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1.
Lancet Infect Dis ; 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39265595

RESUMO

BACKGROUND: No randomised controlled trials have yet reported on the effectiveness of molnupiravir on longer term outcomes for COVID-19. The PANORAMIC trial found molnupiravir reduced time to recovery in acute COVID-19 over 28 days. We aimed to report the effect of molnupiravir treatment for COVID-19 on wellbeing, severe and persistent symptoms, new infections, health care and social service use, medication use, and time off work at 3 months and 6 months post-randomisation. METHODS: This study is a follow-up to the main analysis, which was based on the first 28 days of follow-up and has been previously reported. For this multicentre, primary care, open-label, multi-arm, prospective randomised controlled trial conducted in the UK, participants were eligible if aged at least 50 years, or at least 18 years with a comorbidity, and unwell 5 days or less with confirmed COVID-19 in the community. Participants were randomly assigned to the usual care group or molnupiravir group plus usual care (800 mg twice a day for 5 days), which was stratified by age (<50 years or ≥50 years) and vaccination status (at least one dose: yes or no). The primary outcome was hospitalisation or death (or both) at 28 days; all longer term outcomes were considered to be secondary outcomes and included self-reported ratings of wellness (on a scale of 0-10), experiencing any symptom (fever, cough, shortness of breath, fatigue, muscle ache, nausea and vomiting, diarrhoea, loss of smell or taste, headache, dizziness, abdominal pain, and generally feeling unwell) rated as severe (moderately bad or major problem) or persistent, any health and social care use, health-related quality of life (measured by the EQ-5D-5L), time off work or school, new infections, and hospitalisation. FINDINGS: Between Dec 8, 2021, and April 27, 2022, 25 783 participants were randomly assigned to the molnupiravir plus usual care group (n=12 821) or usual care group (n=12 962). Long-term follow-up data were available for 23 008 (89·2%) of 25 784 participants with 11 778 (91·9%) of 12 821 participants in the molnupiravir plus usual care group and 11 230 (86·6%) of 12 963 in the usual care group. 22 806 (99·1%) of 23 008 had at least one previous dose of a SARS-CoV-2 vaccine. Any severe (3 months: adjusted risk difference -1·6% [-2·6% to -0·6%]; probability superiority [p(sup)]>0·99; number needed to treat [NNT] 62·5; 6 months: -1·9% [-2·9% to -0·9%]; p(sup)>0·99, NNT 52·6) or persistent symptoms (3 months: adjusted risk difference -2·1% [-2·9% to -1·5%]; p(sup)>0·99; NNT 47·6; 6 months: -2·5% [-3·3% to -1·6%]; p(sup)>0·99; NNT 40) were reduced in severity, and health-related quality of life (measured by the EQ-5D-5L) improved in the molnupiravir plus usual care group at 3 months and 6 months (3 months: adjusted mean difference 1·08 [0·65 to 1·53]; p(sup)>0·99; 6 months: 1·09 [0·63 to 1·55]; p(sup)>0·99). Ratings of wellness (3 months: adjusted mean difference 0·15 (0·11 to 0·19); p(sup)>0·99; 6 months: 0·12 (0·07 to 0·16); p(sup)>0·99), experiencing any more severe symptom (3 months; adjusted risk difference -1·6% [-2·6% to -0·6%]; p(sup)=0·99; 6 months: -1·9% [-2·9% to -0·9%]; p(sup)>0·99), and health-care use (3 months: adjusted risk difference -1·4% [-2·3% to -0·4%]; p(sup)>0·99; NNT 71·4; 6 months: -0·5% [-1·5% to 0·4%]; p(sup)>0·99; NNT 200) had high probabilities of superiority with molnupiravir treatment. There were significant differences in persistence of any symptom (910 [8·9%] of 10 190 vs 1027 [11%] of 9332, NNT 67) at 6 months, and reported time off work at 3 months (2017 [17·9%] of 11 274 vs 2385 [22·4%] of 10 628) and 6 months (460 [4·4%] of 10 562 vs 527 [5·4%] of 9846; NNT 100). There were no differences in hospitalisations at long-term follow-up. INTERPRETATION: In a vaccinated population, people treated with molnupiravir for acute COVID-19 felt better, experienced fewer and less severe COVID-19 associated symptoms, accessed health care less often, and took less time off work at 6 months. However, the absolute differences in this open-label design are small with high numbers needed to treat. FUNDING: UK Research and Innovation and National Institute for Health and Care Research.

2.
Drugs Aging ; 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39285122

RESUMO

Corticosteroids play a crucial role as anti-inflammatory and immunomodulatory agents in dermatology and other medical specialties; however, their therapeutic benefits are accompanied by significant risks, especially in older adults. This review examines the broad spectrum of adverse effects (AEs) associated with oral corticosteroid therapy and offers strategies to prevent, monitor, and manage these issues effectively in older adults. AEs associated with systemic corticosteroids include immune suppression, gastrointestinal problems, hyperglycemia, insulin resistance, weight gain, cardiovascular complications, ocular issues, osteoporosis, osteonecrosis, muscle weakness, collagen impairment, psychiatric symptoms, and adrenal suppression. To minimize these AEs, tailored dosing and duration, frequent monitoring, and additional preventative measures can be employed to optimize corticosteroid treatment. By customizing management plans to the specific needs and risk factors associated with each patient, clinicians can promote the safe and effective use of oral corticosteroids, ultimately improving outcomes and quality of life in patients with inflammatory dermatologic disorders.

3.
Nat Commun ; 15(1): 8386, 2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39333485

RESUMO

Wastewater is a geospatially- and temporally-linked microbial fingerprint of a given population, making it a potentially valuable tool for tracking public health across locales and time. Here, we integrate targeted and bulk RNA sequencing (N = 2238 samples) to track the viral, bacterial, and functional content over geospatially distinct areas within Miami Dade County, USA, from 2020-2022. We used targeted amplicon sequencing to track diverse SARS-CoV-2 variants across space and time, and we found a tight correspondence with positive PCR tests from University students and Miami-Dade hospital patients. Additionally, in bulk metatranscriptomic data, we demonstrate that the bacterial content of different wastewater sampling locations serving small population sizes can be used to detect putative, host-derived microorganisms that themselves have known associations with human health and diet. We also detect multiple enteric pathogens (e.g., Norovirus) and characterize viral diversity across sites. Moreover, we observed an enrichment of antimicrobial resistance genes (ARGs) in hospital wastewater; antibiotic-specific ARGs correlated to total prescriptions of those same antibiotics (e.g Ampicillin, Gentamicin). Overall, this effort lays the groundwork for systematic characterization of wastewater that can potentially influence public health decision-making.


Assuntos
COVID-19 , SARS-CoV-2 , Águas Residuárias , Águas Residuárias/microbiologia , Águas Residuárias/virologia , Humanos , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , COVID-19/virologia , COVID-19/epidemiologia , Vigilância em Saúde Pública , Florida , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/classificação , Análise de Sequência de RNA/métodos
4.
Br J Gen Pract ; 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39164029

RESUMO

Background Living in socioeconomically deprived areas is associated with shorter lives, in worse health. GPs working in these areas face additional challenges. Aim Establishing GPs' motivation for working in these areas, what the challenges are, and insights from GPs on potential improvements and changes. Design and Setting An Interpretative Phenomenological Analysis of GPs' lived experiences of working in the most socioeconomically deprived practices, in Northern Ireland (NI), the most deprived country within the UK. Method Interviews with GPs finding out the challenges facing them, why they work in a "Deep End" area and what suggestions, ideas and solutions they have to improve patient care and GP experience at NI's 'Deep End'. Results The challenges related to wider health service failures including the increased demand on GPs and feelings of powerlessness. Patient population challenges included 'missingness', late or crisis presentations, alongside the clinical difficulties of a highly 'medicalised' patient population, as well as the high prevalence of mental health problems. However, GPs choose to work in 'Deep End' areas because it's clinically stimulating and rewarding, as well as feelings of belonging and fulfilling a duty to 'their' area. Improvements focused on providing more flexible access, increased mental health provision and future training and recruitment, particularly around widening participation in medicine. Conclusion Improving the environmental conditions, empowering individuals and investing in communities are essential to achieving health. The current model of providing reactionary acute care is leading to GPs experiencing powerlessness and feelings of helplessness at the 'Deep End'.

5.
Nature ; 632(8027): 1145-1154, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38862028

RESUMO

Spaceflight induces molecular, cellular and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space1-6. Yet current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring the need for rapid development of space medicine databases, tools and protocols. Here we present the Space Omics and Medical Atlas (SOMA), an integrated data and sample repository for clinical, cellular and multi-omic research profiles from a diverse range of missions, including the NASA Twins Study7, JAXA CFE study8,9, SpaceX Inspiration4 crew10-12, Axiom and Polaris. The SOMA resource represents a more than tenfold increase in publicly available human space omics data, with matched samples available from the Cornell Aerospace Medicine Biobank. The Atlas includes extensive molecular and physiological profiles encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiome datasets, which reveal some consistent features across missions, including cytokine shifts, telomere elongation and gene expression changes, as well as mission-specific molecular responses and links to orthologous, tissue-specific mouse datasets. Leveraging the datasets, tools and resources in SOMA can help to accelerate precision aerospace medicine, bringing needed health monitoring, risk mitigation and countermeasure data for upcoming lunar, Mars and exploration-class missions.


Assuntos
Medicina Aeroespacial , Astronautas , Bancos de Espécimes Biológicos , Bases de Dados Factuais , Internacionalidade , Voo Espacial , Animais , Feminino , Humanos , Masculino , Camundongos , Medicina Aeroespacial/métodos , Atlas como Assunto , Citocinas/metabolismo , Conjuntos de Dados como Assunto , Epigenômica , Perfilação da Expressão Gênica , Genômica , Metabolômica , Microbiota/genética , Multiômica , Especificidade de Órgãos , Medicina de Precisão/tendências , Proteômica , Voo Espacial/estatística & dados numéricos , Telômero/metabolismo , Gêmeos
6.
Sci Rep ; 14(1): 12811, 2024 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834738

RESUMO

Macrophages provide a crucial environment for Salmonella enterica serovar Typhi (S. Typhi) to multiply during typhoid fever, yet our understanding of how human macrophages and S. Typhi interact remains limited. In this study, we delve into the dynamics of S. Typhi replication within human macrophages and the resulting heterogeneous transcriptomic responses of macrophages during infection. Our study reveals key factors that influence macrophage diversity, uncovering distinct immune and metabolic pathways associated with different stages of S. Typhi intracellular replication in macrophages. Of note, we found that macrophages harboring replicating S. Typhi are skewed towards an M1 pro-inflammatory state, whereas macrophages containing non-replicating S. Typhi exhibit neither a distinct M1 pro-inflammatory nor M2 anti-inflammatory state. Additionally, macrophages with replicating S. Typhi were characterized by the increased expression of genes associated with STAT3 phosphorylation and the activation of the STAT3 transcription factor. Our results shed light on transcriptomic pathways involved in the susceptibility of human macrophages to intracellular S. Typhi replication, thereby providing crucial insight into host phenotypes that restrict and support S. Typhi infection.


Assuntos
Macrófagos , Fator de Transcrição STAT3 , Salmonella typhi , Febre Tifoide , Humanos , Macrófagos/metabolismo , Macrófagos/microbiologia , Salmonella typhi/genética , Febre Tifoide/microbiologia , Febre Tifoide/imunologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Perfilação da Expressão Gênica , Fenótipo , Transcriptoma , Fosforilação
7.
JAMA ; 331(24): 2114-2124, 2024 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-38809527

RESUMO

Importance: Chronic pruritus, defined as itch experienced for 6 weeks or longer, affects approximately 22% of people in their lifetime. Approximately 1% of physician visits are for the chief concern of chronic pruritus. Chronic pruritus is associated with adverse outcomes, including impaired sleep and reduced quality of life. Observations: Chronic pruritus can be categorized by etiology into inflammatory, neuropathic, or a combination of inflammatory and neuropathic pruritus. Chronic pruritus is due to inflammation in approximately 60% of patients and may be caused by eczema, psoriasis, or seborrheic dermatitis. Chronic pruritus is due to a neuropathic or mixed etiology in approximately 25% of patients. Neuropathic causes of chronic pruritus include postherpetic neuralgia and notalgia paresthetica and are typically due to localized or generalized nerve dysregulation. Approximately 15% of people with chronic pruritus have other causes including systemic diseases with secondary itch, such as uremic pruritus and cholestatic pruritus, medication-induced pruritus such as pruritus due to immunotherapy, and infectious etiologies such as tinea corporis and scabies. When few primary changes are present, a thorough history, review of symptoms, and laboratory evaluation should be performed, particularly for people with chronic pruritus lasting less than 1 year. Clinicians should consider the following tests: complete blood cell count, complete metabolic panel, and thyroid function testing to evaluate for hematologic malignancy, liver disease, kidney disease, or thyroid disease. First-line treatment for inflammatory chronic pruritus includes topical anti-inflammatory therapies such as hydrocortisone (2.5%), triamcinolone (0.1%), or tacrolimus ointment. Approximately 10% of patients do not respond to topical therapies. In these patients, referral to dermatology and systemic oral or injectable treatments such as dupilumab or methotrexate may be considered. When no underlying systemic disease associated with pruritus is identified, patients are likely to have neuropathic chronic pruritus or mixed etiology such as chronic pruritus of unknown origin. In these patients, neuropathic topical treatments such as menthol, pramoxine, or lidocaine can be used either alone or in combination with immunomodulatory agents such as topical steroids. Other effective therapies for neuropathic pruritus include gabapentin, antidepressants such as sertraline or doxepin, or opioid receptor agonist/antagonists such as naltrexone or butorphanol. Conclusions and Relevance: Chronic pruritus can adversely affect quality of life and can be categorized into inflammatory, neuropathic, or a combined etiology. First-line therapies are topical steroids for inflammatory causes, such as hydrocortisone (2.5%) or triamcinolone (0.1%); topical neuropathic agents for neuropathic causes, such as menthol or pramoxine; and combinations of these therapies for mixed etiologies of chronic pruritus.


Assuntos
Antipruriginosos , Prurido , Humanos , Doença Crônica , Prurido/etiologia , Prurido/tratamento farmacológico , Antipruriginosos/uso terapêutico
9.
J Drugs Dermatol ; 23(2): e70-e72, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38306134

RESUMO

In this study, we aimed to analyze the literature to date on the utilization of topical calcineurin inhibitors in the management of pruritus among older adults, ages 65 and older. The 16 studies included in the final analysis demonstrated that topical calcineurin inhibitors are well tolerated across ages and are effective in treating a wide variety of chronic pruritic conditions. Collectively, these findings support that topical calcineurin inhibitors should be considered a safe, plausible option for managing age-associated itch. J Drugs Dermatol. 2024;23(2): doi:10.36849/JDD.7190e.


Assuntos
Inibidores de Calcineurina , Prurido , Humanos , Idoso , Inibidores de Calcineurina/efeitos adversos , Prurido/diagnóstico , Prurido/tratamento farmacológico
10.
Br J Gen Pract ; 74(745): e570-e579, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38228357

RESUMO

BACKGROUND: The cost-effectiveness of molnupiravir, an oral antiviral for early treatment of SARS-CoV-2, has not been established in vaccinated populations. AIM: To evaluate the cost-effectiveness of molnupiravir relative to usual care alone among mainly vaccinated community-based people at higher risk of severe outcomes from COVID-19 over 6 months. DESIGN AND SETTING: An economic evaluation of the PANORAMIC trial in the UK. METHOD: A cost-utility analysis that adopted a UK NHS and personal social services perspective and a 6-month time horizon was performed using PANORAMIC trial data. Cost-effectiveness was expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. Sensitivity and subgroup analyses assessed the impacts of uncertainty and heterogeneity. Threshold analysis explored the price for molnupiravir consistent with likely reimbursement. RESULTS: In the base-case analysis, molnupiravir had higher mean costs of £449 (95% confidence interval [CI] = 445 to 453) and higher mean QALYs of 0.0055 (95% CI = 0.0044 to 0.0067) than usual care (mean incremental cost per QALY of £81 190). Sensitivity and subgroup analyses showed similar results, except for those aged ≥75 years, with a 55% probability of being cost-effective at a £30 000 per QALY threshold. Molnupiravir would have to be priced around £147 per course to be cost-effective at a £15 000 per QALY threshold. CONCLUSION: At the current cost of £513 per course, molnupiravir is unlikely to be cost-effective relative to usual care over a 6-month time horizon among mainly vaccinated patients with COVID-19 at increased risk of adverse outcomes, except those aged ≥75 years.


Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Análise Custo-Benefício , Citidina , Hidroxilaminas , Anos de Vida Ajustados por Qualidade de Vida , SARS-CoV-2 , Humanos , Antivirais/economia , Antivirais/uso terapêutico , Citidina/análogos & derivados , Citidina/uso terapêutico , Citidina/economia , Hidroxilaminas/uso terapêutico , Hidroxilaminas/economia , Reino Unido , COVID-19/prevenção & controle , COVID-19/economia , COVID-19/epidemiologia , Adulto , Pessoa de Meia-Idade , Masculino , Feminino
11.
Blood Adv ; 8(1): 150-163, 2024 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-37782774

RESUMO

ABSTRACT: Mantle cell lymphoma (MCL) is an incurable B-cell non-Hodgkin lymphoma, and patients who relapse on targeted therapies have poor prognosis. Protein arginine methyltransferase 5 (PRMT5), an enzyme essential for B-cell transformation, drives multiple oncogenic pathways and is overexpressed in MCL. Despite the antitumor activity of PRMT5 inhibition (PRT-382/PRT-808), drug resistance was observed in a patient-derived xenograft (PDX) MCL model. Decreased survival of mice engrafted with these PRMT5 inhibitor-resistant cells vs treatment-naive cells was observed (P = .005). MCL cell lines showed variable sensitivity to PRMT5 inhibition. Using PRT-382, cell lines were classified as sensitive (n = 4; 50% inhibitory concentration [IC50], 20-140 nM) or primary resistant (n = 4; 340-1650 nM). Prolonged culture of sensitive MCL lines with drug escalation produced PRMT5 inhibitor-resistant cell lines (n = 4; 200-500 nM). This resistant phenotype persisted after prolonged culture in the absence of drug and was observed with PRT-808. In the resistant PDX and cell line models, symmetric dimethylarginine reduction was achieved at the original PRMT5 inhibitor IC50, suggesting activation of alternative resistance pathways. Bulk RNA sequencing of resistant cell lines and PDX relative to sensitive or short-term-treated cells, respectively, highlighted shared upregulation of multiple pathways including mechanistic target of rapamycin kinase [mTOR] signaling (P < 10-5 and z score > 0.3 or < 0.3). Single-cell RNA sequencing analysis demonstrated a strong shift in global gene expression, with upregulation of mTOR signaling in resistant PDX MCL samples. Targeted blockade of mTORC1 with temsirolimus overcame the PRMT5 inhibitor-resistant phenotype, displayed therapeutic synergy in resistant MCL cell lines, and improved survival of a resistant PDX.


Assuntos
Linfoma de Célula do Manto , Humanos , Camundongos , Animais , Adulto , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Linhagem Celular Tumoral , Recidiva Local de Neoplasia , Transdução de Sinais , Inibidores Enzimáticos/uso terapêutico , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo
12.
Nat Commun ; 14(1): 5866, 2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-37752123

RESUMO

Deep learning-based markerless tracking has revolutionized studies of animal behavior. Yet the generalizability of trained models tends to be limited, as new training data typically needs to be generated manually for each setup or visual environment. With each model trained from scratch, researchers track distinct landmarks and analyze the resulting kinematic data in idiosyncratic ways. Moreover, due to inherent limitations in manual annotation, only a sparse set of landmarks are typically labeled. To address these issues, we developed an approach, which we term GlowTrack, for generating orders of magnitude more training data, enabling models that generalize across experimental contexts. We describe: a) a high-throughput approach for producing hidden labels using fluorescent markers; b) a multi-camera, multi-light setup for simulating diverse visual conditions; and c) a technique for labeling many landmarks in parallel, enabling dense tracking. These advances lay a foundation for standardized behavioral pipelines and more complete scrutiny of movement.


Assuntos
Captura de Movimento , Movimento , Fenômenos Biomecânicos , Movimento (Física)
13.
JAMA Dermatol ; 159(10): 1119-1123, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37610789

RESUMO

Importance: Older adults with atopic dermatitis (AD) face unique treatment challenges, including comorbidities, polypharmacy, and a higher risk for infections (eg, herpes zoster). Furthermore, limited data are available from clinical trials for treatments in this population. In phase 3 studies, tralokinumab showed superior efficacy in moderate-to-severe AD vs placebo, but results were not stratified by age group. Objective: To evaluate the safety and efficacy of tralokinumab in older (≥65 years) patients with moderate-to-severe AD. Design, Setting, and Participants: A post hoc analysis for adults 65 years or older was conducted from a subset of patients in the US, Canada, Europe, and Asia in 3 randomized, placebo-controlled, phase 3 trials (ECZTRA 1 and 2 [monotherapy] and ECZTRA 3 [tralokinumab + topical corticosteroids as needed]). The post hoc data were analyzed in 2022. Main Outcomes and Measures: Pooled data from up to 16 weeks of treatment from ECZTRA 1, 2, and 3 were used to assess safety. Statistical analyses followed prespecifications of primary end points. Separate efficacy analyses were conducted in these trials respectively at 16 weeks. Results: A total of 75 older adults (42 women [56%]) treated with tralokinumab from the ECZTRA 1, 2, and 3 trials were included in this post hoc analysis. Similar proportions of patients reported adverse events (AEs) with tralokinumab and placebo (44 [58%]). Three patients (4%) in the tralokinumab arm and 3 (10.3%) in the placebo arm experienced severe AEs, and 4 (5.3%) and 2 (6.9%), respectively, had AEs leading to discontinuation. More patients achieved 75% or greater improvement in Eczema Area and Severity Index scores with tralokinumab than placebo (33.9% vs 4.8%; P < .001) in ECZTRA 1 and 2. Similar trends, although not statistically significant, were seen in ECZTRA 3. Safety and efficacy outcomes in this population were similar compared with the younger patient cohorts. The small sample size limited generalizations from this analysis. Conclusion and Relevance: The results of this post hoc analysis suggest that tralokinumab is well tolerated and efficacious in patients 65 years or older with moderate-to-severe AD.


Assuntos
Dermatite Atópica , Fármacos Dermatológicos , Humanos , Feminino , Idoso , Dermatite Atópica/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Fármacos Dermatológicos/efeitos adversos , Glucocorticoides/uso terapêutico , Resultado do Tratamento , Índice de Gravidade de Doença , Método Duplo-Cego
14.
Urol Int ; 107(8): 778-784, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37544300

RESUMO

INTRODUCTION: Acute lower uncomplicated urinary tract infection (uUTI) affects a large proportion of women. Increased antimicrobial resistance has created an urgent need for novel therapeutics and the phytotherapeutic drug BNO 1045 (Canephron® N) has previously been shown to be noninferior to standard antimicrobial stewardship. This sub-analysis from a randomized, double-blind, controlled phase III noninferiority clinical trial using BNO 1045 versus fosfomycin to treat uUTI aimed to determine how urine cytokine levels are altered by the two different treatments. METHODS: Urine samples from a predefined subset of women diagnosed with uUTI (18-70 years) and treated with BNO 1045 (n = 58) or fosfomycin (n = 69) were analyzed for urine levels of IL-6 and IL-8, using analyte-to-creatinine ratios. RESULTS: BNO 1045 treatment showed similar effects to fosfomycin treatment in reducing both urine IL-6 and IL-8 levels. Mean IL-6 and IL-8 levels were markedly reduced in all patients regardless of treatment. BNO 1045 treatment decreased urine IL-8 significantly (p = 0.0142) and showed a trend toward reduction of urine IL-6 (p = 0.0551). Fosfomycin treatment reduced both IL-6 and IL-8 levels significantly (p = 0.0038, <0.0001 respectively). CONCLUSION: BNO 1045 is, in addition to reducing symptoms, comparable to fosfomycin treatment in reducing the local inflammatory response associated with uUTI.


Assuntos
Fosfomicina , Infecções Urinárias , Humanos , Feminino , Fosfomicina/uso terapêutico , Interleucina-8 , Interleucina-6 , Infecções Urinárias/tratamento farmacológico , Fitoterapia , Antibacterianos/uso terapêutico
15.
medRxiv ; 2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-37398062

RESUMO

Wastewater, which contains everything from pathogens to pollutants, is a geospatially-and temporally-linked microbial fingerprint of a given population. As a result, it can be leveraged for monitoring multiple dimensions of public health across locales and time. Here, we integrate targeted and bulk RNA sequencing (n=1,419 samples) to track the viral, bacterial, and functional content over geospatially distinct areas within Miami Dade County from 2020-2022. First, we used targeted amplicon sequencing (n=966) to track diverse SARS-CoV-2 variants across space and time, and we found a tight correspondence with clinical caseloads from University students (N = 1,503) and Miami-Dade County hospital patients (N = 3,939 patients), as well as an 8-day earlier detection of the Delta variant in wastewater vs. in patients. Additionally, in 453 metatranscriptomic samples, we demonstrate that different wastewater sampling locations have clinically and public-health-relevant microbiota that vary as a function of the size of the human population they represent. Through assembly, alignment-based, and phylogenetic approaches, we also detect multiple clinically important viruses (e.g., norovirus ) and describe geospatial and temporal variation in microbial functional genes that indicate the presence of pollutants. Moreover, we found distinct profiles of antimicrobial resistance (AMR) genes and virulence factors across campus buildings, dorms, and hospitals, with hospital wastewater containing a significant increase in AMR abundance. Overall, this effort lays the groundwork for systematic characterization of wastewater to improve public health decision making and a broad platform to detect emerging pathogens.

16.
JAMA Dermatol ; 159(8): 805-806, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37342051

RESUMO

This Viewpoint offers potential solutions to research "fever," which is characterized as a symptom of larger problems in our health care and educational systems rather than the fault of residency applicants.


Assuntos
Dermatologia , Internato e Residência , Humanos , Dermatologia/educação , Seleção de Pessoal
17.
Blood ; 142(10): 887-902, 2023 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-37267517

RESUMO

Mantle cell lymphoma (MCL) is an incurable B-cell malignancy with an overall poor prognosis, particularly for patients that progress on targeted therapies. Novel, more durable treatment options are needed for patients with MCL. Protein arginine methyltransferase 5 (PRMT5) is overexpressed in MCL and plays an important oncogenic role in this disease via epigenetic and posttranslational modification of cell cycle regulators, DNA repair genes, components of prosurvival pathways, and RNA splicing regulators. The mechanism of targeting PRMT5 in MCL remains incompletely characterized. Here, we report on the antitumor activity of PRMT5 inhibition in MCL using integrated transcriptomics of in vitro and in vivo models of MCL. Treatment with a selective small-molecule inhibitor of PRMT5, PRT-382, led to growth arrest and cell death and provided a therapeutic benefit in xenografts derived from patients with MCL. Transcriptional reprograming upon PRMT5 inhibition led to restored regulatory activity of the cell cycle (p-RB/E2F), apoptotic cell death (p53-dependent/p53-independent), and activation of negative regulators of B-cell receptor-PI3K/AKT signaling (PHLDA3, PTPROt, and PIK3IP1). We propose pharmacologic inhibition of PRMT5 for patients with relapsed/refractory MCL and identify MTAP/CDKN2A deletion and wild-type TP53 as biomarkers that predict a favorable response. Selective targeting of PRMT5 has significant activity in preclinical models of MCL and warrants further investigation in clinical trials.


Assuntos
Linfoma de Célula do Manto , Fosfatidilinositol 3-Quinases , Adulto , Humanos , Linhagem Celular Tumoral , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo
19.
BJGP Open ; 7(3)2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37019473

RESUMO

BACKGROUND: Increasing the GP workforce will not necessarily level up healthcare provision. Instead, increasing GP training numbers could worsen health inequity and inequalities. This is especially true if there are fewer opportunities to learn, train, and build confidence in underserved, socioeconomically deprived areas. AIM: To investigate the representation of socioeconomic deprivation in postgraduate GP training practices in Northern Ireland (NI). DESIGN & SETTING: An analysis of socioeconomic deprivation indices and scores of GP practices in NI involved in postgraudate GP training. METHOD: The socioeconomic deprivation indices and scores of GP postgraduate training practices were compared against general practice in NI by examining the representation of practices whose patients live in areas of blanket deprivation, higher deprivation, and higher affluence. RESULTS: Of 319 practices in NI, 195 (61%) were registered as postgraduate training practices and had a statistically significantly lower deprivation score (3.02±0.21) compared with non-training practices (3.2±0.32), t(255) -2.02, P = 0.041. The proportion of training practices with blanket deprivation and higher levels of deprivation was underrepresented, with the current postgraduate GP training practices having more affluent populations. CONCLUSION: Postgraduate training practices had a statistically significant lower deprivation score and did not fully reflect the socioeconomic make-up of wider NI general practice. The results, however, are more favourable than in other areas of the UK and better than undergraduate teaching opportunities in general practice. Health inequalities will worsen if the representation of general practice training in areas of greater socioeconomic deprivation is not increased.

20.
Cureus ; 15(2): e35516, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37007318

RESUMO

Introduction In 2020, the British Society of Gastroenterologists (BSG), the Association of Coloproctology of Great Britain and Ireland (ACPGBI), and Public Health England (PHE) published joint guidelines regarding post-polypectomy surveillance. This study aimed to establish clinician adherence at the Royal Devon University Healthcare NHS Foundation Trust to the 2020 guidelines compared to the now-retired 2010 guidelines. Materials and Methods Data on 152 patients treated under the 2010 guidelines and 133 patients treated under the 2020 guidelines were collected retrospectively from the hospital's colonoscopy database. Data were analysed to determine whether patients who had a colonoscopy fulfilled BSG/ACPGBI/PHE guidelines for follow-up. Costs were estimated using the price of colonoscopy in the NHS National Schedule. Results Approximately 41.4% (63/152) of patients were adherent to the 2010 guidelines while 66.2% (88/133) of patients were adherent to the 2020 guidelines. The difference in adherence rate was 24.7% (95% confidence interval 13.5% - 35.9%, p<0.0001). Nearly 37% (35/95) of patients who would have been followed up under the 2010 guidelines did not receive any follow-up as a result of the 2020 guidelines. This represents a cost saving of £36,892.28 per year in our hospital. Approximately 47% (28/60) of patients treated under the 2020 guidelines had surveillance colonoscopy planned when the guidelines recommended no follow-up. If every clinician were fully adherent to the 2020 guidelines, then a further £29,513.82 per year would have been saved. Discussion and Conclusion Following the introduction of the 2020 guidelines, adherence to polyp surveillance guidelines increased in our hospital. However, nearly half of the colonoscopies were performed unnecessarily due to non-adherence. Furthermore, our results demonstrate that the 2020 guidelines have decreased the need for follow-up.

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