Investigating the nexus of metabolic syndrome, serum uric acid, and dementia risk: a prospective cohort study.

BACKGROUND: The global dementia prevalence is surging, necessitating research into contributing factors. We aimed to investigate the association between metabolic syndrome (MetS), its components, serum uric acid (SUA) levels, and dementia risk. METHODS: Our prospective study comprised 466,788 participants without pre-existing MetS from the UK Biobank. We confirmed dementia diagnoses based on the ICD-10 criteria (F00-03). To evaluate the dementia risk concerning MetS, its components, and SUA levels, we applied Cox proportional hazards models, while adjusting for demographic factors. RESULTS: Over a median follow-up of 12.7 years, we identified 6845 dementia cases. Individuals with MetS had a 25% higher risk of all-cause dementia (hazard ratio [HR] = 1.25, 95% confidence interval [CI] = 1.19-1.31). The risk increased with the number of MetS components including central obesity, dyslipidemia for high-density lipoprotein (HDL) cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides. Particularly for those with all five components (HR = 1.76, 95% CI = 1.51-2.04). Dyslipidemia for HDL cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides were independently associated with elevated dementia risk (p < 0.01). MetS was further linked to an increased risk of all-cause dementia (11%) and vascular dementia (VD, 50%) among individuals with SUA levels exceeding 400 µmol/L (all-cause dementia: HR = 1.11, 95% CI = 1.02-1.21; VD: HR = 1.50, 95% CI = 1.28-1.77). CONCLUSIONS: Our study provides robust evidence supporting the association between MetS, its components, and dementia risk. These findings emphasize the importance of considering MetS and SUA levels in assessing dementia risk, offering valuable insights for prevention and management strategies.

Rebuilding to shape a better future: the role of young professionals in the public health workforce.

The COVID-19 pandemic has made clear the extreme needs of the public health workforce. As societies discuss how to build up the capacity and infrastructure of their systems, it is crucial that young professionals are involved. Previous attempts to incorporate young professionals into the public health workforce have wrestled with inaccessibility, tokenisation, and a lack of mentorship, leading to a loss of potential workforce members and a non-representative workforce that reinforces systemic societal exclusion of diverse young people. These barriers must be addressed through robust mentorship structures, intentional recruitment and continuous support, as well as genuine recognition of the contributions of young professionals to build the sustainable, interdisciplinary, unified public health that is necessary for the future.

Bendamustine with rituximab, etoposide and carboplatin (T(R)EC) in relapsed or refractory aggressive lymphoma: a prospective multicentre phase 1/2 clinical trial.

We sought to develop a safe and effective outpatient salvage regimen by replacing ifosfamide within the (R)ICE (rituximab, ifosfomide, carboplatin, etoposide) regimen with bendamustine (T(R)EC) via a multicentre phase I/II study for patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) and classic Hodgkin lymphoma (HL). Therapy consisted of 60-120 mg/m2 per day bendamustine on days 1 and 2 in combination with carboplatin, etoposide and rituximab (only for CD20+ lymphoma) used in the (R)ICE regimen for up to 2 cycles. The objectives were to define a maximally tolerated dose (MTD) of bendamustine, determine safety and toxicity, assess efficacy, and evaluate impact on stem cell collection. Forty-eight patients were treated of which 71% had refractory disease. No dose-limiting toxicities were observed. The recommended phase II dose of bendamustine was 120 mg/m2 per day on days 1 and 2. Response rates were 85% (70% complete response, CR) in HL, and 65% (40% CR) in DLBCL. Stem cell collection was successful in 30 of 32 patients. The most common non-haematological toxicities ≥grade 3 were febrile neutropenia (8%) and dehydration (8%). The T(R)EC regimen safely yields high response rates, successfully mobilizes peripheral blood stem cells and compares favourably to RICE, offering an effective outpatient treatment option for patients with relapsed or refractory DLBCL and HL.

Idarubicin, cytarabine, and pravastatin as induction therapy for untreated acute myeloid leukemia and high-risk myelodysplastic syndrome.

Previous studies suggest that idarubicin/cytarabine(ara-C)/pravastatin (IAP) is an active salvage regimen for patients with AML. We therefore investigated this regimen in patients with newly-diagnosed AML or MDS (≥10% blasts). Patients were eligible if the anticipated treatment-related mortality (TRM) was <10%. Patients received pravastatin (1,280 mg/day po; days 1-8), cytarabine (1.5 g/m(2) /day; days 4-7), and idarubicin (12 mg/m(2) /day, days 4-6). Up to 3 cycles of consolidation with a shortened course was permitted. The primary endpoints were "good CR" rate (CR on day 35 without minimal residual disease) and TRM in the first 28 days. The study was to stop if after each cohort of 5 patients (a) the Bayesian posterior probability was < 5% that the true "good CR rate" was ≥ 70% or (b) the posterior probability was >25% that the TRM rate was ≥5%. Twenty-four patients were included. Conventional CR was achieved in 15 (63%) patients but only 12 (50%) achieved "good CR". 4 of 12 (33%) patients with "good CR" relapsed at median of 16 weeks (10.5-19). Five (21%) patients had refractory disease. Survival probability at 1 year was 72% (48.7-64). Two (8.3%) patients died within 28 days from multiorgan failure. The most common grade 3-4 adverse effects were febrile neutropenia (75%) and diarrhea (25%). Based on the stopping rules accrual ceased after entry of these 24 patients. IAP did not meet the predefined efficacy criteria for success. Therefore, we would not recommend this regimen for phase three testing in this patient subset.

Climate change, biodiversity loss, and Indigenous Peoples' health and wellbeing: a systematic umbrella review protocol.

BACKGROUND: Research that examines the intersections of Indigenous Peoples' health and wellbeing with climate change and biodiversity loss is abundant in the global scholarship. A synthesis of this evidence base is crucial in order to map current pathways of impact, as well as to identify responses across the global literature that advance Indigenous health and wellbeing, all while centering Indigenous voices and perspectives. This protocol details our proposed methodology to systematically conduct an umbrella review (or review of reviews) of the synthesized literature on climate change, biodiversity loss, and the health and wellbeing of Indigenous Peoples globally. METHODS: A multidisciplinary team of Indigenous and non-Indigenous scholars will conduct the review, guided by an engagement process with an Indigenous Experts group. A search hedge will be used to search PubMed®, Scopus®, Web of Science™, CINAHL (via EBSCOHost®), and Campbell Collaboration databases and adapted for use in grey literature sources. Two independent reviewers will conduct level one (title/abstract) and level two (full-text) eligibility screening using inclusion/exclusion criteria. Data will be extracted from included records and analyzed using quantitative (e.g., basic descriptive statistics) and qualitative methods (e.g., thematic analysis, using a constant comparative method). DISCUSSION: This protocol outlines our approach to systematically and transparently review synthesized literature that examines the intersections of climate change, biodiversity loss, and Indigenous Peoples' health and wellbeing globally. SYSTEMATIC REVIEW REGISTRATION: This protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on April 24, 2023 (registration number: CRD42023417060).

Climate change, biodiversity loss, and Indigenous Peoples' health and wellbeing: A systematic umbrella review.

Indigenous Peoples worldwide are experiencing a cascade of impacts on their health and wellbeing as a result of climate change and biodiversity loss. Existing literature at the interface of climate change, biodiversity loss, and Indigenous health tells us that Indigenous Peoples are among those most disproportionately and acutely affected by these impacts. Yet, a gap exists with respect to comprehensively and critically synthesizing the impacts reported across this literature and identifying Indigenous-led responses. Guided by an Indigenous advisory group, we employed a systematic umbrella review methodology, following PRISMA guidelines, to characterize the global secondary literature (PROSPERO registration #: CRD42023417060). In so doing, we identified the proximal, intermediate, distal, and gendered impacts of climate change and biodiversity loss on Indigenous health and wellbeing as well as Indigenous-led responses. Five databases were searched for published reviews, along with a grey literature search that focused on underrepresented geographic regions in the academic literature. Two independent reviewers conducted two-stage screening, data extraction, and quality assessment of retrieved records. Basic descriptive statistics were calculated. Qualitative data were analyzed thematically, using a constant comparative approach. A total of 38 review articles met the eligibility criteria and 37 grey literature records were retrieved and included in the review. Reviews were published between 2010-2023 and geographically clustered in the Circumpolar North. Intersecting proximal, intermediate, and distal impacts were characterized as place-based and specific, and linked to colonialism as an antecedent to and driver of these impacts. Gendered impacts were underexplored within reviews. Reviewed literature underscored the value of engaging diverse knowledge systems; platforming localized, community-led adaptation to climate change and biodiversity loss, while addressing sociopolitical constraints to these efforts; and applying a broader conceptualization of health that aligns with Indigenous frameworks. Going forward, we must foreground equity- and rights-based considerations within integrated responses to climate and biodiversity crises.

Precise prediction of phase-separation key residues by machine learning.

Understanding intracellular phase separation is crucial for deciphering transcriptional control, cell fate transitions, and disease mechanisms. However, the key residues, which impact phase separation the most for protein phase separation function have remained elusive. We develop PSPHunter, which can precisely predict these key residues based on machine learning scheme. In vivo and in vitro validations demonstrate that truncating just 6 key residues in GATA3 disrupts phase separation, enhancing tumor cell migration and inhibiting growth. Glycine and its motifs are enriched in spacer and key residues, as revealed by our comprehensive analysis. PSPHunter identifies nearly 80% of disease-associated phase-separating proteins, with frequent mutated pathological residues like glycine and proline often residing in these key residues. PSPHunter thus emerges as a crucial tool to uncover key residues, facilitating insights into phase separation mechanisms governing transcriptional control, cell fate transitions, and disease development.

A phase I study of pulse high-dose vorinostat (V) plus rituximab (R), ifosphamide, carboplatin, and etoposide (ICE) in patients with relapsed lymphoma.

Given the poor outcomes of relapsed aggressive lymphomas and preclinical data suggesting that ≥2·5 µmol/l concentrations of vorinostat synergize with both etoposide and platinums, we hypothesized that pulse high-dose vorinostat could safely augment the anti-tumour activity of (R)ICE [(rituximab), ifosphamide, carboplatin, etoposide] chemotherapy. We conducted a phase I dose escalation study using a schedule with oral vorinostat ranging from 400 mg/d to 700 mg bid for 5 d in combination with the standard (R)ICE regimen (days 3, 4 and 5). Twenty-nine patients [median age 56 years, median 2 prior therapies, 14 chemoresistant (of 27 evaluable), 2 prior transplants] were enrolled and treated. The maximally tolerated vorinostat dose was defined as 500 mg twice daily × 5 d. Common dose limiting toxicities included infection (n = 2), hypokalaemia (n = 2), and transaminitis (n = 2). Grade 3 related gastrointestinal toxicity was seen in 9 patients. The median vorinostat concentration on day 3 was 4·5 µmol/l (range 4·2-6·0 µmol/l) and in vitro data confirmed the augmented antitumour and histone acetylation activity at these levels. Responses were observed in 19 of 27 evaluable patients (70%) including 8 complete response/unconfirmed complete response. High-dose vorinostat can be delivered safely with (R)ICE, achieves potentially synergistic drug levels, and warrants further study, although adequate gastrointestinal prophylaxis is warranted.

Reorganization of prefrontal network in stroke patients with dyskinesias: evidence from resting-state functional near-infrared spectroscopy.

Stroke usually causes multiple functional disability. To develop novel rehabilitation strategies, it is quite necessary to improve the understanding of post-stroke brain plasticity. Here, we use functional near-infrared spectroscopy to investigate the prefrontal cortex (PFC) network reorganization in stroke patients with dyskinesias. The PFC hemodynamic signals in the resting state from 16 stroke patients and 10 healthy subjects are collected and analyzed with the graph theory. The PFC networks for both groups show small-world attributes. The stroke patients have larger clustering coefficient and transitivity and smaller global efficiency and small-worldness than healthy subjects. Based on the selected network features, the established support vector machine model classifies the two groups of subjects with an accuracy rate of 88.5%. Besides, the clustering coefficient and local efficiency negatively correlate with patients' motor function. This study suggests that the PFC of stroke patients with dyskinesias undergoes specific network reorganization.

Effect of health literacy and shared decision-making on choice of weight-loss plan among overweight or obese participants receiving a prototype artificial intelligence robot intervention facilitating weight-loss management decisions.

Implementation of artificial intelligence (AI) in medical decision-making is still in early development. We developed an AI robot intervention prototype with a health literacy-friendly interface that uses interactive voice response (IVR) surveying to assist in decision-making for weight loss. The weight-specific health literacy instrument (WSHLI) and Shared Decision-Making Questionnaire (SDMQ) were used to measure factors influencing weight-loss decisions. Factors associated with participants choosing to lose weight were analyzed using logistic regression, and factors influencing the selection of specific weight-loss plans were examined with one-way analysis of variance. Our study recruited 144 overweight or obese adults (69.4% women, 58.3% with body mass index (BMI) ≥ 24). After interacting with the AI robot, 78% of the study population made the decision to lose weight. SDMQ score was a significant factor positively influencing the decision for weight-loss (odds ratio [OR]: 2.16, 95% confidence interval [CI]: 1.09-4.29, p = 0.027). Individuals who selected self-monitored lifestyle modification (mean ± SD: 11.52 ± 1.95) had significantly higher health literacy than those who selected dietician-assisted plan (9.92 ± 2.30) and physician-guided treatment (9.60 ± 1.52) (both p = 0.001). The study results demonstrated that our prototype AI robot can effectively encourage individuals to make decisions regarding weight management and that both WSHLI and SDMQ scores affect the choice of weight-loss plans.

THE VALUE OF A REGIONAL 'LIVING' COVID-19 REGISTRY AND THE CHALLENGES OF KEEPING IT ALIVE.

Background: The availability of accurate, reliable, and timely clinical data is crucial for clinicians, researchers, and policymakers so that they can respond effectively to emerging public health threats. This was typified by the recent SARS-CoV-2 pandemic and the critical knowledge and data gaps associated with novel Coronavirus 2019 disease (COVID-19).We sought to create an adaptive, living data mart containing detailed clinical, epidemiologic, and outcome data from COVID-19 patients in our healthcare system. If successful, the approach could then be used for any future outbreak or disease. Methods: From 3/13/2020 onward, demographics, comorbidities, outpatient medications, along with 75 laboratory, 2 imaging, 19 therapeutic, and 4 outcome-related parameters, were manually extracted from the electronic medical record (EMR) of SARS-CoV-2 positive patients. These parameters were entered on a registry featuring calculation, graphing tools, pivot tables, and a macro programming language. Initially, two internal medicine residents populated the database, then professional data abstractors populated the registry. Clinical parameters were developed with input from infectious diseases and critical care physicians and using a modified COVID-19 worksheet from the U.S. Centers for Disease Control and Prevention (CDC). Registry contents were migrated to a browser-based, metadata-driven electronic data capture software platform. Eventually, we developed queries and used various business intelligence (BI) tools which enabled us to semi-automate data ingestion of 147 clinical and outcome parameters from the EMR, via a large U.S. hospital-based, service-level, all-payer database. Statistics were performed in R and Minitab. Results: From March 13, 2020 to May 17, 2021, 549,691 SARS-CoV-2 test results on 236,144 distinct patients, along with location, admission status, and other epidemiologic details are stored on the cloud-based BI platform. From March 2020 until May 2021, extraction of clinical-epidemiologic parameter had to be performed manually. Of those, 543 have had >/=75 parameters fully entered in the registry. Ten clinical characteristics were significantly associated with the need for hospital admission. Only one characteristic was associated with a need for ICU admission. Use of supplemental oxygen, vasopressors and outpatient statin were associated with increased mortality.Initially, 0.5hrs -1.5 hours per patient chart (approximately 450-575 person hours) were required to manually extract the parameters and populate the registry. As of May 17, 2021, semi-automated data ingestion from the U.S. hospital all-payer database, employing user-defined queries, was implemented. That process can ingest and populate the registry with 147 clinical, epidemiologic, and outcome parameters at a rate of 2 hours per 100 patient charts. Conclusion: A living COVID-19 registry represents a mechanism to facilitate optimal sharing of data between providers, consumers, health information networks, and health plans through technology-enabled, secure-access electronic health information. Our approach also involves a diversity of new roles in the field, such as using residents, staff, and the quality department, in addition to professional data extractors and the health informatics team.Initially, due to the overwhelming number of infections that continues to accelerate, and the labor/time intense nature of the project, only a small fraction of all patients with COVID-19 had all parameters entered in the registry. Therefore, this report also offers lessons learned and discusses sustainability issues, should others wish to establish a registry. It also highlights the registry's local and broader public health significance. Beginning in June 2021, whole-genome sequencing results such as lineages harboring important viral mutations, or variants of concern will be linked to the clinical meta-data.

Association between serum cystatin C level and hemodynamically significant aortic stenosis: a prospective cohort study.

BACKGROUND: Cystatin C (CysC) is a cysteine protease inhibitor involved in proteins catabolism and plays an essential role in human vascular pathophysiology. CysC may also increase the risk of aortic stenosis (AS), but limited studies have reported on this association. This study aimed to investigate if elevated serum CysC levels are associated with hemodynamically significant AS. METHODS: Serum CysC levels were estimated in 4,791 participants, samples were collected in 1990-1992. The study population was divided into quintile groups. Follow-up continued in 2011-2013 when participants returned for echocardiography examination. Incidence of aortic valve disease (AVD) was ascertained by Doppler echocardiography through the end of 2013. AVD defined in hemodynamic progression was assessed and classified as aortic sclerosis, mild stenosis, and moderate-to-severe stenosis. RESULTS: Overall, a total of 4,791 participants (mean age: 54.8 ± 5.0 years, females: 57.6%, blacks: 8.2%) were included in this study. During a follow-up of 21 years, we identified 736 cases (15.4%) of aortic sclerosis, 194 cases (4.0%) of mild stenosis, and 42 cases (0.7%) of moderate-to-severe stenosis. Compared with serum CysC levels within individual quintile groups, the odds ratio (OR) was per standard deviation associated with an increased incidence of AVD (OR = 1.15, 95% CI: 1.05-1.26,P = 0.002). CONCLUSIONS: In this large population-based study, an increased serum CysC levels is independently associated with the incidence of hemodynamically significant AS. However, this association appears not to extend to patients with extremely high serum CysC levels and necessitate further investigation.

The effects on public health of climate change adaptation responses: a systematic review of evidence from low- and middle-income countries.

Climate change adaptation responses are being developed and delivered in many parts of the world in the absence of detailed knowledge of their effects on public health. Here we present the results of a systematic review of peer-reviewed literature reporting the effects on health of climate change adaptation responses in low- and middle-income countries (LMICs). The review used the 'Global Adaptation Mapping Initiative' database (comprising 1682 publications related to climate change adaptation responses) that was constructed through systematic literature searches in Scopus, Web of Science and Google Scholar (2013-2020). For this study, further screening was performed to identify studies from LMICs reporting the effects on human health of climate change adaptation responses. Studies were categorised by study design and data were extracted on geographic region, population under investigation, type of adaptation response and reported health effects. The review identified 99 studies (1117 reported outcomes), reporting evidence from 66 LMICs. Only two studies were ex ante formal evaluations of climate change adaptation responses. Papers reported adaptation responses related to flooding, rainfall, drought and extreme heat, predominantly through behaviour change, and infrastructural and technological improvements. Reported (direct and intermediate) health outcomes included reduction in infectious disease incidence, improved access to water/sanitation and improved food security. All-cause mortality was rarely reported, and no papers were identified reporting on maternal and child health. Reported maladaptations were predominantly related to widening of inequalities and unforeseen co-harms. Reporting and publication-bias seems likely with only 3.5% of all 1117 health outcomes reported to be negative. Our review identified some evidence that climate change adaptation responses may have benefits for human health but the overall paucity of evidence is concerning and represents a major missed opportunity for learning. There is an urgent need for greater focus on the funding, design, evaluation and standardised reporting of the effects on health of climate change adaptation responses to enable evidence-based policy action.

Physician attire: physicians perspectives on attire in a community hospital setting among non-surgical specialties.

Background: Several studies have demonstrated a patient preference for physicians wearing a white coat associated with improved patient satisfaction. There are few studies on physicians' perceptions of attire mainly done in the outpatient and surgical specialties. Objective: Assess non-surgical physicians' perception of attire in the hospital and to identify if any difference in the choice of attire amongst generation X and millennial physicians. Methods: We surveyed 86 physicians in the hospital with six sets of pictures of commonly worn physician attires in the hospital setting with a two-part questionnaire. Key Results: Formal attire with a white coat was found to be most favored, followed by formal without a white coat. Casual attire without a white coat was the least preferred across the surveyed attributes. The results were similar in generation X and millennial physicians. Only 49% concordance was observed with what physicians preferred and what they wore. Conclusion: Our study showed that physicians felt wearing a white coat was the best to convey specific attributes like honesty, confidence, professionalism, among others, similar to prior studies done in patients. However, less than half of the physicians surveyed themselves followed the preferred attire.

Changing the treatment paradigm in myelodysplastic syndromes.

The treatment algorithm for the patient with myelodysplastic syndrome (MDS) is in the process of being revitalized based on recent results of clinical trials. Historically, the goal for lower-risk patients was hematologic improvement, and disease modification was reserved for patients in the higher-risk category. Recent data now favor shifting emphasis away from supportive care alone and toward altering the disease course and prolonging survival, particularly in patients with intermediate-2 and high-risk disease. In addition, there is a greater appreciation for the significant morbidity and mortality resulting from MDS and increased efforts to improve quality of life while pursuing treatment. Immunomodulation with lenalidomide has yielded durable cytogenetic and hematologic responses and also has shown potential to alter disease course. Similarly, immunosuppression with antithymocyte globulin has shown sustained hematologic responses in selected patient subgroups. The methyltransferase inhibitors have demonstrated the ability to alter the natural history of disease and thus prolong time to leukemic transformation. In addition, azacitidine has shown the capacity to extend survival compared with the previous gold standard of conventional care regimens. With these new data, evaluation of treatment options should no longer focus on response rates as the sole endpoint but rather on time to leukemic transformation and survival. Timing of available therapies, including stem cell transplantation, should be incorporated into the new treatment paradigm, with end goals of prolonging survival and optimizing patient outcomes.

Phase 1/2 trial of GCLAM with dose-escalated mitoxantrone for newly diagnosed AML or other high-grade myeloid neoplasms.

Outcomes with "7 + 3" are often unsatisfactory in acute myeloid leukemia (AML). Trials demonstrating improved outcomes with high-dose cytarabine, addition of cladribine, or escalated anthracycline doses prompted a phase 1/2 study (NCT02044796) of G-CSF, cladribine, high-dose cytarabine, and dose-escalated mitoxantrone (GCLAM) in adults with newly-diagnosed AML or other high-grade myeloid neoplasms. One hundred and twenty-one patients, median age 60 (range 21-81) years, were enrolled. In phase 1, cohorts of 6-12 patients were assigned to 12-18 mg/m2/day of mitoxantrone as part of GCLAM. Because all dose levels were well-tolerated, mitoxantrone at 18 mg/m2 was declared the recommended phase 2 dose (RP2D). 74/94 (79%) patients treated at the RP2D achieved a complete remission (CR; 67/74 without measureable residual disease [MRD]) for an overall MRDneg CR rate of 71% (primary phase 2 endpoint). Seven patients achieved a CR with incomplete blood count recovery (CRi; 7%, 5 MRDneg) for a CR/CRi rate of 81/94 (86%). Four-week mortality was 2%. After adjustment, the MRDneg CR and CR/CRi rates compared favorably to 100 matched controls treated with 7 + 3 at our center and 245 matched patients treated with 7 + 3 on a cooperative group trial. Our data indicate GCLAM with mitoxantrone at 18 mg/m2/day is safe and induces high-quality remissions in adults with newly-diagnosed AML.