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1.
J Prev Alzheimers Dis ; 11(5): 1348-1354, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39350380

RESUMO

BACKGROUND: There has been little direct examination of how traumatic brain injury (TBI) affects the rate of neurodegeneration for individuals with Alzheimer's disease (AD). METHODS: The study examined 89 cognitively normal adults (65 with and 24 without prior TBI) and 65 with AD (16 with and 49 without prior TBI). Cortical thickness was quantified from T1-weighted MRI scans at baseline and follow-up (mean interval 33.4 months). Partial least squares analysis was used to evaluate the effects of AD and TBI history on the longitudinal change in cortical thickness. RESULTS: Significant group effects were identified throughout the frontal and temporal cortices. Comparison of the AD groups to their control cohorts showed greater relative atrophy for the AD cohort with prior TBI. CONCLUSION: These results indicate that a history of TBI exacerbates longitudinal declines in cortical thickness among AD patients, providing new insights into the shared pathomechanisms between these neurological conditions.


Assuntos
Doença de Alzheimer , Lesões Encefálicas Traumáticas , Imageamento por Ressonância Magnética , Humanos , Doença de Alzheimer/patologia , Doença de Alzheimer/diagnóstico por imagem , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/patologia , Masculino , Feminino , Idoso , Estudos Longitudinais , Córtex Cerebral/patologia , Córtex Cerebral/diagnóstico por imagem , Atrofia , Pessoa de Meia-Idade , Espessura Cortical do Cérebro , Idoso de 80 Anos ou mais
2.
Plast Reconstr Surg ; 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39451147

RESUMO

BACKGROUND: Breast reconstruction following mastectomy for the treatment of breast cancer restores form and enhances patient satisfaction. The Affordable Care Act (ACA) of 2010 aimed to impact trends in breast reconstruction, but recent information regarding racial and ethnic disparities is lacking. METHODS: We analyzed National Surgical Quality Improvement Program (NSQIP) data spanning 2005-2022 to investigate the impact of ACA on racial and ethnic diversity in immediate breast reconstruction post-mastectomy. Patient demographics, including race and ethnicity, were considered. Statistical analyses included Pearson chi-square tests and multivariable logistic regressions to assess trends and disparities over time. RESULTS: In total, 224,506 patients met inclusion criteria. Analysis revealed that in the pre-ACA era, American Indian or Alaska Native, Asian, and Black or African American individuals underwent immediate breast reconstruction at lower rates compared to White patients (P < 0.001). Additionally, Hispanic patients were less likely to undergo breast reconstruction compared to non-Hispanic patients (28.0% vs 33.4%; P < 0.001). In the post-ACA period, this trend persisted with all racial groups undergoing immediate breast reconstruction at lower rates compared to White patients (P < 0.001). However, Hispanic patients were more likely to undergo immediate breast reconstruction compared to non-Hispanic patients (53.8% vs 47.9%, P < 0.001). CONCLUSIONS: Despite legislative efforts and a steady increase in immediate breast reconstruction rates over the years, racial disparities in breast reconstruction rates persist, highlighting the need for ongoing monitoring and targeted interventions to ensure equitable reconstructive care for all patients.

3.
J Craniofac Surg ; 2024 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-39440992

RESUMO

BACKGROUND: The integration of robotic technology into surgical procedures has gained considerable attention for its promise to enhance a variety of clinical outcomes. Robotic deep inferior epigastric perforator (DIEP) flap harvest has emerged as a novel approach for autologous breast reconstruction. This systematic review aims to provide a comprehensive overview of the current techniques, outcomes, and complications of robotic DIEP flap surgery. METHODS: A systematic literature search was conducted after PRISMA 2020 guidelines across databases including PubMed, Embase, Google Scholar, and Web of Science from 2000 to 2023. Articles exploring robotic DIEP flap harvest for breast reconstruction were assessed to compare operative techniques, clinical outcomes, and complications. The risk of bias was evaluated using ROBINS-I and the Newcastle-Ottawa scale. RESULTS: Fourteen studies involving 108 patients were included. Three studies used a totally extraperitoneal (TEP) technique, whereas 11 studies used a transabdominal preperitoneal (TAPP) approach. Preoperative planning utilized computed tomography angiography and magnetic resonance angiography imaging. The mean robotic operative time was 64 minutes, with total operative times averaging 574 minutes for TAPP and 497 minutes for TEP. The mean length of stay was 5 days, and the mean fascial incision length was 3 cm. Overall complication rate was 14.9%, with no significant difference compared with conventional DIEP flap procedures. CONCLUSION: Robotic DIEP flap harvest is a promising technique that may reduce postoperative pain and limiting abdominal donor site morbidity. Potential limitations include longer operative times, variable hospital stays, and increased costs.

4.
World Med Health Policy ; 16(3): 489-505, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39430118

RESUMO

Considerable efforts have been devoted to addressing the problem of conflicts of interest (COI) in health research, policy, education, and practice. An overwhelming body of evidence demonstrates that conflicts associate with deleterious outcomes for the biomedical research enterprise. Nevertheless, little has changed for research, specifically, since the Institute of Medicine's landmark Conflicts of Interest in Medical Research, Practice, and Education was published over a decade ago. In this article, we draw on interdisciplinary research on manufactured controversies in science-policy deliberation to argue that the development of meaningful COI policy has been stymied through argumentative "wedges" designed to delay consensus and policy formation. Argumentative wedges disrupt policy formation by mischaracterizing the evidence base, continuously redefining the terms of the debate and/or recommending overly narrow criteria for who should be allowed to participate in policy deliberation. In this article, we argue researchers and policymakers interested in better addressing the harmful effects of COI can improve their efforts through strategic efforts designed to disrupt the wedges of manufactured controversy. Additionally, we argue that efforts to address COI can be further enhanced through embracing a broader framework for COI inquiry. Specifically, we argue that aggregate approaches to COI can help to disrupt these wedges and provide a strong foundation for future policy.

5.
J Arthroplasty ; 2024 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-39428002

RESUMO

INTRODUCTION: The optimal treatment for periprosthetic fracture (PPfx) around total knee arthroplasty (TKA) remains a topic of debate. Due to its low incidence, comparative studies analyzing arthroplasty and fixation are lacking in the literature. The purpose of this study was to compare the outcomes of distal femoral replacement (DFR) and open reduction and internal fixation (ORIF) for distal femur PPfx. METHODS: We reviewed a consecutive series of 99 patients who underwent DFR (n = 54) or ORIF (n = 45) for distal femur PPfx. The indications for DFR were reviewed. Fractures were classified based on their relation to the implant using the Su classification. The primary outcome was re-revision, while secondary endpoints included inpatient complications, mortality within the first year, and mechanical complications such as loosening and non-union. RESULTS: Type 2 fractures were the most prevalent type in both groups (DFR 37 versus ORIF 48.9%), while Type 1 fractures were more commonly treated with ORIF (35.6 versus 16.7%) and Type 3 with DFR (46.3 versus 15.6%) (P = 0.003). The preferred techniques in the ORIF group were plate osteosynthesis (66.7%) and retrograde nailing (31.1%). At a mean follow-up of 4.2 years (range, 1 to 14.1), DFR and ORIF did not demonstrate any difference in revision rates (13 versus 24.4%, P = 0.140) or mortality (3.7 versus 4.4%, P = 0.887). However, more mechanical complications were noted in the ORIF group (22.2 versus 7.4%, P = 0.035). CONCLUSION: Both distal femoral replacement and open reduction and internal fixation have comparable revision rates, complications, and clinical outcomes when used in supracondylar periprosthetic distal femur fractures. Longer-term studies are needed to assess DFR survivorship as well as outcomes of newer trauma techniques such as nail-plate combinations.

7.
Artigo em Inglês | MEDLINE | ID: mdl-39228099

RESUMO

BACKGROUND: Strengths-based approaches to health care are often seen as an alternative to deficit-based approaches and are common in Aboriginal health settings. Despite this, there is little existing research that describes Aboriginal peoples' perspectives about the strengths of their communities. This paper describes cultural strengths and resources as understood by Aboriginal people living in western Sydney. METHODS: In-depth interviews were used to collect qualitative data from two communities on Dharug and Dharrawal Country in western Sydney Australia. Data come from a larger study, which focused on how cultural strengths supported sexual well-being. Fifty-two interviews were conducted with Aboriginal young people (aged 16-24 years) by trained peer interviewers. Additionally, 16 interviews with Aboriginal adults (25 years and older) were conducted by members of the research team. FINDINGS AND DISCUSSION: While opinions varied, four key areas of cultural strength were identified: (1) strong kinship relationships; (2) knowledge sharing; (3) shared experiences, identities, and values; and (4) knowing Country. Throughout these four themes, the sense of connection and belonging is viewed as an important overarching theme. CONCLUSION: Communities are not homogenous with regard to what they view as cultural strengths. Knowing Country and practising culture meant different things to different individuals while providing a similar sense of belonging, connection, and identity. SO WHAT: Health service providers, policies, and programs can use this information to understand the continuing impacts of past policies and events whilst recognising that each community has strengths that can be drawn upon to improve service engagement, knowledge sharing, and health outcomes.

8.
J Hand Surg Am ; 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39283278

RESUMO

PURPOSE: Time-driven activity-based costing (TDABC) provides a more accurate and granular estimation of direct variable costs compared with traditional accounting methods. This study used TDABC to quantitatively compare the same-day facility costs of open carpal tunnel release (CTR) performed under monitored anesthesia care (MAC) versus wide awake local anesthesia no tourniquet (WALANT). METHODS: We retrospectively identified 474 unilateral CTR (182 MAC and 292 WALANT) performed at an orthopedic specialty hospital between 2015 and 2021. Itemized facility costs were calculated using a TDABC algorithm. Patient demographics, surgical characteristics, and itemized costs were compared between those treated under MAC (MAC-CTR) and WALANT (WALANT-CTR). Multivariable regression was performed to determine the independent effect of MAC on true facility costs. RESULTS: Total facility costs were $170 higher in MAC-CTR compared with WALANT-CTR ($652 vs $482). Monitored anesthesia care-CTR cases had higher personnel costs ($537 vs $394), likely because of higher surgery personnel ($303 vs $185) and postanesthesia care unit personnel costs ($117 vs $95). Monitored anesthesia care-CTR cases also had higher supply costs ($119 vs $81). When controlling for demographics and comorbidities, MAC-CTR was independently associated with an increase in personnel costs by $150.65 (95% CI, $131.09-$170.21), supply costs by $24.99 (95% CI, $9.40-$40.58), and total facility costs by $175.66 (95% CI, $150.18-$201.09) per case. CONCLUSIONS: Using TDABC, MAC-CTR was found to be 35% more costly to the facility compared with WALANT-CTR. Notably, WALANT-CTR facility costs presented here do not include additional cost savings from anesthesiologist service fees or preoperative laboratory clearance required for MAC-CTR surgeries. To reduce costs related to CTR surgery, greater efforts should be made to reduce the number of intraoperative personnel and maximize the use of WALANT-CTR in an outpatient setting. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic and Decision Analysis II.

9.
J Biomed Sci ; 31(1): 86, 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39232783

RESUMO

BACKGROUND: While dengue NS1 antigen has been shown to be associated with disease pathogenesis in some studies, it has not been linked in other studies, with the reasons remaining unclear. NS1 antigen levels in acute dengue are often associated with increased disease severity, but there has been a wide variation in results based on past dengue infection and infecting dengue virus (DENV) serotype. As NS1 engages with many host lipids, we hypothesize that the type of NS1-lipid interactions alters its pathogenicity. METHODS: Primary human monocyte derived macrophages (MDMs) were co-cultured with NS1 alone or with HDL, LDL, LPS and/or platelet activating factor (PAF) from individuals with a history of past dengue fever (DF = 8) or dengue haemorrhagic fever (DHF = 8). IL-1ß levels were measured in culture supernatants, and gene expression analysis carried out in MDMs. Monocyte subpopulations were assessed by flow cytometry. Hierarchical cluster analysis with Euclidean distance calculations were used to differentiate clusters. Differentially expressed variables were extracted and a classifier model was developed to differentiate between past DF and DHF. RESULTS: Significantly higher levels of IL-1ß were seen in culture supernatants when NS1 was co-cultured with LDL (p = 0.01, median = 45.69 pg/ml), but lower levels when NS1 was co-cultured with HDL (p = 0.05, median = 4.617 pg/ml). MDMs of those with past DHF produced higher levels of IL-1ß when NS1 was co-cultured with PAF (p = 0.02). MDMs of individuals with past DHF, were significantly more likely to down-regulate RPLP2 gene expression when macrophages were co-cultured with either PAF alone, or NS1 combined with PAF, or NS1 combined with LDL. When NS1 was co-cultured with PAF, HDL or LDL two clusters were detected based on IL10 expression, but these did not differentiate those with past DF or DHF. CONCLUSIONS: As RPLP2 is important in DENV replication, regulating cellular stress responses and immune responses and IL-10 is associated with severe disease, it would be important to further explore how differential expression of RPLP2 and IL-10 could lead to disease pathogenesis based on NS1 and lipid interactions.


Assuntos
Vírus da Dengue , Dengue , Macrófagos , Proteínas não Estruturais Virais , Humanos , Proteínas não Estruturais Virais/metabolismo , Dengue/virologia , Dengue/imunologia , Macrófagos/metabolismo , Masculino , Adulto , Feminino , Interleucina-1beta/metabolismo , Lipídeos
10.
Public Health Action ; 14(3): 97-104, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39239158

RESUMO

SETTING: Daru Island in Papua New Guinea (PNG) has a high prevalence of TB and multidrug-resistant TB (MDR-TB). OBJECTIVE: To evaluate the early implementation of a community-wide project to detect and treat TB disease and infection, outline the decision-making processes, and change the model of care. DESIGN: A continuous quality improvement (CQI) initiative used a plan-do-study-act (PDSA) framework for prospective implementation. Care cascades were analysed for case detection, treatment, and TB preventive treatment (TPT) initiation. RESULTS: Of 3,263 people screened for TB between June and December 2023, 13.7% (447/3,263) screened positive (CAD4TB or symptoms), 77.9% (348/447) had Xpert Ultra testing, 6.9% (24/348) were diagnosed with TB and all initiated treatment. For 5-34-year-olds without active TB (n = 1,928), 82.0% (1,581/1,928) had tuberculin skin testing (TST), 96.1% (1,519/1,581) had TST read, 23.0% (350/1,519) were TST-positive, 95.4% (334/350) were TPT eligible, and 78.7% (263/334) initiated TPT. Three PDSA review cycles informed adjustments to the model of care, including CAD4TB threshold and TPT criteria. Key challenges identified were meeting screening targets, sputum unavailability from asymptomatic individuals with high CAD4TB scores, and consumable stock-outs. CONCLUSION: CQI improved project implementation by increasing the detection of TB disease and infection and accelerating the pace of screening needed to achieve timely community-wide coverage.


CONTEXTE: L'île de Daru en Papouasie-Nouvelle-Guinée (PNG) présente une forte prévalence de la TB et de la TB multirésistante (MDR-TB). OBJECTIF: Évaluer la mise en œuvre précoce d'un projet à l'échelle de la communauté pour détecter et traiter la TB et l'infection, décrire les processus de prise de décision et changer le modèle de soins. CONCEPTION: Une initiative d'amélioration continue de la qualité (CQI, pour l'anglais « continuous quality improvement ¼) a utilisé un cadre de planification, d'action, d'étude, d'action (PDSA, pour l'anglais «plan-do-study-act ¼) pour la mise en œuvre prospective. Les cascades de soins ont été analysées pour la détection des cas, le traitement et l'initiation du traitement préventif de la TB. RÉSULTATS: Sur 3 263 personnes dépistées pour la TB entre juin et décembre 2023, 13,7% (447/3 263) ont été dépistées positives (CAD4TB ou symptômes), 77,9% (348/447) ont subi un test Xpert Ultra, 6,9% (24/348) ont reçu un diagnostic de TB et toutes ont commencé un traitement. Chez les 5 à 34 ans sans TB active (n = 1 928), 82,0% (1 581/1 928) ont subi un test cutané à la tuberculine (TCT), 96,1% (1 519/1 581) ont eu un test de dépistage du TCT, 23,0% (350/1 519) étaient positifs au TCT, 95,4% (334/350) étaient éligibles au TPT et 78,7% (263/334) ont initié le TPT. Trois cycles d'examen PDSA ont permis d'ajuster le modèle de soins, y compris le seuil CAD4TB et les critères TPT. Les principaux défis identifiés étaient l'atteinte des objectifs de dépistage, l'indisponibilité des expectorations chez les personnes asymptomatiques avec des scores CAD4TB élevés et les ruptures de stock de consommables. CONCLUSION: L'ACQ a amélioré la mise en œuvre du projet en augmentant la détection de la TB et de l'infection et en accélérant le rythme de dépistage nécessaire pour atteindre une couverture à l'échelle de la communauté en temps opportun.

11.
Public Health Action ; 14(3): 83-84, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39239155

RESUMO

Papua New Guinea (PNG) is a high-burden country for TB, with an estimated annual TB incidence rate of 432 per 100,000 population. There are major challenges to the provision of quality care for TB patients with high rates of loss to follow-up, and multidrug-resistant TB is increasingly detected. In 2022-2023, the second Structured Operational Research Training IniTiative (SORT-IT) for TB was undertaken. Eight participants completed the course, and the outputs from these research projects highlight important current operational issues for the PNG TB programme in a range of settings. The first four articles in the series are published in this issue of Public Health Action, with the remainder to follow in subsequent issues.

12.
Public Health Action ; 14(3): 85-90, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39239161

RESUMO

SETTING: Multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB) is now endemic in the National Capital District (NCD), Papua New Guinea. Loss to follow-up (LTFU) is a challenge. OBJECTIVE: To evaluate and identify risk factors for LTFU, including pre-treatment LTFU, in adults with MDR/RR-TB at Port Moresby General Hospital (PMGH). DESIGN: A retrospective analysis of treatment initiation in adults diagnosed with MDR/RR-TB (2018-2022) and outcomes for a cohort treated for MDR/RR-TB (2014-2019). We assessed the factors associated with LTFU using multivariate logistic regression. RESULTS: Of 95 patients diagnosed with MDR/RR-TB at PMGH from 2018 to 2022, 21 (22%) were lost to follow-up before treatment. Of the 658 adults who initiated treatment for MDR/RR-TB at PMGH from 2014 to 2019, 161 (24%) were lost to follow-up during treatment. A higher proportion of patients on injectable-containing long regimens (110/404, 27%) were lost to follow-up than those on the all-oral regimen containing bedaquiline (13/66, 12%). Treatment loss to follow-up was associated with age (35-54 years age group: aOR 0.49, 95% CI 0.32-0.77; 55-75 years age group: aOR 0.42, 95% CI 0.19-0.90; compared to the 15-34 years age group), residence outside of NCD (aOR 1.79, 95% CI 1.04-3.06), and year of treatment initiation. CONCLUSION: Pre-treatment LTFU requires programmatic focus. Shorter oral regimens and decentralised services may address the reasons for higher LTFU in younger people and people living outside NCD.


CONTEXTE: La TB multirésistante/résistante à la rifampicine (MDR-TB/RR-TB, pour l'anglais « multidrug/rifampicin-resistant TB ¼) est maintenant endémique dans le district de la capitale nationale (NCD, pour l'anglais « National Capital District ¼), en Papouasie-Nouvelle-Guinée. La perte de suivi (LTFU, pour l'anglais « loss to follow-up ¼) est un défi. OBJECTIF: Évaluer et identifier les facteurs de risque de LTFU, y compris le LTFU avant le traitement, chez les adultes atteints de MDR-TB/RR-TB à Port Moresby General Hospital (PMGH). CONCEPTION: Une analyse rétrospective de l'initiation du traitement chez les adultes diagnostiqués avec une MDR-TB/RR-TB (2018­2022) et des résultats pour une cohorte traitée pour la MDR-TB/RR-TB (2014­2019). Nous avons évalué les facteurs associés au LTFU à l'aide d'une régression logistique multivariée. RÉSULTATS: Sur les 95 patients diagnostiqués avec une MDR-TB/RR-TB à PMGH de 2018 à 2022, 21 (22%) ont été perdus de vue avant le traitement. Sur les 658 adultes qui ont commencé un traitement pour la MDR-TB/RR-TB à PMGH entre 2014 et 2019, 161 (24%) ont été perdus de vue pendant le traitement. Une proportion plus élevée de patients recevant des régimes longs contenant des injectables (110/404 ; 27%) ont été perdus de vue que ceux recevant un régime entièrement oral contenant de la bédaquiline (13/66 ; 12%). La perte de traitement au suivi était associée à l'âge (groupe d'âge de 35 à 54 ans : aOR 0,49 ; IC à 95% 0,32 à 0,77 ; groupe d'âge de 55 à 75 ans : aOR 0,42 ; IC à 95% 0,19 à 0,90 ; par rapport au groupe d'âge de 15 à 34 ans), à la résidence en dehors des NCD (aOR 1,79 ; IC à 95% 1,04 à 3,06) et à quelques années de début de traitement. CONCLUSION: Le LTFU avant le traitement nécessite une orientation programmatique. Des régimes oraux plus courts et des services décentralisés peuvent s'attaquer aux raisons de l'augmentation du LTFU chez les jeunes et les personnes vivant en dehors des NCD.

13.
Artigo em Inglês | MEDLINE | ID: mdl-39254965

RESUMO

BACKGROUND: Despite the importance of sleep for physiological function, rehabilitation, and recovery, sleep quality after total joint arthroplasty (TJA) remains poor. The objective of this systematic review was to identify, summarize, and evaluate postoperative interventions aimed at improving sleep quality after TJA. METHODS: A systematic review of PubMed (MEDLINE) and Scopus (Embase, MEDLINE, COMPENDEX) from inception to April 2024 was conducted (PROSPERO ID: CRD42023447317). Randomized controlled trials on interventions to improve sleep quality were included. Sleep outcomes, including the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Patient-Reported Outcome Measurement Information System-Sleep Disturbance, Numeric Rating Scale sleep scores,l9 were extracted. Descriptive statistics were used to analyze the available data. RESULTS: Of the 1,549 articles identified, seven randomized trials with a total of 840 patients were included (394 total hip arthroplasties [THA], 446 total knee arthroplasties [TKA]). Pittsburgh Sleep Quality Index was the most commonly used outcome for assessing sleep quality. Among THA studies, zolpidem, combined fascia iliaca compartment block (FICB) and dexmedetomidine (DEX), and perioperative methylprednisolone were shown to markedly improve postoperative sleep quality. Neither topical cannabidiol nor topical essential oil was found to improve postoperative sleep quality after TKA. Melatonin had no effect on sleep outcomes after TJA. CONCLUSION: Zolpidem, FICB + DEX, and perioperative methylprednisolone are effective interventions to improve sleep quality after THA. Topical cannabis, topical essential oil, and melatonin did not improve sleep quality. No effective sleep interventions for TKA patients were identified. Improving sleep quality remains a potential therapeutic goal to improve patient satisfaction after TJA. Continued investigation on this topic is therefore necessary.

14.
iScience ; 27(9): 110837, 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39310750

RESUMO

Systemic immunity plays an important role in cancer immune surveillance and response to therapy, but little is known about the immune status of children with solid cancers. We performed a high-dimensional single-cell analysis of systemic immunity in 50 treatment-naive pediatric cancer patients, comparing them to age-matched healthy children. Children with cancer had a lower frequency of peripheral NK cells, which was not due to tumor sequestration, had lower surface levels of activating receptors and increased levels of the inhibitory NKG2A receptor. Furthermore, the natural killer (NK) cells of pediatric cancer patients were less mature and less cytotoxic when tested in vitro. Culture of these NK cells with interleukin-2 restored their cytotoxicity. Collectively, our data show that NK cells in pediatric cancer patients are impaired through multiple mechanisms and identify rational strategies to restore their functionality.

15.
Res Sq ; 2024 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-39257995

RESUMO

Background: As many studies have shown conflicting results regarding the extent of viraemia and clinical disease severity, we sought to investigate if viraemia during early dengue illness is associated with subsequent clinical disease severity. Methods: Realtime PCR was carried out to identify the dengue virus (DENV serotype), in 362 patients, presenting within the first 4 days of illness, from 2017 to 2022, in Colombo Sri Lanka. To characterize subsequent clinical disease severity, all patients were followed throughout their illness daily and disease severity classified according to WHO 1997 and 2009 disease classification. Results: 263 patients had DF, 99 progressed to develop DHF, and 15/99 with DHF developed shock (DSS). Although the viral loads were higher in the febrile phase in patients who progressed to develop DHF than in patients with DF this was not significant (p=0.5). Significant differences were observed in viral loads in patients infected with different DENV serotypes (p=0.0009), with lowest viral loads detected in DENV2 and the highest viral loads in DENV3. Sub-analysis for association of viraemia with disease severity for each DENV serotyped was again not significant. Although those infected with DENV2 had lower viral loads, infection with DENV2 was significantly associated with a higher risk of developing DHF (p=0.011, Odds ratio 1.9; 95% CI 1.164 to 3.078). Based on the WHO 2009 disease classification, 233 had dengue with warning signs (DWW), 114 dengue without warning signs (DWoWS), and 15 had severe dengue (SD). No significant difference was observed in the viral loads between those with SD, DWW and DWoWS (p=0.27). Conclusions: Viral loads were significantly different in the febrile phase between different DENV serotypes, and do not appear to significantly associate with subsequent clinical disease severity in a large Sri Lankan cohort.

16.
medRxiv ; 2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39228713

RESUMO

Background: Influenza A has been named as a priority pathogen by the WHO due to the potential to cause pandemics. Genomic sequencing of influenza strains is important to understand the evolution of the influenza strains and also to select the appropriate influenza vaccines to be used in the different influenza seasons in Sri Lanka. Therefore, we sought to understand the molecular epidemiology of the influenza viruses in the Western Province of Sri Lanka, including mutational analysis to investigate the evolutionary dynamics. Methodology: A total of 349 individuals presenting with fever and respiratory symptoms were enrolled in this study from November 2022 to May 2024. Nasopharyngeal and oropharyngeal specimens were collected and screened using quantitative PCR to detect Influenza A, Influenza B, and SARS-CoV-2. Subtyping and genomic sequencing was carried out on influenza A strains using Oxford Nanopore Technology. Results: Influenza A was detected in 49 (14 %) patients, influenza B in 20 (5.7%) and SARS-CoV-2 in 41 (11.7%). Co-infections were observed in five participants. The phylogenetic analysis assigned the H1N1 HA gene sequences within the 6B.1A.5a.2a clade. The HA gene of the H1N1 sequences in 2023 were assigned as belonging to the subclades C.1, C.1.2, and C.1.8, while the 2024 sequences were assigned to subclades C.1.8 and C.1.9. The H3N2 sequences from 2023 were assigned to the 3C.2a1b.2a.2a.1b clade and subclade G.1.1.2, while the 2024 sequences were assigned to the 3C.2a1b.2a.2a.3a.1 clade and subclade J.2. The K54Q, A186T, Q189E, E224A, R259K, K308R, I418V, and X215A amino acid substitutions were seen in the H1N1 in the 2023 and 2024 sequences. The 2024 H1N1 sequences additionally exhibited further substitutions, such as V47I, I96T, T120A, A139D, G339X, K156X, and T278S. Conclusion: In this first study using genomic sequencing to characterize the influenza A strains in Sri Lanka, which showed different influenza A viruses circulating in an 18-month period. As the Sri Lankan strains also had certain mutations of unknown significance, it would be important to continue detailed surveillance of the influenza strains in Sri Lanka to choose the most suitable vaccines for the population and the timing of vaccine administration.

17.
Circulation ; 2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39206549

RESUMO

BACKGROUND: The MINT trial raised concern for harm from a restrictive versus liberal transfusion strategy in patients with acute myocardial infarction (MI) and anemia. Type 1 and type 2 MI are distinct pathophysiological entities that may respond differently to blood transfusion. This analysis sought to determine if the effects of transfusion varied among patients with a type 1 or a type 2 MI and anemia. We hypothesized that the liberal transfusion strategy would be of greater benefit in type 2 than in type 1 MI. METHODS: We compared rates of death or MI at 30 days in patients with type 1 (n=1460) and type 2 (n=1955) MI and anemia who were randomly allocated to a restrictive (threshold of 7 to 8 g/dL) or a liberal (threshold of 10 g/dL) transfusion strategy. RESULTS: The primary outcome of death or MI was observed in 16% of type 1 MI and 15.4% of type 2 MI patients. The rate of death or MI was higher in patients with type 1 MI randomized to a restrictive (18.2%) versus liberal (13.2%) transfusion strategy (RR 1.32, 95% CI 1.04 - 1.67) with no difference observed between the restrictive (15.8% ) and liberal (15.1% ) transfusion strategies in patients with type 2 MI (RR 1.05 95% CI 0.85-1.29). The test for a differential effect of transfusion strategy by MI type was not statistically significant (P-interaction = 0.16). CONCLUSIONS: The concern for harm with a restrictive transfusion strategy in patients with acute MI and anemia raised in the MINT primary outcome manuscript may be more apparent in patients with type 1 than type 2 MI. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02981407.

18.
Am Heart J ; 278: 33-40, 2024 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-39182902

RESUMO

BACKGROUND: Co-morbid hypertension is strong predictor of adverse cardiovascular (CV) outcomes in patients with atrial fibrillation (AF) but the optimal target for blood pressure (BP) control in this patient population has not been clearly defined. METHODS: The Cardiovascular Risk reduction in patients with Atrial Fibrillation Trial (CRAFT) is an investigator-initiated and conducted, international, multicenter, open-label, parallel-group, blinded outcome assessed, randomized controlled trial of intensive BP control in patients with AF. The aim is to determine whether intensive BP control (target home systolic blood pressure [SBP] <120 mmHg) is superior to standard BP control (home SBP <135 mmHg) on the hierarchical composite outcome of time to CV death, number of stroke events, time to the first stroke, number of myocardial infarction (MI) events, time to the first MI, number of heart failure hospitalization (HFH) events, and time to the first HFH. A sample size of 1,675 patients is estimated to provide 80% power to detect a win-ratio of 1.50 for intensive versus standard BP control on the primary composite outcome. Study visits are conducted at 1, 2, 3, and 6 months postrandomization, and every 6 months thereafter during the study. CONCLUSIONS: This clinical trial aims to provide reliable evidence of the effects of intensive BP control in patients with AF. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (NCT04347330).

19.
Elife ; 132024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39109999

RESUMO

Prions replicate via the autocatalytic conversion of cellular prion protein (PrPC) into fibrillar assemblies of misfolded PrP. While this process has been extensively studied in vivo and in vitro, non-physiological reaction conditions of fibril formation in vitro have precluded the identification and mechanistic analysis of cellular proteins, which may alter PrP self-assembly and prion replication. Here, we have developed a fibril formation assay for recombinant murine and human PrP (23-231) under near-native conditions (NAA) to study the effect of cellular proteins, which may be risk factors or potential therapeutic targets in prion disease. Genetic screening suggests that variants that increase syntaxin-6 expression in the brain (gene: STX6) are risk factors for sporadic Creutzfeldt-Jakob disease. Analysis of the protein in NAA revealed, counterintuitively, that syntaxin-6 is a potent inhibitor of PrP fibril formation. It significantly delayed the lag phase of fibril formation at highly sub-stoichiometric molar ratios. However, when assessing toxicity of different aggregation time points to primary neurons, syntaxin-6 prolonged the presence of neurotoxic PrP species. Electron microscopy and super-resolution fluorescence microscopy revealed that, instead of highly ordered fibrils, in the presence of syntaxin-6 PrP formed less-ordered aggregates containing syntaxin-6. These data strongly suggest that the protein can directly alter the initial phase of PrP self-assembly and, uniquely, can act as an 'anti-chaperone', which promotes toxic aggregation intermediates by inhibiting fibril formation.


Assuntos
Proteínas Qa-SNARE , Proteínas Qa-SNARE/metabolismo , Proteínas Qa-SNARE/genética , Animais , Camundongos , Humanos , Proteínas Priônicas/metabolismo , Proteínas Priônicas/genética , Proteínas Priônicas/química , Neurônios/metabolismo , Agregados Proteicos , Síndrome de Creutzfeldt-Jakob/metabolismo , Síndrome de Creutzfeldt-Jakob/genética
20.
Res Involv Engagem ; 10(1): 82, 2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39113107

RESUMO

BACKGROUND: Participatory approaches have become a widely applied research approach. Despite their popularity, there are many challenges associated with the evaluation of participatory projects. Here we describe an evaluation of a community-based participatory research study of underserved communities in Ho Chi Minh City (HCMC), Vietnam at risk for hepatitis C virus. The goals of our evaluation were to explore the main benefits and challenges of implementing and participating in a participatory study and to describe study impacts. METHODS: We conducted two meetings with leaders and members of the participating groups followed by in-depth interviews with 10 participants. We then held a dissemination meeting with over 70 participants, including the representatives of each group, researchers from non-governmental organizations (community-based, national and international), and govenrment officials from the Vietnam Ministry of Health and the Department of Health of HCMC. RESULTS: Results include four categories where we describe first the participatory impacts, followed by the collaborative impacts. Then we describe the benefits and challenges of creating and belonging to one of the groups, from members' and leaders' points of view. Finally, we describe the key suggestions that participants provided for future research. CONCLUSION: In conclusion, the evaluation approach led to both a research reflection on the 'success' of the project and enabled participants themselves to reflect on the outcomes and benefits of the study from their point of view.


Participatory approaches in research aim to include participants in an array of aspects of the study, including developing research questions, collecting data, conducting analysis, etc. It has become a more popular method, however there are still challenges surrounding the evaluation of these projects. Here we describe an evaluation of a community-based participatory research study of underserved communities in Ho Chi Minh City (HCMC), Vietnam at risk for hepatitis C virus. The goals of the evaluation were to discuss and explore the main benefits and challenges with those who participated, as well as assess study impacts. To conduct the evaluation, we conducted two meetings with leaders and members of the participating groups followed by interviews with 10 people who were involved. The evaluation results included four categories including impacts for members as well as wider impacts in the community. Then we describe the benefits and challenges of creating and belonging to one of the groups, from members' and leaders' points of view. Finally, we describe the key suggestions that participants provided for future research. In conclusion, the evaluation approach led to both a research reflection on the 'success' of the project and enabled participants themselves to reflect on the outcomes and benefits of the study from their point of view.

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