Citations

Abstract Lead (Pb) poisoning is a significant threat to Aotearoa New Zealand's endangered kea ( Nestor notabilis ), an avian species important to Māori. Historically, exposure was thought to be from lead‐containing building materials; however, recent field observations suggest lead‐based ammunition as an additional source. We used stable lead isotopes to investigate the sources of lead to kea. Comparing 207 Pb/ 206 Pb ratios in kea blood ( n = 91) to both ammunition and building materials, we found approximately one‐third of exposed kea (blood lead > 10 µg/dL) had lead isotope ratios consistent with exposure to lead‐based ammunition. As lead ammunition is still used, including in government‐sponsored culling programs, our data indicate an urgent need to shift toward non‐lead ammunition use to prevent further poisoning and aid conservation efforts. Collaborating with tangata whenua /Māori guardians, we advocate for immediate policy changes to eliminate lead‐based ammunition in kea habitat to safeguard this endangered culturally treasured species from extinction.

Importance Individuals with atopic dermatitis are frequently colonized and infected with Staphylococcus aureus . Empirical antibiotic therapy for individuals with atopic dermatitis is common, but data about the antimicrobial susceptibility profiles of S aureus strains isolated from these individuals are scarce for those living in particular geographic areas. Objective To determine the antimicrobial susceptibility of S aureus from individuals with atopic dermatitis and analyze differences according to the income level of the country of origin and the data collection period. Data Sources A meta-analysis of the literature was performed from the inception of the included databases (MEDLINE, Embase, Web of Science, Scopus, and Cochrane) to June 20, 2023, using predetermined Medical Subject Headings. Study Selection Studies were included if they reported antibiotic susceptibility profiles of 1 or more S aureus cutaneous isolates from individuals with atopic dermatitis. Articles written in English, Spanish, French, or German were included. Data Extraction and Synthesis Working in pairs, 6 of the authors conducted the data extraction. The guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) were followed. Main Outcomes and Measures The outcome of interest was antimicrobial susceptibility. Results A total of 61 studies reported 4091 S aureus isolates from individuals with atopic dermatitis. For 4 of the 11 commonly used antibiotics (36.4%), antimicrobial susceptibility was 85% or less, including for methicillin (binomial proportion, 0.85 [95% CI, 0.76-0.91]), erythromycin (binomial proportion, 0.73 [95% CI, 0.61-0.83]), fusidic acid (binomial proportion, 0.80 [95% CI, 0.62-0.91]), and clindamycin (binomial proportion, 0.79 [95% CI, 0.65-0.89]). Most studies (46; 75.4%) were conducted in high-income countries. Antimicrobial susceptibility to erythromycin, methicillin, and trimethoprim and sulfamethoxazole was significantly lower in lower middle–income countries and upper middle–income countries. Regarding the temporal trends, 33 studies (54.1%) reported data collected from 1998 to 2010. Antimicrobial susceptibility patterns have not changed over time. Conclusions and Relevance In this systematic review and meta-analysis, antimicrobial susceptibility of S aureus to β-lactams, erythromycin, clindamycin, and fusidic acid may be suboptimal for empirical use in individuals with atopic dermatitis. Significant differences in antimicrobial susceptibility patterns were found in high-income countries and in lower middle–income countries and upper middle–income countries for some antibiotics.

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2 , which encodes G αi2 , a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase–mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating G αi2 mutations had clinical presentations that included impaired immunity. Mutant G αi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G αi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)–activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal–regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)–AKT S6 signaling to drive cellular growth and proliferation.

ImportanceExposure to repetitive head impacts (RHI) is associated with increased risk for neurodegeneration. Accumulation of toxic proteins due to impaired brain clearance is suspected to play a role.ObjectiveTo investigate whether perivascular space (PVS) volume is associated with lifetime exposure to RHI in individuals at risk for RHI-associated neurodegeneration.Design, Setting, and ParticipantsThis cross-sectional study was part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project, a 7-year multicenter study consisting of 4 US study sites. Data were collected from September 2016 to February 2020 and analyses were performed between May 2021 and October 2023. After controlling for magnetic resonance image (MRI) and processing quality, former American football players and unexposed asymptomatic control participants were included in analyses.ExposurePrior exposure to RHI while participating in American football was estimated using the 3 cumulative head impact indices (CHII-G, linear acceleration; CHII-R, rotational acceleration; and CHII, number of head impacts).Main Outcomes and MeasuresIndividual PVS volume was calculated in the white matter of structural MRI. Cognitive impairment was based on neuropsychological assessment. Linear regression models were used to assess associations of PVS volume with neuropsychological assessments in former American football players. All analyses were adjusted for confounders associated with PVS volume.ResultsAnalyses included 224 participants (median [IQR] age, 57 [51-65] years), with 170 male former football players (114 former professional athletes, 56 former collegiate athletes) and 54 male unexposed control participants. Former football players had larger PVS volume compared with the unexposed group (mean difference, 0.28 [95% CI, 0.00-0.56]; P = .05). Within the football group, PVS volume was associated with higher CHII-R (β = 2.71 × 10−8 [95% CI, 0.50 × 10−8 to 4.93 × 10−8]; P = .03) and CHII-G (β = 2.24 × 10−6 [95% CI, 0.35 × 10−6 to 4.13 × 10−6]; P = .03). Larger PVS volume was also associated with worse performance on cognitive functioning in former American football players (β = −0.74 [95% CI, −1.35 to −0.13]; P = .04).Conclusions and RelevanceThese findings suggest that impaired perivascular brain clearance, as indicated by larger PVS volume, may contribute to the association observed between RHI exposure and neurodegeneration.

Abstract Gastric adenocarcinoma (GAC) is the fourth leading global cause of cancer mortality and leading infection-associated cancer. High-incidence regions of GAC include Latin America and Eastern Asia. Immigrants from high-incidence regions maintain their GAC risk. GAC is a major U.S. cancer disparity, and its incidence rates are 2 to 10 times higher in non-White populations. Emerging guidelines recommend 3-year surveillance endoscopy for patients with high-risk gastric premalignant conditions (GPMC). Clinical trials of GPMC chemoprevention agents are lacking. We conducted a NCI Division of Cancer Prevention–funded, phase II placebo-controlled chemoprevention trial in patients with GPMCs (atrophic gastritis and intestinal metaplasia) with a highly bioavailable preparation of curcuminoids (Meriva). The trial sites in Puerto Rico and rural Honduras had important characteristics: (i) representative Caribbean and Mesoamerican populations, linked to large U.S. immigrant populations; (ii) high prevalence of Helicobacter pylori infection and GPMCs; (iii) the absence of turmeric and curcuminoids in local diets; and (iv) proven bidirectional collaboration with U.S. academic institutions. H. pylori–negative patients with GPMCs were randomized to the study drug (500 mg po bid) or placebo for 180 days (NCT02782949), with primary outcomes based upon histologic parameters. Principal study challenges included (i) an international regulatory environment; (ii) research infrastructure strengthening, particularly in Central America; (iii) participant recruitment in Honduras, wherein only 10% to 15% are H. pylori negative; (iv) the COVID-19 pandemic; and (v) natural disasters (three hurricanes). There were no losses to follow-up related to the pandemic or natural disasters. In conclusion, the south–south partnership provides a model for chemoprevention and translational studies in Latino populations with prevalent cancers, such as GAC.

Abstract A phase 2, international, open-label, nonrandomized, single-arm trial was conducted to evaluate the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, as monotherapy for relapsed/refractory peripheral T-cell lymphoma (PTCL) and to evaluate tumor mutation profile as a biomarker of response. Adults with relapsed/refractory PTCL received tipifarnib 300 mg orally twice daily for 21 days in a 28-day cycle. The primary end point was objective response rate (ORR); secondary end points included ORR, progression-free survival (PFS), duration of response (DOR), and adverse events (AEs) in specific subtypes. Sixty-five patients with PTCL were enrolled: n = 38 angioimmunoblastic T-cell lymphoma (AITL), n = 25 PTCL not otherwise specified, and n = 2 other T-cell lymphomas. The ORR was 39.7% (95% confidence interval [CI], 28.1-52.5) in all patients and 56.3% (95% CI, 39.3-71.8) for AITL. Median PFS was 3.5 months overall (954% CI, 2.1-4.4), and 3.6 months (95% CI, 1.9-8.3) for AITL. Median DOR was 3.7 months (95% CI, 2.0-15.3), and greatest in patients with AITL (7.8 months; 95% CI, 2.0-16.3). The median overall survival was 32.8 months (95% CI, 14.4 to not applicable). Tipifarnib-related hematologic AEs were manageable and included neutropenia (43.1%), thrombocytopenia (36.9%), and anemia (30.8%); other tipifarnib-related AEs included nausea (29.2%) and diarrhea (27.7%). One treatment-related death occurred. Mutations in RhoA, DNMT3A, and IDH2 were seen in 60%, 33%, and 27%, respectively, in the AITL tipifarnib responder group vs 36%, 9%, and 9% in the nonresponder group. Tipifarnib monotherapy demonstrated encouraging clinical activity in heavily pretreated relapsed/refractory PTCL, especially in AITL, with a manageable safety profile. This trial was registered at www.ClinicalTrials.gov as #NCT02464228.

Abstract INTRODUCTION Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype. METHODS Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments. RESULTS Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word‐finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face‐recognition deficits (60%). Real‐life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations. DISCUSSION This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real‐life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients. Highlights This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses.