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Deaths from measles have risen to new heights in Europe in the past year. The rapid spread of the measles virus has led to more than 3,300 cases and 35 deaths in Romania, Italy, Germany and Portugal.
Prevalence and risk factors for murine typhus, scrub typhus and spotted fever group rickettsioses among adolescent and adult patients presenting to Yangon General Hospital, Yangon, Myanmar.
ObjectivesTo inform patient management and disease prevention, we sought to estimate the prevalence of, and identify risk factors for, scrub typhus, murine typhus, and spotted fever group rickettsioses (SFGR) among febrile patients presenting to hospital in Myanmar.MethodsWe recruited patients ≥12 years old with fever ≥38°C among those seeking care at Yangon General Hospital from 5 October 2015 through 4 October 2016. Standardised clinical and risk factor assessments were conducted. Confirmed scrub typhus, murine typhus, and SFGR infections were defined as a positive polymerase chain reaction or ≥4-fold rise in immunofluorescence assay antibody titre to Orientia tsutsugamushi, Rickettsia typhi or Rickettsia honei or Rickettsia conorii, respectively. Probable infection was defined as IgM titre ≥1:400 to O. tsutsugamushi, an IgM titre of ≥1:800 or IgG ≥1:1600 to R. typhi or an IgG titre of ≥1:200 to R. honeii or R. conorii. Univariate and multivariable logistic regression was used to identify associations.ResultsAmong 944 participants, the median (range) age was 37 (12-94) years, 444 (47.0%) were female, and 704 (74.6%) resided in rural areas. Among participants, 63 (6.7%) had confirmed or probable scrub typhus and 15 (1.6%) had confirmed or probable murine typhus. No SFGR infections were identified. The odds of confirmed or probable scrub typhus were lower among females than males (adjusted odds ratio [aOR] 0.5, p = 0.014), lower among those earning >300,000 Kyat per month compared with those earning less than 100,000 Kyat per month (aOR 0.28, p = 0.039), and higher among agricultural workers compared with others (aOR 2.9, p = 0.004).ConclusionScrub typhus was common among patients presenting with fever in Yangon, murine typhus was uncommon, and SFGR was not found. Empiric treatment of severe febrile illness should include an antimicrobial with activity against rickettsial diseases. Public health campaigns targeting agricultural workers are recommended.
Immunogenicity of standard and extended dosing intervals of BNT162b2 mRNA vaccine.
Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the United Kingdom to accelerate population coverage with a single dose. At this time, trial data were lacking, and we addressed this in a study of United Kingdom healthcare workers. The first vaccine dose induced protection from infection from the circulating alpha (B.1.1.7) variant over several weeks. In a substudy of 589 individuals, we show that this single dose induces severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibody (NAb) responses and a sustained B and T cell response to the spike protein. NAb levels were higher after the extended dosing interval (6-14 weeks) compared with the conventional 3- to 4-week regimen, accompanied by enrichment of CD4+ T cells expressing interleukin-2 (IL-2). Prior SARS-CoV-2 infection amplified and accelerated the response. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective immunogenic protocol.
Medullary Thyroid Cancer Risk and Mortality in Carriers of Incidentally Identified MEN2A RET Variants.
ImportanceRET germline pathogenic variants cause multiple endocrine neoplasia type 2 (MEN2), which is associated with medullary thyroid cancer. With increasing incidental identification of these variants in asymptomatic individuals outside family screening, these individuals' risk of medullary thyroid cancer and all-cause mortality without intervention remain unknown in this context.ObjectiveTo evaluate the risk of medullary thyroid cancer and all-cause mortality in clinically unselected individuals with incidentally identified RET variants and assess whether the risk of medullary thyroid cancer differs from those with clinically ascertained RET variants.Design, setting, and participantsThis prospective cohort study of 383 914 unrelated individuals from the clinically unselected UK population (UK Biobank, recruited in 2006-2010, with follow-up to June 2023) and 122 640 unrelated individuals from a US health system (Geisinger MyCode cohort, recruited 2004-2020, with follow-up to October 2023) compared medullary thyroid cancer risk in these cohorts with 1078 individuals who were clinically ascertained with suspicion of MEN2 from a UK routine practice.ExposuresRET germline pathogenic variants causing MEN2.Main outcomes and measuresFrequency and the spectrum of pathogenic RET variants, risk of clinically present medullary thyroid cancer, and all-cause mortality without thyroidectomy were assessed using proportions with exact binomial 95% CIs and survival analysis adjusted for age at recruitment and sex.ResultsIn the UK Biobank, 169 unrelated individuals (mean [SD] age at recruitment, 57.0 [8.1] years; 94 male [55.6%]) had a pathogenic RET variant (prevalence, 0.04% [95% CI, 0.04%-0.05%]). In the US health system-based cohort, 77 unrelated individuals (mean [SD] age at recruitment, 56.2 [17.8] years; 45 female [58.4%]) had a pathogenic RET variant (prevalence, 0.06% [95% CI, 0.05%-0.78%]). The variants were predominantly from the moderate-risk category per American Thyroid Association guidelines (168 individuals [99.4%] and 75 individuals [94.8%], respectively). The Kaplan-Meier estimated medullary thyroid cancer risk by age 75 years in variant carriers in the UK population was 2.2% (95% CI, 0.7%-6.9) and 19.3% (95% CI, 6.4%-30.2%) in US health system cohort. These risks were significantly lower compared with the clinically ascertained cohort with the matched variants (95.7% [95% CI, 82.1%-99.7%]). In the UK Biobank, most variant carriers (166 [98.2%]) did not undergo thyroidectomy, and their all-cause mortality by age 75 years was similar to noncarriers (6.1% [95% CI, 2.7%-13.8%] vs 5.7% [95% CI, 5.6%-5.8%]), with consistent findings in the US health system cohort.Conclusions and relevanceIn this cohort study, moderate-risk RET variants were most common in incidental cases. The variants were associated with a substantially lower medullary thyroid cancer risk than clinically ascertained cases. This evidence addresses a current knowledge gap, enabling more informed clinical decision-making.
Breast cancer germline multigene panel testing in mainstream oncology based on clinical-public health utility: ESMO Precision Oncology Working Group recommendations.
BackgroundWith widening therapeutic indications, germline genetic testing is offered to an increasing proportion of patients with breast cancer (BC) via mainstream oncology services. However, the gene set tested varies widely from just BRCA1/BRCA2 through to 'pan-cancer' panels of nearly 100 genes. If a germline pathogenic variant (GPV) is detected, the BC proband and other family GPV-carriers may be offered interventions such as risk-reducing surgery and intensive surveillance over decades for the various cancers linked to that gene.MethodsThe European Society for Medical Oncology (ESMO) Precision Oncology Working Group established an international expert working group (EWG) in BC germline genetics. This EWG firstly established a framework of criteria by which to evaluate each breast cancer susceptibility gene (BCSG) for potential inclusion on a breast cancer multigene panel test (BC-MGPT) for universal mainstream testing for BC cases. Next, the EWG scored BCSGs for impact regarding (i) BC risk estimation, (ii) clinical actionability and (iii) cancer-related mortality.ResultsThe group agreed that they would constitute a BC-MGPT based on net clinical-public health utility, as quantified by likelihood of impact on cancer-related mortality. Judged as of high or moderate impact on this basis were six BCSGs: BRCA1, BRCA2, PALB2, RAD51C, RAD51D and TP53 (for BC diagnosed <40 years of age), with possible addition of BRIP1. While potentially informative for BC risk estimation, CHEK2 and ATM were judged to offer insufficient evidence for improving cancer-related mortality. The EWG recommended strongly against inclusion of 'syndromic' genes such as STK11, PTEN, NF1 and CDH1.ConclusionsWith expanded germline testing in patients with BC (and cascade testing into families), the number and nature of resultant GPV-carriers identified will be dictated by the genes included on the upfront BC-MGPT. The potential harms, opportunity and economic costs of decades of surveillance of multiple organs and risk-reducing surgeries for GPV-carriers should be justified by strong evidence of meaningful improvement in cancer-related mortality (or health-related quality of life).
Validating data from multiplex assays of variant effect: A CanVIG-UK national survey of NHS clinical scientists.
Advances in technology have made it possible for multiplex assays of variant effect (MAVEs) to systematically generate functional data for thousands of genetic variants. Robust clinical validation and accessible online resources for MAVE data have previously been identified as barriers to the clinical adoption of new MAVEs. We delivered a survey during the November 2024 Cancer Variant Interpretation Group UK (CanVIG-UK) meeting comprising National Health Service (NHS) clinical scientists and clinical geneticists and received 46 responses from individuals regularly performing variant classification for diagnostic reporting. Only 35% reported they would accept clinical validation of the MAVE provided by the authors who conducted the assay; 20% reported they would attempt clinical validation themselves, and 61% would await clinical validation by a trusted central body. 72% reported they would use MAVE data ahead of a formal peer-reviewed publication if reviewed and clinically validated by a trusted central body. When scoring central bodies on a scale of 1-5 for confidence in their review and validation of MAVEs, CanVIG-UK (median = 5), variant curation expert panels (VCEPs; median = 5), and ClinGen SVI Functional Working Group (median = 4) all scored highly. Participants supported making variant-level data accessible via a relevant web resource (although the majority of participants expressed that additional assay-level or variant-level information would have a low likelihood of altering validation scores provided by a trusted central body). These findings, from a comparatively homogeneous clinical diagnostic group operating in a resource-constrained healthcare setting, indicate that clinical application of new MAVEs for variant classification will be delayed unless robust clinical validations are performed by a trusted central body and made readily accessible.
Impact of moderate-to-severe ulcerative colitis and Crohn's disease on sexual activity: United States and European patient perspectives from the communicating needs and features of IBD experiences (CONFIDE) survey.
BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) negatively affect patients' quality-of-life, and their impact on patients' sexual health is rarely addressed. This study assessed the impact of moderate-to-severe UC and CD on sexual activity using United States (US) and European data from the Communicating Needs and Features of IBD Experiences (CONFIDE) survey. METHODS: Online, quantitative, cross-sectional surveys were conducted among patients with moderate-to-severe UC or CD and health care professionals (HCPs). Moderate-to-severe UC or CD were defined using criteria based on previous treatment, steroid use, and/or hospitalization. The surveys were developed with input from HCPs and patient advisors and included questions on demographics, UC- or CD-related symptoms, and the impact of UC or CD on sexual health. Patients were asked whether they had avoided/decreased sexual activity in the past 3 months and their UC- or CD-related reasons. Patients and HCPs rated levels of impact of UC or CD on sex life/sexual intimacy and patients rated how bowel urgency interferes with their relationship with spouse/partner. Additionally, questions assessing the psychosocial health of patients and identifying gaps and barriers in HCP-patient communication were also included. Descriptive statistics were used to summarize the data. RESULTS: Surveys were completed by 200 US and 556 European patients with UC and 215 US and 547 European patients with CD. Of these, most US (UC: 63%, CD: 69%) and European (UC: 53%, CD: 56%) patients reported avoiding or decreasing sexual activity due to UC or CD in the past 3 months; however, the proportion was significantly greater among US patients (p
In situ cryo-electron microscopy and tomography of cellular and organismal samples.
As cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) continue to advance, the ability to visualize cellular and organismal structures with unprecedented clarity is redefining the landscape of structural biology. Breakthroughs in imaging technology, sample preparation and image processing now enable the detailed elucidation of cellular architecture, macromolecular organization, and dynamic biological processes at sub-nanometer resolution. Recent methodological advances have propelled the field to new frontiers, facilitating the investigation of complex biological questions across scales-from macromolecular complexes to organism-wide structural insights. This review explores rapidly emerging trends, highlights key innovations that are pushing the boundaries of in situ structural biology, and addresses persistent challenges in expanding the applicability of cryo-EM and cryo-ET across diverse biological systems.
The variation of coverage and access to palliative care for cancer patients in eight European countries: an exploratory vignette approach
Abstract Background Palliative care aims to maintain quality of life and offer treatment and person-centred care options for people with serious end-stage illnesses and their families. The purpose of this exploratory study was to compare the statutory coverage and access to palliative care for adult services for people with cancer in 8 European countries using a vignette approach. Methods We used a patient vignette to examine coverage and access to palliative care services across Europe. The palliative care vignette describes a pathway based on guidance for best practices of palliative care patients with incurable cancer. The surveys accompanying the vignette were completed by health services researchers knowledgeable on palliative care, practitioners, government officials, or teams consisting of a health systems expert working together with practitioners. Results Completed vignettes were received from 8 countries: Bulgaria, Estonia, France, Lithuania, the Netherlands, Portugal, Sweden and England. Services provided for palliative care envisioned in the vignette’s pathway are, generally, covered by the statutory health systems. However, in some countries cost sharing exists for hospital stays, certain medicines and medical aids. Furthermore, coverage of social and financial assessments, home equipment and financial advice varied in nearly every country. Travel times to and availability of palliative care specialists were identified as challenges across nearly all countries. Organizational barriers, societal stigmas and knowledge gaps about what palliative care entails were also found to be areas in need of improvement. Conclusions The comparative research presented provides further insight how countries organise palliative care, how services are offered and what levels of access exist around Europe. Our study showed differences in the scope of coverage of and access to the care options in the vignette. While responses showed countries have basic levels of coverage and access to services provided, there were variations, such as availability of specialists or the extent travel and waiting times influence care delivery. Settings where patients receive services also varied. As the need for palliative care grows in the future, health ministries and insurers should be increasingly concerned with how to guarantee coverage of and access to this care, as well as aware of best practices among countries facing similar challenges.
Pf8: an open dataset of Plasmodium falciparum genome variation in 33,325 worldwide samples
We describe the Pf8 data resource, the latest MalariaGEN release of curated genome variation data on over 33,000 Plasmodium falciparum samples from 99 partner studies and 122 locations over more than 50 years. This release provides open access to raw sequencing data and genotypes at over 12 million genomic positions. For the first time, it includes copy-number variation (CNV) calls in the drug-resistance associated genes gch1 and crt. As in Pf7, CNV calls are provided for mdr1 and plasmepsin2/3, along with calls for deletion in hrp2 and hrp3, genes associated with rapid diagnostic test failures. This data resource additionally features derived datasets, interactive web applications for exploring patterns of drug resistance and variation in over 5,000 genes, an updated Python package providing methods for accessing and analysing the data, and open access analysis notebooks that can be used as starting points for further analyses. In addition, informative example analyses show contrasting profiles of the decline of chloroquine resistance-associated mutations in Africa, and variation in copy number variation across 10 distinct sub-populations. To the best of our knowledge, Pf8 is the largest open data set of genome variation in any eukaryotic species, making it an invaluable foundational resource for understanding evolution, including that of pathogens.
Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A
Abstract Chromothripsis, the chaotic shattering and repair of chromosomes, is common in cancer. Whether chromothripsis generates actionable therapeutic targets remains an open question. In a cohort of 64 patients in blast phase of a myeloproliferative neoplasm (BP-MPN), we describe recurrent amplification of a region of chromosome 21q (‘chr. 21amp’) in 25%, driven by chromothripsis in a third of these cases. We report that chr. 21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. DYRK1A, a serine threonine kinase, is the only gene in the 2.7-megabase minimally amplified region that showed both increased expression and chromatin accessibility compared with non-chr. 21amp BP-MPN controls. DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development and is essential for BP-MPN cell proliferation in vitro and in vivo, and represents a druggable axis. Collectively, these findings define chr. 21amp as a prognostic biomarker in BP-MPN, and link chromothripsis to a therapeutic target.
Fecal Calprotectin and C-Reactive Protein Association With Histologic and Endoscopic Endpoints in Mirikizumab-Treated Patients With Ulcerative Colitis.
BackgroundFecal calprotectin (FC) and C-reactive protein (CRP) are noninvasive biomarkers used in ulcerative colitis (UC) clinical trials; however, thresholds defined as "normal" in trials may be higher than "normal" thresholds typically used in clinical practice. We assessed the relationship between FC and CRP improvement in the "normal" range across different cutoff thresholds for patients with moderately to severely active UC treated with mirikizumab.MethodsPatients achieving clinical response to mirikizumab in LUCENT-1 (Weeks 0-12) proceeded to LUCENT-2 (Weeks 12-52 [52 weeks of continuous mirikizumab]). Associations between FC and CRP levels at multiple thresholds and histologic-endoscopic mucosal improvement (HEMI) and histologic-endoscopic mucosal remission (HEMR) at Weeks 12 and 52 were assessed by Fisher's exact test. Least squares means of FC and CRP changes from baseline at Weeks 12 and 52 were calculated using analysis of covariance with HEMI or HEMR status as factors and baseline FC or CRP values as covariates.ResultsAt Weeks 12 and 52, greater proportions of patients with FC thresholds of ≤250, ≤150, ≤100, and ≤50 µg/g, and CRP thresholds of ≤6 and ≤5 mg/L, achieved HEMI and HEMR compared with those not achieving HEMI and HEMR. Changes from baseline in FC and CRP at Week 12 and FC at Week 52 were greater in patients who achieved HEMI and HEMR compared with those not achieving these endpoints.ConclusionsThese results show that FC and CRP analyses may contribute to a noninvasive monitoring strategy in clinical practice.ClinicalTrials.gov numbers: NCT03518086, NCT03524092.
Evaluation of the Wondfo G6PD/Hb Test for glucose-6-phosphate dehydrogenase deficiency: preliminary performance, matrix equivalence, and usability.
BackgroundCurrent treatment guidelines for radical cure of Plasmodium vivax malaria recommend the use of 8-aminoquinolines, which can result in life-threatening complications in people with glucose-6-phsophate dehydrogenase (G6PD) deficiency. Testing for this condition is recommended prior to administering such drugs. The Wondfo G6PD/Hb Test (Guangzhou Wondfo Biotech Co., Ltd., China) is a novel, quantitative point-of-care (POC) G6PD test that may help decentralize testing, expanding access to safe treatment options.MethodsTwo studies were conducted: a retrospective diagnostic accuracy study on frozen venous whole blood specimens and a prospective matrix equivalency study. First, 300 frozen specimens from Mae Sot, Thailand were tested from July-August 2022 using the Wondfo test in laboratory and simulated field conditions. Reference testing for G6PD and Hb (spectrophotometer [Pointe Scientific, USA] and HemoCue [HemoCue AB, Sweden], respectively) was completed in the laboratory. Usability was evaluated among 10 intended users. Next, 225 participants were enrolled into a prospective matrix equivalency study from March-May 2023 in Memphis, Tennessee, USA. The Wondfo test was conducted at the POC with fingerstick capillary blood, and Wondfo and HemoCue tests were completed on fresh venous (K2EDTA) blood within 12 h. Remaining specimens were shipped to PATH for repeat Wondfo and reference testing.ResultsThe Wondfo G6PD measurement showed strong correlation under both laboratory and field conditions (R2>0.9). The area under the curve was 1.00 for deficient (95% CI: 1.00-1.00) and 0.99 for intermediate individuals (95% CI: 0.99-1.00). Sensitivity was high (1.00) across all conditions and groups (lower bound of the 95% CI ≥0.85). Good correlation was observed in both capillary and fresh venous blood against the reference and each other (R2>0.75). McNemar's test showed no significant differences in classification between venous and capillary specimens. The Wondfo test achieved 98.2% (95%CI: 95.5-99.5%) overall agreement. All usability participants successfully completed quality control and test procedures, rating the test system highly for ease of use.ConclusionsThe Wondfo G6PD/Hb Test demonstrates good diagnostic performance using current manufacturer thresholds across various conditions and both venous and capillary specimens. Comparable performance in both specimen types supports matrix equivalence. Usability is acceptable for end users, though refinements were recommended.
Safety and tolerability of metformin in overweight and obese patients with dengue: An open-label clinical trial (MeDO)
Background Despite dengue being a major public health problem, there are no antiviral or adjunctive treatments for the disease. Novel therapeutics are needed, particularly for patients at high risk of severe disease, including those living with obesity. Metformin reduces dengue viral replication in vitro through AMPK activation and may also have beneficial immunomodulatory effects. Methods We conducted an open label trial at the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, enrolling 120 patients with dengue and obesity (60 treatment arm, 60 control arm receiving standard of care only). Within the treatment arm, the first 10 patients were prescribed low dose metformin, and the remaining 50 patients received weight-based dosing of 1-1.5g/day. The primary outcome was the number of adverse events (AEs), and secondary outcomes were clinical and laboratory parameters, including fever clearance time, platelet nadir, percentage of haematocrit change from baseline, maximum creatinine and highest AST/ALT, and the kinetics of plasma viraemia and NS1 antigenaemia. Results The majority of patients in both groups had dengue with warning signs. Six patients in the metformin group and 5 controls developed dengue shock syndrome, and no patients died. There were more AEs recorded in the metformin treated group than in the control group (mean±SD: 15 ± 4 vs. 11 ± 6), particularly the high-dose metformin group (15 ± 5). Twenty-five patients (42%) had to stop the study drug due to AEs, including severe diarrhea (n = 12), dengue shock (n = 5), increased lactate of >3mmol/L (n = 4), hypoglycemia (n = 3), and persistent vomiting (n = 1). There were no clear differences in secondary outcomes between the two groups. Conclusions Metformin was poorly tolerated in patients with dengue, mainly due to gastrointestinal side effects. Metformin did not beneficially affect clinical evolution or virological parameters compared to supportive care alone. Our data does not support progression to larger phase 3 trials of metformin in patients with dengue. Trial registration ClinicalTrials.gov: NCT04377451 (May 6th, 2020).
Targeting GRPR for sex hormone-dependent cancer after loss of E-cadherin
Abstract Sex inequalities in cancer are well documented, but the current limited understanding is hindering advances in precision medicine and therapies1. Consideration of ethnicity, age and sex is essential for the management of cancer patients because they underlie important differences in both incidence and response to treatment2,3. Age-related hormone production, which is a consistent divergence between the sexes, is underestimated in cancers that are not recognized as being hormone dependent4–6. Here, we show that premenopausal women have increased vulnerability to cancers, and we identify the cell–cell adhesion molecule E-cadherin as a crucial component in the oestrogen response in various cancers, including melanoma. In a mouse model of melanoma, we discovered an oestrogen-sensitizing pathway connecting E-cadherin, β-catenin, oestrogen receptor-α and GRPR that promotes melanoma aggressiveness in women. Inhibiting this pathway by targeting GRPR or oestrogen receptor-α reduces metastasis in mice, indicating its therapeutic potential. Our study introduces a concept linking hormone sensitivity and tumour phenotype in which hormones affect cell phenotype and aggressiveness. We have identified an integrated pro-tumour pathway in women and propose that targeting a G-protein-coupled receptor with drugs not commonly used for cancer treatment could be more effective in treating E-cadherin-dependent cancers in women. This study emphasizes the importance of sex-specific factors in cancer management and offers hope of improving outcomes in various cancers.
Optimizing dog population control strategies in Thailand using mathematical and economic modeling.
A mathematical model was constructed to investigate dog population dynamics and explore the impact of population management and rabies prevention. We aimed to evaluate cost-effective sterilization and vaccination strategies for dog population control and rabies prevention in Thailand. The developed compartmental model was calibrated with dog population data from Lopburi province (between 2019 and 2022) and simulated five sterilization scenarios. These measures included a combined 80% coverage of the rabies vaccine and 20% coverage of a sterilization program among non-specific dog types. Our findings indicated that sterilization programs targeting female indoor, outdoor, and stray dogs may prove to be the most effective in reducing the total dog population above 50% over a five-year period, surpassing the efficacy of the current intervention. Furthermore, the cost-effectiveness analysis showed that the two female dog sterilization strategies were cost-saving compared to the current practice, as the total costs of sterilization and vaccination decreased over time due to the reduction in the dog population. In conclusion, targeting female dog sterilization could reduce the population and was cost-saving compared to current strategies. Further data to inform dog population demographic and available resources including manpower, rabies vaccine, sterilization toolkits, and related materials will be required to fully explore intervention accessibility and feasibility within the context of rabies prevention and control in Thailand.