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Background. Gunshot injuries from interpersonal violence are a major cause of mortality. In South Africa (SA), the Firearms Control Act of 2000 sought to address firearm violence by removing illegally owned firearms from circulation, stricter regulation of legally owned firearms, and stricter licensing requirements. Over the last few years, varied implementation of the Act and police corruption have increased firearm availability.Objectives. To investigate whether changes in firearm availability in SA were associated with changes in firearm homicide rates.Methods. This was a retrospective time trend study (1994 - 2013) using postmortem data. Time trends of firearm and non-firearm homicide rates were analysed with generalised linear models. Distinct time periods for temporal trends were assigned based on a priori assumptions regarding changes in the availability of firearms.Results. Firearm and non-firearm homicide rates adjusted for age, sex and race exhibited different temporal trends. Non-firearm homicide rates either decreased or remained stable over the entire period. Firearm homicide increased at 13% annually from 1994 through 2000, and decreased by 15% from 2003 through 2006, corresponding with changes in firearm availability in 2001, 2003, 2007 and 2011. A 21% annual increase in firearm homicide after 2010 coincided with police fast-tracking new firearm licence applications. Cape Town’s coloured population experienced a significantly greater increase than other population groups following additional exposure to illegal firearms from 2007.Conclusions. The strong association between firearm availability and homicide, and the reversal of a decreasing firearm homicide trend during a period of lax enforcement, provide further support for the association between reduced firearm homicide and stricter regulation.Â

Background: Although crackles on chest auscultation represent a fundamental component of the diagnostic suspect for fibrotic interstitial lung disease (ILD), their reliability has not been properly studied. We assessed the agreement among respiratory physicians on the presence and changes over time of audible crackles collected in a prospective longitudinal cohort of patients with fibrotic ILD., Methods: Lung sounds were digitally recorded at baseline and after 12 months at eight anatomical sites. Nine respiratory physicians blindly assessed randomized couples of recordings obtained from the same anatomical site at different timepoints. The physicians indicated the presence of crackles in individual recordings and which recording from each couple eventually had more intense crackles. Fleiss' kappa coefficient was used to measure inter- and intra-rater agreement., Results: Fifty-two patients, mostly with a diagnosis of IPF (n = 40, 76.9%) were prospectively enrolled between October 2019 and May 2021. The final acoustic dataset included 702 single recordings, corresponding to 351 couples of recordings from baseline and 12-months timepoints. Kappa coefficient was 0.57 (95% CI 0.55-0.58) for the presence of crackles and 0.42 (95% CI 0.41-0.43) for acoustic change. Intra-rater agreement, measured for three respiratory physicians on three repeated assessments, ranged from good to excellent for the presence of crackles (κ = 0.87, κ = 0.86, κ = 0.79), and from moderate to good for acoustic change (κ = 0.75, κ = 0.76, κ = 0.57)., Conclusions: Agreement between respiratory physicians for the presence of crackles and acoustic change was acceptable, suggesting that crackles represent a reliable acoustic finding in patients with fibrotic ILD. Their role as a lung-derived indicator of disease progression merits further studies., (© 2024. The Author(s).)

Background and Aim: Familial Pulmonary Fibrosis (FPF) is an emerging group of interstitial lung diseases (ILDs) caused by mutations mainly involving "telomere-related genes" and "surfactant-related genes". Although, in 2023, European Respiratory Society proposed a statement for FPFs management, these still remain a burden. Our work aimed to evaluate the management and impact of FPF in three Italian different medical settings: University Hospitals (UHs), non-University Hospitals (N-UHs) and outpatient clinics., Methods: This survey was created by ILDs Study Group Società Italiana di Pneumologia/ Italian Respiratory Society (SIP-IRS) and diffused via email to all SIP-IRS members. The descriptive statistical analysis was conducted through GraphPad Prism software (version 8.0).  Results: Twenty participants replied to the survey, of which 65% (13/20) worked at UH while the remaining 25% (6/20) and 5% (1/20) worked at N-UH and outpatient clinics, respectively. Centers with, at least, 150 ILD patients visits/year followed a higher number of FPF patients, regardless of University affiliation (p=0.0046). Despite significant discrepancies in genetic testing and availability of counselling were registered, no statistically significant differences in patients' anamnesis assessment were observed between UHs and N-UHs (p=0.4192 and p=0.6525). However, there were relevant differences in the number of FPF patients undergoing genetic assessment in the Centers with Genetics Lab or Unit inside the Hospital (p=0.0253). There was no consensus regarding the impact of FPF diagnosis on lung transplantation and screening of asymptomatic relatives. Similarly, no differences were reported in antifibrotic prescriptions between UHs and N-UHs. Although the typical UIP pattern was the most common radiological pattern observed in FPF patients, there were no differences in the prevalence of histopathological patterns between UH and N-UH., Conclusions: Improving pulmonologists' knowledge of the approach, diagnosis and management of FPF is a global medical topic. Scientific societies can provide significant support in raising physicians' awareness of this issue.

Background: Microcalcifications are acknowledged as a malignancy risk factor in multiple cancers. However, the prevalence and association of intrathoracic lymph node (ILN) calcifications with malignancy remain unexplored., Methods: In this cross-sectional study, we enrolled patients with known/suspected malignancy and an indication for endosonography for diagnosis or ILN staging. We assessed the prevalence and pattern of calcified ILNs and the prevalence of malignancy in ILNs with and without calcifications. In addition, we evaluated the genomic profile and PD-L1 expression in lung cancer patients, stratifying them based on the presence or absence of ILN calcifications., Results: A total of 571 ILNs were sampled in 352 patients. Calcifications were detected in 85 (24.1%) patients and in 94 (16.5%) ILNs, with microcalcifications (78/94, 83%) being the predominant type. Compared with ILNs without calcifications (214/477, 44.9%), the prevalence of malignancy was higher in ILNs with microcalcifications (73/78, 93.6%; P<0.0001) but not in those with macrocalcifications (7/16, 43.7%; P=0.93). In patients with lung cancer, the high prevalence of metastatic involvement in ILNs displaying microcalcifications was independent of lymph node size (< or >1 cm) and the clinical stage (advanced disease; cN2/N3 disease; cN0/N1 disease). The anaplastic lymphoma kinase (ALK) rearrangement was significantly more prevalent in patients with than in those without calcified ILNs (17.4% vs. 1.7%, P<0.001), and all of them exhibited microcalcifications., Conclusion: ILN microcalcifications are common in patients undergoing endosonography for suspected malignancy, and they are associated with a high prevalence of metastatic involvement and ALK rearrangement., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Idiopathic Pulmonary Fibrosis (IPF) is a progressive, irreversible, and fatal lung disease with unmet medical needs. Autotaxin (ATX) is an extracellular enzyme involved in the generation of lysophosphatidic acid (LPA). Preclinical and clinical data have suggested the ATX-LPAR signaling axis plays an important role in the pathogenesis and the progression of IPF., Areas Covered: The aim of this review is to provide an update on the available evidence on autotaxin inhibitors in IPF and further details on the ongoing clinical studies involving these molecules., Expert Opinion: The development of autotaxin inhibitors as a potential therapy for idiopathic pulmonary fibrosis has gained attention due to evidence of their involvement in the disease. Preclinical and early-phase clinical studies have explored these inhibitors' efficacy and safety, offering a novel approach in treating this disease. Combining autotaxin inhibitors with existing anti-fibrotic agents is considered for enhanced therapeutic effects. Large phase III trials assessed Ziritaxestat but yielded disappointing results, highlighting the importance of long-term observation and clinical outcomes in clinical research. Patient stratification and personalized medicine are crucial, as pulmonary fibrosis is a heterogeneous disease. Ongoing research and collaboration are essential for this advancement.

Introduction: In the USA, an estimated 45% of veterans personally own firearms. Firearm access increases the risk of suicide, so suicide prevention efforts in the US Department of Defense (DoD) focus on lethal means safety, including reducing firearm access. Spouse input may enhance effective messaging and intervention delivery of lethal means safety. This study used qualitative methods to explore the perspectives of military spouses or partners on personal firearm storage, including at-home decisions, on-base storage and existing messaging from the DoD., Materials and Methods: Qualitative data were obtained using 1:1 interviews and focus groups with spouses/partners of US military service members (active duty, Reserve, National Guard, recently separated from the military) and representatives from military support organisations. Sessions focused on personal firearm storage (at home or on military installations) and military messaging around secure firearm storage and firearm suicide prevention. Data were analysed using a team-based, mixed deductive-inductive approach., Results: Across 56 participants (August 2022-March 2023), the themes were variability in current home firearm storage and spousal participation in decision-making; uncertainty about firearm storage protocols on military installations; mixed awareness of secure firearm storage messaging from the military; and uncertainty about procedures or protocols for removing firearm access for an at-risk person., Conclusion: US military spouses are important messengers for firearm safety and suicide prevention, but they are currently underutilised. Tailored prevention campaigns should consider spousal dynamics and incorporate education about installation procedures., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The U.S. DoD has identified firearm suicide prevention as a key operational priority. One vital approach to addressing firearm suicides is through promoting lethal means safety, which involves the voluntary use of secure storage for personally owned firearms and/or temporarily moving firearms out of the home during risk periods. Despite promising approaches to lethal means safety, critical gaps remain in research, programming, and communication among and across scientists, DoD programmatic leaders, front-line commanders, and service members. To address these gaps, the first-ever national "Firearm Suicide Prevention in the Military: Messaging and Interventions Summit" was convened in June 2022, bringing together DoD personnel and researchers with expertise in firearm suicide prevention and lethal means safety. The Summit identified 10 recommendations to enhance firearm suicide prevention messaging and interventions in the U.S. military, including (1) repeal or amend prohibitions on questioning service members about personal firearms; (2) develop, examine, and use common language for firearm injury prevention; (3) implement a universal approach to training on comprehensive firearm injury prevention; (4) encourage leadership across disciplines and levels; (5) aim for broad culture change; (6) support innovative research; (7) consider various outcome measures; (8) promote "cultural competence" for better communication; (9) reduce territorialism; and (10) develop creative partnerships. Ultimately, these recommendations can facilitate productive partnerships with a shared goal: to develop, test, and implement strategies that standardize lethal means safety and reduce firearm suicides and other firearm injuries or harm among service members., (© The Association of Military Surgeons of the United States 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The use of pirfenidone and nintedanib in treating Idiopathic Pulmonary Fibrosis (IPF) has shown significant slowing down of the progressive functional decline in these patients. In recent times, antibody-based therapies with precise molecular targets have also been explored as alternative treatments to IPF., Areas Covered: This review aims to summarize the available updates regarding monoclonal antibodies that have been tested in IPF. The drugs describedare developed to antagonize inflammation,immunity pathways and fibrogenesis. Currently, the anti-CTGF pamrevlumab has demonstrated a significant reduction in functional decline as compared to placebo and is undergoing the last stages of phase 3 trial., Expert Opinion: Although antibody-based therapies for IPF have had unsatisfactory results in most trials in the last few years, the pursuit of therapeutic development in this field should continue to deliver a more personalized treatment approach in the future, which is currently not available with existing treatment options. However, several molecules are still under study and some have shown encouraging results in the early phases of clinical trials. Future investigations need to be more carefully designed and valid predictive markers of response to treatment should be used to enhance the effectiveness of future trials.

Background: Bronchial premalignant lesions (PMLs) are composed primarily of cells resembling basal epithelial cells of the airways, which through poorly understood mechanisms have the potential to progress to lung squamous cell carcinoma (LUSC). Despite ongoing efforts that have mapped gene expression and cell diversity across bronchial PML pathologies, signaling and transcriptional events driving malignancy are poorly understood. Evidence has suggested key roles for the Hippo pathway effectors YAP and TAZ and associated TEAD and TP63 transcription factor families in bronchial basal cell biology and LUSC. In this study we examine the functional association of YAP/TAZ, TEADs and TP63 in bronchial epithelial cells and PMLs., Methods: We performed RNA-seq in primary human bronchial epithelial cells following small interfering RNA (siRNA)-mediated depletion of YAP/TAZ, TEADs or TP63, and combined these data with ChIP-seq analysis of these factors. Directly activated or repressed genes were identified and overlapping genes were profiled across gene expression data obtained from progressive or regressive human PMLs and across lung single cell RNA-seq data sets., Results: Analysis of genes regulated by YAP/TAZ, TEADs, and TP63 in human bronchial epithelial cells revealed a converged transcriptional network that is strongly associated with the pathological progression of bronchial PMLs. Our observations suggest that YAP/TAZ-TEAD-TP63 associate to cooperatively promote basal epithelial cell proliferation and repress signals associated with interferon responses and immune cell communication. Directly repressed targets we identified include the MHC Class II transactivator CIITA, which is repressed in progressive PMLs and associates with adaptive immune responses in the lung. Our findings provide molecular insight into the control of gene expression events driving PML progression, including those contributing to immune evasion, offering potential new avenues for lung cancer interception., Conclusions: Our study identifies important gene regulatory functions for YAP/TAZ-TEAD-TP63 in the early stages of lung cancer development, which notably includes immune-suppressive roles, and suggest that an assessment of the activity of this transcriptional complex may offer a means to identify immune evasive bronchial PMLs and serve as a potential therapeutic target., (© 2023. The Author(s).)

Introduction: The two available therapies for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintedanib, slow down but do not halt IPF progression. Therefore, several agents with specific molecular targets have been recently investigated to find a cure for IPF. Phosphodiesterase 4 (PDE4) inhibition is known for its anti-inflammatory and antifibrotic properties. BI 1015550, an oral preferential inhibitor of the isoform PDE4B, could express complementary activity to current therapies in IPF and other forms of progressive pulmonary fibrosis., Areas Covered: In this review, we first provide an overview toof the current IPF treatment market, followed by the description of pharmacokinetics and pharmacodynamics of BI 1015550. The main preclinical and early clinical evidence on BI 1015550 is then described, as well as its potential as an IPF treatment., Expert Opinion: Oral treatment with BI 1015550 was shown to stabilize lung function as compared to placebo over 12 weeks, both among patients with and without background antifibrotic use, with an acceptable safety profile in a phase 2 trial, and a phase 3 trial has been initiated. To date, this represents to date the largest effect size for an IPF investigational drug tested in a phase 2 trial with the shortest duration.

Introduction: Telemetry is ubiquitous in many hospitals despite widely acknowledged limitations, waste, and potential harm associated with inappropriate use. To curb overuse, guidelines such as the 2017 American Heart Association/American College of Cardiology (AHA/ACC) continuous telemetry monitoring practice standards have outlined appropriate telemetry use standards. This study aimed to perform two "plan-do-study-act" (PDSA) cycles and assess whether a nursing (RN)-driven checklist addressing appropriate telemetry use, combined with just-in-time education delivered via an electronic health record (EHR) order set modification, was efficacious in reducing inappropriate telemetry use within a level 1a Veterans Health Administration hospital., Methods: This is a quality improvement intervention study that took place between March 2019 and August 2020. Three cohorts were sequentially studied: a control cohort without any intervention (n = 100), a cohort with only the RN-driven checklist (n = 100), and a cohort with both the RN-driven checklist and an EHR order set modification that provided just-in-time education about telemetry indications (n = 100). Telemetry records were reviewed by a physician to determine indication, duration for each telemetry order, and appropriateness. An order was deemed "appropriate" if it met AHA/ACC classification grade I (telemetry recommended) or IIa/b (telemetry may be considered) and "inappropriate" if it fell under class III (telemetry not recommended). Data were compared between the control cohort and the two intervention cohorts, as well as between intervention cohorts, using Pearson chi-square analysis. A p-value < 0.05 was considered statistically significant., Results: Within the control group, 37% of telemetry orders were deemed inappropriate. After implementation of the RN checklist, a non-statistically significant lower proportion (26%) of orders was deemed inappropriate (p = 0.09). Implementation of the RN checklist, along with the EHR order set, was associated with a significantly lower proportion of inappropriate orders (17%) in comparison to the control cohort (p = 0.001) but not in comparison to the RN checklist cohort (p = 0.12). There was no significant difference in the duration of telemetry use across cohorts., Conclusions: An RN-driven checklist and EHR telemetry order set modification were associated with a decrease in inappropriate telemetry use from 37% to 17%. By prompting the review of telemetry orders via a daily nursing checklist reviewed during bedside interdisciplinary rounds, clinicians received reinforcement regarding appropriate telemetry indications. This education was strengthened by the just-in-time training provided via the EHR order set., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Knees et al.)

Background: Diabetes self-management education and support (DSMES) is a crucial component of diabetes care associated with improved clinical, psychosocial, and behavioral outcomes. The American Association of Diabetes Care and Education Specialists, the American Diabetes Association, and the American Academy of Family Physicians all recommend DSMES yet accessing linguistically and culturally appropriate DSMES is challenging in rural areas. The Diabetes One-Day (D1D) program is an established DSMES group intervention that has not been adapted or evaluated in rural communities., Objective: The specific aims of this paper are (1) to adapt the existing D1D program for use in rural communities, called rural D1D (R-D1D); and (2) to conduct a patient-level randomized controlled trial to examine the effects of R-D1D and standard patient education, guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework., Methods: This is a protocol for a pilot type II hybrid implementation-effectiveness trial of a culturally adapted virtual DSMES program for rural populations, R-D1D. We will use Boot Camp Translation, a process grounded in the principles of community-based participatory research, to adapt an existing DSMES program for rural populations, in both English and Spanish. Participants at 2 rural primary care clinics (4 cohorts of N=16 plus care partners, 2 in English and 2 in Spanish) will be randomized to the intervention or standard education control. The evaluation is guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework. Patient-level effectiveness outcomes (hemoglobin A 1c , diabetes distress, and diabetes self-care behaviors) will be assessed using patient-reported outcomes measures and a home A 1c test kit. Practice-level and patient-level acceptability and feasibility will be assessed using surveys and interviews., Results: This study is supported by the National Institute of Nursing. The study procedures were approved, and the adaptation processes have been completed. Recruitment and enrollment started in July 2021., Conclusions: To our knowledge, this will be the first study to evaluate both effectiveness and implementation outcomes for virtually delivered DSMES, culturally adapted for rural populations. This research has implications for delivery to other rural locations where access to specialty diabetes care is limited., Trial Registration: ClinicalTrials.gov NCT04600622; https://clinicaltrials.gov/ct2/show/NCT04600622., International Registered Report Identifier (irrid): DERR1-10.2196/34255., (©Michelle L Litchman, Bethany M Kwan, Linda Zittleman, Juliana Simonetti, Eli Iacob, Kristen Curcija, Julie Neuberger, Gwen Latendress, Tamara K Oser. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 14.06.2022.)

Background: Over 34 million people in the United States have diabetes, with 1.5 million diagnosed every year. Diabetes self-management education and support (DSMES) is a crucial component of treatment to delay or prevent complications. Rural communities face many unique challenges in accessing DSMES, including geographic barriers and availability of DSMES programs that are culturally adapted to rural context., Objective: Boot Camp Translation (BCT) is an established approach to community-based participatory research used to translate complex clinical and scientific information into concepts, messages, and materials that are understandable, meaningful, and relevant to community members and patients. This study aimed to utilize BCT to adapt an existing DSMES program for delivery in rural primary care for English- and Spanish-speaking people with diabetes., Methods: The High Plains Research Network (HPRN) Community Advisory Council (C.A.C.) partnered with researchers at the University of Colorado and University of Utah to use BCT to aid in translating medical jargon and materials from an existing DSMES program, called "Diabetes One Day (D1D)." BCT consisted of 10 virtual meetings over a 6-month period among the C.A.C., which included 15 diverse community stakeholders. Both English-speaking and bilingual Spanish-English-speaking C.A.C. members were recruited to reflect the diversity of the rural communities in which the adapted program would be delivered., Results: The BCT process guided adaptations to D1D for use in rural settings (R-D1D). R-D1D adaptations reflect both content and delivery to assure that the intervention is appropriate and likely to be accepted by rural English- and Spanish-speaking people with diabetes. Additionally, BCT informed the design of recruitment and program materials and identification of recruitment venues. During the BCT process, the importance of tailoring materials to reflect culture differences in English- and Spanish-speaking patients was identified., Conclusions: BCT was an effective strategy for academic researchers to partner with rural community members to adapt an existing DSMES intervention for delivery in rural areas to both English- and Spanish-speaking patients with diabetes. Through BCT, adaptations to recruitment materials and methods, program content and delivery, and supplemental materials were developed. The need to culturally adapt Spanish materials with input from stakeholders rather than simply translate materials into Spanish was highlighted. The importance of increasing awareness of the connection between diabetes and depression or diabetes distress, adaptations to include local foods, and the importance of the relationship between people with diabetes and their primary care practices were identified., (©Tamara K Oser, Linda Zittleman, Kristen Curcija, Bethany Kwan, Shawnecca Burke, Sindy Gonzalez, Kelsey Huss, Marilee Johnson, Norah Sanchez, Julie Neuberger, Eli Iacob, Juliana Simonetti, Michelle Litchman. Originally published in JMIR Diabetes (https://diabetes.jmir.org), 10.06.2022.)

Novel approach of asthma includes personalised therapy involving specific immune pathways. We describe here a case of T2-high asthma in a 66-year-old woman treated with maximal inhaled therapy and inappropriate usage of oral corticosteroids showing poor symptoms control. Both anti-IgE and (omalizumab) and anti-interleukin (IL)-5 (mepolizumab) monoclonal antibodies treatments were prescribed without significant benefit. Add-on subcutaneous dupilumab, a monoclonal antibody directed against the IL-4 receptor subunit alpha, inhibiting signalling from both IL-4 and IL-13, proved to be an effective and safe medication to obtain rapid asthma control. Considering the previous lack of response to both anti-IgE and anti-eosinophilic strategies, we hypothesise that dupilumab upstream activity could exert different and more relevant effects than the simple inhibition of the two single downstream pathways. The current case highlights the need for a deeper analysis of biomolecular interactions in the framework of different asthma endotypes, to identify peculiar profiles associated with specific treatment responses., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The US Department of Veterans Affairs (VA) introduced electronic consultation (e-consult) to increase access to specialty care. The objective of this study was to understand perceptions of e-consults that may be relevant to increasing adoption in the VA., Methods: Deductive and inductive content analysis of semistructured qualitative telephone interviews with VA primary care practitioners (PCPs), specialists, and specialty division chiefs was performed. Participants were identified based on rates of e-consult in 2016 at the individual and facility level within primary care, hematology, cardiology, gastroenterology, and endocrinology. Interview guide development was informed by the Practical, Robust, Implementation, and Sustainability (PRISM) framework., Results: We interviewed 35 PCPs and 25 specialists working in 36 facilities. Four themes emerged across both PCPs and specialists: (1) e-consults are best suited for certain types of clinical questions; (2) high-quality e-consults include complete background information from the requesting clinician and clear diagnostic or treatment recommendations from the responding clinician; (3) PCPs and specialists perceive e-consults as a novel opportunity to provide efficient, transparent care; and (4) lack of awareness of e-consults hinders adoption despite obvious benefits., Conclusions: We identified themes that are informative for further adoption of high-quality e-consults in the VA. Educating PCPs and specialty practitioners about the benefits of e-consults, and providing support, such as lists of specialties available for e-consults at the facility are 2 such practices., Competing Interests: Author disclosures Dr. Ho is supported by research grants from NHLBI, VA HSR&D, and University of Colorado School of Medicine. He has a research agreement with Bristol-Myers Squibb administered by the University of Colorado. The authors report no other actual or potential conflicts of interest with regard to this article., (Copyright © 2022 Frontline Medical Communications Inc., Parsippany, NJ, USA.)

Objectives: Electronic consultations, or e-consults, between primary care providers and specialists have been shown to improve access to specialty care, shorten wait times, and reduce outpatient visits. The objective of this study was to evaluate differences in health care costs between patients who received an electronic specialty consultation and patients who received a face-to-face specialty consultation., Study Design: Retrospective cohort evaluation of patients who received a specialty consultation in the Veterans Health Administration during 2016., Methods: Patients who received an e-consult were matched 1:1 to patients who received a face-to-face consultation using propensity scores. Total, outpatient, and inpatient health care costs over 3 and 6 months following the specialty consultation were compared using a generalized linear model with a gamma distribution and log link., Results: e-Consults accounted for 1.8% (urology) to 9.6% (hematology) of specialty consultations, on average. Across 11 specialties, patients receiving an e-consult had significantly lower health care costs compared with patients receiving a face-to-face consultation, ranging from 3.6% (cardiology) to 30.7% (hematology) lower. This was largely driven by differences in outpatient costs. Patients receiving an e-consult had significantly lower outpatient costs for all specialties except cardiology, ranging from 6.9% (endocrinology) to 31.2% (hematology) lower. Three-month inpatient costs among those who received an e-consult were significantly lower only in cardiology (5.2%), nephrology (9.3%), pulmonary (13.0%), and gastroenterology (14.3%)., Conclusions: Electronic specialty consultations are a potential mechanism to reduce health care costs and promote the efficient use of health care resources.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the novel coronavirus disease 2019 (COVID-19) pandemic, which spread throughout the world. Acute hypoxemic respiratory failure is the most dangerous complication of COVID-19 pneumonia. To date, no specific therapeutic drugs or vaccines have been proven efficacious. Ventilatory support is still a significant challenge for physicians facing COVID-19. The mechanisms underlying hypoxemia in those patients are not fully understood, but a new physiopathology model has been proposed. Oxygen therapy should be delivered to patients with mild to moderate hypoxemia. More severe patients could benefit from other treatments (high-flow nasal cannula, noninvasive ventilation or intubation, and invasive ventilation). Given the rapid evolution of COVID-19, there has been a paucity of the high-quality data that typically inform clinical practice guidelines from professional societies, and a worldwide consensus is still lacking. This chapter aims to illustrate the potentials of ventilatory support as therapeutic options for adult and pediatric patients affected by COVID-19 pneumonia.

Importance: Electronic consultation (e-consultation) is increasingly being adopted to expand access to specialty care and reduce health care costs. Little is known about clinicians' perceptions of using e-consultations, which may be associated with program adoption., Objective: To identify perceptions of primary care clinicians in the US Veterans Health Administration (VHA) system about e-consultation and workload., Design, Setting, and Participants: A qualitative study using semistructured interviews was conducted from September 2017 through March 2018 in a national sample of VHA primary care clinics in the US. Participants were primary care clinicians who had at least 300 total patient encounters from July 2016 to June 2017, including at least 1 e-consultation request. A convenience sample of participants was recruited using email invitations. Deductive and inductive content analysis were used to identify themes. Data were analyzed from October 2017 to April 2018., Exposures: Use of e-consultation., Main Outcomes and Measures: Primary care clinician perspectives regarding e-consultation and their workload., Results: A total of 34 primary care clinicians enrolled working across 27 VHA clinical sites were included; 9 (26%) were between ages 40-49 years; 23 (68%) were female. Three themes were identified. First, the process of entering, tracking, and following up on e-consultations added a time burden to primary care clinicians. Second, e-consultation was perceived to shift diagnostic and follow-up responsibilities from specialists to primary care clinicians. Third, e-consultations were thought to improve the timeliness and quality of care provided despite a perceived increase in workload., Conclusions and Relevance: In this study, participants perceived e-consultation as valuable for patient care but also as an increase in their workload. Further work is warranted to quantify the workload increase on clinician burnout, job satisfaction, and turnover.

Introduction: The two available therapies for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintedanib, slow down but do not halt IPF progression. As such, in the last few years several agents with specific molecular targets have been investigated to find a cure forIPF. Pamrevlumab, a recombinant human antibody that binds to connective tissue growth factor (CTGF) has emerged as a potential therapy for IPF and has advanced to phase 3 clinical trials., Areas Covered: The authors offer a backdrop to the current IPF treatment market and describe the chemistry, pharmacokinetics and pharmacodynamics of pamrevlumab. They summarize the preclinical and early clinical evidence on pamrevlumab and propose ways of progressing this agent further as a potential IPF treatment., Expert Opinion: Pamrevlumab was effective and safe in patients in a placebo-controlled phase 2 trial, demonstrating its potential to become an alternative therapeutic option for IPF; however, the feasibility of intravenous administration in clinical practice may be a hurdle to its use as a first-line treatment. Further studies are necessary to assess its effects when administered with pirfenidone or nintedanib and this could open up a new era of combined therapeutic approaches for IPF.

Behavioral assays in the mouse can show marked differences between male and female animals of a given genotype. These differences identified in such preclinical studies may have important clinical implications. We recently made a mouse model with impaired presynaptic inhibition through Gβγ-SNARE signaling. Here, we examine the role of sexual dimorphism in the severity of the phenotypes of this model, the SNAP25Δ3 mouse. In males, we already reported that SNAP25Δ3 homozygotes demonstrated phenotypes in motor coordination, nociception, spatial memory and stress processing. We now report that while minimal sexually dimorphic effects were observed for the nociceptive, motor or memory phenotypes, large differences were observed in the stress-induced hyperthermia paradigm, with male SNAP25Δ3 homozygotes exhibiting an increase in body temperature subsequent to handling relative to wild-type littermates, while no such genotype-dependent effect was observed in females. This suggests sexually dimorphic mechanisms of Gβγ-SNARE signaling for stress processing or thermoregulation within the mouse. Second, we examined the effects of heterozygosity with respect to the SNAP25Δ3 mutation. Heterozygote SNAP25Δ3 animals were tested alongside homozygote and wild-type littermates in all of the aforementioned paradigms and displayed phenotypes similar to wild-type animals or an intermediate state. From this, we conclude that the SNAP25Δ3 mutation does not behave in an autosomal dominant manner, but rather displays incomplete dominance for many phenotypes., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Safe firearm storage is associated with lower risk of unintentional and intentionally self-inflicted firearm injuries among children and adolescents. Ten community-based firearm safety events were conducted across Washington state from 2015 to 2018. We sought to describe characteristics of event participants and assess whether presence and age of children in the household were associated with household firearm locking practices. We assessed demographic characteristics and baseline firearm storage behaviors of participants using a 13-item survey. Multivariable Poisson regression models were used to estimate prevalence ratios (PR) and corresponding confidence intervals (CI) for the association of presence and age of children in households with prevalence of storing a household firearm unlocked. Of 2956 participants, 58.3% were male and 57.9% lived with an individual under 18 years. Among the 89.8% participants living with firearms, 40.1% stored at least one firearm unlocked and 39.1% stored at least one firearm loaded. In adjusted analyses, there was no statistically significant difference in prevalence of storing a household firearm unlocked between those living with no children (reference group) and those living with a child <11 years (PR = 0.91; 95% CI: 0.80,1.04), or a child aged 11-18 years (PR = 0.94; 95% CI: 0.81,1.09). A high proportion of participants stored a firearm unlocked or loaded at home and neither living with young children nor adolescents was associated with safe locking practices. In comparison with firearm safety interventions conducted in clinic settings, a majority of the participants in these community-based interventions were male and owned firearms., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Premature mortality observed among the mentally ill is largely attributable to chronic illnesses. Veterans seen within Veterans Affairs (VA) have a higher prevalence of mental illness than the general population but there is limited investigation into the common causes of death of Veterans with mental illnesses., Objective: To characterize the life expectancy of mentally ill Veterans seen in VA primary care, and to determine the most death rates of combinations of mental illnesses., Design: Retrospective cohort study of decedents., Setting/participants: Veterans seen in VA primary care clinics between 2000 and 2011 were included. Records from the VA Corporate Data Warehouse (CDW) were merged with death information from the National Death Index., Main Measures: Mental illnesses were determined using ICD9 codes. Direct standardization methods were used to calculate age-adjusted gender and cause-specific death rates per 1000 deaths for patients with and without depression, anxiety, post-traumatic stress disorder (PTSD), substance use disorder (SUD), serious mental illness (SMI), and combinations of those diagnoses., Key Results: Of the 1,763,982 death records for Veterans with 1 + primary care visit, 556,489 had at least one mental illness. Heart disease and cancer were the two leading causes of death among Veterans with or without a mental illness, accounting for approximately 1 in 4 deaths. Those with SUD (n = 204,950) had the lowest mean age at time of death (64 ± 12 years). Among men, the death rates were as follows: SUD (55.9/1000); anxiety (49.1/1000); depression (45.1/1000); SMI (40.3/1000); and PTSD (26.2/1000). Among women, death rates were as follows: SUD (55.8/1000); anxiety (36.7/1000); depression (45.1/1000); SMI (32.6/1000); and PTSD (23.1/1000 deaths). Compared to men (10.8/1000) and women (8.7/1000) without a mental illness, these rates were multiple-fold higher in men and in women with a mental illness. A greater number of mental illness diagnoses was associated with higher death rates among men and women (p < 0.0001)., Conclusions: Veterans with mental illnesses, particularly those with SUD, and those with multiple diagnoses, had shorter life expectancy than those without a mental illness. Future studies should examine both patient and systemic sources of disparities in providing chronic illness care to Veterans with a mental illness.

Rationale: An increased incidence of Obstructive Sleep Apnea (OSA) in sarcoidosis has been described in small sample size studies. Fatigue is common in sarcoidosis and OSA could be a relevant, treatable comorbidity. To date, the effect of Continuous Positive Airway Pressure (CPAP) on fatigue has never been assessed., Objectives: To investigate the prevalence of OSA in sarcoidosis, fatigue status and daytime sleepiness in patients of our center. To explore the effect of CPAP in fatigue and daytime sleepiness after 3 months using validated questionnaires., Method: Single group, one center, open-label prospective cohort study., Measurements and Main Result: We enrolled 68 patients and OSA was diagnosed in 60 (88.2%): 25 (36.8%) were mild while 35 (51.5%) were moderate-to-severe. 38 (55.9%) patients received CPAP but only 20 (30.9%) were compliant at 3-month evaluation. Questionnaires demonstrated fatigue in 34 (50%) and daytime sleepiness in 21 (30.9%). In multivariate regression analysis, Scadding stage and FAS behave as predictors of Apnea-Hypopnea Index (AHI) severity while sleepiness and steroids weren't associated. FAS score (Δ FAS = 6.3; p = 0.001) and ESS score (Δ ESS = 2.8; p = 0.005) improved after three months of CPAP., Conclusions: OSA is highly prevalent in patients affected by sarcoidosis. ESS questionnaire is not reliable for OSA screening and other pre-test probability tool should be evaluated in further studies. CPAP leads to a significative reduction of fatigue and daytime sleepiness at three-month. Further studies are needed to confirm the high prevalence of OSA in sarcoidosis and the positive role of CPAP in fatigue. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 169-178) ., (Copyright: © 2020 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES.)

Vehicles play an important role in modern life; however, they also generate hazards. Occupational exposed subjects are in long-term contact with harmful products, which sets these professionals in a susceptible group to air pollutant damage. The aims of this study were to quantify individual exposure to pollutant gases and chemical elements and to evaluate oxidative and genetic damage in professional motorcyclists and office workers. We recruited professional motorcyclists and office workers from Porto Alegre, Brazil, between January and December 2016. Individual exposure to air pollutants was assessed by passive monitoring. Fingernail trace elements were determined by using inductively coupled plasma mass spectrometry. Oxidative stress biomarkers were quantified spectrophotometrically, and genotoxicity was evaluated by micronuclei assay. Individual exposure to NO 2 and O 3 , trace element content (Sb, Pt, As, Cd, V, Mn, and Co), oxidative stress factors, and genetic damage were statistically higher in professional motorcyclists (p < 0.05). Moreover, NO 2 and O 3 levels showed very strong positive correlation with plasmatic lipid peroxidation (p < 0.001 and r = 0.8849 and 0.8995) and strong positive correlation with micronuclei frequency (p < 0.001 and r = 0.7683 and 0.7280). Results suggest that professional motorcyclists are at high risk due to long-term air pollution exposure, which implies in the onset of several harmful effects and worsening of pre-existent diseases.

Background: Gunshot injuries from interpersonal violence are a major cause of mortality. In South Africa (SA), the Firearms Control Act of 2000 sought to address firearm violence by removing illegally owned firearms from circulation, stricter regulation of legally owned firearms, and stricter licensing requirements. Over the last few years, varied implementation of the Act and police corruption have increased firearm availability., Objectives: To investigate whether changes in firearm availability in SA were associated with changes in firearm homicide rates., Methods: This was a retrospective time trend study (1994 - 2013) using postmortem data. Time trends of firearm and non-firearm homicide rates were analysed with generalised linear models. Distinct time periods for temporal trends were assigned based on a priori assumptions regarding changes in the availability of firearms., Results: Firearm and non-firearm homicide rates adjusted for age, sex and race exhibited different temporal trends. Non-firearm homicide rates either decreased or remained stable over the entire period. Firearm homicide increased at 13% annually from 1994 through 2000, and decreased by 15% from 2003 through 2006, corresponding with changes in firearm availability in 2001, 2003, 2007 and 2011. A 21% annual increase in firearm homicide after 2010 coincided with police fast-tracking new firearm licence applications. Cape Town's coloured population experienced a significantly greater increase than other population groups following additional exposure to illegal firearms from 2007., Conclusions: The strong association between firearm availability and homicide, and the reversal of a decreasing firearm homicide trend during a period of lax enforcement, provide further support for the association between reduced firearm homicide and stricter regulation.

Background: As the largest integrated US health system, the Veterans Health Administration (VHA) provides unique national data to expand knowledge about the association between neighborhood socioeconomic status (NSES) and health. Although living in areas of lower NSES has been associated with higher mortality, previous studies have been limited to higher-income, less diverse populations than those who receive VHA care., Objective: To describe the association between NSES and all-cause mortality in a national sample of veterans enrolled in VHA primary care., Design: One-year observational cohort of veterans who were alive on December 31, 2011. Data on individual veterans (vital status, and clinical and demographic characteristics) were abstracted from the VHA Corporate Data Warehouse. Census tract information was obtained from the US Census Bureau American Community Survey. Logistic regression was used to model the association between NSES deciles and all-cause mortality during 2012, adjusting for individual-level income and demographics, and accounting for spatial autocorrelation., Participants: Veterans who had vital status, demographic, and NSES data, and who were both assigned a primary care physician and alive on December 31, 2011 (n = 4,814,631)., Main Measures: Census tracts were used as proxies for neighborhoods. A summary score based on census tract data characterized NSES. Veteran addresses were geocoded and linked to census tract NSES scores. Census tracts were divided into NSES deciles., Key Results: In adjusted analysis, veterans living in the lowest-decile NSES tract were 10 % (OR 1.10, 95 % CI 1.07, 1.14) more likely to die than those living in the highest-decile NSES tract., Conclusions: Lower neighborhood SES is associated with all-cause mortality among veterans after adjusting for individual-level socioeconomic characteristics. NSES should be considered in risk adjustment models for veteran mortality, and may need to be incorporated into strategies aimed at improving veteran health.

Background: A high proportion of the US primary care workforce reports burnout, which is associated with negative consequences for clinicians and patients. Many protective factors from burnout are characteristics of patient-centered medical home (PCMH) models, though even positive organizational transformation is often stressful. The existing literature on the effects of PCMH on burnout is limited, with most findings based on small-scale demonstration projects with data collected only among physicians, and the results are mixed., Objective: To determine if components of PCMH related to team-based care were associated with lower burnout among primary care team members participating in a national medical home transformation, the VA Patient Aligned Care Team (PACT)., Design: Web-based, cross-sectional survey and administrative data from May 2012., Participants: A total of 4,539 VA primary care personnel from 588 VA primary care clinics., Main Measures: The dependent variable was burnout, and the independent variables were measures of team-based care: team functioning, time spent in huddles, team staffing, delegation of clinical responsibilities, working to top of competency, and collective self-efficacy. We also included administrative measures of workload and patient comorbidity., Key Results: Overall, 39 % of respondents reported burnout. Participatory decision making (OR 0.65, 95 % CI 0.57, 0.74) and having a fully staffed PACT (OR 0.79, 95 % CI 0.68, 0.93) were associated with lower burnout, while being assigned to a PACT (OR 1.46, 95 % CI 1.11, 1.93), spending time on work someone with less training could do (OR 1.29, 95 % CI 1.07, 1.57) and a stressful, fast-moving work environment (OR 4.33, 95 % CI 3.78, 4.96) were associated with higher burnout. Longer tenure and occupation were also correlated with burnout., Conclusions: Lower burnout may be achieved by medical home models that are appropriately staffed, emphasize participatory decision making, and increase the proportion of time team members spend working to the top of their competency level.

This study examined predictions based upon the right hemisphere (RH) model, the valence-arousal model, and a recently proposed integrated model (Killgore & Yurgelun-Todd, 2007) of emotion processing by testing immediate recall and recognition memory for positive, negative, and neutral verbal stimuli among 35 right-handed women. Building upon methodologies of previous studies, we found that words presented to the right visual field/left hemisphere (RVF/LH) were recalled and recognized more accurately than words presented to the left visual field/right hemisphere (LVF/RH), and we found significant valence by visual field interactions. Some findings were consistent with one of the models evaluated whereas others were consistent with none of the models evaluated. Our findings suggest that an integration of the RH and valence-arousal models may best account for the findings with regard to hemispheric lateralization of memory for emotional stimuli., (2010 Elsevier Inc. All rights reserved.)

Unlabelled: Some individuals who are chronically infected with hepatitis B virus (HBV) eventually lose hepatitis B surface antigen (HBsAg). Hepatocellular carcinoma (HCC) has been demonstrated to occur in a few patients after loss of HBsAg. Neither factors associated with loss of HBsAg nor the incidence of HCC thereafter have been clearly elucidated. We performed a prospective population-based cohort study in 1,271 Alaska Native persons with chronic HBV infection followed for an average of 19.6 years to determine factors associated with loss of HBsAg and risk of developing HCC thereafter. HBsAg loss occurred in 158 persons for a rate of HBsAg clearance of 0.7%/year. Older age, but not sex, was associated with clearance of HBsAg, and loss of HBsAg was not associated with any particular HBV genotypes (A, B, C, D, and F) found in this population. Participants were followed for an average of 108.9 months after HBsAg loss. Six patients, two with cirrhosis and four without, developed HCC a mean of 7.3 years after HBsAg clearance (range, 2.0-15.5 years). The incidence of HCC after clearance of HBsAg was 36.8 per 100,000 per year (95% CI 13.5-80.0) which was significantly lower than the rate in those who remained HBsAg-positive (195.7 cases per 100,000 person-years of follow-up [95% CI 141.1-264.5; P < 0.001]). After loss of HBsAg, HBV DNA was detected in the sera of 28 (18%) of those who cleared a median of 3.6 years after clearance., Conclusion: HCC can occur in persons with chronic hepatitis B who have lost HBsAg, even in the absence of cirrhosis. These persons should still be followed with periodic liver ultrasound to detect HCC early.

Hepatitis B virus (HBV) infection is endemic in Greenland with 5-10% of the population being HBsAg-positive (chronic carriers). Surprisingly, despite of the high prevalence of HBV infection, acute and chronic hepatitis B, liver cirrhosis and primary hepatocellular carcinoma appear much less frequently than expected. The reasons for the low frequencies are unknown, but as a consequence implementation of a childhood HBV vaccination programme, though debated for years, has never been instituted. We describe an outbreak of hepatitis D (HDV) infection among children in a hepatitis B hyper-endemic settlement of 133 inhabitants on the west coast of Greenland. In 2006 a total of 27% of the inhabitants were HBsAg-positive (chronic carriers) and 83% were HBcAb-positive (previously exposed). Forty-six percent of the HBsAg-positive persons were below 20 years of age. On follow-up 1 year later a total of 68% of the HBsAg-positive persons were HDV-IgG positive. Five children, who were HBsAg-positive in 2006, had HDV-seroconverted from 2006 to 2007, indicating a HDV-super-infection. Most of the HDV-IgG positive children had markedly elevated liver enzymes. In the multivariate analysis, among the HBV and HDV markers, presence of HDV-IgG was most strongly associated with elevation of liver enzymes. In conclusion, the HBV-HDV super-infection and presumed HDV outbreak in this settlement challenges the notion that HBV infection may not be as harmless in Greenland as previously anticipated. The findings strongly suggest that HBV vaccination should be included in the child-immunization program in Greenland.

Hepatitis B virus genotype B (HBV/B) has been classified into 5 subgenotypes. Except for Bj/B1 in Japan, the subgenotypes (Ba/B2-B5) have undergone recombination with HBV/C in the core promoter/precore/core genomic region. Phylogenetic analyses of complete sequences show that the Arctic strains belong to a novel subgenotype (HBV/B6) without the recombination, analogous to what is seen with Bj/B1. Comparison of 50 HBV/B6 carriers from the Arctic versus 50 Bj and 50 Ba age- and sex-matched carriers from Asia revealed that clinical characteristics of HBV/B6 carriers were similar to those of Bj/B1 carriers in Japan. The results suggest that HBV/B may be classified into nonrecombinant (Bj/B1 and B6) and recombinant (Ba/B2-B5) types.

Background: We report an interlaboratory comparison of methods for the determination of hepatitis C virus (HCV) serum load and genotype between a recently, established molecular laboratory at the Alaska Native Medical Center (ANMC) and two independent laboratories using different assays. At ANMC, a Real-time quantitative RT-PCR amplification methodology (QPCR) has been developed in which HCV viral loads are determined by interpolation of QPCR results to those of standards calibrated to the World Health Organization (WHO) First International Standard for HCV. HCV genotype is subsequently determined by direct sequencing of the DNA fragment generated from the QPCR assay., Objectives and Study Design: The above methods were statistically compared to results obtained for the same patient sera by two independent laboratories using different commercially available viral load assays; Quantiplex HCV RNA (Bayer Diagnostics) and Amplicor HCV Monitor (v 2.0) (Roche Molecular Systems), as well as two different genotyping assays; restriction fragment length polymorphism (RFLP) and INNO-LiPA HCV II (Innogenetics)., Results: ANMC's Real-time QPCR HCV viral load results compared moderately well with those obtained by the Quantiplex HCV RNA method (R2=0.3813), and compared quite well with recent lot numbers of Amplicor HCV Monitor in which viral loads are derived in IU/ml (R2=0.6408), but compared poorly with earlier lot numbers of Amplicor HCV Monitor in which viral loads were derived in copies/ml (R2=0.0913). The ANMC direct sequencing method for genotype determination compared moderately to very well with both the RFLP (84-86%) and INNO-LiPA (85-97.5%) methods., Conclusions: These viral load comparisons highlight the discrepancies that may occur when patient HCV viral loads are monitored using different types of assays. Comparison of HCV genotype by different methods is more reliable statistically and important clinically for predicting probability of response to antiviral therapy. However, viral loads are important for monitoring response once therapy has begun.

Arctic Alaskan Natives who maintain a traditional lifestyle have a disease profile that is significantly different from the general US population. There is concern that food sources containing environmental pollutants may contribute to this profile. In a preliminary study, umbilical cord blood was examined for the presence of several environmental contaminants. All cord blood samples analyzed thus far contain p,p'-DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene) with an average concentration of 0.33 microg/l. This study was undertaken to ascertain if this concentration of p,p'-DDE had detectable effects on immature cells in culture. NIH 3T3 (embryonic mouse fibroblast) and WS1 (human fetal fibroblast) cultures were exposed to media containing either 1 or 10 times the average cord blood concentration of p,p'-DDE. Initial experiments indicated that exposure to p,p'-DDE resulted in a decrease in the cell number of both cell types. Subsequent analysis revealed that the decrease in cell number was due to cell death in NIH 3T3 cells and to cell-cycle arrest in WS1 cells. Furthermore, p,p'-DDE decreased the long-term survival of NIH 3T3 but not WS1 cells. This study has demonstrated that p,p'-DDE, at relevant environmental concentrations, has significant effects on two immature mammalian cell types in culture. In addition, these results highlight the necessity for further studies to address the specific effects of p,p'-DDE on developing fetal systems.

Deficiencies in DNA mismatch repair (MMR) have been found in hereditary colon cancers (hereditary non-polyposis colon cancer, HNPCC) as well as in sporadic cancers, illustrating the importance of MMR in maintaining genomic integrity. We have examined the interactions of specific mismatch repair proteins in human nuclear extracts. Western blot and co-immunoprecipitation studies indicate two complexes as follows: one consisting of hMSH2, hMSH6, hMLH1, and hPMS2 and the other consisting of hMSH2, hMSH6, hMLH1, and hPMS1. These interactions occur without the addition of ATP. Furthermore, the protein complexes specifically bind to mismatched DNA and not to a similar homoduplex oligonucleotide. The protein complex-DNA interactions occur primarily through hMSH6, although hMSH2 can also become cross-linked to the mismatched substrate when not participating in the MMR protein complex. In the presence of ATP the binding of hMSH6 to mismatched DNA is decreased. In addition, hMLH1, hPMS2, and hPMS1 no longer interact with each other or with the hMutSalpha complex (hMSH2 and hMSH6). However, the ability of hMLH1 to co-immunoprecipitate mismatched DNA increases in the presence of ATP. This interaction is dependent on the presence of the mismatch and does not appear to involve a direct binding of hMLH1 to the DNA.

Repair rates of mismatched nucleotides located at an activating hotspot of mutation, H-ras codon 12, have been analyzed in vivo in mammalian cells. Repair rates at codon 12 are significantly improved in cells synchronized to the G(1) stage of the mammalian cell cycle as compared with non-synchronous cells, demonstrating that mismatch repair mechanisms are active in G(1). Repair rates in non-synchronous cells for the same mismatches at a nearby non-hotspot of mutation, H-ras codon 10, are also significantly improved over repair rates at codon 12 in non-synchronous cells, demonstrating that DNA mismatch repair rates can differ depending on the sequence context. These results suggest that inefficiencies in mismatch repair are responsible, at least in part, for the well documented hotspot of mutation at codon 12. Further experiments involving gel-shift analysis demonstrate a mismatch-specific binding factor for which the degree of binding correlates with in vivo repair rates for each mismatch tested at the codon 12 location. This binding factor appears to be the hMutSalpha heterodimer as identified by monoclonal antibody assay and inhibition of binding by ATP. Furthermore, a lack of binding is observed only for G:A mismatches at the codon 12 location. This lack of binding correlates with the low rate of repair observed in vivo for G:A mismatches at codon 12 versus the improved repair rates for G:A mismatches at codon 10. This may have biological relevance in that G:C-->T:A tranversions are a common mutation at this location in naturally occurring human tumors. These results suggest that there is lowered efficiency in the kinetics of mismatch repair at codon 12. Mismatches at this location are therefore more likely to be replicated before repair, thus resulting in a mutation.

Defective mismatch repair has recently been implicated as the major contributor towards the mutator phenotype observed in tumour cell lines derived from patients diagnosed with hereditary non-polyposis colon cancer (HNPCC). Cell lines from other cancer-prone syndromes, such as xeroderma pigmentosum, have been found to be defective in nucleotide excision repair of damaged bases. Some genetic complementation groups are defective specifically in transcription-coupled excision repair, although this type of repair defect has not been associated with cancer proneness. Mechanisms contributing to the high incidence of activating point mutations in oncogenes (such as H-ras codon 12) are not understood. It is possible that novel mechanisms of misrepair or misreplication occur at these sites in addition to the above DNA repair mechanisms. In this study, we have compared the rate of strand-directed mismatch repair of four mispairs (G:A, A:C, T:C and G:T) at the H-ras codon 12, middle G:C position. Our results indicate that, although this location is not a 'hot spot' for bacterial mismatch repair, it is a 'hot spot' for decreased repair of specific mismatched bases within NIH 3T3 cells. NIH 3T3, unlike Escherichia coli, have an extremely low repair rate of the G:A mispair (35%), as well as the A:C mispair (58%) at this location. NIH 3T3 also have a moderately low repair rate of the T:C mispair (80%) at the codon 12 location. Conversely, NIH 3T3 repair of G:T (100%) is comparable to E. coli repair (94%) of this mismatch. These results demonstrate that a mismatch containing an incorrect adenine on either strand at the H-ras codon 12 middle base pair location is most likely to undergo a mutational event in NIH 3T3 cells. Conversely, a mismatch containing an incorrect thymine in the transcribed strand is least likely to undergo a mutational event.

Acute promyelocytic leukemia (APL; M3 in the FAB classification) is specifically associated with the t(15;17)(q23;q12) and the consequent formation of a PML/RARA fusion gene. A few cases of APL with a t(11;17)(q23;q12) and a PLZF/RARA fusion gene have recently been reported. In addition, a new variant, t(5;17)(q32;q12), with a RARA rearrangement was described in a child with atypical APL. We report an unbalanced der(5)t(5;17) in an atypical APL case showing unusual dysgranulopoiesis and some M2 features. The breakpoints were difficult to localize precisely on chromosome 5, because the translocation may have occurred on a previous del(5q). The karyotype also showed del(8q) and multiple double-minutes (dmin). Molecular studies evidenced RARA rearrangement but showed neither PML rearrangement nor PML/RARA fusion. Fluorescence in situ hybridization revealed that the dmin were of chromosome 8 origin and that they accounted for the MYC amplification observed in Southern blots. The patient did very poorly despite chemotherapy and all-trans retinoic acid (ATRA) treatment. Thus, the t(5;17) could represent a second type of variant translocation in APL that, like the disease associated with t(11;17), does not seem to respond to ATRA therapy. Whereas RARA rearrangement appears sufficient for an APL-like phenotype, it seems that the presence of a classical PML/RARA is required for typical APL with response to ATRA.

We report the case of a patient having Philadelphia-negative, bcr-abl-positive chronic myeloid leukemia. In situ hybridization showed the presence of the bcr-abl fusion on the chromosome 9 long arm in all mitoses observed. Stability of the disease was very difficult to obtain because of serious adverse effects to interferon and chemotherapy, mainly grade IV neutropenia, and a blast crisis occurred 12 months after diagnosis. Only three other patients with such presentation (Philadelphia negative, bcr-abl positive with bcr-abl fusion on the chromosome 9 long arm) have been reported, with a poor therapeutic response and outcome in two of them. Translocation of BCR to chromosome 9 may therefore have a worse prognosis than translocation of ABL to chromosome 22 in Philadelphia-negative chronic myeloid leukemia.

We report a Wiskott-Aldrich patient who underwent allogeneic bone marrow transplantation from his HLA-identical sister at the age of 25. Conditioning regimen consisted of cyclophosphamide (180 mg/kg) and thoraco-abdominal irradiation (6 Grays). Cytogenetic follow-up revealed rapid and complete lymphoid chimaerism, but prolonged mixed bone marrow chimaerism. Correlative interphase cytogenetics performed on bone marrow smears using dual-colour fluorescence in situ hybridization with X and Y specific probes showed that the proportion of donor cells was significantly higher within megakaryocytes than in other lineages. This patient therefore presented with dissociated lineage engraftment, which is not exceptional in congenital diseases and aplastic anaemia, but has not previously been described in Wiskott-Aldrich syndrome. Bone marrow transplantation was successful despite this delayed engraftment which ensured adequate production in the involved cell lines.

Tumor-associated chromosome translocations usually lead to the formation of two reciprocal fusion genes: one thought to be involved in the transformation process, the other the mechanical consequence of the translocation event. In the case of acute promyelocytic leukemia (APL) blasts, the 15;17 chromosome translocation generates the putatively transforming PML/RARa fusion gene and its reciprocal RARa/PML. We report APL cases with submicroscopic 15;17 recombinations leading to the formation of nonreciprocal PML/RARa or RARa/PML fusion genes. Therefore, each of the two reciprocal translocation products may be independently formed and selected by the leukemic phenotype, implying that both are involved in tumorigenesis.

To assess changes in occupational preferences of health-care workers in response to the AIDS epidemic, attitudes for nine issues concerning AIDS in the workplace were gathered in 1990 and 1992. AIDS-aversive patterns strengthened for both health-care and non-health-care workers over time as AIDS incidence rose. Compared to non-health-care workers, significantly more health-care workers showed greater concern over job related AIDS exposure, and over time they also reported more approval of testing and status disclosure for AIDS. Despite these concerns, significantly more health-care workers than non-health-care workers were willing to work with an AIDS-infected coworker or boss, and significantly fewer health-care workers than non-health-care workers believed they had a right to refuse work with an AIDS-infected coworker. Training had little effect on AIDS-aversive preferences among health-care workers. But significantly more non-health-care workers with AIDS-related "protective" training reported a self-protective rejection of AIDS-infected coworkers. Implications for health-care management are explored.

CD40 is a surface glycoprotein, member of the nerve growth factor receptor family, which is expressed on B cells and plays an important role in their development, growth, and differentiation. Using chromosomal in situ hybridization, we localized the CD40 gene to the long arm of chromosome 20, bands q12-q13.2. This localization correlates well with the mapping of the murine CD40 gene to the distal region of chromosome 2, syntenic to the human 20q11-q13 region.

The consistency of the breakpoint on chromosome 5 at band 5q35 occurring in Ki-1 non-Hodgkin's lymphomas is highly suggestive of the involvement of a locally altered gene in this disease. In this study, we analyzed the potential involvement, in the translocation, of two receptor tyrosine kinase genes and putative oncogenes, FLT4 and FGFR4, previously localized near this breakpoint. Fluorescence in situ chromosomal hybridization allowed us to refine their localization to sub-band 5q35.3 and to show that both genes are translocated to the derivative chromosomes in Ki-1 cell lines containing either a t(2;5) or a t(3;5). Pulsed-field gel electrophoresis showed that the FLT4 and FGFR4 genes are not physically linked, nor are they altered by the translocation. Finally, Northern blot analysis showed that neither FLT4 nor FGFR4 is expressed in the Ki-1 cell lines, suggesting that they are not implicated in the genesis of Ki-1 lymphomas.