Reviewing the science on 50 years of conservation: Knowledge production biases and lessons for practice.

Drawing on 662 studies from 102 countries, we present a systematic review of published empirical studies about site-level biodiversity conservation initiated between 1970 and 2019. Within this sample, we find that knowledge production about the Global South is largely produced by researchers in the Global North, implying a neocolonial power dynamic. We also find evidence of bias in reported ecological outcomes linked to lack of independence in scientific studies, serving to uphold narratives about who should lead conservation. We explore relationships in the sample studies between conservation initiative types, the extent of Indigenous Peoples' and local communities' influence in governance, and reported social and ecological outcomes. Findings reveal positive ecological and social outcomes are strongly associated with higher levels of influence of Indigenous Peoples and local communities and their institutions, implying equity in conservation practice should be advanced not only for moral reasons, but because it can enhance conservation effectiveness.

Childhood Opportunity and Acute Interstage Outcomes: A National Pediatric Cardiology Quality Improvement Collaborative Analysis.

BACKGROUND: The interstage period after discharge from stage 1 palliation carries high morbidity and mortality. The impact of social determinants of health on interstage outcomes is not well characterized. We assessed the relationship between childhood opportunity and acute interstage outcomes. METHODS: Infants discharged home after stage 1 palliation in the National Pediatric Quality Improvement Collaborative Phase II registry (2016-2022) were retrospectively reviewed. Zip code-level Childhood Opportunity Index (COI), a composite metric of 29 indicators across education, health and environment, and socioeconomic domains, was used to classify patients into 5 COI levels. Acute interstage outcomes included death or transplant listing, unplanned readmission, intensive care unit admission, unplanned catheterization, and reoperation. The association between COI level and acute interstage outcomes was assessed using logistic regression with sequential adjustment for potential confounders. RESULTS: The analysis cohort included 1837 patients from 69 centers. Birth weight (P<0.001) and proximity to a surgical center at birth (P=0.02) increased with COI level. Stage 1 length of stay decreased (P=0.001), and exclusive oral feeding rate at discharge increased (P<0.001), with higher COI level. More than 98% of patients in all COI levels were enrolled in home monitoring. Death or transplant listing occurred in 101 (5%) patients with unplanned readmission in 987 (53%), intensive care unit admission in 448 (24%), catheterization in 345 (19%), and reoperation in 83 (5%). There was no difference in the incidence or time to occurrence of any acute interstage outcome among COI levels in unadjusted or adjusted analysis. There was no interaction between race and ethnicity and childhood opportunity in acute interstage outcomes. CONCLUSIONS: Zip code COI level is associated with differences in preoperative risk factors and stage 1 palliation hospitalization characteristics. Acute interstage outcomes, although common across the spectrum of childhood opportunity, are not associated with COI level in an era of highly prevalent home monitoring programs. The role of home monitoring in mitigating disparities during the interstage period merits further investigation.

Rapid Quantification of Oxidized and Reduced Forms of Glutathione Using Ortho -phthalaldehyde in Cultured Mammalian Cells In Vitro.

Glutathione has long been considered a key biomarker for determining the antioxidant response of the cell. Hence, it is a primary marker for reactive oxygen species studies. The method utilizes Ortho-phthalaldehyde (OPA) to quantify the cellular concentration of glutathione(s). OPA conjugates with reduced glutathione (GSH) via sulfhydryl binding to subsequently form an isoindole, resulting in a highly fluorescent conjugate. To attain an accurate result of both oxidized glutathione (GSSG) and GSH, a combination of masking agents and reducing agents, which have been implemented in this protocol, are required. Treatments may also impact cellular viability. Hence, normalization via protein assay is presented in this multiparametric assay. The assay demonstrates a pseudo-linear detection range of 0.234 - 30µM (R2=0.9932±0.007 (N=12)) specific to GSH. The proposed assay also allows for the determination of oxidized glutathione with the addition of the masking agent N-ethylmaleimide to bind reduced glutathione, and the reducing agent tris(2-carboxyethyl) phosphine is introduced to cleave the disulfide bond in GSSG to produce two molecules of GSH. The assay is used in combination with a validated bicinchoninic acid assay for protein quantification and an adenylate kinase assay for cytotoxicity assessment.

Indeterminate measurable residual disease by multiparameter flow cytometry is associated with an intermediate risk of clinical relapse in adult patients with acute leukaemia.

Measurable residual disease (MRD) is useful for prognostication and for monitoring response to treatment in patients with acute leukaemia. MRD by multiparametric flow cytometry (MFC-MRD) utilises the leukaemia-associated immunophenotype (LAIP) and difference from normal (DfN) strategies to identify the leukaemic clone. Difficulties arise when the LAIP overlaps with normal regeneration, there is clonal evolution, or when the abnormal clone population is exceptionally small e.g., <0.01% of CD45+ cells. Such cases are reported as 'indeterminate'; however, there is little international consensus on this reporting. The relationship between clinical outcomes and indeterminate MFC-MRD is unknown. Here we determine the rate of indeterminate MFC-MRD reporting, its relationship to concurrent molecular MRD results when available, and to clinical outcomes to 12 months. We performed an internal audit of all adult testing for MFC-MRD between January and December 2021. A total of 153 consecutive patients with a diagnosis of acute leukaemia were included. Successive MFC-MRD results and clinical outcomes were recorded over a 12-month period from time of inclusion into the study. In total, 460 MFC-MRD tests from 153 patients were reviewed and 73 (16%) MFC-MRD tests from 54 (35%) patients were reported as indeterminate. The majority (70%) were at low levels between 0.01-0.1% of CD45+ cells. Compared to patients with a negative result, acute myeloid leukaemia (AML) was more frequent in patients who had an indeterminate MFC-MRD (70% vs 36%), and B-cell acute lymphoblastic leukaemia was less common (20% vs 55%). In patients with indeterminate MFC-MRD results, one-third had received either chemotherapy or allogeneic haemopoietic stem cell transplant (aHSCT) within the preceding 3 months. Agreement between MFC and molecular MRD testing was low. Patients with indeterminate MFC-MRD had leukaemia relapse rates below patients with a positive MFC-MRD, but greater than those with negative MFC-MRD (positive 33% vs indeterminate 21% vs negative 8%, p = 0.038). Overall, these findings indicate that indeterminate MFC-MRD results are more common in adults with AML and also in those who have received chemotherapy or aHSCT within the previous 3 months. We report for the first time that indeterminate MFC-MRD is a finding of potential clinical significance, which associates with a numerically higher median relapse rate within 12 months when compared to a negative MFC-MRD result.

Risk Factors for Death or Transplant After Stage 2 Palliation for Single Ventricle Heart Disease.

Background: For infants with single ventricle heart disease, the time after stage 2 procedure (S2P) is believed to be a lower risk period compared with the interstage period; however, significant morbidity and mortality still occur. Objectives: This study aimed to identify risk factors for mortality or transplantation referral between S2P surgery and the first birthday. Methods: Retrospective cohort analysis of infants in the National Pediatric Cardiology Quality Improvement Collaborative who underwent staged single ventricle palliation from 2016 to 2022 and survived to S2P. Multivariable logistic regression and classification and regression trees were performed to identify risk factors for mortality and transplantation referral after S2P. Results: Of the 1,455 patients in the cohort who survived to S2P, 5.2% died and 2.3% were referred for transplant. Overall event rates at 30 and 100 days after S2P were 2% and 5%, respectively. Independent risk factors for mortality and transplantation referral included the presence of a known genetic syndrome, shunt type at stage 1 procedure (S1P), tricuspid valve repair at S1P, longer time to extubation and reintubation after S1P, ≥ moderate tricuspid regurgitation prior to S2P, younger age at S2P, and the risk groups identified in the classification and regression tree analysis (extracorporeal membrane oxygenation after S1P and longer S2P cardiopulmonary bypass time without extracorporeal membrane oxygenation). Conclusions: Mortality and transplantation referral rates after S2P to 1 year of age remain high ∼7%. Many of the identified risk factors after S2P are similar to those established for interstage factors around the S1P, whereas others may be unique to the period after S2P.

Biosimilar candidate CT-P42 in diabetic macular edema: 24-week results from a randomized, active-controlled, Phase III study.

OBJECTIVE: To demonstrate the therapeutic similarity of CT-P42 compared to reference aflibercept (Eylea®) in adult patients with diabetic macular edema (DME). DESIGN: Randomized, active-controlled, double-masked, Phase III clinical trial PARTICIPANTS: Patients with a diagnosis of either type 1 or 2 diabetes mellitus (DM) with DME involving the center of the macula. METHODS: Patients were randomized (1:1) to receive either CT-P42 or reference aflibercept (2 mg/0.05 mL) by intravitreal injection every 4 weeks (5 doses) then every 8 weeks (4 doses) in the main study period. Results up to Week 24 are reported herein. MAIN OUTCOME MEASURES: The primary endpoint was mean change from baseline at Week 8 in best corrected visual acuity (BCVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Equivalence between CT-P42 and reference aflibercept was to be concluded if the two-sided 95% confidence interval (CI) (global assumptions) and two-sided 90% CI (US Food and Drug Administration [FDA] assumptions) for the treatment difference fell entirely within the equivalence margin of ±3 letters, as assessed in the full analysis set. RESULTS: Overall, 348 patients were randomized (CT-P42: 173; reference aflibercept: 175). BCVA improved from baseline to Week 8 in both groups, with a least squares mean (standard error) improvement of 9.43 (0.798) and 8.85 (0.775) letters in the CT-P42 and reference aflibercept groups, respectively. The estimated between-group treatment difference was 0.58 letters, with the CIs within the pre-defined equivalence margin of ±3 letters (95% CI -0.73, 1.88 [global]; 90% CI -0.52, 1.67 [FDA]). Through Week 24, other efficacy results for the two groups, in terms of change in BCVA and retinal central subfield thickness, as well as ETDRS Diabetic Retinopathy Severity Scale score, supported therapeutic similarity. Pharmacokinetics, usability, safety (including the proportions of patients experiencing at least one treatment-emergent adverse event [CT-P42: 50.3%; reference aflibercept: 53.7%]), and immunogenicity were also comparable between groups. CONCLUSIONS: This study in patients with DME demonstrated equivalence between CT-P42 and reference aflibercept (2 mg/0.05 mL) in terms of efficacy, with similar pharmacokinetic, usability, safety, and immunogenicity profiles.

Proteome profiling of cerebrospinal fluid using machine learning shows a unique protein signature associated with APOE4 genotype.

INTRODUCTION: Proteome changes associated with APOE4 variant carriage that are independent of Alzheimer's disease (AD) pathology and diagnosis are unknown. This study investigated APOE4 proteome changes in people with AD, mild cognitive impairment, and no impairment. METHODS: Clinical, APOE genotype, and cerebrospinal fluid (CSF) proteome and AD biomarker data was sourced from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Proteome profiling was done using supervised machine learning. RESULTS: We found an APOE4-specific proteome signature that was independent of cognitive diagnosis and AD pathological biomarkers, and increased risk of progression to cognitive impairment. Proteins were enriched in brain regions including the caudate and cortex and cells including endothelial cells, oligodendrocytes, and astrocytes. Enriched peripheral immune cells included T cells, macrophages, and B cells. DISCUSSION: APOE4 carriers have a unique CSF proteome signature associated with a strong brain and peripheral immune and inflammatory phenotype that likely underlies APOE4 carriers' vulnerability to cognitive decline and AD.

Comparison of the efficacy and safety of SCD411 and reference aflibercept in patients with neovascular age-related macular degeneration.

To compare the efficacy and safety of the proposed aflibercept biosimilar SCD411 and reference aflibercept in patients with neovascular age-related macular degeneration, this randomized, double-masked, parallel-group, multicenter study was conducted in 14 countries from 13 August 2020 to 8 September 2022. Patients with neovascular age-related macular degeneration. With subfoveal, juxtafoveal, or extrafoveal choroidal neovascularization were aged 50 years or older. Intravitreal injection of SCD411 or aflibercept (2.0 mg) were administered every 4 weeks for the first three injections and every 8 weeks until week 48. The primary efficacy endpoint was the change in best-corrected visual acuity from baseline to week 8 with an adjusted equivalence margin of ± 3.0 letters. Patients were randomly assigned to receive either SCD411 (n = 288) or reference aflibercept (n = 288). A total of 566 participants (98.3%) completed week 8 of the study. The least-squares mean difference of change in best-corrected visual acuity from baseline to week 8 (SCD411-aflibercept) was - 0.4 letters (90% confidence interval = - 1.6 to 0.9). The incidence of ocular (69 of 287 [24.0%] vs. 71 of 286 [24.8%]) and serious ocular (5 of 287 [1.7%] vs. 3 of 286 [1.0%]) treatment-emergent adverse effects were similar between the SCD411 and aflibercept groups. Immunogenicity analysis revealed a low incidence of neutralizing antibody formation in both groups. In conclusion, SCD411 has equivalent efficacy compared with reference aflibercept in patients with neovascular age-related macular degeneration and has a comparable safety profile. The results support the potential use of SCD411 for the treatment of neovascular age-related macular degeneration.

Association between PM2.5 from a coal mine fire and FeNO concentration 7.5 years later.

BACKGROUND AND AIM: There are few long-term studies of respiratory health effects of landscape fires, despite increasing frequency and intensity due to climate change. We investigated the association between exposure to coal mine fire PM2.5 and fractional exhaled nitric oxide (FeNO) concentration 7.5 years later. METHODS: Adult residents of Morwell, who were exposed to the 2014 Hazelwood mine fire over 6 weeks, and unexposed residents of Sale, participated in the Hazelwood Health Study Respiratory Stream in 2021, including measurements of FeNO concentration, a marker of eosinophilic airway inflammation. Individual exposure to coal mine fire PM2.5 was modelled and mapped to time-location diaries. The effect of exposure to PM2.5 on log-transformed FeNO in exhaled breath was investigated using multivariate linear regression models in the entire sample and stratified by potentially vulnerable subgroups. RESULTS: A total of 326 adults (mean age: 57 years) had FeNO measured. The median FeNO level (interquartile range [IQR]) was 17.5 [15.0] ppb, and individual daily exposure to coal mine fire PM2.5 was 7.2 [13.8] µg/m3. We did not identify evidence of association between coal mine fire PM2.5 exposure and FeNO in the general adult sample, nor in various potentially vulnerable subgroups. The point estimates were consistently close to zero in the total sample and subgroups. CONCLUSION: Despite previous short-term impacts on FeNO and respiratory health outcomes in the medium term, we found no evidence that PM2.5 from the Hazelwood coal mine fire was associated with any long-term impact on eosinophilic airway inflammation measured by FeNO levels.

MANAGEMENT OF LARGE FULL-THICKNESS MACULAR HOLES: Long-Term Outcomes of Internal Limiting Membrane Flaps and Internal Limiting Membrane Peels.

BACKGROUND/PURPOSE: To determine and compare the efficacy of a surgical internal limiting membrane (ILM) flap technique with the traditional ILM peel on long-term visual and anatomical outcomes for large (>400 µm) full-thickness macular holes. METHODS: From October 2016 to July 2022, patients undergoing initial full-thickness macular hole repair with the ILM flap or ILM peel technique were reviewed. Final outcomes were recorded and based on size in microns: 401 to 800, 801 to 1,200, and >1,200. RESULTS: Patients treated with ILM flap (n = 52, 94.2% closure rate) or ILM peel (n = 407, 93.6% closure rate) were followed with a mean follow-up time of 15.0 ± 10.2 and 20.0 ± 13.4 months, respectively. Success rates for ILM flaps and ILM peels were compared for full-thickness macular holes of 401 to 800 (100%, 95.8%, P = 0.39), 801 to 1,200 (95%, 93%, P = 0.74), and >1,200 (86.7%, 86.7%, P = 1.0) µm. Mean best-recorded logarithm of the minimal angle of resolution visual acuity for ILM flaps and ILM peels, respectively, was 1.02 ± 0.46 and 0.87 ± 0.47 preoperatively, with follow-up acuity of 0.48 ± 0.32 (P < 0.03) and 0.39 ± 0.42 (P < 0.01) at Year 3. CONCLUSION: Both techniques provide a similar anatomical closure rate and functional improvement in vision. Comparisons should be cautiously made based on difference in preoperative hole size.

APOBEC3 mutagenesis drives therapy resistance in breast cancer.

Acquired genetic alterations commonly drive resistance to endocrine and targeted therapies in metastatic breast cancer 1-7 , however the underlying processes engendering these diverse alterations are largely uncharacterized. To identify the mutational processes operant in breast cancer and their impact on clinical outcomes, we utilized a well-annotated cohort of 3,880 patient samples with paired tumor-normal sequencing data. The mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) enzymes were highly prevalent and enriched in post-treatment compared to treatment-naïve hormone receptor-positive (HR+) cancers. APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ metastatic breast cancer. Whole genome sequencing (WGS) of breast cancer models and selected paired primary-metastatic samples demonstrated that active APOBEC3 mutagenesis promoted resistance to both endocrine and targeted therapies through characteristic alterations such as RB1 loss-of-function mutations. Evidence of APOBEC3 activity in pre-treatment samples illustrated a pervasive role for this mutational process in breast cancer evolution. The study reveals APOBEC3 mutagenesis to be a frequent mediator of therapy resistance in breast cancer and highlights its potential as a biomarker and target for overcoming resistance.

Incorporating Microdebrider Use in a Community-Based Thyroidectomy Practice.

Objectives: Substernal goiters often require surgery, yet their location presents challenges. Most can be removed via transcervical approach, but extent and relationship to mediastinal structures can merit consideration of sternotomy and assistance of colleagues. Despite widespread use in sinus surgery and previous literature reports, microdebrider use to facilitate transcervical removal of substernal goiters has not been broadly adopted. Our objective was to report our experience with use of the soft tissue shaver to facilitate substernal goiter deliver through a cervical incision in a community-based thyroidectomy practice. Methods: We reviewed thyroidectomy cases performed by a general otolaryngologist (D.M.Y.) in a community setting from January 2017 through December 2019. Four patients required microdebrider use for intracapsular debulking of substernal goiter to allow for transcervical removal. We discuss pre- and perioperative considerations, present computed tomography (CT) and operative images, review surgical technique, and report estimated blood loss (EBL), surgical time (T), complications, and length of stay. Results: Average EBL was 237.5 ml (range 100-500 ml). Average T was 137 minutes (range 121-170 minutes). No patients required sternotomy. One patient developed postoperative hematoma requiring evacuation and cautery of a bleeding site. No other complications were encountered, all patients were discharged after overnight observation. Conclusions: The microdebrider can be safely utilized by general otolaryngologists to facilitate transcervical removal of substernal goiters. Adoption of this familiar tool for a different surgical application can reduce the need for sternotomy, assistance of colleagues, or referral to a tertiary care center, with associated decrease in risk, morbidity, surgical time, length of stay, and cost, and improved patient convenience and satisfaction.

New technology to address affected vs nonaffected arm contributions to ergometer performance in people poststroke.

BACKGROUND: When pedaling a coupled-crank arm ergometer, individuals with hemiplegia may experience nonparetic arm overcompensation, and paretic arm resistance, due to neuromechanical deficits. Technologies that foster independent limb contributions may increase the effectiveness of exercise for people poststroke. OBJECTIVE: Examine the speed during uncoupled pedaling with the Advanced Virtual Exercise Environment Device among individuals poststroke and non-impaired comparisons. METHODS: We recruited 2 groups:Poststroke and Comparison. Participants attended one lab session and performed peak speed tests and a graded exercise repeated for bilateral pedaling, unilateral (left, right). RESULTS: Thirty-one participants completed the protocol (16 women, 15 men). Poststroke participants pedaled slower during the bilateral speed test (64 ± 39 RPM, p < .001), and graded exercise, (54 ± 28 RPM, p < .001) versus comparisons (141 ± 19, 104 ± 12 RPM). Poststroke individuals had lower peak RPM during the unilateral speed test with their paretic arm (70 ± 46 RPM, p < .001) and graded exercise (58 ± 33 RPM, p < .001) compared to their unilateral speed test (130 ± 37 RPM) and graded exercise (108 ± 25 RPM) with their nonparetic arm. Comparisons did not differ between arms during speed tests and graded exercise. Poststroke participants demonstrated lower peak speed with their affected arm during the bilateral speed test (52 ± 42 RPM, p < .001) and graded exercise (49 ± 28 RPM, p = .008) compared to the same arm during unilateral speed (70 ± 46 RPM) and graded exercise (58 ± 33 RPM). CONCLUSIONS: Poststroke participants pedaled faster with their affected arm unilaterally versus bilateral pedaling, suggesting interhemispheric interference that reduces the ability to recruit the paretic arm during bilateral exercise.

Jerks are Useful: Extracting pulse rate from wrist-placed accelerometry jerk during sleep in children.

STUDY OBJECTIVES: Evaluate wrist-placed accelerometry predicted heartrate compared to electrocardiogram (ECG) heartrate in children during sleep. METHODS: Children (n=82, 61% male, 43.9% Black) wore a wrist-placed Apple Watch Series 7 (AWS7) and ActiGraph GT9X during a polysomnogram. 3-Axis accelerometry data was extracted from AWS7 and the GT9X. Accelerometry heartrate estimates were derived from jerk (the rate of acceleration change), computed using the peak magnitude frequency in short time Fourier Transforms of Hilbert transformed jerk computed from acceleration magnitude. Heartrates from ECG traces were estimated from R-R intervals using R-pulse detection. Lin's Concordance Correlation Coefficient (CCC), mean absolute error (MAE) and mean absolute percent error (MAPE) assessed agreement with ECG estimated heartrate. Secondary analyses explored agreement by polysomnography sleep stage and a signal quality metric. RESULTS: The developed scripts are available on Github. For the GT9X, CCC was poor at -0.11 and MAE and MAPE were high at 16.8 (SD=14.2) beats/minute and 20.4% (SD=18.5%). For AWS7, CCC was moderate at 0.61 while MAE and MAPE were lower at 6.4 (SD=9.9) beats/minute and 7.3% (SD=10.3%). Accelerometry estimated heartrate for AWS7 was more closely related to ECG heartrate during N2, N3 and REM sleep than lights on, wake, and N1 and when signal quality was high. These patterns were not evident for the GT9X. CONCLUSIONS: Raw accelerometry data extracted from AWS7, but not the GT9X, can be used to estimate heartrate in children while they sleep. Future work is needed to explore the sources (i.e., hardware, software, etc.) of the GT9X's poor performance.

Does diet quality moderate the long-term effects of discrete but extreme PM2.5 exposure on respiratory symptoms? A study of the Hazelwood coalmine fire.

In 2014, a fire at an open cut coalmine in regional Victoria, Australia burned for 6 weeks. Residents of the nearby town of Morwell were exposed to smoke, which included high levels of fine particulate matter (PM2.5). We investigated whether the long-term effects of PM2.5 on respiratory health were moderated by diet quality. A cross-sectional analysis was conducted of data collected 8.5 years after the mine fire from 282 residents of Morwell and 166 residents from the nearby unexposed town of Sale. Primary outcomes were respiratory symptoms. Exposure was coalmine fire-related PM2.5 and diet quality was assessed as Australian Recommended Food Score (ARFS) derived using the Australian Eating Survey (AES). The moderating effect of diet quality on respiratory outcomes associated with PM2.5 was assessed using logistic regression models, adjusting for potential confounders. Diet quality was poor in this sample, with 60% in the lowest category of overall diet quality. Overall diet quality and fruit and vegetable quality significantly attenuated the association between PM2.5 and prevalence of chronic cough and phlegm. Sauce/condiment intake was associated with a greater effect of PM2.5 on COPD prevalence. No other moderating effects were significant. The moderating effects of overall diet quality and vegetable and fruit intake aligned with a priori hypotheses, suggesting potential protective benefits. While more evidence is needed to confirm these findings, improving diets, especially fruit and vegetable intake, may provide some protection against the effects of smoke exposure from fire events.

Pathway for Development and Validation of Multi-domain Endpoints for Amyloid Light Chain (AL) Amyloidosis.

Immunoglobin light chain (AL) amyloidosis is a rare disease in which a plasma cell dyscrasia leads to deposition of insoluble amyloid fibrils in multiple organs. To facilitate development of new therapies for this heterogenous disease, a public-private partnership was formed between the nonprofit Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research. In 2020, the Amyloidosis Forum launched an initiative to identify clinical trial endpoints and analytic strategies across affected organ systems and life impacts via specialized working groups. This review summarizes the proceedings of the Statistical Group and proposes a pathway for development and validation of multi-domain endpoints (MDEs) for potential use in AL amyloidosis clinical trials. Specifically, drawing on candidate domain-specific endpoints recommended by each organ-specific working group, different approaches to constructing MDEs were considered. Future studies were identified to assess the validity, meaningfulness and performance of MDEs through use of natural history and clinical trial data. Ultimately, for drug development, the context of use in a regulatory evaluation, the specific patient population, and the investigational therapeutic mechanism should drive selection of appropriate endpoints. MDEs for AL amyloidosis, once developed and validated, will provide important options for advancing patient-focused drug development in this multi-system disease.

Radiocarbon chronology of Iron Age Jerusalem reveals calibration offsets and architectural developments.

Reconstructing the absolute chronology of Jerusalem during the time it served as the Judahite Kingdom's capital is challenging due to its dense, still inhabited urban nature and the plateau shape of the radiocarbon calibration curve during part of this period. We present 103 radiocarbon dates from reliable archaeological contexts in five excavation areas of Iron Age Jerusalem, which tie between archaeology and biblical history. We exploit Jerusalem's rich past, including textual evidence and vast archaeological remains, to overcome difficult problems in radiocarbon dating, including establishing a detailed chronology within the long-calibrated ranges of the Hallstatt Plateau and recognizing short-lived regional offsets in atmospheric 14C concentrations. The key to resolving these problems is to apply stringent field methodologies using microarchaeological methods, leading to densely radiocarbon-dated stratigraphic sequences. Using these sequences, we identify regional offsets in atmospheric 14C concentrations c. 720 BC, and in the historically secure stratigraphic horizon of the Babylonian destruction in 586 BC. The latter is verified by 100 single-ring measurements between 624 to 572 BC. This application of intense 14C dating sheds light on the reconstruction of Jerusalem in the Iron Age. It provides evidence for settlement in the 12th to 10th centuries BC and that westward expansion had already begun by the 9th century BC, with extensive architectural projects undertaken throughout the city in this period. This was followed by significant damage and rejuvenation of the city subsequent to the mid-eight century BC earthquake, after which the city was heavily fortified and continued to flourish until the Babylonian destruction.

Drug use and COVID-19 testing, vaccination, and infection among underserved, minority communities in Miami, Florida.

The Coronavirus Disease 2019 (COVID-19) pandemic has disproportionately impacted people who use drugs (PWUD). This study explored relationships between drug use, COVID-19 testing, vaccination, and infection. This cross-sectional study was conducted in Miami, Florida between March 2021 and October 2022 as part of the National Institutes of Health (NIH) Rapid Acceleration of Diagnostics-Underserved Populations (RADx-UP) initiative and the Miami Adult Studies on HIV (MASH) cohort. Users of cannabis, cocaine/crack, heroin/fentanyl, methamphetamines, hallucinogens, and/or prescription drug misuse in the previous 12 months were considered PWUD. Sociodemographic data, COVID-19 testing history, and vaccination-related beliefs were self-reported. Vaccinations were confirmed with medical records and positivity was determined with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. Statistical analyses included chi-square tests and logistic regression. Of 1,780 participants, median age was 57 years, 50.7% were male, 50.2% Non-Hispanic Black, and 66.0% reported an annual income less than $15,000. Nearly 28.0% used drugs. PWUD were less likely than non-users to self-report ever testing positive for SARS-CoV-2 (14.7% vs. 21.0%, p = 0.006). However, 2.6% of participants tested positive for SARS-CoV-2, with no significant differences between PWUD and non-users (3.7% vs. 2.2%, p = 0.076). PWUD were more likely than non-users to experience difficulties accessing testing (10.2% vs. 7.1%, p = 0.033), vaccine hesitancy (58.9% vs. 43.4%, p = 0.002) and had lower odds of receiving any dose of a COVID-19 vaccine compared to non-users (aOR, 0.63; 95% CI, 0.49-0.81; p<0.001). PWUD presented with greater difficulties accessing COVID-19 testing, greater vaccine hesitancy, and lower odds of vaccination. Testing and immunization plans that are tailored to the needs of PWUD and consider access, trust-building campaigns, and education may be needed.

SUPRACHOROIDAL SPACE INJECTION TECHNIQUE: Expert Panel Guidance.

PURPOSE: To develop professional guidelines for best practices for suprachoroidal space (SCS) injection, an innovative technique for retinal therapeutic delivery, based on current published evidence and clinical experience. METHODS: A panel of expert ophthalmologists reviewed current published evidence and clinical experience during a live working group meeting to define points of consensus and key clinical considerations to inform the development of guidelines for in-office SCS injection. RESULTS: Core consensus guidelines for in-office SCS injection were reached and reported by the expert panel. Current clinical evidence and physician experience supported SCS injection as a safe and effective method for delivering retinal and choroidal therapeutics. The panel established consensus on the rationale for SCS injection, including potential benefits relative to other intraocular delivery methods and current best practices in patient preparation, pre- and peri-injection management, SCS-specific injection techniques, and postinjection management and follow-up. CONCLUSION: These expert panel guidelines may support and promote standardization of SCS injection technique, with the goal of optimizing patient safety and outcomes. Some aspects of the procedure may reasonably be modified based on the clinical setting and physician judgment, as well as additional study.