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1.
Bull World Health Organ ; 102(10): 736-741, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39318888

RESUMO

Problem: The Malaita and Western provinces in Solomon Islands had low routine immunization coverage due to disruptions in health services caused by the coronavirus disease 2019 pandemic in early 2022. Approach: The country introduced the World Health Organization (WHO) Reaching Every District (RED) approach in 2002. Between July and September 2022, we strengthened supportive supervision, monitoring and use of data for decision-making, especially for microplanning and re-establishing outreach to prioritized areas. Health workers were supported to identify key concerns and develop strategies to improve performance. Monthly updates of reported immunization coverage, reporting completeness and fieldwork findings were widely disseminated. Local setting: Solomon Islands' population is 748 606 people, of whom 165 345 reside in Malaita and 105 367 in Western Province. Relevant changes: In Malaita Province, reported coverage of third dose of pentavalent vaccine and first dose of measles-rubella vaccine increased from 40% (757/1892) of eligible children to 121% (1144/946) and from 30% (568/1892) to 159% (1504/946), respectively; and in Western Province reported coverage increased from 38% (443/1165) to 191% (1113/583) and from 44% (513/1165) to 149% (868/583), respectively. Reported coverage for the remaining provinces increased from 64% (3380/5282) to 88% (2325/2641) and from 59% (3116/5282) to 137% (3619/2641), respectively. These findings led the programme on immunization to re-expand the WHO RED approach nationwide. Lessons learnt: Supportive supervision, systematic monitoring and use of data for decision-making helped restoring reported immunization coverage in two low-coverage provinces. However, sustaining these results at a national level is necessary. The WHO RED approach remains relevant, even during a pandemic.


Assuntos
COVID-19 , Programas de Imunização , Cobertura Vacinal , Humanos , Melanesia , Cobertura Vacinal/estatística & dados numéricos , Programas de Imunização/organização & administração , COVID-19/prevenção & controle , COVID-19/epidemiologia , Organização Mundial da Saúde , Lactente , SARS-CoV-2 , Pré-Escolar
2.
Childs Nerv Syst ; 2024 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-39243333

RESUMO

PURPOSE: Hemispherotomy is an effective surgery for intractable pediatric hemispheric epilepsy. Over the years, the surgical goal has shifted from a complete hemispheric resection (anatomical hemispherectomy) to a disconnective hemispherotomy (DH). Multiple techniques for DH have been described, and often, anterior temporal lobectomy (ATL, with hippocampal resection) is performed. The goal of the current study is to assess the role of hippocampal resection in DH. METHODS: We retrospectively collected all clinical data of children (< 18 years old) who underwent DH between 2001 and 2022 at two tertiary large centers. Epilepsy status and surgical outcome were compared, based on whether the hippocampus was resected (as part of an ATL) or disconnected at the amygdala and atrial segment of the fornix (with no ATL). RESULTS: A total of 86 patients (32 females) were included. The most common epilepsy etiologies were stroke (31), Rasmussen's encephalitis (16), cortical dysplasia (10), and hemimegaloencephaly (9). The mean age at surgery was 7 (± 4.9) years. The average number of anti-seizure medications (ASMs) at surgery was 3 (± 1.2). Hemispherotomy techniques included peri-insular (54), vertical (23 [19 endoscopic + 4 parasagittal]), and trans-sylvian (9). The mean follow-up was 41.5 (± 38) months. Forty-three patients had hippocampal resection, and 43 patients had a hippocampal disconnection. Both groups had similar Engel outcome scores (p = 0.53). CONCLUSIONS: Disconnective hemispherotomy is highly effective for pediatric intractable hemispheric epilepsy. Our data suggest that the inclusion of hippocampal resection does not provide additional benefit.

3.
Artigo em Inglês | MEDLINE | ID: mdl-39238198

RESUMO

OBJECTIVE: Glial fibrillary acidic protein (GFAP) is expressed in astrocytes and may be a useful marker of non-active progressive multiple sclerosis (MS). We evaluate serum GFAP (sGFAP) in a large cohort of MS patients to determine if it predicts progression independent of relapse activity (PIRA), future gait aid, and conversion to secondary progressive disease (SPMS). METHODS: Adults with clinically isolated syndrome or any subtype of MS who were listed in the Brigham MS Center Research Database and had at least one sGFAP result were included. All clinic visits following first sample were analyzed for PIRA, future gait aid, and conversion to SPMS. Future cognitive dysfunction and fatigue were evaluated as secondary outcomes. RESULTS: In total, 741 patients were included (average age: 42.3, average disease duration: 3.7 years, median EDSS: 2, and median follow-up duration: 10.0 years). Of 643 patients (86.8%) without progressive disease at baseline, 15.9% developed SPMS. Among all 741, 50.5% had PIRA and 18.6% developed a gait aid requirement. sGFAP level predicted PIRA, future gait aid, and conversion to SPMS in univariable models (p < 0.001, <0.001, and 0.002). sGFAP remained predictive for PIRA and future gait aid in multivariable models in those younger than 50 (p = 0.048, 0.003). Change in sGFAP level over time was not predictive. There was no association between sGFAP and future fatigue or cognitive dysfunction. INTERPRETATION: sGFAP helps to predict PIRA, future gait aid, and conversion to SPMS in a large cohort of MS patients. Our data suggest that baseline levels may be more useful than the change over time.

5.
Nat Commun ; 15(1): 7357, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39191779

RESUMO

Image-guided percutaneous cryoablation is an established minimally invasive oncologic treatment. We hypothesized that cryoablation may modify the immune microenvironment through direct modulation of the tumor, thereby generating an anti-tumor response in tumors refractory to immune checkpoint inhibition (ICI). In this non-randomized phase II single-center study (NCT03290677), subjects with unresectable melanoma progressing on ICI underwent cryoablation of an enlarging metastasis, and ICI was continued for a minimum of two additional cycles. The primary endpoints were safety, feasibility and tumor response in non-ablated lesions. From May 2018 through July 2020, 17 patients were treated on study. The study met its primary endpoints with the combination strategy found to be safe and feasible with an objective response rate of 23.5% and disease control rate of 41% (4 partial response, 3 stable disease). Our data support further study of this synergistic therapeutic approach.


Assuntos
Criocirurgia , Inibidores de Checkpoint Imunológico , Melanoma , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/cirurgia , Melanoma/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Criocirurgia/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Progressão da Doença , Adulto , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/cirurgia , Microambiente Tumoral/imunologia , Metástase Neoplásica , Resultado do Tratamento , Terapia Combinada , Idoso de 80 Anos ou mais
7.
J Perinatol ; 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-39103473

RESUMO

OBJECTIVE: To evaluate the association between enteral sodium supplementation on growth and hypertension (HTN) in preterm infants. STUDY DESIGN: A retrospective cohort study of infants born between 22-32 weeks and weighing 450-1500 grams (N = 821). Enteral sodium supplementation amounts, systolic blood pressures (SBP), weight gain, and other infant and maternal risk factors for HTN were electronically extracted. RESULTS: Infants receiving sodium supplementation were smaller and less mature. Sodium supplementation improved serum sodium levels, weight gain, and head circumference growth without causing hypernatremia. There was no correlation between urine and serum sodium or urine sodium and weight gain. Although infants receiving sodium had higher average SBP and rates of HTN, analysis demonstrated sodium supplementation did not increase odds of hypertension (ORADJ 1.02;0.64-1.64). Postnatal steroids were associated with HTN. CONCLUSIONS: In preterm infants with poor weight gain, enteral sodium supplementation improved growth without increasing hypertension or hypernatremia.

8.
Gastro Hep Adv ; 3(3): 385-395, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39131151

RESUMO

Background and Aims: Survival rates for esophageal squamous cell carcinoma (ESCC) are extremely low due to the late diagnosis of most cases. An understanding of the early molecular processes that lead to ESCC may facilitate opportunities for early diagnosis; however, these remain poorly defined. Tylosis with esophageal cancer (TOC) is a rare syndrome associated with a high lifetime risk of ESCC and germline mutations in RHBDF2, encoding iRhom2. Using TOC as a model of ESCC predisposition, this study aimed to identify early-stage transcriptional changes in ESCC development. Methods: Esophageal biopsies were obtained from control and TOC individuals, the latter undergoing surveillance endoscopy, and adjacent diagnostic biopsies were graded as having no dysplasia or malignancy. Bulk RNA-Seq was performed, and findings were compared with sporadic ESCC vs normal RNA-Seq datasets. Results: Multiple transcriptional changes were identified in TOC samples, relative to controls, and many were detected in ESCC. Accordingly, pathway analyses predicted an enrichment of cancer-associated processes linked to cellular proliferation and metastasis, and several transcription factors were predicted to be associated with TOC and ESCC, including negative enrichment of GRHL2. Subsequently, a filtering strategy revealed 22 genes that were significantly dysregulated in both TOC and ESCC. Moreover, Keratin 17, which was upregulated in TOC and ESCC, was also found to be overexpressed at the protein level in 'normal' TOC esophagus tissue. Conclusion: Transcriptional changes occur in TOC esophagus prior to the onset of dysplasia, many of which are associated with ESCC. These findings support the utility of TOC to help reveal the early molecular processes that lead to sporadic ESCC.

9.
Artigo em Inglês | MEDLINE | ID: mdl-39187984

RESUMO

We performed a clinical trial in non-muscle invasive urothelial cancer (NMIUC) patients randomized (2:1) to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib or placebo (either orally once weekly x 3 doses prior to scheduled surgery) to assess for a difference in EGFR phosphorylation in tumor adjacent normal urothelium <24 hours post-study dose and tolerance of weekly erlotinib. Thirty-seven volunteers (6 female/31 male, mean age 70, 35 white/2 non-white) with confirmed or suspected NMIUC were enrolled into either erlotinib (n=24; 900 mg-13, 600 mg-11) or placebo (n=13). Immunohistochemical assessment of phosphorylated and total EGFR in adjacent normal urothelium (20 erlotinib; 9 placebo) or tumor (21 erlotinib and 11 placebo subjects) at study end observed no significant difference between those receiving erlotinib or placebo. This was also true for other assessed tissue biomarkers (phosphorylated ERK, ERK, e-cadherin, p53 and Ki67). Adverse events were more common, in a dose-related fashion, in participants receiving erlotinib, e.g. 38% experienced Grade 1 with rare grade 2 diarrhea and skin toxicity vs 8% in placebo. Clinically insignificant, but statistically significant (p=0.001) elevations in serum total bilirubin and creatinine were observed in erlotinib participants. Serum erlotinib and metabolite concentrations (OSI-420) confirmed compliance in all erlotinib subjects and did not significantly differ between the 600 and 900 mg doses. Despite compelling pre-clinical and clinical data for targeted EGFR inhibition in bladder cancer prevention, these data do not support the use of weekly erlotinib to prevent progression of NMI bladder cancer.

10.
J Neurosurg Pediatr ; : 1-9, 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-39213676

RESUMO

OBJECTIVE: The goal of this study was to survey the members of the American Society of Pediatric Neurosurgeons (ASPN) to assess the prevalence and associated risks of burnout among pediatric neurosurgeons. The authors aimed to identify the factors that most significantly contributed to this risk to provide a baseline group of characteristics to improve physician well-being. METHODS: Institutional Review Board approval from the University of Arizona was obtained, and the 7-question and 9-question Mayo Physician Well-Being Index (WBI) was distributed to members of the ASPN (n = 275). This index screens for many different aspects of distress for physicians, including burnout risk, stress, depression, fatigue, suicidal ideation, and low career satisfaction. RESULTS: An analysis of 111 pediatric neurosurgeons (111/275 [40% response rate]) was completed. Respondent ages were distributed, with those aged 56-60 years representing the highest proportion (20%). University practice represented a majority (72%). One-third (32%) of respondents reported practicing greater than 25 years, and most physicians in the survey were married (76%). One-third of surgeons spend 61-70 hours working per week (33%), and a plurality are on call between 6 and 10 days per month (42%). Most surgeons reported treating fewer than 200 cases per year (37% reported 100-150 cases; 23%, 151-200). Most pediatric neurosurgeons (63%) stated their annual salary was sufficient. Analysis of each WBI question was performed to identify which factors specifically contributed to the risk of burnout. An overwhelming majority of respondents reported that they make significant efforts to do at least one thing each week that brings them joy (97%), and they either agree or strongly agree that they perform meaningful work (98% of all participants, 97% of females, and 98% of men, p = 0.010). Nearly half of all respondents (49%) reported feelings of burnout and a majority of them were female (67% of women and 42% of men, p = 0.021). Time, environment, case volumes, and quality-of-life concerns are all factors that significantly contribute to the overall risk of burnout and well-being. CONCLUSIONS: This survey study of the ASPN membership revealed a 49% rate of burnout with females at higher risk (67%). Factors associated with burnout were salary, more than 10 days on call per month, electronic medical record stressors, and work-life incongruity. The aforementioned notwithstanding, respondents believe pediatric neurosurgery is a meaningful career. This study provides evidence supporting a moral imperative toward recognition of burnout symptoms and a pivot point toward implementing change.

11.
J Craniofac Surg ; 2024 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-39186061

RESUMO

Osteomas are benign bony lesions that can occur throughout the craniofacial skeleton. Surgical excision can be an effective treatment, as recurrence is relatively uncommon. Outside of incomplete resection, causes of recurrence are poorly documented, especially in the pediatric population. Exchange cranioplasty is an autologous reconstructive surgical option for patients of all ages, and it can be effective in the treatment of large calvarial osteomas. Recurrent lesions of the cranioplasty site have not been well described in the literature, with only 3 documented reports. In this study, we present a unique case of a recurrent osteoma at the site of a prior exchange cranioplasty. The authors also provide a systematic review of the literature for recurrent osteomas and highlight causes and conclusions for these lesions. Utilizing the PRISMA guidelines, a systematic review of articles published across databases was performed to identify accounts of recurrent osteomas at prior cranioplasty sites. Our systematic review illustrates that recurrent osteomas overlying different cranioplasty biomaterials is a rare entity and is due to incomplete resection of the galea and periosteum during the index procedure. Biomaterial selection for the pediatric population requires careful consideration before reconstruction. Though limited by 3 articles previously published and without a direct link to recurrence, long-term studies are needed to further guide biomaterial selection in the pediatric population to evaluate potential recurrences.

12.
Radiography (Lond) ; 30(5): 1349-1354, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39098063

RESUMO

INTRODUCTION: Shared decision-making (SDM) is on the NHS policy agenda, and the preferred model for preference-sensitive decisions. This study establishes baseline patient-perceived SDM in a radical head and neck cohort, and explores patients' views on SDM in a large, specialist trust. METHODS: An SDM questionnaire was distributed to all radical head and neck radiotherapy patients (N = 165), June-December 2023. This combined a well-validated instrument for measuring SDM from the patient perspective, SDM-Q-9, with additional questions exploring patient views. Thematic analysis was used to construct and interpret themes. RESULTS: 65/165 (39%) questionnaires were returned. SDM-Q-9 mean standardised score was 78.6 (SD 26.3). There was a moderate ceiling effect (26%). Scores were not sensitive to sex (p = 0.64) or age (ρ = 0.1). Higher levels of SDM were perceived by participants who stated SDM was very important (51/65, 79%) than somewhat or not at all important (82.4 vs. 62.7; p = 0.02; Cohen d = 0.75). Individuals who discussed their personal priorities with the clinician (46/65, 70.8%), were more likely to be very satisfied with their involvement in SDM (89.1% vs. 52.9%). Thematic analysis generated three themes: Control, Desire for Transparency and Understanding, and Doctor as the Expert. CONCLUSION: Patient-perceived SDM levels are high for head and neck patients. Participants who value SDM also perceive higher levels of SDM. Patient satisfaction increases when individuals discuss their personal priorities. The modest response rate and self-selection bias affect the generalisability of the results. Only radiotherapy patients were included; those who chose alternative treatment may perceive different levels of SDM. The moderate ceiling effect may limit the use of SDM-Q-9 to measure impact of future interventions to improve SDM. IMPLICATIONS FOR PRACTICE: SDM-Q-9 should be combined with an objective, observer measure of SDM.


Assuntos
Tomada de Decisão Compartilhada , Neoplasias de Cabeça e Pescoço , Humanos , Neoplasias de Cabeça e Pescoço/psicologia , Neoplasias de Cabeça e Pescoço/radioterapia , Masculino , Feminino , Pessoa de Meia-Idade , Inquéritos e Questionários , Idoso , Participação do Paciente/psicologia , Adulto , Satisfação do Paciente , Estudos de Coortes
13.
Ann Surg Oncol ; 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39090498

RESUMO

BACKGROUND: Conventional advice to reduce the risk of breast cancer-related lymphedema (BCLE) suggests avoidance of daily-living risks, and limited research has investigated these risks. OBJECTIVE: This study aimed to examine the occurrence, patterns, and effects of daily-living risks on BCLE. METHODS: A cross-sectional design was used to collect data from 567 patients at a metropolitan cancer center in the United States. The Lymphedema Risk-Reduction Behavior Checklist was used to assess the occurrence of 11 daily-living risks. Descriptive, regression, and factor analyses were performed. RESULTS: Significant odds of BCLE were associated with infection (odds ratio [OR] 2.58, 95% confidence interval [CI] 1.95-3.42), cuts/scratches (OR 2.65, 95% CI 1.97-3.56), sunburn (OR 1.89, 95% CI 1.39-3.56), oil splash or steam burns (OR 2.08, 95% CI 1.53-3.83), and insect bites (OR 1.59, 95% CI 1.18-2.13). The daily-living risks were clustered into factors related to skin trauma and carrying objects. Skin trauma risk was significantly associated with BCLE (B = 0.539, z = 3.926, OR 1.714, 95% CI 1.312-2.250; p < 0.001). Having three, four, or five skin trauma risks significantly increased the odds of BCLE to 4.31, 5.14, and 6.94 times, respectively. The risk of carrying objects had no significant or incremental effects on BCLE. CONCLUSION: Complete avoidance of daily-living risks is challenging given 52.73% of patients incurred more than five daily-living risks. Our study findings underscore the importance of 'what to do' strategies to minimize infection and skin trauma.

14.
Genome Med ; 16(1): 94, 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39085949

RESUMO

BACKGROUND: Previous studies have identified a diverse group of microbial taxa that differ between patients with multiple sclerosis (MS) and the healthy population. However, interpreting findings on MS-associated microbiota is challenging, as there is no true consensus. It is unclear whether there is gut microbiota commonly altered in MS across studies. METHODS: To answer this, we performed a meta-analysis based on the 16S rRNA gene sequencing data from seven geographically and technically diverse studies comprising a total of 524 adult subjects (257 MS and 267 healthy controls). Analysis was conducted for each individual study after reprocessing the data and also by combining all data together. The blocked Wilcoxon rank-sum test and linear mixed-effects regression were used to identify differences in microbial composition and diversity between MS and healthy controls. Network analysis was conducted to identify bacterial correlations. A leave-one-out sensitivity analysis was performed to ensure the robustness of the findings. RESULTS: The microbiome community structure was significantly different between studies. Re-analysis of data from individual studies revealed a lower relative abundance of Prevotella in MS across studies, compared to controls. Meta-analysis found that although alpha and beta diversity did not differ between MS and controls, a higher abundance of Actinomyces and a lower abundance of Faecalibacterium were reproducibly associated with MS. Additionally, network analysis revealed that the recognized negative Bacteroides-Prevotella correlation in controls was disrupted in patients with MS. CONCLUSIONS: Our meta-analysis identified common gut microbiota associated with MS across geographically and technically diverse studies.


Assuntos
Microbioma Gastrointestinal , Esclerose Múltipla , RNA Ribossômico 16S , Humanos , Esclerose Múltipla/microbiologia , Microbioma Gastrointestinal/genética , RNA Ribossômico 16S/genética , Bactérias/genética , Bactérias/classificação , Adulto , Masculino , Feminino , Estudos de Casos e Controles
15.
Nat Med ; 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38961225

RESUMO

APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD), with increased odds ratios in female carriers. Targeting amyloid plaques shows modest improvement in male non-APOE4 carriers. Leveraging single-cell transcriptomics across APOE variants in both sexes, multiplex flow cytometry and validation in two independent cohorts of APOE4 female carriers with AD, we identify a new subset of neutrophils interacting with microglia associated with cognitive impairment. This phenotype is defined by increased interleukin (IL)-17 and IL-1 coexpressed gene modules in blood neutrophils and in microglia of cognitively impaired female APOE ε4 carriers, showing increased infiltration to the AD brain. APOE4 female IL-17+ neutrophils upregulated the immunosuppressive cytokines IL-10 and TGFß and immune checkpoints, including LAG3 and PD-1, associated with accelerated immune aging. Deletion of APOE4 in neutrophils reduced this immunosuppressive phenotype and restored the microglial response to neurodegeneration, limiting plaque pathology in AD mice. Mechanistically, IL-17F upregulated in APOE4 neutrophils interacts with microglial IL-17RA to suppress the induction of the neurodegenerative phenotype, and blocking this axis supported cognitive improvement in AD mice. These findings provide a translational basis to target IL-17F in APOE ε4 female carriers with cognitive impairment.

16.
Neurosurg Focus Video ; 11(1): V8, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38957428

RESUMO

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder. Tubers of the central nervous system are a hallmark of the disorder and often cause epilepsy. Many TSC patients fail to achieve seizure control with medication alone. Several case series have demonstrated high seizure freedom rates after resective surgery. However, the technique for the resection of epileptogenic tubers has largely been unreported. Here the authors present 2 cases to illustrate their multistage approach for localizing and resecting the seizure onset zone in patients with TSC. At their institution, they have excellent seizure outcomes and a low complication rate with this technique. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID2411.

17.
BMC Psychiatry ; 24(1): 492, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38977965

RESUMO

BACKGROUND: In recognition of the burden of Perinatal Mental Health problems, NHS England invested £365 million to transform women's access to mental health care, including investment in Community Perinatal Mental Health Services. This study examined how elements of provider care affected women's engagement with these services. METHODS: Semi-structured interviews were conducted with 139 women and explored their experiences of care from 10 different Community Perinatal Mental Health Teams; including which service components participants believed made a difference to their initial and continued engagement. Realist analysis was used to create context-mechanism-outcome configurations (CMOCs) across interviews, since not all parts of the configurations were always articulated within singular interviews. RESULTS: Four key pillars for engagement were identified: perinatal competence, relationship building, accurate reassurance, and reliability. The way perinatal competencies were relayed to women mattered; compassion, understanding and consistency were critical interactional styles. The extent to which these factors affected women's engagement varied by their context and personal characteristics. CONCLUSIONS: As mental health problems increase, disproportionately affecting vulnerable populations, it is critical to continue to ensure support is not only available, but appropriately meets the needs of those individuals. Our findings suggest that key staff behaviours applied at the right time can support women's engagement and potentially contribute to better treatment outcomes.


Assuntos
Serviços Comunitários de Saúde Mental , Assistência Perinatal , Humanos , Feminino , Adulto , Gravidez , Inglaterra , Transtornos Mentais/terapia , Pesquisa Qualitativa , Adulto Jovem
18.
Brain Commun ; 6(4): fcae147, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39045090

RESUMO

The associations between human concussions and subsequent sequelae of chronic neuropsychiatric and cardiovascular diseases such as hypertension have been reported; however, little is known about the underlying biological processes. We hypothesized that dietary changes, including a high-salt diet, disrupt the bidirectional gut-brain axis, resulting in worsening neuroinflammation and emergence of cardiovascular and behavioural phenotypes in the chronic period after repetitive closed head injury in adolescent mice. Adolescent mice were subjected to three daily closed head injuries, recovered for 12 weeks and then maintained on a high-salt diet or a normal diet for an additional 12 weeks. Experimental endpoints were haemodynamics, behaviour, microglial gene expression (bulk RNA sequencing), brain inflammation (brain tissue quantitative PCR) and microbiome diversity (16S RNA sequencing). High-salt diet did not affect systemic blood pressure or heart rate in sham or injured mice. High-salt diet increased anxiety-like behaviour in injured mice compared to sham mice fed with high-salt diet and injured mice fed with normal diet. Increased anxiety in injured mice that received a high-salt diet was associated with microgliosis and a proinflammatory microglial transcriptomic signature, including upregulation in interferon-gamma, interferon-beta and oxidative stress-related pathways. Accordingly, we found upregulation of tumour necrosis factor-alpha and interferon-gamma mRNA in the brain tissue of high salt diet-fed injured mice. High-salt diet had a larger effect on the gut microbiome composition than repetitive closed head injury. Increases in gut microbes in the families Lachnospiraceae, Erysipelotrichaceae and Clostridiaceae were positively correlated with anxiety-like behaviours. In contrast, Muribaculaceae, Acholeplasmataceae and Lactobacillaceae were negatively correlated with anxiety in injured mice that received a high-salt diet, a time-dependent effect. The findings suggest that high-salt diet, administered after a recovery period, may affect neurologic outcomes following mild repetitive head injury, including the development of anxiety. This effect was linked to microbiome dysregulation and an exacerbation of microglial inflammation, which may be physiological targets to prevent behavioural sequelae in the chronic period after mild repetitive head injury. The data suggest an important contribution of diet in determining long-term outcomes after mild repetitive head injury.

19.
J Clin Oncol ; 42(25): 3033-3046, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38954785

RESUMO

PURPOSE: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts. METHODS: This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208). RESULTS: The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.


Assuntos
Anilidas , Protocolos de Quimioterapia Combinada Antineoplásica , Ipilimumab , Nivolumabe , Piridinas , Neoplasias Urogenitais , Humanos , Masculino , Anilidas/uso terapêutico , Anilidas/efeitos adversos , Ipilimumab/uso terapêutico , Ipilimumab/efeitos adversos , Ipilimumab/administração & dosagem , Nivolumabe/uso terapêutico , Nivolumabe/efeitos adversos , Piridinas/uso terapêutico , Piridinas/efeitos adversos , Pessoa de Meia-Idade , Idoso , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Neoplasias Urogenitais/tratamento farmacológico , Neoplasias Urogenitais/patologia , Idoso de 80 Anos ou mais , Intervalo Livre de Progressão
20.
J Clin Neurophysiol ; 41(5): 405-409, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38935653

RESUMO

PURPOSE: Stereoelectroencephalography (SEEG) is widely performed on individuals with medically refractory epilepsy for whom invasive seizure localization is desired. Despite increasing adoption in many centers across the world, no standardized electrode naming convention exists, generating confusion among both clinical and research teams. METHODS: We have developed a novel nomenclature, named the Standardized Electrode Nomenclature for SEEG Applications system. Concise, unique, informative, and unambiguous labels provide information about entry point, deep targets, and relationships between electrodes. Inter-rater agreement was evaluated by comparing original electrode names from 10 randomly sampled cases (including 136 electrodes) with those prospectively assigned by four additional blinded raters. RESULTS: The Standardized Electrode Nomenclature for SEEG Application system was prospectively implemented in 40 consecutive patients undergoing SEEG monitoring at our institution, creating unique electrode names in all cases, and facilitating implantation design, SEEG recording and mapping interpretation, and treatment planning among neurosurgeons, neurologists, and neurophysiologists. The inter-rater percent agreement for electrode names among two neurosurgeons, two epilepsy neurologists, and one neurosurgical fellow was 97.5%. CONCLUSIONS: This standardized naming convention, Standardized Electrode Nomenclature for SEEG Application, provides a simple, concise, reproducible, and informative method for specifying the target(s) and relative position of each SEEG electrode in each patient, allowing for successful sharing of information in both the clinical and research settings. General adoption of this nomenclature could pave the way for improved communication and collaboration between institutions.


Assuntos
Eletrodos Implantados , Eletroencefalografia , Técnicas Estereotáxicas , Terminologia como Assunto , Humanos , Eletroencefalografia/normas , Eletroencefalografia/métodos , Técnicas Estereotáxicas/normas , Epilepsia/diagnóstico , Epilepsia/fisiopatologia , Feminino , Masculino , Encéfalo/fisiopatologia , Encéfalo/fisiologia , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsia Resistente a Medicamentos/classificação
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