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PURPOSE: For patients with celiac disease (CeD), the only current management option is adherence to a strict gluten-free diet (GFD); however, many patients on a GFD continue to experience symptoms with a significant impact on quality of life. Potential new treatments for CeD are under development and a validated patient-reported outcome measure is required to evaluate their utility in clinical trials. The purpose of this article is to provide a history of the development of the Celiac Disease Symptom Diary (CDSD) 2.1© for use in clinical trials. METHODS: Qualitative and quantitative studies were conducted from 2010 to 2021, including concept elicitation and cognitive debriefing interviews with adult and adolescent participants with CeD (N = 93) diagnosed via biopsy and/or serology and input from eight interviews with CeD clinical experts. During these studies, different iterations of the CDSD were presented to the US Food and Drug Administration and the European Medicines Agency, and modifications were made in line with their feedback. RESULTS: These studies ultimately led to the development of CDSD 2.1©, a daily diary which focuses on key symptoms of CeD (abdominal pain, bloating, diarrhea, nausea and tiredness). This patient-reported outcome measure was readily understood by adult and adolescent participants with CeD and content validity was demonstrated in both populations. CONCLUSION: CDSD 2.1© is a content-valid patient-reported outcome measure developed in accordance with best practices and regulatory guidance. A thorough exploration of the psychometric properties of CDSD 2.1© for both adult and adolescent participants with CeD is ongoing to support utilization in clinical trials.
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The evolution of sophisticated technology has brought about the rise of endoscopic strategies for managing iatrogenic esophageal perforation. This approach is reserved for stable patients with limited contamination. The most commonly performed procedures are reviewed, focusing on procedural steps and outcomes. Esophageal stenting remains the most widely implemented strategy with promising success rates. Clipping, endoluminal vacuum therapy, and suturing are also viable options. Patient selection and further study are paramount to establishing this less invasive strategy as a more standard approach.
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Perforación del Esófago , Esofagoscopía , Enfermedad Iatrogénica , Humanos , Perforación del Esófago/cirugía , Perforación del Esófago/etiología , Esofagoscopía/métodos , StentsRESUMEN
Objective: To describe two main pillars of the Maryland Maternal Health Innovation Program (MDMOM): (1) centering equity and (2) fostering broad stakeholder collaboration and trust. Methods: We summarized MDMOM's key activities and used severe maternal morbidity (SMM) surveillance and program monitoring data to quantify MDMOM's work on the two pillars. We developed measures of hospital engagement with MDMOM (participation in quality improvement [QI] activities, participation in check-in meetings, staff involvement) and with other partners (participation in QI activities, representation in state-level groups). We examined Bonferroni-adjusted correlations between these hospital engagement measures and with key hospital characteristics: level of maternity care, annual delivery volume, and SMM rate. Results: Over 100 national and state organizations and individual stakeholders contributed to our building the MDMOM program and implementing key activities centering equity: hospital-based SMM surveillance in 20 of Maryland's 32 hospitals; almost 5,000 trainings offered to perinatal health care providers; two telemedicine/telehealth interventions; training of home visitors and community-based organization staff. Birthing hospitals represent MDMOM's main implementation partners. The strength of their participation in MDMOM QI activities is positively correlated to their participation in check-in meetings and with the degree of involvement by physicians in such activities. Higher engagement in MDMOM QI activities is also positively correlated to hospitals' participation in other state-level maternal health initiatives or groups. Conclusion: Our experience with the MDMOM program demonstrates that an equity focus and broad stakeholder collaboration building strong relationships and providing implementation support can lead to high levels of engagement in innovative maternal health interventions.
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In many ways, the COVID-19 pandemic provided a natural experiment for alternate ways of living and working. Although alcohol supply was one of many aspects impacted by COVID-19 restrictions, few of those alcohol-related measures have been continued. This commentary presents a unique case study from the Gove Peninsula in northern Australia, where pandemic restrictions acted as a catalyst for a review of an established alcohol management system. A permit system was introduced on the Gove Peninsula in 2008 to control who can purchase takeaway alcohol and how much they could buy each day. Development of the system was rooted in the principles of community development and self-determination. This commentary describes how COVID-19 and associated changes in levels of alcohol harms mobilised community support for a review of the system, that had operated unchanged for the past decade. COVID-19 was adventitious in revealing compelling localised information which encouraged examination of potential improvements to the system. An updated regime is now being trialled, which sets daily limits on the alcohol purchases of everyone in the area. This experience illustrates the benefits of timely and relevant data to assist communities in formulating local solutions to local problems.
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Consumo de Bebidas Alcohólicas , COVID-19 , Humanos , COVID-19/prevención & control , COVID-19/epidemiología , Consumo de Bebidas Alcohólicas/prevención & control , Política de Salud , Bebidas Alcohólicas , Australia , Northern TerritoryRESUMEN
BACKGROUND: Lung retransplantation is offered to select patients with chronic allograft dysfunction. Given the increased risk of morbidity and mortality conferred by retransplantation, post-transplant function should be considered in the decision of who and when to list. The aim of this study is to identify predictors of post-operative disability in patients undergoing lung retransplantation. METHODS: Data were collected from the UNOS national dataset and included all patients who underwent lung retransplant from May 2005-March 2023. Pre- and post-operative function was reported by the Karnofsky Performance Status (KPS) and patients were stratified based on their needs. Cumulative link mixed effects models identified associations between pre-transplant variables and post-transplant function. RESULTS: A total of 1275 lung retransplant patients were included. After adjusting for between-group differences, pre-operative functional status was predictive of post-transplant function; patients requiring Total Assistance ( n = 740) were 74% more likely than No/Some Assistance patients (n = 535) to require more assistance in follow-up (OR 1.74, 95% CI 1.13-2.68, p = .012). Estimated one year survival of Total Assistance patients is lower than No/Some Assistance Recipients (72% vs. 82%, CI 69%-75%; 79%-86%) but similar to overall re-transplant survival (76%, CI 74%-79%). CONCLUSION: Both survival and regain of function in patients requiring Total Assistance prior to retransplant may be higher than previously reported. Pre-operative functional status is predictive of post-operative function and should weigh in the selection, timing and post-operative care of patients considered for lung retransplantation.
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Trasplante de Pulmón , Pulmón , Humanos , Trasplante de Pulmón/efectos adversos , Trasplante Homólogo , Reoperación , Estudios RetrospectivosRESUMEN
BACKGROUND: During 2017-18, the Northern Territory (NT) introduced a Banned Drinker Register (BDR) and Minimum Unit Price (MUP) NT-wide; Police Auxiliary Liquor Inspectors (PALIs) in three regional towns; and restrictions on daily purchases/opening hours (DPOH) in one regional town. The BDR is an individual-level alcohol ban; MUP is a pricing policy; and PALIs enforce bans on restricted areas at takeaway outlets. This study examines the impact of these policies on adult domestic and family violence (DFV). METHODS: We examined DFV assaults and breaches of violence orders from January 2014 - February 2020 using interrupted time series models for NT, Greater Darwin, Katherine, Tennant Creek, and Alice Springs. To account for increasing numbers of individuals on the BDR we tested two timepoints (Sept 2017, March 2018). FINDINGS: Following DPOH, assaults (78 %) and alcohol-involved assaults (92 %) decreased in Tennant Creek. After PALIs, assaults (79 %) in Tennant Creek, and breaches (39 %) and alcohol-involved breaches (58 %) in Katherine decreased. After MUP, assaults (11 %), alcohol-involved assaults (21 %) and alcohol-involved breaches (21%) decreased NT wide. After MUP/PALIs in Alice Springs, alcohol-involved assaults (33 %), breaches (42 %), and alcohol-involved breaches (57 %) decreased. BDR (Sept 2017) found increases in assaults (44 %) and alcohol-involved assaults (39 %) in Katherine and assaults (10%) and alcohol-involved assaults NT-wide (17 %). There were increases of 21 %-45 % in breaches NT-wide, in Darwin, Katherine, and Alice Springs. Following March 2018 found increases in assaults (33 %) and alcohol-involved assaults (48 %) in Katherine. There were increases - from 20 % to 56 % - in breaches in NT-wide, Katherine, and Alice Springs. CONCLUSION: PALIs and DPOH were associated with some reductions in DFV; the BDR was associated with some increases. The upward trend commences prior to the BDR, so it is also plausible that the BDR had no effect on DFV outcomes. Although MUP was associated with reductions in the NT-wide model, there were no changes in sites without cooccurring PALIs.
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Consumo de Bebidas Alcohólicas , Bebidas Alcohólicas , Violencia Doméstica , Policia , Humanos , Northern Territory/epidemiología , Consumo de Bebidas Alcohólicas/epidemiología , Bebidas Alcohólicas/provisión & distribución , Bebidas Alcohólicas/economía , Adulto , Violencia Doméstica/estadística & datos numéricos , Femenino , Comercio/estadística & datos numéricos , Comercio/legislación & jurisprudencia , Masculino , Análisis de Series de Tiempo InterrumpidoRESUMEN
When faced with starvation, the bacterium Bacillus subtilis transforms itself into a dormant cell type called a "spore". Sporulation initiates with an asymmetric division event, which requires the relocation of the core divisome components FtsA and FtsZ, after which the sigma factor σF is exclusively activated in the smaller daughter cell. Compartment-specific activation of σF requires the SpoIIE phosphatase, which displays a biased localization on one side of the asymmetric division septum and associates with the structural protein DivIVA, but the mechanism by which this preferential localization is achieved is unclear. Here, we isolated a variant of DivIVA that indiscriminately activates σF in both daughter cells due to promiscuous localization of SpoIIE, which was corrected by overproduction of FtsA and FtsZ. We propose that the core components of the redeployed cell division machinery drive the asymmetric localization of DivIVA and SpoIIE to trigger the initiation of the sporulation program.
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Bacillus subtilis , Proteínas Bacterianas , Bacillus subtilis/metabolismo , Activación Transcripcional , Proteínas Bacterianas/metabolismo , Esporas Bacterianas/genética , Esporas Bacterianas/metabolismo , División Celular/genética , Factor sigma/genética , Factor sigma/metabolismoRESUMEN
BACKGROUND: Experience with lung transplantation (LT) in patients with human immunodeficiency virus (HIV) is limited. Many studies have demonstrated the success of kidney and liver transplantation in HIV-seropositive (HIV+) patients. Our objective was to conduct a national registry analysis comparing LT outcomes in HIV+ to HIV-seronegative (HIV-) recipients. METHODS: The United Network for Organ Sharing database was queried to identify LTs performed in adult HIV+ patients between 2016 and 2023. Patients with unknown HIV status, multiorgan transplants, and redo transplants were excluded. The primary endpoints were mortality and graft rejection. Survival time was analyzed using Kaplan-Meier analysis. RESULTS: The study included 17 487 patients, 67 of whom were HIV+. HIV+ recipients were younger (59 vs. 62 years, p = .02), had higher pulmonary arterial pressure (28 vs. 25 mm Hg, p = .04), and higher lung allocation scores (47 vs. 41, p = .01) relative to HIV- recipients. There were no differences in graft/recipient survival time between groups. HIV+ recipients had higher rates of post-transplant dialysis (18% vs. 8.4%, p = .01), but otherwise had similar post-transplant outcomes to HIV-recipients. CONCLUSIONS: This national registry analysis suggests LT outcomes in HIV+ patients are not inferior to outcomes in HIV- patients and that well-selected HIV+ recipients can achieve comparable patient and graft survival rates relative to HIV- recipients.
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Infecciones por VIH , Trasplante de Pulmón , Adulto , Humanos , VIH , Supervivencia de Injerto , Sistema de Registros , Rechazo de Injerto/epidemiología , Rechazo de Injerto/etiología , Infecciones por VIH/complicaciones , Infecciones por VIH/cirugíaRESUMEN
INTRODUCTION: Between 2017 and 2018 three major alcohol policy changes were introduced in the Northern Territory (NT): the Banned Drinker Register, an individual-level ban enforced via ID scanners at takeaway outlets; a Minimum Unit Price on alcohol; and Police Auxiliary Liquor Inspectors, who monitor takeaway outlets to prevent purchase by people who do not have a legal place to consume alcohol. We aimed to: (i) describe alcohol-involved adult sexual assault in the NT; and (ii) estimate the impacts of these alcohol policies on police-recorded adult sexual assault. METHODS: We used victim records for sexual assault where victims were aged 15 years and over. We undertook descriptive analyses for the NT from 2014 to 2020 and used interrupted time series analysis to assess policy impacts across the NT and in Greater Darwin. RESULTS: In 2020, the NT adult victimisation rate was 105 per 100,000. A large minority (40%) of adult sexual assaults involved alcohol. Interrupted time series analyses showed no effect of the Banned Drinker Register or Minimum Unit Price on sexual assault across the NT or in Greater Darwin. DISCUSSION AND CONCLUSIONS: The rate of adult sexual assaults in the NT is extremely high and many involve alcohol. Neither the Banned Drinker Register or Minimum Unit Price were associated with changes in police-recorded adult sexual assault in Greater Darwin or across the NT. Due to small counts, we were unable to assess policy impacts in three of the four main towns, highlighting the challenges of assessing impacts of policies on sexual assault in small population areas.
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Víctimas de Crimen , Delitos Sexuales , Adulto , Humanos , Policia , Northern Territory/epidemiología , Etanol , Política Pública , Delitos Sexuales/prevención & controlRESUMEN
BACKGROUND: With new variants challenging the effectiveness of preventive measures, we are beginning to recognize the reality that COVID-19 will continue to pose an endemic threat. The manifestations of COVID-19 in lung transplant recipients during index admission are poorly understood with very few cases reported in recent lung transplant recipients. Optimal management of immunosuppression and antiviral therapy in recent transplant recipients is challenging. METHODS: We performed a retrospective analysis identifying lung transplant recipients at our institution who contracted COVID-19 in the immediate postoperative period (within index admission). In addition, we performed a systematic review from January 2020 to August 2023 identifying all publications on the PUBMED database regarding COVID-19 infection in lung transplant recipients during index admission. RESULTS: We report four cases of COVID-19 pneumonia in lung transplant recipients in the immediate postoperative period and we describe the clinical course, treatment options, and immunosuppression changes to manage this unique clinical problem. All patients made a full recovery and were eventually discharged home. Within our review of the literature, the most prevalent presenting symptoms were cough, dyspnea, and fatigue. Six (75%) patients decreased or held their antimetabolite. The two most common treatments were monoclonal antibodies (38%) and remdesivir (63%). CONCLUSION: Although previous literature demonstrates that COVID-19 can be deadly in recent lung transplant recipients, rapid treatment with anti-viral therapy/immunotherapy, deescalating immunosuppression, and treatment of respiratory decompensation with Decadron was effective in our patients.
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When faced with starvation, the bacterium Bacillus subtilis transforms itself into a dormant cell type called a "spore". Sporulation initiates with an asymmetric division event, which requires the relocation of the core divisome components FtsA and FtsZ, after which the sigma factor σF is exclusively activated in the smaller daughter cell. Compartment specific activation of σF requires the SpoIIE phosphatase, which displays a biased localization on one side of the asymmetric division septum and associates with the structural protein DivIVA, but the mechanism by which this preferential localization is achieved is unclear. Here, we isolated a variant of DivIVA that indiscriminately activates σF in both daughter cells due to promiscuous localization of SpoIIE, which was corrected by overproduction of FtsA and FtsZ. We propose that a unique feature of the sporulation septum, defined by the cell division machinery, drives the asymmetric localization of DivIVA and SpoIIE to trigger the initiation of the sporulation program.
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BACKGROUND: Most idiopathic pulmonary fibrosis (IPF) lung transplant recipients (IPF-LTRs) have short telomere (ST) length. Inherited mutations in telomere-related genes are associated with the development of T cell immunodeficiency. Despite this, IPF-LTRs with telomere-related rare variants are not protected from acute cellular rejection (ACR). We set out to determine the impact of both age and telomere length on the circulating T cell compartment and ACR burden of IPF-LTRs. METHODS: We identified 106 IPF-LTRs who had telomere length testing using flowFISH (57 with short telomeres and 49 with long telomeres) as well as a subset from both cohorts who had cryopreserved PBMC at least 1 time point, 6 months posttransplantation. Circulating T cells from before transplantation and at 6 and 12 months posttransplantation were analyzed using multiparameter flow cytometry to study phenotype and functional capacity, and bulk T cell receptor sequencing was performed to study repertoire diversity. Linear regression was used to study the relationship of age and telomere length on early (within 1 year) and late (between 1 and 2 years) ACR. RESULTS: IPF-LTRs with ST were found to have premature "aging" of their circulating T cell compartment, with age-agnostic elevations in posttransplant terminal differentiation of CD8+ T cells, increased granzyme B positivity of both CD8+ and CD4+ T cells, upregulation of the exhaustion marker, CD57, and chemotactic protein CCR5, and enhanced T cell receptor clonal expansion. Additionally, we found a significant decline in early ACR burden with increasing age, but only in the ST cohort. CONCLUSIONS: IPF-LTRs with ST have premature "aging" of their circulating T cell compartment posttransplantation and a clear age-related decline in ACR burden.
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Fibrosis Pulmonar Idiopática , Trasplante de Pulmón , Humanos , Lactante , Leucocitos Mononucleares , Linfocitos T CD8-positivos , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/cirugía , Telómero , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
BACKGROUND: This study sought to characterize perioperative risk factors of acute kidney injury (AKI) and report outcomes associated with its development in the immediate postoperative setting after lung transplantation. METHODS: Study investigator performed a retrospective analysis of all adult patients undergoing primary lung transplantation at a single institution from January 1, 2011 to December 31, 2021 AKI was defined using Kidney Disease: Improving Global Outcomes (KDIGO) criteria after lung transplantation and was stratified on the basis of whether patients required renal replacement therapy (RRT; AKI-no RRT vs AKI-RRT). RESULTS: Of the 754 patients included, 369 (48.9%) any AKI developed in the postoperative period (252 AKI-no RRT vs 117 AKI-RRT). Risk factors for postoperative AKI included higher preoperative creatinine levels (odds ratio [OR], 5.15; P < .001), lower preoperative estimated glomerular filtration rate (OR, 0.99; P < 0.018), delayed chest closure (OR, 2.72; P < .001), and higher volumes of postoperative blood products (OR, 1.09; P < .001) in the multivariable analysis. On univariate analysis, both AKI groups were also associated with higher rates of pneumonia (P < .001), reintubation (P < .001), mortality on index admission (P < 0.001), longer ventilator duration (P < .001), longer intensive care unit length of stay (P < .001), and longer hospital length of stay (P < .001), with the highest rates in the AKI-RRT group. In a multivariable survival analysis, postoperative AKI-no RRT (hazard ratio [HR], 1.50; P = .006) and AKI-RRT (HR, 2.70; P < .001) were associated with significantly worse survival independent of severe grade 3 primary graft dysfunction at 72 hours (HR, 1.45; P = .038). CONCLUSIONS: The development of postoperative AKI was associated with numerous preoperative and intraoperative factors. Postoperative AKI remained significantly associated with poorer posttransplantation survival. Severe cases of AKI necessitating RRT portended the worst survival after lung transplantation.
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OBJECTIVES: To determine how the intrinsic severity of successively dominant SARS-CoV-2 variants changed over the course of the pandemic. METHODS: A retrospective cohort analysis in the NHS Greater Glasgow and Clyde (NHS GGC) Health Board. All sequenced non-nosocomial adult COVID-19 cases in NHS GGC with relevant SARS-CoV-2 lineages (B.1.177/Alpha, Alpha/Delta, AY.4.2 Delta/non-AY.4.2 Delta, non-AY.4.2 Delta/Omicron, and BA.1 Omicron/BA.2 Omicron) during analysis periods were included. Outcome measures were hospital admission, ICU admission, or death within 28 days of positive COVID-19 test. We report the cumulative odds ratio; the ratio of the odds that an individual experiences a severity event of a given level vs all lower severity levels for the resident and the replacement variant after adjustment. RESULTS: After adjustment for covariates, the cumulative odds ratio was 1.51 (95% CI: 1.08-2.11) for Alpha versus B.1.177, 2.09 (95% CI: 1.42-3.08) for Delta versus Alpha, 0.99 (95% CI: 0.76-1.27) for AY.4.2 Delta versus non-AY.4.2 Delta, 0.49 (95% CI: 0.22-1.06) for Omicron versus non-AY.4.2 Delta, and 0.86 (95% CI: 0.68-1.09) for BA.2 Omicron versus BA.1 Omicron. CONCLUSIONS: The direction of change in intrinsic severity between successively emerging SARS-CoV-2 variants was inconsistent, reminding us that the intrinsic severity of future SARS-CoV-2 variants remains uncertain.
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COVID-19 , SARS-CoV-2 , Adulto , Humanos , SARS-CoV-2/genética , Estudios Retrospectivos , HospitalizaciónRESUMEN
OBJECTIVE: From October 1, 2018, the Northern Territory (NT) of Australia introduced a minimum unit price (MUP) for alcohol of AU$1.30 per standard drink. The MUP was introduced to address the high alcohol consumption rates and harms within the NT. This study aimed to investigate the unique short-term impact of the MUP on alcohol-related assaults across the NT, for the NT overall and separately for four key regions (Darwin and Palmerston, Alice Springs, Katherine, and Tennant Creek); which allowed for the consideration of differences in concurrent alcohol interventions and population (e.g., Alice Springs had Police Auxiliary Liquor Inspectors (PALIs) introduced on October 1, 2018, whereas Darwin and Palmerston only had the MUP introduced in this period). PALIs effectively equate to a police officer being stationed in every off-premise liquor vendor. METHOD: Using data from January 2013 to September 2019, interrupted time series (ITS) analyses assessed the short-term impact of the MUP on the monthly rate of police-recorded alcohol-related assaults. RESULTS: A 14% reduction (B = -3.07 [-5.40, -0.74], p < .010) was found for alcohol-related assault offenses per 10,000 in Darwin/Palmerston. Significant reductions were also noted in Alice Springs and the NT overall, although PALIs are likely to have contributed to these reductions in addition to the MUP. CONCLUSIONS: This short-term impact warrants longer-term follow-up to determine whether the reductions in alcohol-related assaults following the introduction of MUP are maintained, and the extent to which assault rates are influenced by other alcohol-policy interventions in the NT.
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Víctimas de Crimen , Policia , Humanos , Northern Territory/epidemiología , Bebidas Alcohólicas , Consumo de Bebidas Alcohólicas/epidemiología , ComercioRESUMEN
OBJECTIVES: The SARS-CoV-2 Alpha variant was associated with increased transmission relative to other variants present at the time of its emergence and several studies have shown an association between Alpha variant infection and increased hospitalisation and 28-day mortality. However, none have addressed the impact on maximum severity of illness in the general population classified by the level of respiratory support required, or death. We aimed to do this. METHODS: In this retrospective multi-centre clinical cohort sub-study of the COG-UK consortium, 1475 samples from Scottish hospitalised and community cases collected between 1st November 2020 and 30th January 2021 were sequenced. We matched sequence data to clinical outcomes as the Alpha variant became dominant in Scotland and modelled the association between Alpha variant infection and severe disease using a 4-point scale of maximum severity by 28 days: 1. no respiratory support, 2. supplemental oxygen, 3. ventilation and 4. death. RESULTS: Our cumulative generalised linear mixed model analyses found evidence (cumulative odds ratio: 1.40, 95% CI: 1.02, 1.93) of a positive association between increased clinical severity and lineage (Alpha variant versus pre-Alpha variants). CONCLUSIONS: The Alpha variant was associated with more severe clinical disease in the Scottish population than co-circulating lineages.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Estudios Retrospectivos , Escocia/epidemiología , GenómicaRESUMEN
PURPOSE: Acquired RET fusions have been reported at resistance to treatment with EGFR inhibitors in EGFR-mutant non-small cell lung cancer (NSCLC); however, a multicenter cohort of patients with EGFR-mutant lung cancers treated with osimertinib and selpercatinib for RET fusion-mediated osimertinib resistance has not previously been published. PATIENTS AND METHODS: Patients who received selpercatinib in combination with osimertinib on a prospective expanded access clinical trial (NCT03906331) and single-patient compassionate use programs across five countries were centrally analyzed. All patients had advanced EGFR-mutant NSCLC with a RET fusion detected from tissue or plasma following osimertinib therapy. Clinicopathologic and outcomes data were collected. RESULTS: Fourteen patients with EGFR-mutant and RET fusion-positive lung cancers who experienced prior progression on osimertinib received osimertinib and selpercatinib. EGFR exon 19 deletions (±T790M, 86%) and non-KIF5B fusions (CCDC6-RET 50%, NCOA4-RET 36%) predominated. Osimertinib 80 mg daily and selpercatinib 80 mg twice daily were the most commonly administered dosages. The response rate, disease control rate, and median treatment duration were 50% [95% confidence interval (CI), 25%-75%, n = 12], 83% (95% CI, 55%-95%), and 7.9 months (range, 0.8-25+), respectively. Resistance was complex, involving EGFR on-target (EGFR C797S), RET on-target (RET G810S), and off-target (EML4-ALK/STRN-ALK, KRAS G12S, BRAF V600E) mechanisms; RET fusion loss; or polyclonal mechanisms. CONCLUSIONS: For patients with EGFR-mutant NSCLC with an acquired RET fusion as a mechanism of EGFR inhibitor resistance, the addition of selpercatinib to osimertinib was feasible and safe and offered clinical benefit, supporting the prospective evaluation of this combination. See related commentary by Krebs and Popat, p. 2951.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Mutación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Compuestos de Anilina/farmacología , Proteínas Proto-Oncogénicas c-ret/genéticaRESUMEN
BACKGROUND: The safety of lung transplantation using ex vivo lung perfusion (EVLP) has been confirmed in multiple clinical studies; however, limited evidence is currently available regarding the potential effects of EVLP on posttransplant graft complications and survival with mid- to long-term follow-up. In this study, we reviewed our institutional data to better understand the impact of EVLP. METHODS: Lungs placed on EVLP from 2014 through 2020 and transplant outcomes were retrospectively analyzed. Data were compared between lungs transplanted and declined after EVLP, between patients with severe primary graft dysfunction (PGD3) and no PGD3 after EVLP, and between matched patients with lungs transplanted with and without EVLP. RESULTS: In total, 98 EVLP cases were performed. Changes in metabolic indicators during EVLP were correlated with graft quality and transplantability, but not changes in physiological parameters. Among 58 transplanted lungs after EVLP, PGD3 at 72 h occurred in 36.9% and was associated with preservation time, mechanical support prior to transplant, and intraoperative transfusion volume. Compared with patients without EVLP, patients who received lungs screened with EVLP had a higher incidence of PGD3 and longer ICU and hospital stays. Lung grafts placed on EVLP exhibited a significantly higher chance of developing airway anastomotic ischemic injury by 30 days posttransplant. Acute and chronic graft rejection, pulmonary function, and posttransplant survival were not different between patients with lungs screened on EVLP versus lungs with no EVLP. CONCLUSION: EVLP use is associated with an increase of early posttransplant adverse events, but graft functional outcomes and patient survival are preserved.
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Trasplante de Pulmón , Pulmón , Humanos , Circulación Extracorporea , Pulmón/fisiología , Trasplante de Pulmón/efectos adversos , Perfusión , Estudios RetrospectivosRESUMEN
ISSUE ADDRESSED: It is well-established that health education and promotion programs work best when they have been tailored to meet local contextual needs. In this brief report we describe a health education program and how it identified and incorporated local priorities into its delivery in two remote Aboriginal communities in the "Top End" of the Northern Territory. METHODS: During the first visit to each community team members met with local stakeholders and ran an inaugural HealthLAB session. Fieldnotes were taken during or directly after each interaction. At the end of each day team members debriefed regarding their fieldnotes. After both trips had been completed, priority areas were extracted from fieldnotes and synthesised. RESULTS: Although some health priorities were congruent across all groups, Community Members and Childcare staff tended to identify practical solutions while School and Clinic staff were focused on the clinical outcome. Community Members were particularly focused on the wider social and systemic factors impacting health. CONCLUSION: In response to the need for practical support, HealthLAB modified their health education packages to upskill mothers and sports coaches to provide brief health education sessions to local children and young people. SO WHAT?: It is recognised that many health promotion programs focus on individual behaviours without creating supportive environments. While it was out of scope for HealthLAB to address physical environmental factors, by building local capacity and knowledge to deliver health education, the program can contribute to a healthier and supportive social environment.