Dominantly acting KIF5B variants with pleiotropic cellular consequences cause variable clinical phenotypes.

Kinesins are motor proteins involved in microtubule (MT)-mediated intracellular transport. They contribute to key cellular processes, including intracellular trafficking, organelle dynamics and cell division. Pathogenic variants in kinesin-encoding genes underlie several human diseases characterized by an extremely variable clinical phenotype, ranging from isolated neurodevelopmental/neurodegenerative disorders to syndromic phenotypes belonging to a family of conditions collectively termed as 'ciliopathies.' Among kinesins, kinesin-1 is the most abundant MT motor for transport of cargoes towards the plus end of MTs. Three kinesin-1 heavy chain isoforms exist in mammals. Different from KIF5A and KIF5C, which are specifically expressed in neurons and established to cause neurological diseases when mutated, KIF5B is an ubiquitous protein. Three de novo missense KIF5B variants were recently described in four subjects with a syndromic skeletal disorder characterized by kyphomelic dysplasia, hypotonia and DD/ID. Here, we report three dominantly acting KIF5B variants (p.Asn255del, p.Leu498Pro and p.Leu537Pro) resulting in a clinically wide phenotypic spectrum, ranging from dilated cardiomyopathy with adult-onset ophthalmoplegia and progressive skeletal myopathy to a neurodevelopmental condition characterized by severe hypotonia with or without seizures. In vitro and in vivo analyses provide evidence that the identified disease-associated KIF5B variants disrupt lysosomal, autophagosome and mitochondrial organization, and impact cilium biogenesis. All variants, and one of the previously reported missense changes, were shown to affect multiple developmental processes in zebrafish. These findings document pleiotropic consequences of aberrant KIF5B function on development and cell homeostasis, and expand the phenotypic spectrum resulting from altered kinesin-mediated processes.

Outcomes in 14 live births resulting from Pegvaliase-treated pregnancies in PKU-affected females.

BACKGROUND: Adults with PKU have difficulty maintaining plasma phenylalanine (Phe) in the range that is safe for neurologic function. Elevated plasma Phe is a risk factor for congenital anomalies and developmental delay in offspring resulting from pregnancies with poor Phe control in women with PKU. Enzyme supplementation with pegvaliase allows adults with PKU to eat an unrestricted diet and have plasma Phe levels in a safe range for pregnancy but pegvaliase has not been approved for use in pregnant females with PKU. We report the results of chart review of 14 living offspring of females affected with PKU who were responsive to pegvaliase and chose to remain on pegvaliase throughout their pregnancy. METHODS: Fourteen pregnancies (one triplet pregnancy) and their offspring were identified at eight PKU treatment centers and medical records from pregnancy and birth were submitted for this study. Institutional Review Board approval was obtained. Responses to a dataset were provided to a single center and analyzed. RESULTS: Six females and eight males were born without congenital anomalies and all offspring had normal growth parameters. While mothers had preexisting comorbidities, no additional comorbidities were reported in the offspring. Four of eleven infants (excluding triplet pregnancies) were delivered preterm (36%), a higher rate than the general population (12%). A single first trimester (eight weeks) miscarriage in a 40y was not counted in this cohort of 14 live born infants. CONCLUSION: This retrospective study suggests that pegvaliase is effective at maintaining safe maternal blood Phe levels during pregnancy without deleterious effects on mother or child. A tendency toward premature birth (4/11; 36%) is higher than expected.

Democratizing Native Hawaiian and Pacific Islander Data: Examining Community Accessibility of Data for Health and the Social Drivers of Health.

Making data accessible to communities is essential for developing community-driven solutions to address health inequities. In this analytic essay, we highlight the importance of democratizing data for Native Hawaiians and Pacific Islanders (NHPIs)-diverse populations that historically have had little access to their data-in the context of achieving equity in health and the social drivers of health. We provide a framework for evaluating community accessibility of data, which includes concepts of data availability, salience, cost, and report back. We apply the framework to evaluate community accessibility of NHPI data from 29 federal data sources. In addition, we provide results from a survey of NHPI-serving community organizations in California conducted from December 2021 to February 2022 to assess community data needs. Findings reveal federal gaps in data accessibility, as well as NHPI community organizational needs for increased data accessibility, data saliency, and technical capacity. Furthermore, organization leads expressed concerns about data privacy, security, and misuse. We provide recommendations for data custodians to improve accessibility of timely, accurate, and robust data to support NHPI communities. (Am J Public Health. 2024;114(S1):S103-S111. https://doi.org/10.2105/AJPH.2023.307503).

Genomic analysis, immunomodulation and deep phenotyping of patients with nodding syndrome.

The aetiology of nodding syndrome remains unclear, and comprehensive genotyping and phenotyping data from patients remain sparse. Our objectives were to characterize the phenotype of patients with nodding syndrome, investigate potential contributors to disease aetiology, and evaluate response to immunotherapy. This cohort study investigated members of a single-family unit from Lamwo District, Uganda. The participants for this study were selected by the Ugandan Ministry of Health as representative for nodding syndrome and with a conducive family structure for genomic analyses. Of the eight family members who participated in the study at the National Institutes of Health (NIH) Clinical Center, three had nodding syndrome. The three affected patients were extensively evaluated with metagenomic sequencing for infectious pathogens, exome sequencing, spinal fluid immune analyses, neurometabolic and toxicology testing, continuous electroencephalography and neuroimaging. Five unaffected family members underwent a subset of testing for comparison. A distinctive interictal pattern of sleep-activated bursts of generalized and multifocal epileptiform discharges and slowing was observed in two patients. Brain imaging showed two patients had mild generalized cerebral atrophy, and both patients and unaffected family members had excessive metal deposition in the basal ganglia. Trace metal biochemical evaluation was normal. CSF was non-inflammatory and one patient had CSF-restricted oligoclonal bands. Onchocerca volvulus-specific antibodies were present in all patients and skin snips were negative for active onchocerciasis. Metagenomic sequencing of serum and CSF revealed hepatitis B virus in the serum of one patient. Vitamin B6 metabolites were borderline low in all family members and CSF pyridoxine metabolites were normal. Mitochondrial DNA testing was normal. Exome sequencing did not identify potentially causal candidate gene variants. Nodding syndrome is characterized by a distinctive pattern of sleep-activated epileptiform activity. The associated growth stunting may be due to hypothalamic dysfunction. Extensive testing years after disease onset did not clarify a causal aetiology. A trial of immunomodulation (plasmapheresis in two patients and intravenous immunoglobulin in one patient) was given without short-term effect, but longer-term follow-up was not possible to fully assess any benefit of this intervention.

Immigration status microaggressions: A moderated mediation analysis of cultural stress, fear, internalization, and psychological stress among Latinx and Asian college students.

OBJECTIVES: Latinx and Asian people are experiencing an elevated rate of immigration status-related oppression-both systematically and individually-despite actual nationality, and this type of cultural stressor has seen a rampant increase recently in the United States. We aimed to assess the relation and effect of immigration status microaggressions on psychological stress and some mechanisms connected to these experiences. METHOD: Using a sample of Latinx and Asian college students (N = 776), we unpack the relationships between individual cultural stressors, such as immigration status microaggressions, and psychological stress, by exploring their mediating relation with internalized racism (Mediator 1), and fear of foreign objectification (Mediator 2), using Hayes's (2012) PROCESS Model 6-serial mediation. Furthermore, we expanded on this model, highlighting differences between Latinx and Asian participants (moderator) using a moderated mediation. RESULTS: Findings suggest a full serial mediation. Specifically, the psychological stress associated with immigration status microaggressions was mediated by internalized racism and fear of foreign objectification. Results also highlighted that Latinx participants, compared to Asian ones, showed a significant positive association between immigration status microaggressions with internalized racism and fear of foreign objectification. Furthermore, a significant interaction for Latinx who experience more fear of foreign objectification was positively associated with psychological stress. Indirect effects for each group are discussed. CONCLUSION: Our study is one of the first to explore cultural stress in the form of immigration status microaggressions in connection with more general forms of psychological stress and internalizing processes for two groups historically persecuted around immigration in the United States. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Prevalence and predictors of depressive symptoms among caregivers of patients with epilepsy in Hong Kong.

STUDY AIM: To estimate the prevalence of high caregiving burden and depressive symptoms among caregivers (CG) of patients with epilepsy (PWEs) in Hong Kong and identify risk and protective factors for both outcomes after the Model of Stress and Carer Burden (MSCB). METHODS: This cross-sectional study recruited participants from local epilepsy clinics to complete a 15-minute survey on a tablet. Caregiving burden (CB) was assessed using the 4-item Zarit Caregiver Burden Interview. Depressive symptoms were assessed using the 2-item Patient Health Questionnaire. Family functioning was assessed using the Short-Form Family Assessment Device General Functioning Subscale. Sociodemographic data of the caregivers and clinical data of the PWE they cared for were described. Hierarchical logistic regression models were used to analyze the factors associated with the outcomes. RESULTS: A hundred and fifty-one CGs of PWEs were recruited for this study. The prevalence of high caregiving burden (ZBI-4 > 7) for CGs of PWEs was 58.9% (n = 89), whereas the prevalence of high depressive symptoms (PHQ2 > 2) was 23.8% (n = 36). Hierarchical logistic regression analysis revealed that entering patient characteristics and care situations did not enhance the model's predictability. In the full model, a high perceived CB was a risk factor for elevated depressive symptoms. Good physical health protects against depressive symptoms. CONCLUSIONS: Among caregivers of PWE in Hong Kong, a high perceived caregiving burden was a risk factor for elevated depressive symptoms; however, the clinical characteristics of the PWEs were not. Self-reported physical health is a protective factor against increased depressive symptoms.

No difference in revision risk between autologous hamstring graft less than 8 mm versus hybrid graft 8 mm or larger in anterior cruciate ligament reconstruction.

PURPOSE: Hamstring autograft (HA) is commonly used for primary anterior cruciate ligament reconstruction (ACLR). However, if the harvested HA is inadequate in diameter, it is often augmented with an allograft tendon, forming a hybrid graft (HY). This study sought to evaluate aseptic revision risk following HA versus HY ACLR. METHODS: A retrospective cohort study was performed using data obtained from our healthcare system's ACLR registry. Patients ≤ 25 years of age who underwent primary isolated ACLR were identified (2005-2020). Graft type and diameter size was the primary exposure of interest: < 8 mm HA and ≥ 8 mm HY. A secondary analysis was performed to examine 7 mm HA and 7.5 mm HA vs ≥ 8 mm HY. Propensity score-weighted Cox proportional hazard regression was used to evaluate the risk of aseptic revision. RESULTS: The study sample included 1,945 ACLR: 548 ≥ 8 mm HY, 651 7 mm HA, and 672 7.5 mm HA. The crude cumulative aseptic revision probability at 8-years for ≥ 8 mm HY was 9.1%, 11.1% for 7 mm HA, and 11.2% for 7.5 mm HA. In adjusted analysis, no difference in revision risk was observed for < 8 mm HA (hazard ratio [HR] 1.15, 95% confidence interval [CI] 0.72-1.82), 7 mm HA (HR 1.23, 95% CI 0.71-2.11), or 7.5 mm HA (HR 1.16, 95% CI 0.74-1.82) compared to ≥ 8 mm HY. CONCLUSION: In a US-based cohort of ACLR patients aged ≤ 25 years, we failed to observe any differences in aseptic revision risk for HA < 8 mm compared to HY ≥ 8 mm. Augmentation of a HA as small as 7 mm is not necessary to prevent a revision surgery. LEVEL OF EVIDENCE: Level III.

Association between same-day discharge shoulder arthroplasty and risk of adverse events in patients with American Society of Anesthesiologists classification ≥3: a cohort study.

BACKGROUND: Same-day discharge for shoulder arthroplasty (SA) is well-supported in the literature; however, most studies have focused on healthier patients. Indications for same-day discharge SA have expanded to include patients with more comorbidities, but safety of same-day discharge in this population remains unknown. We sought to compare outcomes following same-day discharge vs. inpatient SA in a cohort of patients considered higher risk for adverse events, defined as an American Society of Anesthesiologists (ASA) classification of ≥3. METHODS: Data from Kaiser Permanente's SA registry were utilized to conduct a retrospective cohort study. All patients with an ASA classification of ≥3 who underwent primary elective anatomic or reverse SA in a hospital from 2018 to 2020 were included. The exposure of interest was in-hospital length of stay: same-day discharge vs. ≥1-night hospital inpatient stay. The likelihood of 90-day post-discharge events, including emergency department (ED) visit, readmission, cardiac complication, venous thromboembolism, and mortality, was evaluated using propensity score-weighted logistic regression with noninferiority testing using a margin of 1.10. RESULTS: The cohort included a total of 1814 SA patients, of whom 1005 (55.4%) had same-day discharge. In propensity score-weighted models, same-day discharge was not inferior to an inpatient stay SA regarding 90-day readmission (odds ratio [OR] = 0.64, one-sided 95% upper bound [UB] = 0.89) and overall complications (OR = 0.67, 95% UB = 1.00). We lacked evidence in support of noninferiority for 90-day ED visit (OR = 0.96, 95% UB = 1.18), cardiac event (OR = 0.68, 95% UB = 1.11), or venous thromboembolism (OR = 0.91, 95% UB = 2.15). Infections, revisions for instability, and mortality were too rare to evaluate using regression analysis. CONCLUSIONS: In a cohort of over 1800 patients with an ASA of ≥3, we found same-day discharge SA did not increase the likelihood of ED visits, readmissions, or complications compared with an inpatient stay, and same-day discharge was not inferior to an inpatient stay with regard to readmissions and overall complications. These findings suggest that it is possible to expand indications for same-day discharge SA in the hospital setting.

Utilization of Total Joint Arthroplasty by Rural-Urban Designation in Patients With Osteoarthritis in a Universal Coverage System.

BACKGROUND: Utilization of total joint arthroplasty (TJA) is affected by differences linked to sex, race, and socioeconomic status; there is little information about how geographic variation contributes to these differences. We sought to determine whether discrepancies in TJA utilization exist in patients diagnosed with osteoarthritis (OA) based upon urban-rural designation in a universal coverage system. METHODS: We conducted a cohort study using data from a US-integrated healthcare system (2015 to 2019). Patients aged ≥50 years who had a diagnosis of hip or knee OA were included. Total hip arthroplasty and total knee arthroplasty utilization (in respective OA cohorts) was evaluated by urban-rural designation (urban, mid, and rural). Incidence rate ratios (IRRs) for urban-rural regions were modeled using multivariable Poisson regressions. RESULTS: The study cohort included 93,642 patients who have hip OA and 275,967 patients who had knee OA. In adjusted analysis, utilization of primary total hip arthroplasty was lower in patients living in urban areas (IRR = 0.87, 95% confidence interval = 0.81 to 0.94) compared to patients in rural regions. Similarly, total knee arthroplasty was used at a lower rate in urban areas (IRR = 0.88, 95% confidence interval = 0.82 to 0.95) compared with rural regions. We found no differences in the hip and knee groups within the mid-region. CONCLUSIONS: In hip and knee OA patients enrolled in a universal coverage system, we found patients living in urban areas had lower TJA utilization compared to patients living in rural areas. Further research is needed to determine how patient location contributes to differences in elective TJA utilization. LEVEL OF EVIDENCE: III.

Prolonged Opioid Usage Following Hip Fracture Surgery in Opioid-Naïve Older Patients.

BACKGROUND: While the risk of long-term dependence following the opioid treatment of musculoskeletal injury is often studied in younger populations, studies in older patients have centered on short-term risks such as oversedation and delirium. This study investigated prolonged opioid usage after hip fracture in older individuals, focusing on prevalence, risk factors, and changes over time. METHODS: In this retrospective cohort study of 47,309 opioid-naïve patients aged ≥ 60 years who underwent hip fracture surgery (2009 to 2020), outpatient opioid use was evaluated in 3 postoperative time periods: P1 (day 0 to 30 postsurgery); P2 (day 31 to 90); and P3 (day 91 to 180). The primary outcome was prolonged outpatient opioid use, defined as having one or more opioid prescriptions dispensed in all 3 time periods. RESULTS: The incidence of prolonged opioid usage among patients surviving to P3 was 6.3% (2,834 of 44,850). Initial prescription quantities decreased over time, as did the risk of prolonged opioid usage (from 8.0% in 2009 to 3.9% in 2019). In the multivariable analyses, risk factors for prolonged opioid usage included younger age, women, current/former smoking, fracture fixation (as compared to hemiarthroplasty), and anxiety. Prolonged opioid usage was less common among patients who were Asian or had a history of dementia. CONCLUSIONS: While prior research on the hazards of opioids in the elderly has focused on short-term risks such as oversedation and delirium, these findings suggest that prolonged opioid usage may be a risk for this older population as well. As initial prescription amounts have decreased, declines in prolonged opioid medication usage have also been observed.

Single Wedge Femoral Stem Designs are Associated With a Higher Risk for Revision After Cementless Primary Total Hip Arthroplasty.

BACKGROUND: Cementless total hip arthroplasty (THA) femoral stems are the most commonly selected prostheses in the United States. Optimal stem geometry remains controversial with excellent survivorship reported for many designs. We compared cause-specific stem revision of single-wedge versus double-wedge designs from a multicenter US cohort. METHODS: Data from an integrated healthcare network's total joint replacement registry were used to conduct a cohort study. Primary elective cementless THAs were identified (2001 to 2018). Implant exposure groups were classified by design geometry using the system proposed by Khanuja et al. Type 1 single-wedge (n = 11,082) and type 2 double-wedge (n = 32,380) designs were compared, and other design types were excluded; the final study cohort comprised 43,462 THAs. Cause-specific multivariable Cox regressions were used to evaluate risk for revision due to infection or aseptic reasons, including loosening, instability, periprosthetic fracture, or other reasons. RESULTS: After adjustment for covariates, a higher aseptic revision risk was observed for type 1 when compared to type 2 designs (hazard ratio = 1.91, 95% confidence interval = 1.33-2.75). When looking at specific revision reasons, revision for aseptic loosening (hazard ratio = 3.46, 95% confidence interval = 2.24-5.34) was higher for type 1 versus type 2 designs. No differences were found for septic revision, instability, periprosthetic fracture, or revisions for other reasons. CONCLUSIONS: Type 1 single-wedge designs were found to have a higher risk of revision due to aseptic loosening relative to type 2 double-wedge designs. Femoral stem geometry should be considered when selecting a cementless femoral implant. LEVEL OF EVIDENCE: Level III.

Robust Detection, Segmentation, and Metrology of High Bandwidth Memory 3D Scans Using an Improved Semi-Supervised Deep Learning Approach.

Recent advancements in 3D deep learning have led to significant progress in improving accuracy and reducing processing time, with applications spanning various domains such as medical imaging, robotics, and autonomous vehicle navigation for identifying and segmenting different structures. In this study, we employ the latest developments in 3D semi-supervised learning to create cutting-edge models for the 3D object detection and segmentation of buried structures in high-resolution X-ray semiconductors scans. We illustrate our approach to locating the region of interest of the structures, their individual components, and their void defects. We showcase how semi-supervised learning is utilized to capitalize on the vast amounts of available unlabeled data to enhance both detection and segmentation performance. Additionally, we explore the benefit of contrastive learning in the data pre-selection step for our detection model and multi-scale Mean Teacher training paradigm in 3D semantic segmentation to achieve better performance compared with the state of the art. Our extensive experiments have shown that our method achieves competitive performance and is able to outperform by up to 16% on object detection and 7.8% on semantic segmentation. Additionally, our automated metrology package shows a mean error of less than 2 µm for key features such as Bond Line Thickness and pad misalignment.

The use of antibiotic-loaded bone cement and systemic antibiotic prophylactic use in 2,971,357 primary total knee arthroplasties from 2010 to 2020: an international register-based observational study among countries in Africa, Europe, North America, and Oceania.

BACKGROUND AND PURPOSE: Antibiotic-loaded bone cement (ALBC) and systemic antibiotic prophylaxis (SAP) have been used to reduce periprosthetic joint infection (PJI) rates. We investigated the use of ALBC and SAP in primary total knee arthroplasty (TKA). PATIENTS AND METHODS: This observational study is based on 2,971,357 primary TKAs reported in 2010-2020 to national/regional joint arthroplasty registries in Australia, Denmark, Finland, Germany, Italy, the Netherlands, New Zealand, Norway, Romania, South Africa, Sweden, Switzerland, the UK, and the USA. Aggregate-level data on trends and types of bone cement, antibiotic agents, and doses and duration of SAP used was extracted from participating registries. RESULTS: ALBC was used in 77% of the TKAs with variation ranging from 100% in Norway to 31% in the USA. Palacos R+G was the most common (62%) ALBC type used. The primary antibiotic used in ALBC was gentamicin (94%). Use of ALBC in combination with SAP was common practice (77%). Cefazolin was the most common (32%) SAP agent. The doses and duration of SAP used varied from one single preoperative dosage as standard practice in Bolzano, Italy (98%) to 1-day 4 doses in Norway (83% of the 40,709 TKAs reported to the Norwegian arthroplasty register). CONCLUSION: The proportion of ALBC usage in primary TKA varies internationally, with gentamicin being the most common antibiotic. ALBC in combination with SAP was common practice, with cefazolin the most common SAP agent. The type of ALBC and type, dose, and duration of SAP varied among participating countries.

Expanding the genotype and phenotype spectrum of SYT1-associated neurodevelopmental disorder.

PURPOSE: Synaptotagmin-1 (SYT1) is a critical mediator of neurotransmitter release in the central nervous system. Previously reported missense SYT1 variants in the C2B domain are associated with severe intellectual disability, movement disorders, behavioral disturbances, and electroencephalogram abnormalities. In this study, we expand the genotypes and phenotypes and identify discriminating features of this disorder. METHODS: We describe 22 individuals with 15 de novo missense SYT1 variants. The evidence for pathogenicity is discussed, including the American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria, known structure-function relationships, and molecular dynamics simulations. Quantitative behavioral data for 14 cases were compared with other monogenic neurodevelopmental disorders. RESULTS: Four variants were located in the C2A domain with the remainder in the C2B domain. We classified 6 variants as pathogenic, 4 as likely pathogenic, and 5 as variants of uncertain significance. Prevalent clinical phenotypes included delayed developmental milestones, abnormal eye physiology, movement disorders, and sleep disturbances. Discriminating behavioral characteristics were severity of motor and communication impairment, presence of motor stereotypies, and mood instability. CONCLUSION: Neurodevelopmental disorder-associated SYT1 variants extend beyond previously reported regions, and the phenotypic spectrum encompasses a broader range of severities than initially reported. This study guides the diagnosis and molecular understanding of this rare neurodevelopmental disorder and highlights a key role for SYT1 function in emotional regulation, motor control, and emergent cognitive function.

Association between the risk of seizure and COVID-19 vaccinations: A self-controlled case-series study.

OBJECTIVE: The risk of seizure following BNT162b2 and CoronaVac vaccinations has been sparsely investigated. This study aimed to evaluate this association. METHOD: Patients who had their first seizure-related hospitalization between February 23, 2021 and January 31, 2022, were identified in Hong Kong. All seizure episodes happening on the day of vaccination (day 0) were excluded, since clinicians validated that most of the cases on day 0 were syncopal episodes. Within-individual comparison using a modified self-controlled case series analysis was applied to estimate the incidence rate ratio (IRR) with 95% confidence intervals (CIs) of seizure using conditional Poisson regression. RESULTS: We identified 1656 individuals who had their first seizure-related hospitalization (BNT162b2: 426; CoronaVac: 263; unvaccinated: 967) within the observation period. The incidence of seizure was 1.04 (95% CI .80-1.33) and 1.11 (95% CI .80-1.50) per 100 000 doses of BNT162b2 and CoronaVac administered, respectively. Sixteen and 17 individuals, respectively, received a second dose after having a first seizure within 28 days after the first dose of BNT162b2 and CoronaVac vaccinations. None had recurrent seizures after the second dose. There was no increased risk during day 1-6 after the first (BNT162b2: IRR = 1.39, 95% CI = .75-2.58; CoronaVac: IRR = 1.19, 95% CI = .50-2.83) and second doses (BNT162b2: IRR = 1.36, 95% CI = .72-2.57; CoronaVac: IRR = .71, 95% CI = .22-2.30) of vaccinations. During 7-13, 14-20, and 21-27 days post-vaccination, no association was observed for either vaccine. SIGNIFICANCE: The findings demonstrated no increased risk of seizure following BNT162b2 and CoronaVac vaccinations. Future studies will be warranted to evaluate the risk of seizure following COVID-19 vaccinations in different populations, with subsequent doses to ensure the generalizability.

Antiepileptic drugs for the primary and secondary prevention of seizures after stroke.

BACKGROUND: Seizures after stroke are an important clinical problem and may result in poor outcomes. The indications of antiepileptic drugs (AEDs) for seizure prophylaxis after stroke remain unclear. This is an updated version of the Cochrane Review previously published in 2014. OBJECTIVES: To assess the effects of AEDs for the primary and secondary prevention of seizures after stroke. For primary prevention, we aimed to assess whether AEDs reduce the likelihood of seizures in people who have a stroke but do not have a seizure. For secondary prevention, we aimed to assess whether AEDs reduce the likelihood of further seizures in people who have a stroke and at least one post-stroke seizure. SEARCH METHODS: We searched the following databases on 9 March 2021: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to March 08, 2021). CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organisation International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialised Registers of Cochrane Review Groups including Epilepsy and Stroke. We also checked the reference lists of articles retrieved from these searches. SELECTION CRITERIA: We selected randomised and quasi-randomised controlled studies that recruited participants with a clinical diagnosis of stroke, either ischaemic or haemorrhagic. We excluded studies that only recruited participants with subarachnoid haemorrhage, subdural haemorrhage, extradural haemorrhage, or other non-stroke diagnoses such as tumour- or infection-related infarction or haemorrhage. We also excluded studies that recruited only participants who had undergone neurosurgery. We included participants of all ages suffering any seizure type who were assigned to AEDs or placebo groups. DATA COLLECTION AND ANALYSIS: In accordance with standard methodological procedures expected by The Cochrane Collaboration, two review authors independently assessed trials for inclusion before evaluating trial risk of bias and extracting relevant data. The primary outcome assessed was the proportion of participants who experienced seizures in the follow-up period. We presented results as summary risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences (MDs) with 95% CIs for continuous outcomes. Where we had sufficient data, we calculated random-effects (Mantel-Haenszel) meta-analyses for dichotomous outcomes; otherwise, we reported results narratively. We used the I2 statistic to analyse statistical heterogeneity. We planned to use funnel plots to assess publication bias in meta-analyses with at least 10 included studies. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: Two studies with a total of 856 subjects were included. AEDs were not shown to be effective in primary prophylaxis of post-stroke seizure (RR 0.65, 95% CI 0.34 to 1.26; 2 studies, 856 participants; moderate-certainty evidence). The first study was a randomised double-blind study comparing valproic acid with placebo for primary seizure prevention up to one year after stroke. The study included 72 adults with intracerebral haemorrhage. There was no difference in the risk of post-stroke seizures (RR 0.88, 95% CI 0.35 to 2.16) or of death (RR 1.20, 95% CI 0.40 to 3.58). The second study was a substudy on the use of diazepam in acute stroke. It was a randomised double-blind study, comparing a three-day diazepam treatment versus placebo for primary seizure prevention up to three months after stroke in 784 adults with acute stroke. There was no evidence of a difference in the risk of post-stroke seizures for all stroke or subgroups of haemorrhagic or ischaemic stroke (RR for all stroke 0.47, 95% CI 0.18 to 1.22). In a subgroup analysis of anterior circulation cortical infarcts, primary prophylaxis with diazepam was associated with a reduced risk of post-stroke seizures (RR 0.21, 95% CI 0.05 to 0.95). Risks of mortality did not differ between the diazepam and the placebo group at two weeks (RR 0.84, 95% CI 0.56 to 1.26) and three months follow-up (RR 0.95, 95% CI 0.72 to 1.26). We assessed both studies to be at a low overall risk of bias. Using the GRADE approach, we assessed the overall certainty of the evidence as low to moderate. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the routine use of AEDs on the primary and secondary prevention of seizures after stroke. Further well-conducted studies are warranted for this important clinical problem.

In utero ultrafine particulate matter exposure causes offspring pulmonary immunosuppression.

Early life exposure to fine particulate matter (PM) in air is associated with infant respiratory disease and childhood asthma, but limited epidemiological data exist concerning the impacts of ultrafine particles (UFPs) on the etiology of childhood respiratory disease. Specifically, the role of UFPs in amplifying Th2- and/or Th17-driven inflammation (asthma promotion) or suppressing effector T cells (increased susceptibility to respiratory infection) remains unclear. Using a mouse model of in utero UFP exposure, we determined early immunological responses to house dust mite (HDM) allergen in offspring challenged from 0 to 4 wk of age. Two mice strains were exposed throughout gestation: C57BL/6 (sensitive to oxidative stress) and BALB/C (sensitive to allergen exposure). Offspring exposed to UFPs in utero exhibited reduced inflammatory response to HDM. Compared with filtered air (FA)-exposed/HDM-challenged mice, UFP-exposed offspring had lower white blood cell counts in bronchoalveolar lavage fluid and less pronounced peribronchiolar inflammation in both strains, albeit more apparent in C57BL/6 mice. In the C57BL/6 strain, offspring exposed in utero to FA and challenged with HDM exhibited a robust response in inflammatory cytokines IL-13 and Il-17. In contrast, this response was lost in offspring exposed in utero to UFPs. Circulating IL-10 was significantly up-regulated in C57BL/6 offspring exposed to UFPs, suggesting increased regulatory T cell expression and suppressed Th2/Th17 response. Our results reveal that in utero UFP exposure at a level close to the WHO recommended PM guideline suppresses an early immune response to HDM allergen, likely predisposing neonates to respiratory infection and altering long-term pulmonary health.

Efficacy of Ultrasound-Guided Glenohumeral Joint Injections of Leukocyte-Poor Platelet-Rich Plasma Versus Hyaluronic Acid in the Treatment of Glenohumeral Osteoarthritis: A Randomized, Double-Blind Controlled Trial.

OBJECTIVE: To compare the efficacy of ultrasound-guided hyaluronic acid (HA) versus leukocyte-poor platelet-rich plasma (LP-PRP) injection in the treatment of glenohumeral osteoarthritis. DESIGN: Double-blind randomized controlled trial. SETTING: Academic institution. PATIENTS: Seventy patients with chronic glenohumeral osteoarthritis were randomly assigned to receive a single injection of HA (n = 36) or LP-PRP (n = 34). INTERVENTIONS: Leukocyte-poor platelet-rich plasma was processed using Harvest/TerumoBCT Clear PRP kits. Ultrasound-guided injections of 6 mL HA or 6 mL LP-PRP into the glenohumeral joint were performed. Patients, the injecting physician, and outcomes assessor were blinded to treatment assignments. MAIN OUTCOME MEASURES: Shoulder Pain and Disability Index (SPADI), American Shoulder and Elbow Surgeons (ASES) score, current/average numerical rating scale (NRS) pain scores, satisfaction, and side effects were assessed at the 5 follow-up time points over 12 months. RESULTS: Baseline characteristics were similar between groups. There were no significant between-group differences regarding SPADI, ASES, and current/average NRS pain scores at any time point up to 12 months postinjection ( P > 0.05). However, significant improvements in SPADI, ASES, and current/average NRS pain scores were observed in both groups starting at 1 or 2 months ( P < 0.01, P < 0.01, P < 0.001, and P < 0.01, respectively). These improvements were observed regardless of osteoarthritis severity. For patients who received LP-PRP, there was no effect of platelet yield on outcomes. Side effect and satisfaction rates were similar between groups. CONCLUSIONS: There were no differences in pain and functional outcomes after a single injection of LP-PRP versus HA. However, significant improvements in pain and function were observed after both treatments in patients with glenohumeral osteoarthritis.

Acute and subacute anterior cruciate ligament reconstructions are associated with a higher risk of revision and reoperation.

PURPOSE: (1) Report concomitant cartilage and meniscal injury at the time of anterior cruciate ligament reconstruction (ACLR), (2) evaluate the risk of aseptic revision ACLR during follow-up, and (3) evaluate the risk of aseptic ipsilateral reoperation during follow-up. METHODS: Using a United States integrated healthcare system's ACLR registry, patients who underwent primary isolated ACLR were identified (2010-2018). Multivariable Cox proportional-hazards regression was used to evaluate the risk of aseptic revision, with a secondary outcome evaluating ipsilateral aseptic reoperation. Outcomes were evaluated by time from injury to ACLR: acute (< 3 weeks), subacute (3 weeks-3 months), delayed (3-9 months), and chronic (≥ 9 months). RESULTS: The final sample included 270 acute (< 3 weeks), 5971 subacute (3 weeks-3 months), 5959 delayed (3-9 months), and 3595 chronic (≥ 9 months) ACLR. Medial meniscus [55.4% (1990/3595 chronic) vs 38.9% (105/270 acute)] and chondral injuries [40.0% (1437/3595 chronic) vs 24.8% (67/270 acute)] at the time of ACLR were more common in the chronic versus acute groups. The crude 6-year revision rate was 12.9% for acute ACLR, 7.0% for subacute, 5.1% for delayed, and 4.4% for chronic ACLR; reoperation rates a 6-year follow-up was 15.0% for acute ACLR, 9.6% for subacute, 6.4% for delayed, and 8.1% for chronic ACLR. After adjustment for covariates, acute and subacute ACLR had higher risks for aseptic revision (acute HR 1.70, 95% CI 1.07-2.72, p = 0.026; subacute HR 1.25, 95% CI 1.01-1.55, p = 0.040) and aseptic reoperation (acute HR 2.04, 95% CI 1.43-2.91, p < 0.001; subacute HR 1.31, 95% CI 1.11-1.54, p = 0.002) when compared to chronic ACLR. CONCLUSIONS: In this cohort study, while more meniscal and chondral injuries were reported for ACLR performed ≥ 9 months after the date of injury, a lower risk of revision and reoperation was observed following chronic ACLR relative to patients undergoing surgery in acute or subacute fashions.

No Equity without Data Equity: Data Reporting Gaps for Native Hawaiians and Pacific Islanders as Structural Racism.

Data on the health and social determinants for Native Hawaiians and Pacific Islanders (NHPIs) in the United States are hidden, because data are often not collected or are reported in aggregate with other racial/ethnic groups despite decades of calls to disaggregate NHPI data. As a form of structural racism, data omissions contribute to systemic problems such as inability to advocate, lack of resources, and limitations on political power. The authors conducted a data audit to determine how US federal agencies are collecting and reporting disaggregated NHPI data. Using the COVID-19 pandemic as a case study, they reviewed how states are reporting NHPI cases and deaths. They then used California's neighborhood equity metric-the California Healthy Places Index (HPI)-to calculate the extent of NHPI underrepresentation in communities targeted for COVID-19 resources in that state. Their analysis shows that while collection and reporting of NHPI data nationally has improved, federal data gaps remain. States are vastly underreporting: more than half of states are not reporting NHPI COVID-19 case and death data. The HPI, used to inform political decisions about allocation of resources to combat COVID-19 in at-risk neighborhoods, underrepresents NHPIs. The authors make recommendations for improving NHPI data equity to achieve health equity and social justice.