotics with defined breakpoints. This suggests that disk diffusion should be avoided for AST of B. cereus group isolates. Further, we detected antimicrobial resistance genes with ARIBA and ABRIcate to calculate the sensitivity and specificity for predicting phenotypic resistance determined using broth microdilution based on the presence of detected antimicrobial resistance genes (ARGs). ARGs with poor sensitivity and high specificity included rph (rifampicin, 0%, 93%), mph (erythromycin, 0%, 99%), bla1 (penicillin, 29%, 100%), and blaZ (penicillin, 56%, 100%). Compared to penicillin, bla1 and blaZ had lower specificity for the prediction of ampicillin resistance. Overall, none of the ARGs had both high sensitivity and specificity, suggesting the need for further study of the mechanisms underlying phenotypic antimicrobial resistance in the B. cereus group. IMPORTANCE Bacillus cereus group includes human pathogens that can cause severe infections requiring antibiotic treatment. Screening of environmental and food isolates for antimicrobial resistance can provide insight into what antibiotics may be more effective therapeutic options based on the lower prevalence of resistance. Currently, the comparison of antimicrobial susceptibility testing results using the disk diffusion method is complicated by the fact that many previous studies have used Staphylococcus spp. breakpoints to interpret their results. In this study, we compared the results of disk diffusion interpreted using the Staphylococcus spp. breakpoints against the results of broth microdilution interpreted using Bacillus spp. breakpoints. We demonstrated that the disk diffusion method does not produce reliable results for B. cereus group isolates and should therefore be avoided. This study also provides new insight into poor associations between the presence of antimicrobial resistance genes and resistance phenotypes for the B. cereus group.

The Impact of COVID-19 on Primary Care Teamwork: a Qualitative Study in Two States.

BACKGROUND: The emergence of coronavirus disease 2019 (COVID-19) disrupted how primary care physicians (PCPs) and their staff delivered team-based care. OBJECTIVE: To explore PCPs' perspectives about the impact of stay-at-home orders and the increased use of telemedicine on interactions and working relationships with their practice staff during the first 9 months of the pandemic. DESIGN: Qualitative research. PARTICIPANTS: Participants included PCPs from family and community medicine, general internal medicine, and pediatrics. APPROACH: One-on-one, semi-structured video interviews with 42 PCPs were conducted between July and December 2020. Physicians were recruited from 30 primary care practices in Massachusetts and Ohio using a combination of purposeful, convenience, and snowball sampling. Interview questions focused on work changes and work relationships with other staff members during the pandemic as well as their experiences delivering telemedicine. All interviews were audio-recorded, transcribed verbatim, and coded using deductive and inductive approaches. KEY RESULTS: Across respondents and states, the context of the pandemic was reported to have four major impacts on primary care teamwork: (1) staff members' roles were repurposed to support telemedicine; (2) PCPs felt disconnected from staff; (3) PCPs had difficulty communicating with staff; and (4) many PCPs were demoralized during the pandemic. CONCLUSIONS: The lack of in-person contact, and less synchronous communication, negatively impacted PCP-staff teamwork and morale during the pandemic. These challenges further highlight the importance for practice leaders to recognize and attend to clinicians' relational and work-related needs as the pandemic continues.