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1.
PLOS Ment Health ; 1(1)2024.
Artigo em Inglês | MEDLINE | ID: mdl-39188639

RESUMO

Understanding and eliminating mental illness stigma is crucial for improving population mental health. In many settings, this stigma is gendered, from the perspectives of both the stigmatized and the stigmatizers. We aimed to find the differences in the level of stigma across different mental disorders while considering the gender of the study participants as well as the gender of the people depicted in the vignettes. This was a population-based, experimental vignette study conducted in Buyende District of Eastern Uganda in 2023. We created 8 vignettes describing both men and women with alcohol use disorder, major depressive disorder, generalized anxiety disorder, and schizophrenia consistent with DSM-5 criteria. Participants from 20 villages in rural Buyende District of Uganda (N=379) were first read a randomly selected vignette and administered a survey eliciting their attitudes (Personal Acceptance Scale [PAS] and Broad Acceptance Scale [BAS]) towards the person depicted in the vignette. We used analysis of variance (ANOVA) with Bonferroni-adjusted, empirical p-values to compare levels of acceptance across disorders and genders. Attitudes towards people with mental illness, as measured by the PAS, varied across different mental disorders (p=0.002). In pairwise mean comparisons, the greater acceptance of anxiety disorder vs. schizophrenia was statistically significant (Mean [SD] PAS: 2.91 [3.15] vs 1.62 [1.95], p=0.008). Secondary analyses examining differences in acceptance across gender combinations within mental disorders showed that PAS varied across gender combinations for depression (p=0.017), suggesting that acceptance is higher for women with depression than men with depression. In this population-based vignette study from rural Uganda, we found that people with schizophrenia were less accepted compared to people with anxiety disorders. We also found that there was greater acceptance of women with depression than men with depression. Anti-stigma initiatives may need to be targeted to specific disorders and genders.

2.
Transplant Proc ; 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39164137

RESUMO

BACKGROUND: To review the impact of the operating microscope (OM) for reconstruction of the hepatic artery (HA) by comparing the outcomes with standard loupe reconstruction (SL) in pediatric liver transplantation (LT). METHODS: Studies comparing the application of OM and SL for the reconstruction of the HA in primary pediatric LT were included from a systematic search of MEDLINE, Cochrane Library and EMBASE from inception to June 2022. Re-transplantation, dual grafts and auxiliary transplants were excluded. Primary outcome was the rate of HA thrombosis (HAT). Secondary outcomes were graft loss and mortality. RESULTS: There were 1261 liver recipients from 9 included studies published until June 2022. There were 484 patients in the OM group and 777 patients in the SL group. HAT incidence with OM was significantly lower with OR = 0.18 (95% CI: 0.07-0.48). The 1-year graft survival was significantly better in the OM group with OR = 2.77 (95% CI: 1.13-6.80). 1-year overall mortality was also significantly lower with OM with OR = 0.39 (0.18-0.86). The use of OM did not significantly impact the incidence of HAT in the living donor liver transplant subgroup. Differences in time for hepatic HA reconstruction, total operating time and length of hospital stay did not reach statistical significance. CONCLUSION: The use of OM has reduced the risk of HAT, graft loss and mortality in pediatric liver transplantation. Adoption of microsurgical principles in general may have contributed to the improved outcomes with SL reconstruction of HA in pediatric LT.

3.
Pediatr Surg Int ; 40(1): 228, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39147909

RESUMO

PURPOSE: This retrospective cohort study explores the impact of the COVID-19 pandemic on pediatric trauma cases in Singapore's National University Hospital from January 2015 to July 2021. The pandemic prompted unprecedented measures, altering societal dynamics. The study hypothesizes a reduction in major trauma incidents during the pandemic period. METHODS: This is a single-center retrospective study including all pediatric patients presenting with trauma-related ICD-9 codes, and an Injury Severity Score (ISS) greater than 8. Patients were stratified into two time periods: pre-pandemic (January 2015 to March 2020) and pandemic (April 2020 to July 2021) periods. RESULTS: Out of 254 pediatric trauma cases, 201 occurred pre-pandemic, and 53 during the pandemic. While overall trauma incidence remained similar, the pandemic period saw a shift in injury patterns. Home-based falls increased, vehicular accidents decreased, while deliberate self-harm and caregiver abuse rose significantly. The incidence of serious trauma attributed to non-accidental injury increased during the pandemic. CONCLUSION: The study reveals changing trauma patterns, emphasizing the importance of understanding societal impacts during pandemics. Notably cases of deliberate self-harm and caregiver abuse surged, echoing global concerns highlighted in other studies during the pandemic. The study underscores the need to preempt physical and psychological stressors in vulnerable populations during future pandemics.


Assuntos
COVID-19 , Comportamento Autodestrutivo , Populações Vulneráveis , Ferimentos e Lesões , Humanos , COVID-19/epidemiologia , Estudos Retrospectivos , Criança , Feminino , Masculino , Ferimentos e Lesões/epidemiologia , Ferimentos e Lesões/psicologia , Singapura/epidemiologia , Populações Vulneráveis/estatística & dados numéricos , Pré-Escolar , Comportamento Autodestrutivo/epidemiologia , Comportamento Autodestrutivo/psicologia , Incidência , Adolescente , Cuidadores/psicologia , Cuidadores/estatística & dados numéricos , Lactente , SARS-CoV-2 , Pandemias , Escala de Gravidade do Ferimento
4.
Ann Dermatol ; 36(4): 236-246, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39082660

RESUMO

BACKGROUND: A set of criteria for severity classification is essential in alopecia areata (AA). Currently, no guidelines are universally accepted for defining AA severity. OBJECTIVE: This study aimed to establish a set of consensus criteria for classifying the severity of and identifying treatment refractoriness in AA. METHODS: A preliminary draft of the definition for moderate-to-severe AA was crafted based on available evidence, and members of the Korean Hair Research Society (KHRS) subsequently endorsed the recommendation through an online survey. RESULTS: In the first Delphi round, consensus was attained on 15 questions. After refining certain items in the second round, consensus was achieved on 23 out of 26 questions. The KHRS first defined AA severity using the severity of alopecia tool (SALT). SALT ≥50 was defined as severe, 20≤ SALT <50 as moderate, and SALT <20 as mild. Moderate AA was considered severe if it meets one or more of the following criteria: dermatology life quality index >10, presence of accompanying eyebrow or eyelash loss, positive hair loss activity, or treatment-refractory AA. CONCLUSION: These consensus criteria can help clinicians accurately diagnose AA, provide appropriate treatment, and monitor its progression.

5.
Pediatr Surg Int ; 40(1): 212, 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39085697

RESUMO

PURPOSE: The workup of jaundiced infants may be variable and protracted, thereby delaying the diagnosis and timely intervention for biliary atresia (BA). This potentially leads to inferior outcomes. We developed a practical score to stratify infantile cholestasis according to the risk of having BA. METHOD: The score (0-7) [gallbladder length ≤ 15 mm (+ 1), common bile duct (CBD) diameter < 0.5 mm(+ 1), pre-portal vein (PV) echogenicity(+ 1), direct-to-total bilirubin ratio (D/T) ≥ 0.7(+ 2), and gamma-glutamyl transferase (GGT) ≥ 200 IU/L(+ 2)] are derived from logistic regression of data from a retrospective cohort of cholestatic infants (n = 58, 41 BA) in our institution. It was then validated with a separate retrospective cohort (n = 28, 17 BA) from another institution. Final diagnoses were as per intraoperative cholangiogram (IOC) and liver histopathology. RESULTS: A cutoff score of ≥ 3 diagnosed BA with 100% and 94% sensitivity in the derivative cohort (area under receiver operating characteristic curve, AUROC 0.869) and validation cohort (AUROC 0.807), respectively. D/T ratio was the most sensitive (93%) and CBD diameter was the most specific (88%) parameter. The score accurately predicted non-BA in 11(65%) and 7(63%) infants in the derivative and validation cohorts, respectively, with one missed BA in the latter. CONCLUSION: We propose a validated, simple, yet sensitive diagnostic score to risk-stratify cholestatic infants, aiming to expedite definitive management of BA.


Assuntos
Atresia Biliar , Colestase , Humanos , Atresia Biliar/diagnóstico , Estudos Retrospectivos , Lactente , Masculino , Colestase/diagnóstico , Feminino , Recém-Nascido , Colangiografia/métodos , Curva ROC , Bilirrubina/sangue , gama-Glutamiltransferase/sangue , Vesícula Biliar/diagnóstico por imagem , Vesícula Biliar/patologia
6.
Chemosphere ; 364: 142966, 2024 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-39074666

RESUMO

Glyphosate, the most widely used herbicide in the United States, is applied to control broadleaf weeds and grasses. Public concern is mounting over how pesticides affect human and environmental health. Glyphosate toxicity in animals is known, but human carcinogenicity is controversial, and limited epidemiologic evidence suggests associations between exposure and respiratory diseases (e.g., asthma) and adverse child neurodevelopment. Understanding the extent of the general U.S. population exposure to glyphosate is important. To examine temporal trends in exposure to glyphosate, we determined urinary concentrations of glyphosate among U.S. children and adults from three cycles of the National Health and Nutrition Examination Survey (NHANES) conducted 2013-2018. Most of the population (70.0%-81.7%, depending on cycle) was exposed, including children as young as 3 years of age. Concentrations decreased from 2013 to 2018 by 38%; the decline was smaller in younger age groups. The downward trend likely reflects changes in glyphosate use resulting, at least in part, from changes in agricultural practices, regulatory actions, and shifts in public awareness regarding glyphosate toxicity. Continuing glyphosate biomonitoring will help understand how changes in use and actions to restrict applications of this common pesticide affect human exposures.

7.
JAMA Netw Open ; 7(7): e2423563, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-39028668

RESUMO

Importance: The use of oral corticosteroids for prolonged periods may be associated with adverse events (AEs). Nevertheless, the risk of AEs with oral corticosteroids, especially among patients with atopic dermatitis (AD), has not been comprehensively investigated and lacks evidence on duration of treatment. Objective: To assess the association between long-term exposure to oral corticosteroids and AEs among adult patients with AD. Design, Setting, and Participants: This nested case-control study used data from the Health Insurance Review and Assessment Service database of South Korea between January 1, 2012, and October 31, 2021, which included 1 year prior to the cohort entry date of January 1, 2013, for assessing exclusion criteria and baseline characteristics, and 1 year after the study end date of October 31, 2020, to ensure a minimum duration for assessing exposure. Among the population of adults with AD, patients diagnosed with any of 11 AEs were matched with patients who had never received a diagnosis of any of the 11 AEs. Exposure: Long-term use of oral corticosteroids was defined as cumulative supply of more than 30 days or more than 90 days of oral corticosteroid prescription per year. Main Outcomes and Measures: We used multivariable conditional logistic regression analyses to measure the risk of 11 individual outcomes (osteoporosis, fracture, type 2 diabetes, hyperlipidemia, hypertension, myocardial infarction, stroke, heart failure, avascular necrosis, cataract, or glaucoma) as the composite outcome, controlling for potential confounders. We further classified the composite outcome to individual outcomes to evaluate the AE-specific risk. Results: Among 1 025 270 patients with AD between 2013 and 2020, 164 809 cases (mean [SD] age, 39.4 [14.8]; 56.9% women) were matched with 328 303 controls (mean [SD] age, 39.3 [14.7]; 56.9% women) for sex, age, cohort entry date, follow-up duration, and severity of AD, where the balance of most baseline characteristics was achieved. A total of 5533 cases (3.4%) and 10 561 controls (3.2%) were exposed to oral corticosteroids for more than 30 days, while 684 cases (0.4%) and 1153 controls (0.4%) were exposed to oral corticosteroids for more than 90 days. Overall, there was no increased risk of AEs with use of oral corticosteroids for more than 30 days (adjusted odds ratio [AOR], 1.00; 95% CI, 0.97-1.04), whereas the risk was slightly higher with use of oral corticosteroids for more than 90 days (AOR, 1.11; 95% CI, 1.01-1.23). The small elevation in experiencing an AE was observed with each cumulative or consecutive year of ever long-term use. Conclusions and Relevance: This case-control study found a slightly increased risk of AEs associated with use of oral corticosteroids for more than 90 days per year, which warrants future research to fully elucidate the observed findings.


Assuntos
Corticosteroides , Dermatite Atópica , Humanos , Dermatite Atópica/tratamento farmacológico , Masculino , Feminino , Estudos de Casos e Controles , Adulto , Administração Oral , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Corticosteroides/administração & dosagem , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Osteoporose/tratamento farmacológico , Fraturas Ósseas/induzido quimicamente , Fraturas Ósseas/epidemiologia , Idoso , Diabetes Mellitus Tipo 2/tratamento farmacológico
8.
Sci Rep ; 14(1): 15491, 2024 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-38969701

RESUMO

Our study aims to compare the efficacy of oral antidiabetic therapy to early insulinization on glycemic control among newly diagnosed type 2 diabetes patients in real-world clinical practice. A retrospective cohort study conducted at a medical center in Taiwan analyzed 1256 eligible patients from January 2007 to December 2017. Propensity score matching resulted in well-balanced groups of 94 patients each in the oral antidiabetic drug (OAD) and early insulinization cohorts. Glycemic outcomes were assessed in both groups. Patients exclusively using OAD showed consistently lower glycated hemoglobin (HbA1c) levels at 3, 12, 24, and 36 months compared to insulin users. At later periods, 77.7% of OAD users achieved glycemic control versus 64.9% of insulin users, with a marginally significant difference. Subgroup analyses suggested a trend favoring well-controlled diabetes in the OAD group, though not statistically significant. Our study finds oral antidiabetic therapy is not inferior to early insulinization for glycemic control in newly diagnosed type 2 diabetes patients, irrespective of initial HbA1c levels. This supports oral therapy as a rational treatment option, even in cases with elevated HbA1c at diagnosis.


Assuntos
Diabetes Mellitus Tipo 2 , Hemoglobinas Glicadas , Controle Glicêmico , Hipoglicemiantes , Insulina , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/administração & dosagem , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Controle Glicêmico/métodos , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/metabolismo , Insulina/administração & dosagem , Administração Oral , Idoso , Glicemia/análise , Taiwan , Resultado do Tratamento
9.
iScience ; 27(7): 110137, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39006481

RESUMO

Pituitary adenoma-induced excess endocrine growth hormone (GH) secretion can lead to breast cancer development and metastasis. Herein, we used an acromegaly mouse model to investigate the role of excess endocrine GH on triple-negative breast cancer (TNBC) growth and metastasis. Additionally, we aimed to elucidate the molecular mechanism of transcription factor 20 (TCF20)/nuclear factor erythroid 2-related factor 2 (NRF2) signaling-mediated aggressiveness and metastasis of TNBC. Excess endocrine GH induced TCF20 activates the transcription of NRF2 and NRF2-target genes to facilitate TNBC metastasis. Inhibition of GH receptor (GHR) and TCF20 activity using the GHR antagonist or small-interfering RNA-induced gene knockdown resulted in reduced tumor volume and metastasis, suggesting that excess endocrine GH stimulates TCF20/NRF2 pathways in TNBC and promotes metastasis to the lung. GHR inhibitors present an effective therapeutic strategy to prevent TNBC cell growth and metastasis. Our findings revealed functional and mechanistic roles of the GH-TCF20-NRF2 signaling axis in TBNC progression.

10.
J Pers Med ; 14(6)2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38929831

RESUMO

Many physical factors influence post-stroke functional outcomes. However, few studies have examined the influence of height on these outcomes. Here, data from the Korean Stroke Cohort for Functioning and Rehabilitation were used and patients' height was categorized into three groups: short (lower 25%), middle (middle 50%), and tall (upper 25%). Differences in the modified Rankin scale (mRS), functional ambulatory category (FAC), and Korean-translated version of the Modified Barthel Index (K-MBI) scores were analyzed for each group at 6 months post-stroke. A subgroup analysis was conducted based on the initial Fugl-Meyer Assessment (FMA) score. We analyzed functional outcomes in 5296 patients at 6 months post-stroke, adjusting for age and body mass index. The short-height group exhibited higher mRS scores (1.88 ± 0.043), lower FAC scores (3.74 ± 0.045), and lower K-MBI scores (82.83 ± 0.748) than the other height groups (p < 0.05). In the subgroup analysis, except for the very severe FMA group, the short-height group also exhibited worse outcomes in terms of mRS, FAC, and K-MBI scores (p < 0.05). Taken together, the short-height group exhibited worse outcomes related to disability, gait function, and ADLs at 6 months post-stroke.

11.
J Dermatolog Treat ; 35(1): 2359511, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38880494

RESUMO

Botulinum toxin type A (BoNT-A) was first isolated in 1946, and since then, several formulations have been developed and widely used to treat wrinkles by inducing muscle paralysis. This multicenter, double-blind, randomized, parallel-group, active-controlled phase 3 clinical trial was designed to evaluate the efficacy and safety of a newly developed BoNT-A formulation, BMI2006, in improving moderate to severe glabellar wrinkles and to compare with existing onabotulinumtoxin A (OBoNT) injections. A total of 276 subjects were enrolled and received 20 units of the randomized material, which was intramuscularly injected into five different locations on the forehead. The primary endpoint, assessed at 4 weeks, showed no statistically significant difference in the improvement rate of glabellar wrinkles between the two groups, with BMI2006 demonstrating non-inferiority to comparator BoNT-A. Secondary endpoints, evaluated by both treating investigators and independent investigators, also exhibited similar improvement rates throughout the study period. Both groups reported high levels of satisfaction with no statistical difference between the two groups. Safety evaluations indicated mild and transient adverse events, with no serious reactions observed. In conclusion, BMI2006 is an effective and safe BoNT-A for treating glabellar wrinkles with an expected duration of action between 8 and 12 weeks.


Assuntos
Povo Asiático , Toxinas Botulínicas Tipo A , Testa , Fármacos Neuromusculares , Envelhecimento da Pele , Humanos , Toxinas Botulínicas Tipo A/administração & dosagem , Toxinas Botulínicas Tipo A/efeitos adversos , Método Duplo-Cego , Envelhecimento da Pele/efeitos dos fármacos , Feminino , Pessoa de Meia-Idade , Masculino , Adulto , Resultado do Tratamento , Injeções Intramusculares , Fármacos Neuromusculares/administração & dosagem , Fármacos Neuromusculares/efeitos adversos , Satisfação do Paciente
12.
Dermatol Ther (Heidelb) ; 14(7): 1959-1968, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38904749

RESUMO

INTRODUCTION: Alopecia areata (AA) is an autoimmune disease associated with high rates of emotional and psychosocial distress. The analysis reported here describes the evolution of measures assessing health-related quality of life (HRQoL) and symptoms of anxiety and depression up to week 104 in patients who achieved sustained scalp hair regrowth during treatment with baricitinib in the BRAVE-AA phase III trials. METHODS: This post-hoc analysis included data from the double-blind, parallel-group, randomized, placebo-controlled phase III trials BRAVE-AA1 (ClinicalTrials.gov number: NCT03570749) and BRAVE-AA2 (ClinicalTrials.gov number: NCT03899259). Adults with severe AA (defined as a Severity of Alopecia Tool [SALT] score ≥ 50) randomized to baricitinib 4 mg or baricitinib 2 mg at baseline who achieved SALT score ≤ 20 by week 36 and maintained SALT score ≤ 20 through week 104 on the same dose of baricitinib were included in this analysis of integrated data. Scalp hair regrowth (SALT score) and improvements in Skindex-16 AA Scale and Hospital Anxiety and Depression Scale (HADS) domain scores were analyzed over the 104-week period using descriptive statistics. RESULTS: In total, 131 patients (88 on baricitinib 4 mg and 43 on baricitinib 2 mg) were included in this analysis. Across the two groups, the mean age (standard deviation) was 37.2 years (12.7), and 84 (64.1%) patients were female. The interquartile range) for time to achieve a SALT score ≤ 20 for patients treated with baricitinib 4 mg and baricitinib 2 mg was 13.1 and 19.6 weeks, respectively. By week 104, 91% (baricitinib 2 mg) and 96% (baricitinib 4 mg) of patients had achieved a SALT score ≤ 10 on baricitinib treatment. In both groups, progressive improvements in the Skindex-16 AA and HADS domain scores were observed up to week 104. CONCLUSION: This analysis of adults with severe AA treated with baricitinib revealed that achievement of sustained clinically meaningful scalp hair regrowth (SALT score ≤ 20) was associated with improvements in both measures of HRQoL and symptoms of anxiety and depression up to week 104.

13.
Artigo em Inglês | MEDLINE | ID: mdl-38944393

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) play important roles in therapeutic applications by regulating immune responses. OBJECTIVE: We investigated the safety and efficacy of allogenic human bone marrow-derived clonal MSCs (hcMSCs) in subjects with moderate to severe atopic dermatitis (AD). METHODS: The study included a phase 1 open-label trial followed by a phase 2 randomized, double-blind, placebo-controlled trial that involved 72 subjects with moderate to severe AD. RESULTS: In phase 1, intravenous administration of hcMSCs at 2 doses (1 × 106 and 5 × 105 cells/kg) was safe and well tolerated in 20 subjects. Because there was no difference between the 2 dosage groups (P = .9), it was decided to administer low-dose hcMSCs only for phase 2. In phase 2, subjects receiving 3 weekly intravenous infusions of hcMSCs at 5 × 105 cells/kg showed a higher proportion of an Eczema Area and Severity Index (EASI)-50 response at week 12 compared to the placebo group (P = .038). The differences between groups in the Dermatology Life Quality Index and pruritus numeric rating scale scores were not statistically significant. Most adverse events were mild or moderate and resolved by the end of the study period. CONCLUSIONS: The hcMSC treatment resulted in a significantly higher rate of EASI-50 at 12 weeks compared to the control group in subjects with moderate to severe AD. The safety profile of hcMSC treatment was acceptable. Further larger-scale studies are necessary to confirm these preliminary findings.

14.
Sensors (Basel) ; 24(7)2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38610533

RESUMO

In this paper, we introduce a novel artificial intelligence technique with an attention mechanism for half-space electromagnetic imaging. A dielectric object in half-space is illuminated by TM (transverse magnetic) waves. Since measurements can only be made in the upper space, the measurement angle will be limited. As a result, we apply a back-propagation scheme (BPS) to generate an initial guessed image from the measured scattered fields for scatterer buried in the lower half-space. This process can effectively reduce the high nonlinearity of the inverse scattering problem. We further input the guessed images into the generative adversarial network (GAN) and the self-attention generative adversarial network (SAGAN), respectively, to compare the reconstruction performance. Numerical results prove that both SAGAN and GAN can reconstruct dielectric objects and the MNIST dataset under same measurement conditions. Our analysis also reveals that SAGAN is able to reconstruct electromagnetic images more accurately and efficiently than GAN.

15.
Cancer Discov ; 14(8): 1457-1475, 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-38587317

RESUMO

Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumors, and WRN inhibitors are in development. In this study, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth in vitro and in vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA repeats and DNA damage. Assessment of biomarkers in preclinical models linked TA-repeat expansions and mismatch repair alterations to compound activity. Efficacy was confirmed in immunotherapy-resistant organoids and patient-derived xenograft models. The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic lethal targeting of WRN in MSI cancer and tools to dissect WRN biology. Significance: We report the discovery and characterization of potent, selective WRN helicase inhibitors for MSI cancer treatment, with biomarker analysis and evaluation of efficacy in vivo and in immunotherapy-refractory preclinical models. These findings pave the way to translate WRN inhibition into MSI cancer therapies and provide tools to investigate WRN biology. See related commentary by Wainberg, p. 1369.


Assuntos
Helicase da Síndrome de Werner , Humanos , Helicase da Síndrome de Werner/genética , Camundongos , Animais , Instabilidade de Microssatélites , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico
16.
Am J Case Rep ; 25: e943071, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38576141

RESUMO

BACKGROUND Meckel's diverticulum is a congenital remnant of the omphalomesenteric duct and is the most common congenital gastrointestinal malformation. Most patients are asymptomatic, but a rare presentation is with subacute small bowel obstruction (SBO) due to herniation of bowel loops through an internal hernia formed by the Meckel's diverticulum and adjacent mesentery that forms an internal hernia. This report is of a 15-year-old girl presenting as an emergency with vomiting and small bowel obstruction due to an internal hernia associated with Meckel's diverticulum. CASE REPORT We present a case of a 15-year-old girl who presented to the Children's Emergency (CE) department with persistent vomiting and abdominal distension and tenderness. X-rays demonstrated dilated small bowel loops, prompting admission under Pediatric Surgery (PAS). A subsequent computed tomography (CT) scan was performed, which demonstrated multiple dilated small bowel loops, confirming SBO, and a blind-ending "C-shaped" bowel loop at the region of the terminal ileum. A diagnostic laparotomy was performed, which confirmed the presence of a Meckel's diverticulum. The tip of the Meckel's diverticulum was adherent to part of the small bowel mesentery, forming an internal hernia defect through which a loop of proximal ileum had herniated, resulting in SBO. She then underwent a laparoscopy-assisted transumbilical Meckel's diverticulectomy (LATUM). The patient recovered uneventfully and was discharged on the 4th postoperative day. CONCLUSIONS In children presenting with SBO, the possibility of Meckel's diverticulum as an etiology should be considered as a differential diagnosis. Early diagnosis and prompt intervention will improve clinical outcomes and avoid complications.


Assuntos
Hérnia Abdominal , Obstrução Intestinal , Divertículo Ileal , Adolescente , Feminino , Humanos , Hérnia Abdominal/complicações , Hérnia Interna/complicações , Obstrução Intestinal/diagnóstico por imagem , Obstrução Intestinal/etiologia , Obstrução Intestinal/cirurgia , Divertículo Ileal/complicações , Divertículo Ileal/diagnóstico por imagem , Divertículo Ileal/cirurgia , Vômito
17.
BMC Infect Dis ; 24(1): 397, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38609851

RESUMO

BACKGROUND: Cryptococcal osteomyelitis is a rare and potentially serious condition, typically encountered in individuals with compromised immune systems. This case underscores the unusual occurrence of disseminated Cryptococcosis in an immunocompetent person, involving multiple bones and lungs, with Cryptococcus neoformans identified as the causative agent. CASE PRESENTATION: An Indonesian man, previously in good health, presented with a chief complaint of successive multiple bone pain lasting for more one month, without any prior history of trauma. Additionally, he reported a recent onset of fever. On physical examination, tenderness was observed in the left lateral chest wall and right iliac crest. Laboratory findings indicated mildly elevated inflammatory markers. A computed tomography (CT) scan of the chest revealed an ovoid solid nodule in the right lower lung and multifocal osteolytic lesions in the sternum, ribs, and humeral head. A magnetic resonance imaging (MRI) study of the sacrum showed multiple lesions in the bilateral iliac bone and the lower L4 vertebral body. Confirmation of Cryptococcal osteomyelitis involved a fine-needle biopsy and culture, identifying Cryptococcus neoformans in the aspirate. The patient responded positively to targeted antifungal treatments, leading to a gradual improvement in his condition. CONCLUSIONS: This case emphasizes the need to consider Cryptococcus neoformans osteomyelitis in immunocompetent patients with bone pain. A definitive diagnosis involves a fine-needle biopsy for pathology and culture, and prompt initiation of appropriate antifungal treatment has proven effective in preventing mortality.


Assuntos
Criptococose , Cryptococcus neoformans , Osteomielite , Masculino , Humanos , Antifúngicos/uso terapêutico , Criptococose/diagnóstico , Criptococose/tratamento farmacológico , Pulmão , Osteomielite/diagnóstico , Osteomielite/tratamento farmacológico , Dor
18.
Medicina (Kaunas) ; 60(4)2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38674206

RESUMO

Long-term changes in caregiver burden should be clarified considering that extended post-stroke disability can increase caregiver stress. We assessed long-term changes in caregiver burden severity and its predictors. This study was a retrospective analysis of the Korean Stroke Cohort for Functioning and Rehabilitation. Patients with an acute first-ever stroke were enrolled from August 2012 to May 2015. Data were collected at 6 months and 6 years after stroke onset. The caregiver burden was measured with a subjective caregiver burden questionnaire based on the Korean version of the Caregiver Burden Inventory. The caregivers' characteristics and patients' clinical and functional status were also examined at each follow-up. A high caregiver burden, which suggests a risk of burnout, was reported by 37.9% and 51.7% of caregivers at 6 months and 6 years post-stroke, respectively. Both the caregiver burden total score and proportion of caregivers at risk of burnout did not decrease between 6 months and 6 years. The patients' disability (OR = 11.60; 95% CI 1.58-85.08; p = 0.016), caregivers' self-rated stress (OR = 0.03; 95% CI 0.00-0.47; p = 0.013), and caregivers' quality of life (OR = 0.76; 95% CI 0.59-0.99; p = 0.042) were burden predictors at 6 months. At 6 years, only the patients' disability (OR = 5.88; 95% CI 2.19-15.82; p < 0.001) and caregivers' psychosocial stress (OR = 1.26; 95% CI 1.10-1.44; p = 0.001) showed significance. Nearly half of the caregivers were at risk of burnout, which lasted for 6 years after stroke onset. The patients' disability and caregivers' stress were burden predictors in both subacute and chronic phases of stroke. The findings suggest that consistent interventions, such as emotional support or counseling on stress relief strategies for caregivers of stroke survivors, may reduce caregiver burden. Further research is needed to establish specific strategies appropriate for Korean caregivers to alleviate their burden in caring for stroke patients.


Assuntos
Sobrecarga do Cuidador , Cuidadores , Qualidade de Vida , Acidente Vascular Cerebral , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/psicologia , Acidente Vascular Cerebral/complicações , Estudos Retrospectivos , Cuidadores/psicologia , Cuidadores/estatística & dados numéricos , Idoso , Inquéritos e Questionários , República da Coreia , Qualidade de Vida/psicologia , Sobrecarga do Cuidador/psicologia , Sobreviventes/psicologia , Sobreviventes/estatística & dados numéricos , Adulto , Estresse Psicológico/psicologia , Estresse Psicológico/complicações , Estresse Psicológico/etiologia , Reabilitação do Acidente Vascular Cerebral/psicologia , Reabilitação do Acidente Vascular Cerebral/estatística & dados numéricos
19.
Am J Case Rep ; 25: e943056, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38483097

RESUMO

BACKGROUND Bilious vomiting in a child potentially portends the dire emergency of intestinal malrotation with volvulus, necessitating prompt surgical management, with differentials including small-bowel atresia, duodenal stenosis, annular pancreas, and intussusception. Although the upper-gastrointestinal series (UGI) is the diagnostic investigation of choice, up to 15% of the studies are inconclusive, thereby posing a diagnostic challenge. CASE REPORT We report a case series of 3 children referred for bilious vomiting, whose initial UGI was inconclusive and who were eventually confirmed to have intestinal malrotation at surgery. The first child was a female born at 37 weeks with antenatally diagnosed situs inversus and levocardia, who developed bilious vomiting on day 1 of life. The duodenojejunal flexure (DJ) could not be visualized on the UGI because of faint opacification on first pass of the contrast and subsequent overlap with the proximal jejunal loops. The second child was a male born at 36 weeks, presenting at age 4 months with bilious vomiting of 2 days duration. The third child was a female born at 29 weeks, presenting with bilious aspirates on day 3 of life. UGI for all 3 showed persistent hold-up of contrast at the proximal duodenum with no opacification of the distal duodenum or small bowel.Adjunctive techniques during the UGI and ultrasound examination helped achieve a preoperative diagnosis of malrotation in these children. CONCLUSIONS Application of diagnostic adjuncts to an inconclusive initial UGI may help elucidate a preoperative diagnosis of intestinal malrotation in infantile bilious vomiting.


Assuntos
Atresia Intestinal , Volvo Intestinal , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Duodeno/cirurgia , Atresia Intestinal/complicações , Volvo Intestinal/diagnóstico , Volvo Intestinal/cirurgia , Volvo Intestinal/complicações , Náusea , Vômito/etiologia
20.
Research (Wash D C) ; 7: 0307, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38439995

RESUMO

Stochastic computing (SC) has a substantial amount of study on application-specific integrated circuit (ASIC) design for artificial intelligence (AI) edge computing, especially the convolutional neural network (CNN) algorithm. However, SC has little to no optimization on field-programmable gate array (FPGA). Scaling up the ASIC logic without FPGA-oriented designs is inefficient, while aggregating thousands of bitstreams is still challenging in the conventional SC. This research has reinvented several FPGA-efficient 8-bit SC CNN computing architectures, i.e., SC multiplexer multiply-accumulate, multiply-accumulate function generator, and binary rectified linear unit, and successfully scaled and implemented a fully parallel CNN model on Kintex7 FPGA. The proposed SC hardware only compromises 0.14% accuracy compared to binary computing on the handwriting Modified National Institute of Standards and Technology classification task and achieved at least 99.72% energy saving per image feedforward and 31× more data throughput than modern hardware. Unique to SC, early decision termination pushed the performance baseline exponentially with minimum accuracy loss, making SC CNN extremely lucrative for AI edge computing but limited to classification tasks. The SC's inherent noise heavily penalizes CNN regression performance, rendering SC unsuitable for regression tasks.

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