Safety and Efficacy of SAB-185 for Non-hospitalized Adults with COVID-19: A Randomized Clinical Trial.

BACKGROUND: To address the need for novel COVID-19 therapies, we evaluated the fully-human polyclonal antibody product SAB-185 in a phase 3 clinical trial. METHODS: Non-hospitalized high-risk adults within 7 days of COVID-19 symptom onset were randomized 1:1 to open-label SAB-185 3,840 units/kg or casirivimab/imdevimab 1200 mg. Non-inferiority comparison was undertaken for the pre-Omicron population (casirivimab/imdevimab expected to be fully active) and superiority comparison for the Omicron population (casirivimab/imdevimab not expected to be active). Primary outcomes were the composite of all-cause hospitalizations/deaths and grade ≥3 treatment-emergent adverse events (TEAEs) through day 28. Secondary outcomes included time to sustained symptom improvement and resolution. RESULTS: Enrollment was terminated early due to low hospitalization/death rates upon Omicron emergence. 733 adults were randomized, 255 included in pre-Omicron and 392 in Omicron analysis populations. Hospitalizations/deaths occurred in 6 (5.0%) and 3 (2.2%) of pre-Omicron SAB-185 and casirivimab/imdevimab arms, respectively (absolute difference [95% CI] 2.7% [-2.3%, 8.6%]), inconclusive for non-inferiority; and 5 (2.5%) versus 3 (1.5%) (absolute difference 1.0% [-2.3%, 4.5%]) for Omicron. Risk ratios for grade ≥3 TEAEs were 0.94 [0.52, 1.71] (pre-Omicron) and 1.71 [0.96, 3.07] (Omicron). Time to symptom improvement and resolution were shorter for SAB-185, median 11 vs 14 (pre-Omicron) and 11 vs 13 days (Omicron) (symptom improvement), and 16 vs 24 days and 18 vs >25 days (symptom resolution), p<0.05 for symptom resolution for Omicron only. CONCLUSIONS: SAB-185 had an acceptable safety profile with faster symptom resolution in the Omicron population. Additional studies are needed to characterize its efficacy for COVID-19.

Low Prevalence of Nirmatrelvir-Ritonavir Resistance-Associated Mutations in SARS-CoV-2 Lineages From Botswana.

Background: We evaluated naturally occurring nirmatrelvir-ritonavir (NTV/r) resistance-associated mutations (RAMs) among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains from Botswana, a country with no NTV/r use to date, in order to recommend the usage of the agent for high-risk patients with coronavirus disease 2019 (COVID-19). Methods: We conducted a retrospective analysis using 5254 complete SARS-CoV-2 sequences from Botswana (September 2020-September 2023). We evaluated the mutational landscape of SARS-CoV-2 3-Chymotrypsin-like protease (3CLpro) relative to the highlighted list of RAMs granted Food and Drug Administration Emergency Use Authorization in 2023. Results: The sequenced 5254 samples included Beta variants of concerns (VOCs; n = 323), Delta VOCs (n = 1314), and Omicron VOCs (n = 3354). Overall, 77.8% of the sequences exhibited at least 1 polymorphism within 76/306 amino acid positions in the nsp5 gene. NTV/rRAMs were identified in 34/5254 (0.65%; 95% CI, 0.43%-0.87%) and occurred at 5 distinct positions. Among the NTV/r RAMS detected, A191V was the most prevalent (24/34; 70.6%). Notably, T21I mutation had a prevalence of 20.6% (7/34) and coexisted with either K90R (n = 3) polymorphism in Beta sequences with RAMs or P132H (n = 3) polymorphism for Omicron sequences with RAMs. Other NTV/r RAMs detected included P108S, with a prevalence of 5.88% (2/34), and L50F, with a prevalence of 2.94% (1/34). NTV/r RAMs were significantly higher (P < .001) in Delta (24/35) compared with Beta (4/34) and Omicron (6/34) sequences. Conclusions: The frequency of NTV/r RAMs in Botswana was low. Higher rates were observed in Delta VOCs compared to Omicron and Beta VOCs. As NTV/r use expands globally, continuous surveillance for drug-resistant variants is essential, given the RAMs identified in our study.

SARS-CoV-2 monoclonal antibody treatment followed by vaccination shifts human memory B cell epitope recognition suggesting antibody feedback.

Therapeutic monoclonal antibodies (mAbs) have been studied in humans, but the impact on immune memory of mAb treatment during an ongoing infection has remained unclear. We evaluated the effect of infusion of the anti-SARS-CoV-2 spike receptor binding domain (RBD) mAb bamlanivimab on memory B cells (MBCs) in SARS-CoV-2-infected individuals. Bamlanivimab treatment skewed the repertoire of memory B cells targeting Spike towards non-RBD epitopes. Furthermore, the relative affinity of RBD memory B cells was weaker in mAb-treated individuals compared to placebo-treated individuals over time. Subsequently, after mRNA COVID-19 vaccination, memory B cell differences persisted and mapped to a specific reduction in recognition of the class II RBD site, the same RBD epitope recognized by bamlanivimab. These findings indicate a substantial role of antibody feedback in regulating memory B cell responses to infection, and single mAb administration can continue to impact memory B cell responses to additional antigen exposures months later.

Effect of Metal d Band Position on Anion Redox in Alkali-Rich Sulfides.

New energy storage methods are emerging to increase the energy density of state-of-the-art battery systems beyond conventional intercalation electrode materials. For instance, employing anion redox can yield higher capacities compared with transition metal redox alone. Anion redox in sulfides has been recognized since the early days of rechargeable battery research. Here, we study the effect of d-p overlap in controlling anion redox by shifting the metal d band position relative to the S p band. We aim to determine the effect of shifting the d band position on the electronic structure and, ultimately, on charge compensation. Two isostructural sulfides LiNaFeS2 and LiNaCoS2 are directly compared to the hypothesis that the Co material should yield more covalent metal-anion bonds. LiNaCoS2 exhibits a multielectron capacity of ≥1.7 electrons per formula unit, but despite the lowered Co d band, the voltage of anion redox is close to that of LiNaFeS2. Interestingly, the material suffers from rapid capacity fade. Through a combination of solid-state nuclear magnetic resonance spectroscopy, Co and S X-ray absorption spectroscopy, X-ray diffraction, and partial density of states calculations, we demonstrate that oxidation of S nonbonding p states to S2 2- occurs in early states of charge, which leads to an irreversible phase transition. We conclude that the lower energy of Co d bands increases their overlap with S p bands while maintaining S nonbonding p states at the same higher energy level, thus causing no alteration in the oxidation potential. Further, the higher crystal field stabilization energy for octahedral coordination over tetrahedral coordination is proposed to cause the irreversible phase transition in LiNaCoS2.

Understanding early HIV-1 rebound dynamics following antiretroviral therapy interruption: The importance of effector cell expansion.

Most people living with HIV-1 experience rapid viral rebound once antiretroviral therapy is interrupted; however, a small fraction remain in viral remission for an extended duration. Understanding the factors that determine whether viral rebound is likely after treatment interruption can enable the development of optimal treatment regimens and therapeutic interventions to potentially achieve a functional cure for HIV-1. We built upon the theoretical framework proposed by Conway and Perelson to construct dynamic models of virus-immune interactions to study factors that influence viral rebound dynamics. We evaluated these models using viral load data from 24 individuals following antiretroviral therapy interruption. The best-performing model accurately captures the heterogeneity of viral dynamics and highlights the importance of the effector cell expansion rate. Our results show that post-treatment controllers and non-controllers can be distinguished based on the effector cell expansion rate in our models. Furthermore, these results demonstrate the potential of using dynamic models incorporating an effector cell response to understand early viral rebound dynamics post-antiretroviral therapy interruption.

Severe Acute Respiratory Syndrome Coronavirus 2 Plasma Antibody and Nucleocapsid Antigen Status Predict Outcomes in Outpatients With Coronavirus Disease 2019.

BACKGROUND: Reliable biomarkers of coronavirus disease 2019 (COVID-19) outcomes are critically needed. We evaluated associations of spike antibody (Ab) and plasma nucleocapsid antigen (N Ag) with clinical outcomes in nonhospitalized persons with mild-to-moderate COVID-19. METHODS: Participants were nonhospitalized adults with mild-to-moderate COVID-19 enrolled in ACTIV-2 between January and July 2021 and randomized to placebo. We used quantitative assays for severe acute respiratory syndrome coronavirus 2 spike Ab and N Ag in blood and determined numbers of hospitalization/death events within 28 days and time to symptom improvement. RESULTS: Of 209 participants, 77 (37%) had quantifiable spike Ab and 139 (67%) quantifiable N Ag. Median age was 50 years; 111 (53%) were female, 182 (87%) White, and 105 (50%) Hispanic/Latino. Higher risk of hospitalization/death was seen with unquantifiable (22/132 [16.7%]) versus quantifiable (1/77 [1.3%]) spike Ab (risk ratio [RR], 12.83 [95% confidence interval {CI}, 1.76-93.34]) and quantifiable (22/139 [15.8%]) vs unquantifiable (1/70 [1.4%]) N Ag (RR, 11.08 [95% CI, 1.52-80.51]). Increasing risk of hospitalizations/deaths was seen with increasing N Ag levels. Time to symptom improvement was longer with unquantifiable versus quantifiable spike Ab (median, 14 [interquartile range {IQR}, 8 to >27] vs 8 [IQR, 4-22] days; adjusted hazard ratio [aHR], 0.66 [95% CI, .45-.96]) and with quantifiable versus unquantifiable N Ag (median, 12 [7 to >27] vs 10 [5-22] days; aHR, 0.79 [95% CI, .52-1.21]). CONCLUSIONS: Absence of spike Ab and presence of plasma N Ag predicted hospitalization/death and delayed symptom improvement in COVID-19 outpatients.

In-vivo characterization of scleral rigidity in myopic eyes using fundus-pulsation optical coherence elastography.

The sclera plays an important role in the structural integrity of the eye. However, as myopia progresses, the elongation of the eyeball exerts stretching forces on the posterior sclera, which typically happens in conjunction with scleral remodeling that causes rigidity loss. These biomechanical alterations can cause localized eyeball deformation and vision impairment. Therefore, monitoring scleral rigidity is clinically important for the management and risk assessment of myopia. In this study, we propose fundus pulsation optical coherence elastography (FP-OCE) to characterize posterior scleral rigidity in living humans. This methodology is based on a choroidal pulsation model, where the scleral rigidity is inversely associated with the choroidal max strain obtained through phase-sensitive optical coherence tomography (PhS-OCT) measurement of choroidal deformation and thickness. Using FP-OCE, we conducted a pilot clinical study to explore the relationship between choroidal strain and myopia severity. The results revealed a significant increase in choroidal max strain in pathologic myopia, indicating a critical threshold beyond which scleral rigidity decreases significantly. Our findings offer a potential new method for monitoring myopia progression and evaluating therapies that alter scleral mechanical properties.

A deep learning approach based on graphs to detect plantation lines.

Identifying plantation lines in aerial images of agricultural landscapes is re-quired for many automatic farming processes. Deep learning-based networks are among the most prominent methods to learn such patterns and extract this type of information from diverse imagery conditions. However, even state-of-the-art methods may stumble in complex plantation patterns. Here, we propose a deep learning approach based on graphs to detect plantation lines in UAV-based RGB imagery, presenting a challenging scenario containing spaced plants. The first module of our method extracts a feature map throughout the backbone, which consists of the initial layers of the VGG16. This feature map is used as an input to the Knowledge Estimation Module (KEM), organized in three concatenated branches for detecting 1) the plant positions, 2) the plantation lines, and 3) the displacement vectors between the plants. A graph modeling is applied considering each plant position on the image as vertices, and edges are formed between two vertices (i.e. plants). Finally, the edge is classified as pertaining to a certain plantation line based on three probabilities (higher than 0.5): i) in visual features obtained from the backbone; ii) a chance that the edge pixels belong to a line, from the KEM step; and iii) an alignment of the displacement vectors with the edge, also from the KEM step. Experiments were conducted initially in corn plantations with different growth stages and patterns with aerial RGB imagery to present the advantages of adopting each module. We assessed the generalization capability in the other two cultures (orange and eucalyptus) datasets. The proposed method was compared against state-of-the-art deep learning methods and achieved superior performance with a significant margin considering all three datasets. This approach is useful in extracting lines with spaced plantation patterns and could be implemented in scenarios where plantation gaps occur, generating lines with few-to-no interruptions.

Comparison of manual and artificial intelligence-automated choroidal thickness segmentation of optical coherence tomography imaging in myopic adults.

BACKGROUND: Myopia affects 1.4 billion individuals worldwide. Notably, there is increasing evidence that choroidal thickness plays an important role in myopia and risk of developing myopia-related conditions. With the advancements in artificial intelligence (AI), choroidal thickness segmentation can now be automated, offering inherent advantages such as better repeatability, reduced grader variability, and less reliance for manpower. Hence, we aimed to evaluate the agreement between AI-automated and manual segmented measurements of subfoveal choroidal thickness (SFCT) using two swept-source optical coherence tomography (OCT) systems. METHODS: Subjects aged ≥ 16 years, with myopia of ≥ 0.50 diopters in both eyes, were recruited from the Prospective Myopia Cohort Study in Singapore (PROMYSE). OCT scans were acquired using Triton DRI-OCT and PLEX Elite 9000. OCT images were segmented both automatically with an established SA-Net architecture and manually using a standard technique with adjudication by two independent graders. SFCT was subsequently determined based on the segmentation. The Bland-Altman plot and intraclass correlation coefficient (ICC) were used to evaluate the agreement. RESULTS: A total of 229 subjects (456 eyes) with mean [± standard deviation (SD)] age of 34.1 (10.4) years were included. The overall SFCT (mean ± SD) based on manual segmentation was 216.9 ± 82.7 µm with Triton DRI-OCT and 239.3 ± 84.3 µm with PLEX Elite 9000. ICC values demonstrated excellent agreement between AI-automated and manual segmented SFCT measurements (PLEX Elite 9000: ICC = 0.937, 95% CI: 0.922 to 0.949, P < 0.001; Triton DRI-OCT: ICC = 0.887, 95% CI: 0.608 to 0.950, P < 0.001). For PLEX Elite 9000, manual segmented measurements were generally thicker when compared to AI-automated segmented measurements, with a fixed bias of 6.3 µm (95% CI: 3.8 to 8.9, P < 0.001) and proportional bias of 0.120 (P < 0.001). On the other hand, manual segmented measurements were comparatively thinner than AI-automated segmented measurements for Triton DRI-OCT, with a fixed bias of - 26.7 µm (95% CI: - 29.7 to - 23.7, P < 0.001) and proportional bias of - 0.090 (P < 0.001). CONCLUSION: We observed an excellent agreement in choroidal segmentation measurements when comparing manual with AI-automated techniques, using images from two SS-OCT systems. Given its edge over manual segmentation, automated segmentation may potentially emerge as the primary method of choroidal thickness measurement in the future.

Maternal SARS-CoV-2 impacts fetal placental macrophage programs and placenta-derived microglial models of neurodevelopment.

BACKGROUND: The SARS-CoV-2 virus activates maternal and placental immune responses. Such activation in the setting of other infections during pregnancy is known to impact fetal brain development. The effects of maternal immune activation on neurodevelopment are mediated at least in part by fetal brain microglia. However, microglia are inaccessible for direct analysis, and there are no validated non-invasive surrogate models to evaluate in utero microglial priming and function. We have previously demonstrated shared transcriptional programs between microglia and Hofbauer cells (HBCs, or fetal placental macrophages) in mouse models. METHODS AND RESULTS: We assessed the impact of maternal SARS-CoV-2 on HBCs isolated from 24 term placentas (N = 10 SARS-CoV-2 positive cases, 14 negative controls). Using single-cell RNA-sequencing, we demonstrated that HBC subpopulations exhibit distinct cellular programs, with specific subpopulations differentially impacted by SARS-CoV-2. Assessment of differentially expressed genes implied impaired phagocytosis, a key function of both HBCs and microglia, in some subclusters. Leveraging previously validated models of microglial synaptic pruning, we showed that HBCs isolated from placentas of SARS-CoV-2 positive pregnancies can be transdifferentiated into microglia-like cells (HBC-iMGs), with impaired synaptic pruning behavior compared to HBC models from negative controls. CONCLUSION: These findings suggest that HBCs isolated at birth can be used to create personalized cellular models of offspring microglial programming.

Oral 8-aminoguanine against age-related retinal degeneration.

Visual decline in the elderly is often attributed to retinal aging, which predisposes the tissue to pathologies such as age-related macular degeneration. Currently, effective oral pharmacological interventions for retinal degeneration are limited. We present a novel oral intervention, 8-aminoguanine (8-AG), targeting age-related retinal degeneration, utilizing the aged Fischer 344 rat model. A low-dose 8-AG regimen (5 mg/kg body weight) via drinking water, beginning at 22 months for 8 weeks, demonstrated significant retinal preservation. This was evidenced by increased retinal thickness, improved photoreceptor integrity, and enhanced electroretinogram responses. 8-AG effectively reduced apoptosis, oxidative damage, and microglial/macrophage activation associated with aging retinae. Age-induced alterations in the retinal purine metabolome, characterized by elevated levels of inosine, hypoxanthine, and xanthine, were partially mitigated by 8-AG. Transcriptomics highlighted 8-AG's anti-inflammatory effects on innate and adaptive immune responses. Extended treatment to 17 weeks further amplified the retinal protective effects. Moreover, 8-AG showed temporary protective effects in the RhoP23H/+ mouse model of retinitis pigmentosa, reducing active microglia/macrophages. Our study positions 8-AG as a promising oral agent against retinal aging. Coupled with previous findings in diverse disease models, 8-AG emerges as a promising anti-aging compound with the capability to reverse common aging hallmarks.

Understanding early HIV-1 rebound dynamics following antiretroviral therapy interruption: The importance of effector cell expansion.

Most people living with HIV-1 experience rapid viral rebound once antiretroviral therapy is interrupted; however, a small fraction remain in viral remission for an extended duration. Understanding the factors that determine whether viral rebound is likely after treatment interruption can enable the development of optimal treatment regimens and therapeutic interventions to potentially achieve a functional cure for HIV-1. We built upon the theoretical framework proposed by Conway and Perelson to construct dynamic models of virus-immune interactions to study factors that influence viral rebound dynamics. We evaluated these models using viral load data from 24 individuals following antiretroviral therapy interruption. The best-performing model accurately captures the heterogeneity of viral dynamics and highlights the importance of the effector cell expansion rate. Our results show that post-treatment controllers and non-controllers can be distinguished based on the effector cell expansion rate in our models. Furthermore, these results demonstrate the potential of using dynamic models incorporating an effector cell response to understand early viral rebound dynamics post-antiretroviral therapy interruption.

Safety, Efficacy, and Pharmacokinetics of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies BMS-986414 (C135-LS) and BMS-986413 (C144-LS) Administered Subcutaneously in Non-Hospitalized Persons with COVID-19 in a Phase 2 Trial.

Background: Outpatient COVID-19 monoclonal antibody (mAb) treatment via subcutaneous delivery, if effective, overcomes the logistical burdens of intravenous administration. Methods: ACTIV-2/A5401 was a randomized, masked placebo-controlled platform trial where participants with COVID-19 at low risk for progression were randomized 1:1 to subcutaneously administered BMS-986414 (C135-LS) 200 mg, plus BMS-986413 (C144-LS) 200 mg, (BMS mAbs), or placebo. Coprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events (TEAEs) through 28 days. Results: A total of 211 participants (105 BMS mAbs and 106 placebo) initiated study product. Time to symptom improvement favored the active therapy but was not significant (median 8 vs 10 days, P=0.19). There was no significant difference in the proportion with SARS-CoV-2 RNA

Characterization of treatment resistance and viral kinetics in the setting of single- versus dual-active monoclonal antibodies against SARS-CoV-2.

BACKGROUND: Monoclonal antibodies (mAbs) represent a crucial antiviral strategy for SARS-CoV-2 infection, but it is unclear whether combination mAbs offer a benefit over single-active mAb treatment. Amubarvimab and romlusevimab significantly reduced the risk of hospitalizations or death in the ACTIV-2/A5401 trial. Certain SARS-CoV-2 variants are intrinsically resistant against romlusevimab, leading to only single-active mAb therapy with amubarvimab in these variants. We evaluated virologic outcomes in individuals treated with single- versus dual-active mAbs. METHODS: Participants were non-hospitalized adults at higher risk of clinical progression randomized to amubarvimab plus romlusevimab or placebo. Quantitative SARS-CoV-2 RNA levels and targeted S gene next-generation sequencing was performed on anterior nasal samples. We compared viral load kinetics and resistance emergence between individuals treated with effective single- versus dual-active mAbs depending on the infecting variant. RESULTS: Study participants receiving single- and dual-active mAbs had similar demographics, baseline nasal viral load, symptom score, and symptom duration. Compared to single-active mAb, treatment with dual-active mAbs led to faster viral load decline at study day 3 (p < 0.001) and day 7 (p < 0.01). Treatment-emergent resistance mutations were more likely to be detected after amubarvimab plus romlusevimab treatment than placebo (2.6% vs 0%, P < 0.001), and more frequently detected in the setting of single-active compared to dual-active mAb treatment (7.2% vs 1.1%, p < 0.01). Single-active and dual-active mAb treatment resulted in similar decrease in rates of hospitalizations or death. CONCLUSION: Compared to single-active mAb therapy, dual-active mAbs led to similar clinical outcomes, but significantly faster viral load decline and a lower risk of emergent resistance.

Modeling the emergence of viral resistance for SARS-CoV-2 during treatment with an anti-spike monoclonal antibody.

To mitigate the loss of lives during the COVID-19 pandemic, emergency use authorization was given to several anti-SARS-CoV-2 monoclonal antibody (mAb) therapies for the treatment of mild-to-moderate COVID-19 in patients with a high risk of progressing to severe disease. Monoclonal antibodies used to treat SARS-CoV-2 target the spike protein of the virus and block its ability to enter and infect target cells. Monoclonal antibody therapy can thus accelerate the decline in viral load and lower hospitalization rates among high-risk patients with variants susceptible to mAb therapy. However, viral resistance has been observed, in some cases leading to a transient viral rebound that can be as large as 3-4 orders of magnitude. As mAbs represent a proven treatment choice for SARS-CoV-2 and other viral infections, evaluation of treatment-emergent mAb resistance can help uncover underlying pathobiology of SARS-CoV-2 infection and may also help in the development of the next generation of mAb therapies. Although resistance can be expected, the large rebounds observed are much more difficult to explain. We hypothesize replenishment of target cells is necessary to generate the high transient viral rebound. Thus, we formulated two models with different mechanisms for target cell replenishment (homeostatic proliferation and return from an innate immune response antiviral state) and fit them to data from persons with SARS-CoV-2 treated with a mAb. We showed that both models can explain the emergence of resistant virus associated with high transient viral rebounds. We found that variations in the target cell supply rate and adaptive immunity parameters have a strong impact on the magnitude or observability of the viral rebound associated with the emergence of resistant virus. Both variations in target cell supply rate and adaptive immunity parameters may explain why only some individuals develop observable transient resistant viral rebound. Our study highlights the conditions that can lead to resistance and subsequent viral rebound in mAb treatments during acute infection.

MR-linac MLC positioning QA by digitally stitching dual double-exposed films.

PURPOSE: The picket fence (PF) test is highly recommended for multi-leaf collimator (MLC) quality assurance. However, since the electronic portal imaging device (EPID) on the Elekta Unity only covers a small area, it is not feasible to perform the PF test for the entire MLC. Here, we propose a technique for the PF test by stitching two double-exposed films. METHODS: Two EBT3 films were used to encompass the entire MLC, with each one covering one half of the area. Two fields were employed to apply double exposure: a PF pattern consisting of 11 2 mm wide pickets and a 2.84 cm x 22 cm open field. The edges of the open field defined by the diaphragms were used to correct film rotation as well as align them horizontally. The PF pattern was also measured with the EPID where the pickets were used to align the films vertically. Individual leaf positions were detected on the merged film for quantitative analysis. Various MLC positioning errors were introduced to evaluate the technique's sensitivity. RESULTS: The merged films covered 72 leaf pairs properly (four leaf pairs on both sides were outside the treatment couch). With the EPID, the leaf positioning accuracy was -0.02 ± 0.07 mm (maximum: 0.29 mm) and the picket width variation was 0.00 ± 0.03 mm (maximum: 0.11 mm); with the films, the position accuracy and width variation were -0.03 ± 0.13 mm (maximum: 0.80 mm) and 0.00 ± 0.13 mm (maximum: 0.74 mm), respectively. The EPID was able to detect errors of 0.5 mm or above with submillimeter accuracy; the films were only able to detect errors > 1.0 mm. CONCLUSION: We developed a quantitative technique for the PF test on the Elekta Unity. The merged films covered nearly the entire MLC leaf banks. The technique exhibited clinically acceptable accuracy and sensitivity to MLC positioning errors.

Safety and Immune Responses Following Anti-PD-1 Monoclonal Antibody Infusions in Healthy Persons With Human Immunodeficiency Virus on Antiretroviral Therapy.

Background: T cells in people with human immunodeficiency virus (HIV) demonstrate an exhausted phenotype, and HIV-specific CD4+ T cells expressing programmed cell death 1 (PD-1) are enriched for latent HIV, making antibody to PD-1 a potential strategy to target the latent reservoir. Methods: This was a phase 1/2, randomized (4:1), double-blind, placebo-controlled study in adults with suppressed HIV on antiretroviral therapy with CD4+ counts ≥350 cells/µL who received 2 infusions of cemiplimab versus placebo. The primary outcome was safety, defined as any grade 3 or higher adverse event (AE) or any immune-related AE (irAE). Changes in HIV-1-specific polyfunctional CD4+ and CD8+ T-cell responses were evaluated. Results: Five men were enrolled (median CD4+ count, 911 cells/µL; median age, 51 years); 2 received 1 dose of cemiplimab, 2 received 2 doses, and 1 received placebo. One participant had a probable irAE (thyroiditis, grade 2); another had a possible irAE (hepatitis, grade 3), both after a single low-dose (0.3 mg/kg) infusion. The Safety Monitoring Committee recommended no further enrollment or infusions. All 4 cemiplimab recipients were followed for 48 weeks. No other cemiplimab-related serious AEs, irAEs, or grade 3 or higher AEs occurred. One 2-dose recipient of cemiplimab had a 6.2-fold increase in polyfunctional, Gag-specific CD8+ T-cell frequency with supportive increases in plasma HIV RNA and decreases in total HIV DNA. Conclusions: One of 4 participants exhibited increased HIV-1-specific T-cell responses and transiently increased HIV-1 expression following 2 cemiplimab infusions. The occurrence of irAEs after a single, low dose may limit translating the promising therapeutic results of cemiplimab for cancer to immunotherapeutic and latency reversal strategies for HIV. Clinical Trials Registration. NCT03787095.

Long-term outcomes of PGA-TMC absorbable synthetic scaffold in both clean and contaminated ventral hernia repairs.

BACKGROUND: Biosynthetic meshes afford the cost advantages of being made from fully synthetic material, but are also biodegradable, making them a versatile option that can be used in both clean and contaminated cases. The aim of this study is to evaluate the safety profile and long-term outcomes of using GORE BIO-A (BIO-A) as an adjunct to abdominal wall reconstruction in all wound classes. METHODS: A retrospective review identified patients undergoing abdominal hernia repair using BIO-A from October 2008 to June 2018. The primary outcome was hernia recurrence rate. Only patients with at least 6-month follow-up were included when looking at recurrence rates. Secondary outcomes included 30-day morbidity categorized according to CDC Surgical Site Infection Criteria, return to operating/procedure room (RTOR), 30-day readmission, length of stay (LOS), and mortality. RESULTS: A total of 207 patients were identified, CDC Wound Classification breakdown was 127 (61.4%), 41 (19.8%), 14 (6.8%), and 25 (12.1%) for wound classes I, II, III, and IV, respectively. Median follow-up was 55.4 months (range 0.2-162.4). Overall recurrence rate was 17.4%. Contaminated cases experienced higher recurrence rates (28.8% versus 10.4%, p = 0.002) at a mean follow up of 46.9 and 60.8 months for contaminated and clean patients, respectively. Recurrent patients had higher BMI (32.4 versus 28.4 kg/m2, p = 0.0011), larger hernias (162.2 versus 106.7 cm2, p = 0.10), higher LOS (11.1 versus 5.6 days, p = 0.0051), and higher RTOR rates (16.7% versus 5.6%, p = 0.053). 51 (24.5%) patients experienced some morbidity, including 19 (9.2%) surgical site occurences, 7 (3.4%) superficial surgical site infections, 16 (7.7%) deep surgical site infections, and 1 (0.5%) organ space infection. CONCLUSION: This study affirms the use of biosynthetic mesh as a cost-effective alternative in all wound classifications, yielding good outcomes, limited long-term complications, and low recurrence. rates.

An Analysis of Trainee Status of the Primary Care Physician and Ambulatory Care Outcomes.

PURPOSE: Prior studies report disparities in outcomes for patients cared for by trainees versus faculty physicians at academic medical centers. This study examined the effect of having a trainee as the primary care physician versus a faculty member on routine population health outcomes after adjusting for differences in social determinants of health and primary care retention. METHOD: This cohort study assessed 38,404 patients receiving primary care at an academic hospital-affiliated practice by 60 faculty and 110 internal medicine trainees during academic year 2019. The effect of primary care practitioner trainee status on routine ambulatory care metrics was modeled using log-binomial regression with generalized estimating equation methods to account for physician-level clustering. Risk estimates before and after adjusting for social determinants of health and loss to follow-up are presented. RESULTS: Trainee and faculty cohorts had similar distributions of acute illness burden; however, patients in the trainee cohort were significantly more likely to identify as a race other than White (2,476 [52.6%] vs 14,785 [38.5%], P < .001), live in a zip code associated with poverty (1,688 [35.9%] vs 9,122 [23.8%], P < .001), use public health insurance (1,021 [21.7%] vs 6,108 [15.9%], P < .001), and have limited English proficiency (1,415 [30.1%] vs 5,203 [13.6%], P < .001). In adjusted analyses, trainee status of primary care physician was not associated with lack of breast cancer screening but was associated with missed opportunities to screen for colorectal cancer (relative risk [RR], 0.77; 95% confidence interval [CI], 0.68-0.88), control type 2 diabetes mellitus (RR, 0.78; 95% CI, 0.64-0.94), and control hypertension (RR, 0.80; 95% CI, 0.69-0.94). CONCLUSIONS: Primary care physician trainee status was associated with poorer quality of care in the ambulatory setting after adjusting for differences in socioeconomic factors and loss to follow-up, highlighting a potential ambulatory training gap.