Improving assessment of alcohol treatment barriers among Latino and White adults with an alcohol use disorder: Development of the barriers to specialty alcohol treatment scale.

INTRODUCTION: The present study's aims were two-fold. First, we sought to validate a novel measure to assess barriers to specialty alcohol treatment among White and Latino individuals with an alcohol use disorder (AUD): The Barriers to Specialty Alcohol Treatment (BSAT) scale. Second, we sought to demonstrate that the BSAT scale could be used to explain Latino-White disparities in barriers to alcohol treatment. METHODS: In 2021, we recruited an online national sample of 1200 White and Latino adults with a recent AUD. Participants completed an online questionnaire that included the BSAT items. Confirmatory and exploratory factor analyses were conducted to validate the BSAT. Multiple group analyses across race/ethnicity and language were also performed using the final model. RESULTS: The final model consisted of 36 items across 7 factors that reflect barriers related to low problem recognition, recovery goals, low perceived treatment efficacy, cultural factors, immigration-related concerns, low perceived social support, and logistical barriers. The final model's factor structure and factor loadings held up across race/ethnicity and language. The top endorsed barriers were low problem recognition, recovery goals, low perceived social support, logistical issues, and low perceived treatment efficacy. Compared to Whites, Latinos were more likely to report perceived lack of social support, logistical barriers, low perceived treatment efficacy, cultural barriers, and immigration-related concerns as barriers. CONCLUSION: Findings provide empirical support for the validity of the BSAT scale, which offers improved measurement of specialty alcohol treatment barriers and can be used to explore Latino-White disparities in a future study.

Meteorological data rescue: Citizen science lessons learned from Southern Weather Discovery.

Daily weather reconstructions (called "reanalyses") can help improve our understanding of meteorology and long-term climate changes. Adding undigitized historical weather observations to the datasets that underpin reanalyses is desirable; however, time requirements to capture those data from a range of archives is usually limited. Southern Weather Discovery is a citizen science data rescue project that recovered tabulated handwritten meteorological observations from ship log books and land-based stations spanning New Zealand, the Southern Ocean, and Antarctica. We describe the Zooniverse-hosted Southern Weather Discovery campaign, highlight promotion tactics, and replicate keying levels needed to obtain 100% complete transcribed datasets with minimal type 1 and type 2 transcription errors. Rescued weather observations can augment optical character recognition (OCR) text recognition libraries. Closer links between citizen science data rescue and OCR-based scientific data capture will accelerate weather reconstruction improvements, which can be harnessed to mitigate impacts on communities and infrastructure from weather extremes.

Loa loa filariasis in a tropical savanna area: report of one case in Ouagadougou.

Loa loa filariasis is usually found in the forest areas of Central and West Africa. We report a case that was diagnosed in Ouagadougou (Burkina Faso), a savanna area. The patient lived in Gabon but was visiting his family in Ouagadougou. He complained of fatigue, fever, itchy legs with scratch marks, and intermittent edema of the legs. A blood smear was first examined for malaria parasites, but Loa loa microfilariae were observed. Laboratory tests showed hypereosinophilia (30%). Transient angioedema (Calabar edema) was observed. Loa loa filariasis was diagnosed based on these findings. There were no other laboratory test abnormalities, and ophthalmological examination was normal. The patient received a single dose of ivermectin at 200 µg/kg. After 1 month, the patient's course was favorable and a control blood smear was negative.

General regression model for the subdistribution of a competing risk under left-truncation and right-censoring.

Left-truncation poses extra challenges for the analysis of complex time-to-event data. We propose a general semiparametric regression model for left-truncated and right-censored competing risks data that is based on a novel weighted conditional likelihood function. Targeting the subdistribution hazard, our parameter estimates are directly interpretable with regard to the cumulative incidence function. We compare different weights from recent literature and develop a heuristic interpretation from a cure model perspective that is based on pseudo risk sets. Our approach accommodates external time-dependent covariate effects on the subdistribution hazard. We establish consistency and asymptotic normality of the estimators and propose a sandwich estimator of the variance. In comprehensive simulation studies we demonstrate solid performance of the proposed method. Comparing the sandwich estimator with the inverse Fisher information matrix, we observe a bias for the inverse Fisher information matrix and diminished coverage probabilities in settings with a higher percentage of left-truncation. To illustrate the practical utility of the proposed method, we study its application to a large HIV vaccine efficacy trial dataset.

Degradation in cone-plate rheometry.

We analyze quantitatively the oxidative degradation of a sample in a cone-plate rheometer, as oxygen diffuses inward, radially, from the free boundary. We examine rheometer error mitigation by means of nitrogen blanketing, and also, of cone-plate partitioning. We arrive at exact analytical expressions for the oxygen concentration, and thus, for the degradation rate. We then integrate this rate over time to get the amount of oxygen reacted as a function of radial position and time in the degrading sample. To illustrate the usefulness of our analytical expressions, we provide two worked examples investigating the effect of nitrogen blanketing and cone-plate partitioning. We find that, though nitrogen blanketing always produces less degradation, its benefits are limited for short times. Additionally, cone-plate partitioning provides a simpler solution and allows samples to be run for longer times without degradation compromising measurement, even in samples initially saturated with oxygen. We close by considering the effect of antioxidants.

Determination of fatty acid and sphingoid base composition of eleven ceramide subclasses in stratum corneum by UHPLC/scheduled-MRM.

INTRODUCTION: Ceramides play a key role in skin barrier function in homeostatic and pathological conditions and can be sampled non-invasively through stratum corneum collection. OBJECTIVES: To develop a novel UHPLC/Scheduled MRM method for the identification and relative distribution of eleven classes of ceramides, which are separated by UHPLC and determined by their specific retention times. The precise composition of the fatty acid and sphingoid base parts of each individual ceramide is determined via mass fragmentation. METHODS: More than 1000 human and pig ceramides were identified. Three human and minipig ceramide classes, CER[AS], CER[NS] and CER[EOS] have been investigated in depth. RESULTS: Sphingoid bases were characterized by a prevalence of chain lengths with sizes from C16 to C22, whereas fatty acids were mainly observed in the range of C22-C26. Overall, the ceramide profiles between human and minipig stratum corneum were similar. Differences in the CER[AS] and CER[NS] classes included a more homogeneous distribution of fatty acids (16-30 carbon atoms) in minipig, whereas in human longer fatty acid chains (> 24 carbon atoms) predominated. CONCLUSION: The method will be useful for the analysis of healthy and pathological skin in various specie, and the measurement of the relative distribution of ceramides as biomarkers for pharmacodynamic studies.

Stage-specific differences in secretory profile of mesenchymal stromal cells (MSCs) subjected to early- vs late-stage OA synovial fluid.

OBJECTIVE: Although, mesenchymal stromal cells (MSCs) are being clinically investigated for their use in osteoarthritis (OA), it is unclear whether their postulated therapeutic properties are equally effective in the early- and late-stages of OA. In this study we investigated MSC cytokine secretion post-exposure to synovial fluid (SF), obtained from early- vs late-stage knee OA patients to justify a potential patient stratification strategy to maximize MSC-mediated treatment effects. METHOD: Subjects were recruited and categorized into early- [Kellgren-Lawrence (KL) grade I/II, n = 12] and late-stage (KL-III/IV, n = 12) knee OA groups. SF samples were obtained, and their proteome was tested using multiplex assays, after 3-days culture, with and without MSCs. SFs cultured without MSCs were used as a baseline to identify MSC-secreted factors into SFs cultured with MSCs. Linear mixed-effect models and non-parametric tests were used to identify alterations in the MSC secretome during exposure to OA SF (3-days). MSCs cultured for 3-days in 0.5% fetal bovine serum (FBS)-supplemented medium were used to compare SF results with culture medium. RESULTS: Following exposure to OA SF, the MSC secretome contained proteins that are involved in tissue repair, angiogenesis, chemotaxis, matrix remodeling and the clotting process. However, chemokine (C-X-C motif) ligand-8 (CXCL8; chemoattractant), interleukin-6 (IL6) and chemokine (C-C motif) ligand 2 (CCL2) were elevated in the MSC-secretome in response to early- vs late-stage OA SF. CONCLUSION: Early- vs late-stage OA SF samples elicit a differential MSC secretome response, arguing for stratification of OA patients to maximize MSC-mediated therapeutic effects.

Doubly robust nonparametric inference on the average treatment effect.

Doubly robust estimators are widely used to draw inference about the average effect of a treatment. Such estimators are consistent for the effect of interest if either one of two nuisance parameters is consistently estimated. However, if flexible, data-adaptive estimators of these nuisance parameters are used, double robustness does not readily extend to inference. We present a general theoretical study of the behaviour of doubly robust estimators of an average treatment effect when one of the nuisance parameters is inconsistently estimated. We contrast different methods for constructing such estimators and investigate the extent to which they may be modified to also allow doubly robust inference. We find that while targeted minimum loss-based estimation can be used to solve this problem very naturally, common alternative frameworks appear to be inappropriate for this purpose. We provide a theoretical study and a numerical evaluation of the alternatives considered. Our simulations highlight the need for and usefulness of these approaches in practice, while our theoretical developments have broad implications for the construction of estimators that permit doubly robust inference in other problems.

A study of vaccine-induced immune pressure on breakthrough infections in the Phambili phase 2b HIV-1 vaccine efficacy trial.

INTRODUCTION: The Merck Adenovirus-5 Gag/Pol/Nef HIV-1 subtype-B vaccine evaluated in predominately subtype B epidemic regions (Step Study), while not preventing infection, exerted vaccine-induced immune pressure on HIV-1 breakthrough infections. Here we investigated if the same vaccine exerted immune pressure when tested in the Phambili Phase 2b study in a subtype C epidemic. MATERIALS AND METHODS: A sieve analysis, which compares breakthrough viruses from placebo and vaccine arms, was performed on 277 near full-length genomes generated from 23 vaccine and 20 placebo recipients. Vaccine coverage was estimated by computing the percentage of 9-mers that were exact matches to the vaccine insert. RESULTS: There was significantly greater protein distances from the vaccine immunogen sequence in Gag (p=0.045) and Nef (p=0.021) in viruses infecting vaccine recipients compared to placebo recipients. Twenty-seven putative sites of vaccine-induced pressure were identified (p<0.05) in Gag (n=10), Pol (n=7) and Nef (n=10), although they did not remain significant after adjustment for multiple comparisons. We found the epitope sieve effect in Step was driven by HLA A∗02:01; an allele which was found in low frequency in Phambili participants compared to Step participants. Furthermore, the coverage of the vaccine against subtype C Phambili viruses was 31%, 46% and 14% for Gag, Pol and Nef, respectively, compared to subtype B Step virus coverage of 56%, 61% and 26%, respectively. DISCUSSION: This study presents evidence of sieve effects in Gag and Nef; however could not confirm effects on specific amino acid sites. We propose that this weaker signal of vaccine immune pressure detected in the Phambili study compared to the Step study may have been influenced by differences in host genetics (HLA allele frequency) and reduced impact of vaccine-induced immune responses due to mismatch between the viral subtype in the vaccine and infecting subtypes.

Fourier decomposition of polymer orientation in large-amplitude oscillatory shear flow.

In our previous work, we explored the dynamics of a dilute suspension of rigid dumbbells as a model for polymeric liquids in large-amplitude oscillatory shear flow, a flow experiment that has gained a significant following in recent years. We chose rigid dumbbells since these are the simplest molecular model to give higher harmonics in the components of the stress response. We derived the expression for the dumbbell orientation distribution, and then we used this function to calculate the shear stress response, and normal stress difference responses in large-amplitude oscillatory shear flow. In this paper, we deepen our understanding of the polymer motion underlying large-amplitude oscillatory shear flow by decomposing the orientation distribution function into its first five Fourier components (the zeroth, first, second, third, and fourth harmonics). We use three-dimensional images to explore each harmonic of the polymer motion. Our analysis includes the three most important cases: (i) nonlinear steady shear flow (where the Deborah number [Formula: see text] is zero and the Weissenberg number [Formula: see text] is above unity), (ii) nonlinear viscoelasticity (where both [Formula: see text] and [Formula: see text] exceed unity), and (iii) linear viscoelasticity (where [Formula: see text] exceeds unity and where [Formula: see text] approaches zero). We learn that the polymer orientation distribution is spherical in the linear viscoelastic regime, and otherwise tilted and peanut-shaped. We find that the peanut-shaping is mainly caused by the zeroth harmonic, and the tilting, by the second. The first, third, and fourth harmonics of the orientation distribution make only slight contributions to the overall polymer motion.

Effect of tibial plateau levelling osteotomy on patellar tendon angle: a prospective clinical study.

OBJECTIVE: To evaluate the effect of the tibial plateau levelling osteotomy (TPLO) procedure on the patellar tendon angle (PTA) in dogs with naturally occurring cranial cruciate ligament rupture. STUDY DESIGN: Prospective observational clinical study. ANIMALS: Dogs with naturally occurring CrCL rupture that had a TPLO performed (n = 40). METHODS: Preoperative tibial plateau angle (TPA) and PTA were measured on radiographic images of affected stifle joints at 90° and standing angle (135°) respectively. The TPA and PTA were measured after TPLO was performed. Regression analysis was performed to evaluate the effect of preoperative TPA and PTA and postoperative TPA on postoperative PTA. Linear regression analysis was performed to evaluate the correlation between postoperative TPA and PTA. RESULTS: The mean (± SD) preoperative TPA and PTA were 26.5 ± 3.8° and 105.7 ± 3.8° respectively. The postoperative TPA and PTA values were 7.6 ± 3.3° and 91.4 ± 5.5°, respectively. Regression analysis showed that higher preoperative PTA and postoperative TPA are associated with a larger difference between the postoperative PTA and 90°. There was a positive correlation between postoperative TPA and PTA. CONCLUSION: The TPLO procedure alters the PTA to 90° in dogs with cranial cruciate ligament rupture similar to tibial tuberosity advancement (TTA). CLINICAL SIGNIFICANCE: The TPLO may provide dynamic stability to the cranial cruciate deficient stifle by altering the TPA relative to the patellar tendon and creating a PTA of 90°. The biomechanical principle and mechanism of action of TPLO may be similar to TTA.

Long-term effects of breast aging in patients undergoing explantation: analysis of breast aesthetics from before augmentation to after explantation.

PURPOSE: Although most patients with implants have an uneventful course, some will require explantation. Moreover, women's breasts and their perception of their body habitus change with time. This study covering greater than a 32-year period will address the reconstruction options available after breast implant explantation. METHODS: Augmentation mammoplasty was performed on 42 patients who subsequently underwent explantation. The following data were recorded: age at time of implantation and explantation, length of implant, type, reason for explantation, and decision after explantation. Recommendations were made based on patient preferences, degree of ptosis, clinical history, opinions regarding scars, and breast contour. Reconstruction options were categorized into none, mastopexy, capsulectomy and reaugmentation with saline implants, and mastopexy with immediate or delayed augmentation. RESULTS: The average age of patients at implantation was 32.3 years, 46.8 years at explantation, with a length of implantation of 14.4 years. Thirty-six (86%) of 42 patients received explantation for capsular contracture, 7 (17%) for negative publicity of silicone implants, 7 (17%) for change in body habitus and perception of implants, 6 (14%) for rupture, 5 (12%) for ptosis, and 1 (2.4%) each for synmastia, breast cancer, and painful implants. Sixteen (38%) patients underwent mastopexy after explantation, 15 (36%) underwent no reconstruction after explantation, 6 (14%) with mastopexy and reaugmentation (2 immediate and 4 delayed), 4 (9.5%) with implant exchange, and 1 (2.4%) with mastectomy and reconstruction. All patients demonstrated satisfactory to excellent results. CONCLUSIONS: This study provides long-term results of augmentation mammoplasty by a single surgeon (G.P.G.) evaluating available options and reasonable expectations after explantation. Although most of the augmentation patients have a good outcome, some require removal of implants for a variety of reasons and long-term satisfactory options do exist after explantation.

Mark-specific hazard ratio model with multivariate continuous marks: an application to vaccine efficacy.

In randomized placebo-controlled preventive HIV vaccine efficacy trials, an objective is to evaluate the relationship between vaccine efficacy to prevent infection and genetic distances of the exposing HIV strains to the multiple HIV sequences included in the vaccine construct, where the set of genetic distances is considered as the continuous multivariate "mark" observed in infected subjects only. This research develops a multivariate mark-specific hazard ratio model in the competing risks failure time analysis framework for the assessment of mark-specific vaccine efficacy. It allows improved efficiency of estimation by employing the semiparametric method of maximum profile likelihood estimation in the vaccine-to-placebo mark density ratio model. The model also enables the use of a more efficient estimation method for the overall log hazard ratio in the Cox model. In addition, we propose testing procedures to evaluate two relevant hypotheses concerning mark-specific vaccine efficacy. The asymptotic properties and finite-sample performance of the inferential procedures are investigated. Finally, we apply the proposed methods to data collected in the Thai RV144 HIV vaccine efficacy trial.

Low copper and high manganese levels in prion protein plaques.

Accumulation of aggregates rich in an abnormally folded form of the prion protein characterize the neurodegeneration caused by transmissible spongiform encephalopathies (TSEs). The molecular triggers of plaque formation and neurodegeneration remain unknown, but analyses of TSE-infected brain homogenates and preparations enriched for abnormal prion protein suggest that reduced levels of copper and increased levels of manganese are associated with disease. The objectives of this study were to: (1) assess copper and manganese levels in healthy and TSE-infected Syrian hamster brain homogenates; (2) determine if the distribution of these metals can be mapped in TSE-infected brain tissue using X-ray photoelectron emission microscopy (X-PEEM) with synchrotron radiation; and (3) use X-PEEM to assess the relative amounts of copper and manganese in prion plaques in situ. In agreement with studies of other TSEs and species, we found reduced brain levels of copper and increased levels of manganese associated with disease in our hamster model. We also found that the in situ levels of these metals in brainstem were sufficient to image by X-PEEM. Using immunolabeled prion plaques in directly adjacent tissue sections to identify regions to image by X-PEEM, we found a statistically significant relationship of copper-manganese dysregulation in prion plaques: copper was depleted whereas manganese was enriched. These data provide evidence for prion plaques altering local transition metal distribution in the TSE-infected central nervous system.

Detection of meniscal tears by arthroscopy and arthrotomy in dogs with cranial cruciate ligament rupture: a retrospective, cohort study.

OBJECTIVES: To evaluate and compare detection of meniscal tears associated with cranial cruciate ligament insufficiency by either arthroscopy or arthrotomy. METHODS: A retrospective, cohort study was completed with stifles (n = 531) of dogs with cranial cruciate ligament rupture. Either a medial parapatellar arthrotomy or an arthroscopy procedure was performed and groups were compared for significant differences in meniscal tears detected using logistic regression analysis. RESULTS: Arthroscopy was performed on 58.8% and arthrotomy on 41.2% of the stifles. In total, 44.4% of the examined stifles had meniscal tears. Meniscal tears were found in 38.8% of the stifles examined by arthrotomy, and 48.4% of those examined by arthroscopy. Overall, the rate of detection of a meniscal tear was significantly different (p = 0.019) between the groups, and meniscal tears were observed more frequently by arthroscopy than by arthrotomy (odds ratio 1.54; 95% confidence interval 1.07 - 2.22). CLINICAL SIGNIFICANCE: These results suggest that arthroscopy may be more sensitive than arthrotomy for detection of meniscal pathology in clinical patients. However, these results must be interpreted with caution since this was a retrospective study. Randomized prospective clinical studies are required to further test this hypothesis.

Fears of compassion and happiness in relation to alexithymia, mindfulness, and self-criticism.

BACKGROUND: There is increasing research to suggest that fears of, and resistances to, affiliative and positive emotions are linked to self-criticism and a range of psychopathologies. It is unclear how these fears and resistances are linked to each other and how these in turn are linked to psychological processes, such as abilities to be mindful and recognize and describe emotions. OBJECTIVES: This research explores the relationship between fears of compassion and happiness in general, with capacities for emotional processing (alexithymia), capacities for mindfulness, and empathic abilities. To advance this research, a new scale was developed to measure general fears of positive feelings - the Fear of Happiness Scale. RESULTS: The results showed that fears of compassion for self, from others and in particular fear of happiness, were highly linked to different aspects of alexithymia, mindfulness, empathy, self-criticism and depression, anxiety and stress. Especially noteworthy was the very high correlation between fear of happiness and depression (r= .70). CONCLUSION: While the development of positive emotions, especially those linked to affiliation and connectedness are increasingly seen as important therapeutic targets, little research has focused on the blocks and fears to positive emotions. This study used newly developed fears of positive affect scales (e.g., compassion and happiness) to explore these aspects and found they were significantly linked to psychopathology variables self-criticism and difficulties such as alexithymia.

Phase I safety and immunogenicity evaluations of an alphavirus replicon HIV-1 subtype C gag vaccine in healthy HIV-1-uninfected adults.

On the basis of positive preclinical data, we evaluated the safety and immunogenicity of an alphavirus replicon HIV-1 subtype C gag vaccine (AVX101), expressing a nonmyristoylated form of Gag, in two double-blind, randomized, placebo-controlled clinical trials in healthy HIV-1-uninfected adults. Escalating doses of AVX101 or placebo were administered subcutaneously to participants in the United States and Southern Africa. Because of vaccine stability issues, the first trial was halted prior to completion of all dose levels and a second trial was implemented. The second trial was also stopped prematurely due to documentation issues with the contract manufacturer. Safety and immunogenicity were evaluated through assessments of reactogenicity, reports of adverse events, and assessment of replication-competent and Venezuelan equine encephalitis (VEE) viremia. Immunogenicity was measured using the following assays: enzyme-linked immunosorbent assay (ELISA), chromium 51 ((51)Cr)-release cytotoxic T lymphocyte (CTL), gamma interferon (IFN-γ) ELISpot, intracellular cytokine staining (ICS), and lymphoproliferation assay (LPA). Anti-vector antibodies were also measured. AVX101 was well tolerated and exhibited only modest local reactogenicity. There were 5 serious adverse events reported during the trials; none were considered related to the study vaccine. In contrast to the preclinical data, immune responses in humans were limited. Only low levels of binding antibodies and T-cell responses were seen at the highest doses. This trial also highlighted the difficulties in developing a novel vector for HIV.