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BACKGROUNDCOVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined.METHODSThis secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization-equivalent anti-Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis.RESULTSSARS-CoV-2 anti-S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01).CONCLUSIONIn unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use.TRIAL REGISTRATIONClinicalTrials.gov NCT04373460.FUNDINGDepartment of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

Abstract Roberts syndrome (RBS) is an autosomal recessive disorder with profound growth deficiency and limb reduction caused by ESCO2 loss-of-function variants. Here, we elucidate the pathogenesis of limb reduction in an Esco2 fl/fl;Prrx1-Cre Tg/0 mouse model using bulk- and single-cell-RNA-seq and gene co-expression network analyses during embryogenesis. Our results reveal morphological and vascular defects culminating in hemorrhage of mutant limbs at E12.5. Underlying this abnormal developmental progression is a pre-apoptotic, mesenchymal cell population specific to mutant limb buds enriched for p53-related signaling beginning at E9.5. We then characterize these p53-related processes of cell cycle arrest, DNA damage, cell death, and the inflammatory leukotriene signaling pathway in vivo. In utero treatment with pifithrin-α, a p53 inhibitor, rescued the hemorrhage in mutant limbs. Lastly, significant enrichments were identified among genes associated with RBS, thalidomide embryopathy, and other genetic limb reduction disorders, suggesting a common vascular etiology among these conditions.

(1) Purpose: The purpose of this study was to describe the outcomes of diagnostic breast imaging and the incidence of delayed breast cancer diagnosis in the study population. (2) Methods: We collected the outcome data from diagnostic mammograms and/or breast ultrasounds (USs) performed on women between the ages of 30 and 50 with symptomatic breast clinical presentations between 2018 and 2019. (3) Results: Out of 171 eligible patients, 10 patients (5.8%) had BIRADS 0, 90 patients (52.6%) had benign findings (BIRADS 1 and 2), 41 (24.0%) patients had probable benign findings requiring short-term follow-up (BIRADS 3), while 30 (17.5%) patients had findings suspicious of malignancy (BIRADS 4 and 5). In the BIRADS 3 group, 92.7% had recommended follow-up, while in BIRADS 4 and 5, only 83.3% underwent recommended biopsy at a mean time of 1.7 weeks (range 0–22 wks) from their follow-up scan. Ten (6%) patients were diagnosed with breast cancer, all of whom had BIRADS 4 or 5, with a mean time of breast cancer diagnosis from initial diagnostic imaging of 2.2 weeks (range 1–22 wks). No patients had delayed breast cancer diagnosis in our cohort. (4) Conclusions: We conclude that diagnostic mammograms and breast US are appropriate investigations for clinical breast concerns in women aged 30–50 years.

Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.

Subject-specific finite element (FE) modeling of the mandible bone has recently gained attention for its higher accuracy. A critical modeling factor is including personalized material properties from medical images especially when bone quality has to be respected. However, there is no consensus on the material model for the mandible that realistically estimates the Young's modulus of the bone. Therefore, the present study aims to review FE studies employing heterogeneous material modeling of the human mandible bone, synthesizing these models, investigating their origins, and assessing their risk of bias.A systematic review using PRISMA guidelines was conducted on publications before 1st July 2024, involving PubMed, Scopus, and Web of Science. The search string considered (a) anatomical site (b) modeling strategy, and (c) metrics of interest. Two inclusion and five exclusion criteria were defined.A review of 77 FE studies identified 12 distinct heterogeneous material models, built based on different in vitro or computational methodologies leading to varied performance and highly deviated range of estimated Young's modulus. They are proposed for bones from five different anatomical sites than mandible and for both trabecular and cortical bone domains. The original studies were characterized with a low to medium risk of bias.This review assessed the current state of material modeling for subject-specific FE models in the craniomaxillofacial field. Recommendations are provided to support researchers in selecting density-modulus relationships. Future research should focus on standardizing experimental protocols, validating models through combined simulation and experimental approaches, and investigating the anisotropic behaviour of the mandible bone.

Summary: Astrocytes and oligodendrocytes in the ventrobasal thalamus are electrically coupled through gap junctions. We have previously shown that these cells form large panglial networks, which have a key role in the transfer of energy substrates to postsynapses for sustaining neuronal activity. Here, we show that the efficiency of these transfer networks is regulated by synaptic activity: preventing the generation and propagation of action potentials resulted in reduced glial coupling. Systematic analyses of mice deficient for individual connexin isoforms revealed that oligodendroglial Cx32 and Cx47 are the targets of this modulation. Importantly, we show that during a critical time window, sensory deprivation through whisker trimming reduces the efficiency of the glial transfer networks also in vivo. Together with our previous results the current findings indicate that neuronal activity and provision of energy metabolites through panglial coupling are interdependent events regulated in a bidirectional manner.

BackgroundThe efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection.MethodsThis double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed coronavirus disease 2019 (COVID-19) in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was new SARS-CoV-2 infection.ResultsIn total, 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for screening SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) positivity. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs 25.2 days; P = .49) and COVID-19 (26.3 vs 25.9 days; P = .35) was similar for both groups.ConclusionsAdministration of high-titer CCP as post-exposure prophylaxis, although appearing safe, did not prevent SARS-CoV-2 infection.Clinical trials registrationNCT04323800.

The regeneration dynamics of understory vegetation in recent forests, arising from extensive agricultural land abandonment, is closely related to soil properties and proximity to ancient forests. However, the role of topography in shaping this regeneration process, especially in mountainous regions, remains unclear.This study addresses this gap by investigating the regeneration rate of understory vegetation in mountainous recent forests within the NE Carpathians, a region profoundly shaped by large-scale population displacements in the 1940s, leading to widespread agricultural land abandonment and the subsequent development of new forests.We quantified the understory regeneration rate of recent forests through extensive phytosociological relevé surveys conducted in one vegetation season. Data were collected from 194 randomly selected plots of recent forests and 100 plots of ancient forests, each exhibiting diverse topographic characteristics. By calculating the Forest Maturity Index based on ancient forest species and employing a parametrized multiple regression model, we identified key factors influencing the understory regeneration process. We further used the obtained regression formula to model the forest regeneration rate across the entire study area (40,975 ha).Proximity to ancient forests positively influenced understory regeneration. Elevation and slope also emerged as significant determinants, with the understory regeneration rate decreasing with elevation and increasing with slope steepness. Furthermore, a higher cover of pine in the tree stand had a suppressive effect. The above-mentioned dependencies resulted in substantial variations in the modeled understory regeneration of post-agricultural forests.The utilization of the Forest Maturity Index offers invaluable insights into identifying and subsequently safeguarding well-regenerated forests. Given the prevalence of forest secondary succession in various regions, this index emerges as a key indicator for future assessments and management strategies.

Purpose: To evaluate associations of plasma levels of inflammatory biomarkers with age-related macular degeneration (AMD) and cataract in persons with AIDS. Design: Nested case–control study (analysis 1) and nested cohort study (analysis 2). Participants: Analysis 1: persons with AIDS and incident intermediate-stage AMD (n = 26) and controls without AMD matched for age, race/ethnicity, and gender (n = 49) from The Longitudinal Study of Ocular Complications of AIDS. Analysis 2: 475 persons from LSOCA with baseline plasma biomarker levels followed prospectively for cataract. Methods: In both analyses, cryopreserved plasma specimens obtained at baseline were assayed for monocyte chemoattractant protein (MCP)-1 (CC motif chemokine ligand [CCL] 2), macrophage inflammatory protein (MIP)-1β (CCL4), soluble tumor necrosis factor receptor (sTNFR) 2, interleukin (IL)-18, and fractalkine (CX3 motif chemokine ligand 1 [CX3CL1]). Main Outcome Measures: Analysis 1: mean difference (cases − controls) in plasma biomarker levels. Analysis 2: incident cataract. Results: After adjusting for plasma human immunodeficiency virus RNA level, CD4+ T-cell count, and smoking, elevated baseline plasma levels of sTNFR2 and IL-18 (mean differences [cases − controls] 0.11 log10[pg/mL]; 95% confidence interval [CI], 0.01–0.20; P = 0.024 and 0.13 log10[pg/mL]; 95% CI, 0.01–0.24; P = 0.037, respectively) each were associated with incident AMD. In a competing risk (with mortality) analysis, elevated baseline standardized log10 plasma levels of MCP-1, sTNFR2, IL-18, and fractalkine each were associated with a decreased cataract risk. Conclusions: When combined with previous data suggesting that AMD is associated with elevated plasma levels of C-reactive protein, soluble CD14, and possibly IL-6, the association of elevated plasma levels of sTNFR2 and IL-18 with incident AMD, but not with incident cataract, suggests that innate immune system activation, and possibly NLRP3 inflammasome activation, may play a role in the pathogenesis of AMD in this population. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article.

BackgroundPolyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain.MethodsIn this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion.ResultsParticipants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized.ConclusionsIn participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.).

The number of people with HIV (PWH) aged 50 years or older continues to steadily increase. The convergence of age- and HIV-related complications in these individuals presents a challenge for both patients and clinicians alike. New findings continue to emerge, as numerous researchers evaluate the combined impact of these two factors on quality of life, physiological systems, and mental health in PWH. Since its first occurrence in 2009, the International Workshop on HIV and Aging has served as a multidisciplinary meeting to share basic biomedical data, clinical trial results, treatment strategies, and epidemiological recommendations, toward better understanding and outcomes among like-minded scientific professionals. In this article, we share a selection of key findings presented in plenary talks at the 11th Annual International Workshop on HIV and Aging, held virtually from September 30, 2020 to October 2, 2020. We will also address the future directions of HIV and aging research, to further assess how the aging process intersects with chronic HIV.

Purpose: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown. Methods: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model. Results: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine mapping of 7q21.3 identified a craniofacial transcriptional enhancer (eDlx36) within the linkage region of the top variant (rs4727341; odds ratio [95% confidence interval], 0.48[0.39-0.59]; P = 1.2E−12) that was located in SEM1 intron and enriched in 4 rare risk variants. In zebrafish, the activity of the transfected human eDlx36 enhancer was observed in the frontonasal prominence and calvaria during skull development and was reduced when the 4 rare risk variants were introduced into the sequence. Conclusion: Our findings support a polygenic nature of cNCS risk and functional role of craniofacial enhancers in cNCS susceptibility with potential broader implications for bone health.

Objective Evaluate the association between cancer incidence and immunosuppressive treatment in patients with ocular inflammatory disease (OID).Methods and analysis We performed a retrospective cohort study of patients from 10 US OID subspecialty practices. Patients with non-infectious OID were included; HIV-infected patients were excluded. Time-dependent exposure to drug classes (ie, antimetabolites, calcineurin inhibitors, alkylating agents, tumour necrosis factor (TNF) inhibitors) and drugs were evaluated. Cancer incidence was ascertained by linkage to 12 state cancer registries from 1996 to 2015. Cancer incidence was analysed using Cox regression survival analysis, using 0-year, 3-year and 5-year lags after immunosuppression began.Results The cancer incidence cohort comprised 10 872 individuals at risk of incident cancer and residing in one of the 12 states covered; 812 primary cancers were identified through cancer incidence tracing with median follow-up time of 10 years. Neither TNF inhibitor, antimetabolite, calcineurin inhibitor nor alkylating agent classes were associated with statistically significant increases in cancer incidence adjusting for covariates. We found statistically significant reduced hazards in the systemic inflammatory disease (SID)-including cohort for adalimumab and chlorambucil, increased hazards for tacrolimus and etanercept in the non-SID cohort and reduced hazards for methotrexate in both. Other immunosuppressive drugs were not associated with overall cancer incidence.Conclusions We found no increased risk of overall or site-specific cancer incidence associated with short-term (non-transplant) therapy with most commonly used immunosuppressive drug classes and many specific drugs. Further research may clarify potentially protective or harmful effects of specific agents that were not consistently associated with reduced or increased cancer incidence.Trial registration number NCT00116090.

The FaceBase Consortium was established by the National Institute of Dental and Craniofacial Research in 2009 as a 'big data' resource for the craniofacial research community. Over the past decade, researchers have deposited hundreds of annotated and curated datasets on both normal and disordered craniofacial development in FaceBase, all freely available to the research community on the FaceBase Hub website. The Hub has developed numerous visualization and analysis tools designed to promote integration of multidisciplinary data while remaining dedicated to the FAIR principles of data management (findability, accessibility, interoperability and reusability) and providing a faceted search infrastructure for locating desired data efficiently. Summaries of the datasets generated by the FaceBase projects from 2014 to 2019 are provided here. FaceBase 3 now welcomes contributions of data on craniofacial and dental development in humans, model organisms and cell lines. Collectively, the FaceBase Consortium, along with other NIH-supported data resources, provide a continuously growing, dynamic and current resource for the scientific community while improving data reproducibility and fulfilling data sharing requirements.

Glycosylation is a topic of intense current interest in the development of biopharmaceuticals because it is related to drug safety and efficacy. This work describes results of an interlaboratory study on the glycosylation of the Primary Sample (PS) of NISTmAb, a monoclonal antibody reference material. Seventy-six laboratories from industry, university, research, government, and hospital sectors in Europe, North America, Asia, and Australia submitted a total of 103 reports on glycan distributions. The principal objective of this study was to report and compare results for the full range of analytical methods presently used in the glycosylation analysis of mAbs. Therefore, participation was unrestricted, with laboratories choosing their own measurement techniques. Protein glycosylation was determined in various ways, including at the level of intact mAb, protein fragments, glycopeptides, or released glycans, using a wide variety of methods for derivatization, separation, identification, and quantification. Consequently, the diversity of results was enormous, with the number of glycan compositions identified by each laboratory ranging from 4 to 48. In total, one hundred sixteen glycan compositions were reported, of which 57 compositions could be assigned consensus abundance values. These consensus medians provide community-derived values for NISTmAb PS. Agreement with the consensus medians did not depend on the specific method or laboratory type. The study provides a view of the current state-of-the-art for biologic glycosylation measurement and suggests a clear need for harmonization of glycosylation analysis methods.

Abstract Background Cancer-associated fibroblasts (CAFs) are considered to play a fundamental role in pancreatic ductal adenocarcinoma (PDAC) progression and chemoresistance. Patient-derived organoids have demonstrated great potential as tumor avatars for drug response prediction in PDAC, yet they disregard the influence of stromal components on chemosensitivity. Methods We established direct three-dimensional (3D) co-cultures of primary PDAC organoids and patient-matched CAFs to investigate the effect of the fibroblastic compartment on sensitivity to gemcitabine, 5-fluorouracil and paclitaxel treatments using an image-based drug assay. Single-cell RNA sequencing was performed for three organoid/CAF pairs in mono- and co-culture to uncover transcriptional changes induced by tumor-stroma interaction. Results Upon co-culture with CAFs, we observed increased proliferation and reduced chemotherapy-induced cell death of PDAC organoids. Single-cell RNA sequencing data evidenced induction of a pro-inflammatory phenotype in CAFs in co-cultures. Organoids showed increased expression of genes associated with epithelial-to-mesenchymal transition (EMT) in co-cultures and several potential receptor-ligand interactions related to EMT were identified, supporting a key role of CAF-driven induction of EMT in PDAC chemoresistance. Conclusions Our results demonstrate the potential of personalized PDAC co-cultures models not only for drug response profiling but also for unraveling the molecular mechanisms involved in the chemoresistance-supporting role of the tumor stroma.

PurposeTo evaluate relationships among retinal vascular caliber and biomarkers of systemic inflammation in patients with AIDS.MethodsA total of 454 participants with AIDS had retinal vascular caliber (central retinal artery equivalent and central retinal vein equivalent) determined from enrollment retinal photographs by reading center graders masked to clinical and biomarker information. Cryopreserved plasma specimens were assayed for inflammatory biomarkers, including C-reactive protein (CRP), IL-6, interferon-γ inducible protein (IP)-10, kynurenine/tryptophan (KT) ratio, and intestinal fatty acid binding protein (I-FABP).ResultsIn the simple linear regression of retinal vascular caliber on plasma biomarkers, elevated CRP, IL-6, and IP-10 were associated with retinal venular dilation, and elevated KT ratio with retinal arteriolar narrowing. In the multiple linear regression, including baseline characteristics and plasma biomarkers, AMD was associated with dilation of retinal arterioles (mean difference: 9.1 μm; 95% confidence interval [CI] 5.2, 12.9; P < 0.001) and venules (mean difference, 10.9 μm; 95% CI, 5.3, 16.6; P < 0.001), as was black race (P < 0.001). Hyperlipidemia was associated with retinal venular narrowing (mean difference, -7.5 μm; 95% CI, -13.7, -1.2; P = 0.02); cardiovascular disease with arteriolar narrowing (mean difference, -5.2 μm; 95% CI, -10.3, -0.1; P = 0.05); age with arteriolar narrowing (slope, -0.26 μm/year; 95% CI, -0.46, -0.06; P = 0.009); and IL-6 with venular dilation (slope, 5.3 μm/standard deviation log10[plasma IL-6 concentration]; 95% CI, 2.7, 8.0; P < 0.001).ConclusionsThese data suggest that retinal vascular caliber is associated with age, race, AMD, hyperlipidemia, cardiovascular disease, and selected biomarkers of systemic inflammation.

PurposeTo evaluate the comparative effectiveness of 3 regional corticosteroid injections for uveitic macular edema (ME): periocular triamcinolone acetonide (PTA), intravitreal triamcinolone acetonide (ITA), and the intravitreal dexamethasone implant (IDI).DesignMulticenter, randomized clinical trial.ParticipantsPatients with uveitic ME.MethodsPatients were randomized 1:1:1 to receive 1 of the 3 therapies. Patients with bilateral ME were assigned the same treatment for both eyes.Main outcome measuresThe primary outcome was the proportion of baseline (PropBL) central subfield thickness (CST) at 8 weeks (CST at 8 weeks/CST at baseline) assessed with OCT by masked readers. Secondary outcomes included ≥20% improvement and resolution of ME, best-corrected visual acuity (BCVA), and intraocular pressure (IOP) events over 24 weeks.ResultsAll treatment groups demonstrated improved CST during follow-up. At 8 weeks, each group had clinically meaningful reductions in CST relative to baseline (PropBL: 0.77, 0.61, and 0.54, respectively, which translates to reductions of 23%, 39%, and 46% for PTA, ITA, and IDI, respectively). Intravitreal triamcinolone acetonide (PropBL ITA/PropBL PTA, hazard ratio [HR], 0.79; 99.87% confidence interval [CI], 0.65-0.96) and IDI (PropBL IDI/PropBL PTA, HR, 0.69; 99.87% CI, 0.56-0.86) had larger reductions in CST than PTA (P < 0.0001). Intravitreal dexamethasone implant was noninferior to ITA at 8 weeks (PropBL IDI/PropBL ITA, HR, 0.88; 99.87% CI, 0.71-1.08). Both ITA and IDI treatments also were superior to PTA treatment in improving and resolving uveitic ME. All treatment groups demonstrated BCVA improvement throughout follow-up. Both ITA and IDI groups had improvements in BCVA that was 5 letters greater than in the PTA group at 8 weeks (P < 0.004). The risk of having IOP ≥24 mmHg was higher in the intravitreal treatment groups compared with the periocular group (HR, 1.83; 95% CI, 0.91-3.65 and HR, 2.52; 95% CI, 1.29-4.91 for ITA and IDI, respectively); however, there was no significant difference between the 2 intravitreal treatment groups.ConclusionsIntravitreal triamcinolone acetonide and the IDI were superior to PTA for treating uveitic ME with modest increases in the risk of IOP elevation. This risk did not differ significantly between intravitreal treatments.

Abstract Background Healthcare workers (HCW) are at increased risk of infection with SARS-CoV-2. Vulnerable patient populations in particular must be protected, and clinics should not become transmission hotspots to avoid delaying medical treatments independent of COVID. Because asymptomatic transmission has been described, routine screening of asymptomatic HCW would potentially be able to interrupt chains of infection through early detection. Methods A systematic search was conducted in the Cochrane COVID-19 Study Register, Web of Science and WHO COVID‐19 Global literature on coronavirus with regard to non-incident related testing of healthcare workers using polymerase chain reaction on May 4th 2021. Studies since January 2020 were included. An assessment of risk of bias and representativeness was performed. Results The search identified 39 studies with heterogeneous designs. Data collection of the included studies took place from January to August 2020. The studies were conducted worldwide and the sample size of the included HCW ranged from 70 to 9449 participants. In total, 1000 of 51,700 (1.9%) asymptomatic HCW were tested positive for SARS-CoV-2 using PCR testing. The proportion of positive test results ranged between 0 and 14.3%. No study reported on HCW-screening related reductions in infected person-days. Discussion and conclusions The heterogeneous proportions might be explained by different regional incidences, lock-downs, and pre-analytical pitfalls that reduce the sensitivity of the nasopharyngeal swab. The very high prevalence in some studies indicates that screening HCW for SARS-CoV-2 may be important particularly in geographical regions and pandemic periods with a high-incidence. With low numbers and an increasing rate of vaccinated HCW, a strict cost–benefit consideration must be made, especially in times of low incidences. Since we found no studies that reported on HCW-screening related reductions in infected person-days, re-evaluation should be done when these are available.

Abstract Background For effective prevention of nosocomial transmissions continuous training and motivation of health care workers (HCW) are essential to maintain and increase compliance with high rates of hand hygiene. The use of Virtual Reality (VR) seems to be a contemporary and interesting approach for hand hygiene training in HCW. Nevertheless, HCW should be asked for their preferences as intrinsic motivation is essential for compliance with hand hygiene and training success should be evaluated. Methods A prospective, cross-controlled trial was conducted at two wards in a tertiary care hospital comparing a conventional lecture for hand hygiene to the use of VR. Both interventions were assigned at ward level. Primary outcome was HCW acceptance, which was verified in a third ward, secondary outcomes were hand rub consumption and compliance to indications for hand hygiene as proposed by WHO. Results In summary, 81 trainings were conducted, 48 VR trainings and 33 trainings by lecture. VR training was well accepted by HCW with a mean score in all items from 3.9 to 4.3 (out of 5). While most HCW (69%) would prefer VR teaching rather than a lecture for hand hygiene education, only 4% preferred the traditional lecture. 400 observations of hand hygiene indications were made, 50 before intervention and 50 after each intervention at the three wards. Mean proportion of correct and indication-appropriate performances was 81% before intervention, 87% after VR training (p = 0.12), and 95% after lecture (p = 0.04). Hand rub consumption did not change significantly in any group. Conclusions Due to the high acceptance of VR technology among healthcare workers, it can be considered an interesting addition to conventional lectures for teaching hand hygiene. However, the hypothesis that VR teaching has a higher impact on hand rub use and hand hygiene compliance than a conventional lecture cannot be confirmed.

PurposeTo evaluate the relationship between retinal vascular caliber and AMD in patients with AIDS.MethodsParticipants enrolled in the Longitudinal Study of the Ocular Complications of AIDS had retinal photographs taken at enrollment. Retinal vascular caliber (central retinal artery equivalent [CRAE] and central retinal vein equivalent [CRVE]) and intermediate-stage AMD were determined from these retinal photographs. Photographs were evaluated by graders at a centralized reading center, using the Age-Related Eye Disease Study grading system for AMD and semiautomated techniques for evaluating retinal vascular caliber.ResultsOf the 1171 participants evaluated, 110 (9.4%) had AMD and 1061 (90.6%) did not. Compared with participants without AMD, participants with AMD had larger mean CRAEs (151 ± 16 μm versus 147 ± 16 μm; P = 0.009) and mean CRVEs (228 ± 24 μm versus 223 ± 25 μm; P = 0.02). The unadjusted differences were: CRAE, 4.3 μm (95% confidence interval [CI] 1.1-7.5; P = 0.009) and CRVE, 5.5 μm (95% CI 0.7-10.3; P = 0.02). After adjustment for age, race/ethnicity, sex, human immunodeficiency syndrome (HIV) transmission category, smoking, enrollment and nadir CD4+ T cells, and enrollment and maximum HIV load, the differences between patients with and without AMD were as follows: CRAE, 5.4 μm (95% CI 2.3-8.5; P = 0.001) and CRVE, 6.0 μm (95% CI 1.4-10.6; P = 0.01).ConclusionsIn patients with AIDS, AMD is associated with greater retinal arteriolar and venular calibers, suggesting a role for shared pathogenic mechanisms, such as persistent systemic inflammation.

Craniofacial development depends on formation and maintenance of sutures between bones of the skull. Here the authors identify enriched expression of the hedgehog inhibitor Hhip, specifically in the mesenchyme of the murine coronal suture, and show sutural dysgenesis in Hhip−/− mutants.

Pancreatic tumors are frequently divided into basal and classical subtypes. Here, the authors use single cell sequencing to investigate organoids derived from pancreatic cancer tissue and find a hierarchy of distinct cell states, and classical and basal cells existing within the same tumor.

Background/Aims The recommendations on the time interval between pre-cleaning and reprocessing of endoscopes differ in international guidelines, with a low level of evidence. The aim of this study was to investigate the influence of postponing reprocessing on the reprocessing quality after pre-cleaning the flexible endoscopes. Methods We reprocessed 124 standardized test tubes simulating endoscope channels after soiling and contamination and determined the reprocessing performance. In addition, we examined contaminated gastroscopes, colonoscopes, and bronchoscopes. The duration of interim storage after pre-cleaning was 16 h for 100 test tubes and up to 24 h for 18 endoscopes. We determined the residual protein content and germ load as markers for cleaning and disinfection performance. In addition, we determined biofilm formation by photometry of crystal violet staining. Results All test tubes and flexible endoscopes showed residual protein content and germ load significantly below legally prescribed threshold values, independent of the interval between pre-cleaning and reprocessing. Conclusions Our findings indicate that flexible endoscopes could be stored overnight after pre-cleaning without any influence on the quality of reprocessing. While ensuring patient safety, this could simplify logistical processes and enable cost savings.

PurposeTo evaluate the incidence of intermediate-stage age-related macular degeneration (AMD) in patients with acquired immunodeficiency syndrome (AIDS).DesignCohort study.MethodsPatients enrolled in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) underwent 5- and 10-year follow-up retinal photographs. Intermediate-stage AMD (AREDS stage 3) was determined from these photographs by graders at a centralized Reading Center, using the Age-Related Eye Disease Study-2 grading system. The incidence of AMD in LSOCA was compared with that in the Multi-Ethnic Study of Atherosclerosis (MESA), a Human Immunodeficiency Virus (HIV)-uninfected cohort, which used a similar photographic methodology.ResultsThe incidence of AMD in LSOCA was 0.65/100 person-years (PY). In a multivariate analysis the only significant risk factor for AMD in LSOCA was smoking; the relative risk vs never-smokers was 3.4 for former smokers (95% confidence interval [CI] 1.3, 9.5; P = .02) and 3.3 for current smokers (95% CI 1.1, 9.7; P = .03). Compared with the MESA cohort, the race/ethnicity- and sex-adjusted risk of AMD in LSOCA was 1.75 (95% CI 1.16, 2.64; P = .008), despite the fact that the mean age of the MESA cohort was 17 years greater than the LSOCA cohort (61 ± 9 years vs 44 ± 8 years).ConclusionsPatients with AIDS have a 1.75-fold increased race- and sex-adjusted incidence of intermediate-stage AMD compared with that found in an HIV-uninfected cohort. This increased incidence is consistent with the increased incidence of other age-related diseases in antiretroviral-treated, immune-restored, HIV-infected persons when compared with HIV-uninfected persons.