Epistemic injustice, healthcare disparities and the missing pipeline: reflections on the exclusion of disabled scholars from health research.

People with disabilities are subject to multiple forms of health-related and wider social disparities; carefully focused research is required to inform more inclusive, safe and effective healthcare practice and policy. Through lived experience, disabled people are well positioned to identify and persistently pursue problems and opportunities within existing health provisions that may be overlooked by a largely non-disabled research community. Thus, the academy can play an important role in shining a light on the perspectives and insights from within the disability community, and combined with policy decisions, these perspectives and insights have a better opportunity to become integrated into the fabric of public life, within healthcare and beyond. However, despite the potential benefits that could be yielded by greater inclusivity, in this paper we describe barriers within the UK academy confronting disabled people who wish to embark on health research. We do this by drawing on published findings, and via the lived experience of the first author, who has struggled for over 3 years to find an accessible PhD programme as a person with energy limiting conditions who is largely confined to the home in the UK. First, we situate the discussion in the wider perspective of epistemic injustice in health research. Second, we consider evidence of epistemic injustice among disabled researchers, focusing primarily on what philosophers Kidd and Carel (2017, p 184) describe as 'strategies of exclusion'. Third, we offer recommendations for overcoming these barriers to improve the pipeline of researchers with disabilities in the academy.

Facilitators and Barriers to Adherence to Anti-Retroviral Treatment Among Pregnant or Breastfeeding Women Living with HIV and Perinatally Infected Infants: A Scoping Review.

In 2022, 54% of 1.5 million children (age 0-14) living with HIV had access to anti-retroviral medication (ART). Adherence to ART for pregnant or breastfeeding HIV + women is critical for maintaining their personal health and to prevent mother-to-child-transmission (MTCT). For HIV + infants, adherence is essential to establish early viremic control and is contingent on caregiver administration. We conducted a scoping review to systematically identify and categorize the influences on ART adherence for pregnant or breastfeeding HIV + women and their HIV + infants. We searched databases in June 2023 and employed the Social-Ecological Model (SEM) to organize facilitators and barriers to adherence referenced in published articles. All articles published before 2016 were excluded due to updated guidelines from WHO on MTCT and ART. Our analysis included 52 articles. 50/52 took place in Africa and used cross-sectional and mixed-methods design. Barriers to adherence for pregnant or breastfeeding HIV + women included maternal education, self-efficacy, social support, and social/economic context. Barriers to infant adherence included development, nutrition, age of treatment initiation, disclosure, and ART side effects. Additional facilitators and barriers to adherence are presented at family, extra-familial, and socio-cultural SEM levels. Stigma was the most salient barrier referenced across the entire continuum of HIV care and all SEM levels. This review revealed a dearth of literature focusing on HIV + infants who are dependent on their caregivers for ART adherence and lack of a standard adherence measure. We identified multi-leveled influences on adherence impacting both the mother and infant and are amenable to public health intervention.

Bivalent mRNA COVID vaccines elicit predominantly cross-reactive CD4+ T cell clonotypes.

Bivalent COVID vaccines containing mRNA for ancestral and Omicron BA.5 spike proteins do not induce stronger T cell responses to Omicron BA.5 spike proteins than monovalent vaccines that contain only ancestral spike mRNA. The reasons for this finding have not been elucidated. Here, we show that healthy donors (HDs) and people living with HIV (PLWH) on antiretroviral therapy mostly target T cell epitopes that are not affected by BA.5 mutations. We use the functional expansion of specific T cells (FEST) assay to determine the percentage of CD4+ T cells that cross-recognize both spike proteins and those that are monoreactive for each protein. We show a predominance of cross-reactive CD4+ T cells; less than 10% percent of spike-specific CD4+ T cell receptors were BA.5 monoreactive in most HDs and PLWH. Our data suggest that the current bivalent vaccines do not induce robust BA.5-monoreactive T cell responses.

Longitudinal patterns in indeterminate HIV rapid antibody test results: a population-based, prospective cohort study.

Rapid HIV tests are critical to HIV surveillance and universal testing and treatment programs. We assessed longitudinal patterns in indeterminate HIV rapid test results in an African population-based cohort. Prospective HIV rapid antibody test results, defined by two parallel rapid tests, among participants aged 15-49 years from three survey rounds of the Rakai Community Cohort Study, Uganda, from 2013 to 2018, were assessed. An indeterminate result was defined as any weak positive result or when one test was negative and the other was positive. A total of 31,405 participants contributed 54,459 person-visits, with 15,713 participants contributing multiple visits and 7,351 participants contributing 3 visits. The prevalence of indeterminate results was 2.7% (1,490/54,469). Of the participants with multiple visits who initially tested indeterminate (n = 591), 40.4% were negative, 18.6% were positive, and 41.0% were indeterminate at the subsequent visit. Of the participants with two consecutive indeterminate results who had a third visit (n = 67), 20.9% were negative, 9.0% were positive, and 70.2% remained indeterminate. Compared to a prior negative result, a prior indeterminate result was strongly associated with a subsequent indeterminate result [adjusted prevalence ratio, 23.0 (95% CI = 20.0-26.5)]. Compared to men, women were more likely to test indeterminate than negative [adjusted odds ratio, 2.3 (95% CI = 2.0-2.6)]. Indeterminate rapid HIV test results are highly correlated within an individual and 0.6% of the population persistently tested indeterminate over the study period. A substantial fraction of people with an indeterminate result subsequently tested HIV positive at the next visit, underscoring the importance of follow-up HIV testing protocols.IMPORTANCERapid HIV tests are a critical tool for expanding HIV testing and treatment to end the HIV epidemic. The interpretation and management of indeterminate rapid HIV test results pose a unique challenge for connecting all people living with HIV to the necessary care and treatment. Indeterminate rapid HIV test results are characterized by any weak positive result or discordant results (when one test is negative and the other is positive). We systematically tested all participants of a Ugandan population-based, longitudinal cohort study regardless of prior test results or HIV status to quantify longitudinal patterns in rapid HIV test results. We found that a substantial fraction (>15%) of participants with indeterminate rapid test results subsequently tested positive upon follow-up testing at the next visit. Our findings demonstrate the importance of follow-up HIV testing protocols for indeterminate rapid HIV test results.

Compositional Variations between Adult and Infant Skin Microbiome: An Update.

Human skin and its commensal microbiome form the first layer of protection to the outside world. A dynamic microbial ecosystem of bacteria, fungi and viruses, with the potential to respond to external insult, the skin microbiome has been shown to evolve over the life course with an alteration in taxonomic composition responding to altered microenvironmental conditions on human skin. This work sought to investigate the taxonomic, diversity and functional differences between infant and adult leg skin microbiomes. A 16S rRNA gene-based metataxonomic analysis revealed significant differences between the infant and adult skin groups, highlighting differential microbiome profiles at both the genus and species level. Diversity analysis reveals differences in the overall community structure and associated differential predicted functional profiles between the infant and adult skin microbiome suggest differing metabolic processes are present between the groups. These data add to the available information on the dynamic nature of skin microbiome during the life course and highlight the predicted differential microbial metabolic process that exists on infant and adult skin, which may have an impact on the future design and use of cosmetic products that are produced to work in consort with the skin microbiome.

Making space for disability studies within a structurally competent medical curriculum: reflections on long Covid.

While critically informed approaches to medical education are increasingly advocated in literature, discussion of the potential role of disability studies in informing pedagogy and practice is largely lacking. The emergence of long Covid, alongside the strong possibility of a wave of covid-related disability, underlines an urgent need for medicine to develop more contextualised, nuanced and structurally competent understandings of chronic illness and disability. This article argues that the integration of thinking from disability studies into medical curricula offers a pathway to such understanding, informing a more equitable, holistic and patient-centred approach to practice. Further, a structurally competent, antiableist approach positions clinicians and patients as allies, working together within a structural context that constrains both parties. Such positioning may mitigate tensions within the clinical encounter, tensions that are well documented in the realm of marginalised chronic illness and disability. While the possibilities arising from a partnership between disability studies and medicine are numerous, the foci here are the social relational model of disability and the concept of psycho-emotional disablism, within a broader framework of critical disability studies. It is argued that inadequate healthcare provision and policy in the realm of long Covid can be understood as a form of structural and psycho-emotional disablism, arising from and reinforcing an ableist psychosocial imaginary permeated with neoliberal assumptions, and carrying a risk of furthering both disability and impairment. After considering long Covid through these particular lenses, the article concludes with a discussion of how a partnership between disability studies and a structurally competent approach to medical education might translate into practice.

Long Covid at the crossroads: Comparisons and lessons from the treatment of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Whilst parallels have been drawn between Long Covid and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), there is a well-documented history of negative stereotyping and marginalisation of patients with ME/CFS. A socio-politically oriented comparison of scientific, clinical and societal responses to Long Covid and ME/CFS is thus important to prevent similar harms arising among Long Covid patients. We identify four reasons for injustices in the treatment of ME/CFS patients, and discuss the risk of Long Covid following a similar trajectory. We conclude with policy and practice recommendations to help prevent such injustices arising again, including consideration of critical reflexivity in medical education.

Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis.

The microbiota comprises the microorganisms that live in close contact with the host, with mutual benefit for both counterparts. The contribution of the gut microbiota to the emergence of castration-resistant prostate cancer (CRPC) has not yet been addressed. We found that androgen deprivation in mice and humans promotes the expansion of defined commensal microbiota that contributes to the onset of castration resistance in mice. Specifically, the intestinal microbial community in mice and patients with CRPC was enriched for species capable of converting androgen precursors into active androgens. Ablation of the gut microbiota by antibiotic therapy delayed the emergence of castration resistance even in immunodeficient mice. Fecal microbiota transplantation (FMT) from CRPC mice and patients rendered mice harboring prostate cancer resistant to castration. In contrast, tumor growth was controlled by FMT from hormone-sensitive prostate cancer patients and Prevotella stercorea administration. These results reveal that the commensal gut microbiota contributes to endocrine resistance in CRPC by providing an alternative source of androgens.

Overexpression of zmm28 increases maize grain yield in the field.

Increasing maize grain yield has been a major focus of both plant breeding and genetic engineering to meet the global demand for food, feed, and industrial uses. We report that increasing and extending expression of a maize MADS-box transcription factor gene, zmm28, under the control of a moderate-constitutive maize promoter, results in maize plants with increased plant growth, photosynthesis capacity, and nitrogen utilization. Molecular and biochemical characterization of zmm28 transgenic plants demonstrated that their enhanced agronomic traits are associated with elevated plant carbon assimilation, nitrogen utilization, and plant growth. Overall, these positive attributes are associated with a significant increase in grain yield relative to wild-type controls that is consistent across years, environments, and elite germplasm backgrounds.

Acute interaction between oral glucose (75 g as Lucozade) and inorganic nitrate: Decreased insulin clearance, but lack of blood pressure-lowering.

AIMS: Dietary inorganic nitrate (NO3- ) lowers peripheral blood pressure (BP) in healthy volunteers, but lacks such effect in individuals with, or at risk of, type 2 diabetes mellitus (T2DM). Whilst this is commonly assumed to be a consequence of chronic hyperglycaemia/hyperinsulinaemia, we hypothesized that acute physiological elevations in plasma [glucose]/[insulin] blunt the haemodynamic responses to NO3- , a pertinent question for carbohydrate-rich Western diets. METHODS: We conducted an acute, randomized, placebo-controlled, double-blind, crossover study on the haemodynamic and metabolic effects of potassium nitrate (8 or 24 mmol KNO3 ) vs. potassium chloride (KCl; placebo) administered 1 hour prior to an oral glucose tolerance test in 33 healthy volunteers. RESULTS: Compared to placebo, there were no significant differences in systolic or diastolic BP (P = 0.27 and P = 0.30 on ANOVA, respectively) with KNO3 , nor in pulse wave velocity or central systolic BP (P = 0.99 and P = 0.54 on ANOVA, respectively). Whilst there were significant elevations from baseline for plasma [glucose] and [C-peptide], no differences between interventions were observed. A significant increase in plasma [insulin] was observed with KNO3 vs. KCl (n = 33; P = 0.014 on ANOVA) with the effect driven by the high-dose cohort (24 mmol, n = 13; P < 0.001 on ANOVA; at T = 0.75 h mean difference 210.4 pmol/L (95% CI 28.5 to 392.3), P = 0.012). CONCLUSIONS: In healthy adults, acute physiological elevations of plasma [glucose] and [insulin] result in a lack of BP-lowering with dietary nitrate. The increase in plasma [insulin] without a corresponding change in [C-peptide] or [glucose] suggests that high-dose NO3- decreases insulin clearance. A likely mechanism is via NO-dependent inhibition of insulin-degrading enzyme.

Single-Cell Analyses of Prostate Cancer Liquid Biopsies Acquired by Apheresis.

Purpose: Circulating tumor cells (CTCs) have clinical relevance, but their study has been limited by their low frequency.Experimental Design: We evaluated liquid biopsies by apheresis to increase CTC yield from patients suffering from metastatic prostate cancer, allow precise gene copy-number calls, and study disease heterogeneity.Results: Apheresis was well tolerated and allowed the separation of large numbers of CTCs; the average CTC yield from 7.5 mL of peripheral blood was 167 CTCs, whereas the average CTC yield per apheresis (mean volume: 59.5 mL) was 12,546 CTCs. Purified single CTCs could be isolated from apheresis product by FACS sorting; copy-number aberration (CNA) profiles of 185 single CTCs from 14 patients revealed the genomic landscape of lethal prostate cancer and identified complex intrapatient, intercell, genomic heterogeneity missed on bulk biopsy analyses.Conclusions: Apheresis facilitated the capture of large numbers of CTCs noninvasively with minimal morbidity and allowed the deconvolution of intrapatient heterogeneity and clonal evolution. Clin Cancer Res; 24(22); 5635-44. ©2018 AACR.

SPOP-Mutated/CHD1-Deleted Lethal Prostate Cancer and Abiraterone Sensitivity.

Purpose: CHD1 deletions and SPOP mutations frequently cooccur in prostate cancer with lower frequencies reported in castration-resistant prostate cancer (CRPC). We monitored CHD1 expression during disease progression and assessed the molecular and clinical characteristics of CHD1-deleted/SPOP-mutated metastatic CRPC (mCRPC).Experimental Design: We identified 89 patients with mCRPC who had hormone-naive and castration-resistant tumor samples available: These were analyzed for CHD1, PTEN, and ERG expression by IHC. SPOP status was determined by targeted next-generation sequencing (NGS). We studied the correlations between these biomarkers and (i) overall survival from diagnosis; (ii) overall survival from CRPC; (iii) duration of abiraterone treatment; and (iv) response to abiraterone. Relationship with outcome was analyzed using Cox regression and log-rank analyses.Results: CHD1 protein loss was detected in 11 (15%) and 13 (17%) of hormone-sensitive prostate cancer (HSPC) and CRPC biopsies, respectively. Comparison of CHD1 expression was feasible in 56 matched, same patient HSPC and CRPC biopsies. CHD1 protein status in HSPC and CRPC correlated in 55 of 56 cases (98%). We identified 22 patients with somatic SPOP mutations, with six of these mutations not reported previously in prostate cancer. SPOP mutations and/or CHD1 loss was associated with a higher response rate to abiraterone (SPOP: OR, 14.50 P = 0.001; CHD1: OR, 7.30, P = 0.08) and a longer time on abiraterone (SPOP: HR, 0.37, P = 0.002, CHD1: HR, 0.50, P = 0.06).Conclusions: SPOP-mutated mCRPCs are strongly enriched for CHD1 loss. These tumors appear highly sensitive to abiraterone treatment. Clin Cancer Res; 24(22); 5585-93. ©2018 AACR.

Manualization of Occupational Therapy Using Ayres Sensory Integration® for Autism.

This article reports on the development of a Stage 3 manual (following pilot effectiveness study) for implementing occupational therapy using Ayres Sensory Integration® (OT/ASI) for children with autism spectrum disorders to enhance participation in daily occupations. Three stakeholder groups were surveyed to aid in translation of manual from research to practice (i.e., Stage 3 manual) and an expert consensus meeting was held to finalize recommendations. Data indicated that the manuals usability could be improved by including a section on frequently encountered problems and solutions, and by including video case examples. Also recommended were greater chapter uniformity, improved clarity of forms and charts, and inclusion of a glossary. Changes were made and subject to expert review and consensus using modified Delphi process. The Stage 3 manual has been rigorously vetted and is ready for practice and research replication.

An Improved Variant of Soybean Type 1 Diacylglycerol Acyltransferase Increases the Oil Content and Decreases the Soluble Carbohydrate Content of Soybeans.

Kinetically improved diacylglycerol acyltransferase (DGAT) variants were created to favorably alter carbon partitioning in soybean (Glycine max) seeds. Initially, variants of a type 1 DGAT from a high-oil, high-oleic acid plant seed, Corylus americana, were screened for high oil content in Saccharomyces cerevisiae Nearly all DGAT variants examined from high-oil strains had increased affinity for oleoyl-CoA, with S0.5 values decreased as much as 4.7-fold compared with the wild-type value of 0.94 µm Improved soybean DGAT variants were then designed to include amino acid substitutions observed in promising C. americana DGAT variants. The expression of soybean and C. americana DGAT variants in soybean somatic embryos resulted in oil contents as high as 10% and 12%, respectively, compared with only 5% and 7.6% oil achieved by overexpressing the corresponding wild-type DGATs. The affinity for oleoyl-CoA correlated strongly with oil content. The soybean DGAT variant that gave the greatest oil increase contained 14 amino acid substitutions out of a total of 504 (97% sequence identity with native). Seed-preferred expression of this soybean DGAT1 variant increased oil content of soybean seeds by an average of 3% (16% relative increase) in highly replicated, single-location field trials. The DGAT transgenes significantly reduced the soluble carbohydrate content of mature seeds and increased the seed protein content of some events. This study demonstrated that engineering of the native DGAT enzyme is an effective strategy to improve the oil content and value of soybeans.

Application of Data-Driven Decision Making Using Ayres Sensory Integration(®) With a Child With Autism.

Health care and educational legislation and policy require that clinicians demonstrate, using measurement and report of outcomes, accountability for services rendered. Clinical algorithms have been developed and are used by various health care professionals to assist with hypothesis generation and systematic clinical reasoning; however, they do not explicitly guide measurement of outcomes as part of the reasoning process. Schaaf and colleagues developed the Data-Driven Decision Making (DDDM) process to address the greater need for outcome measurement, systematically support decision making, target intervention more precisely, and measure and document outcomes. This article describes the application of the DDDM process with a child with ASD who received occupational therapy using Ayres Sensory Integration(®).

Paradoxical normoxia-dependent selective actions of inorganic nitrite in human muscular conduit arteries and related selective actions on central blood pressures.

BACKGROUND: Inorganic nitrite dilates small resistance arterioles via hypoxia-facilitated reduction to vasodilating nitric oxide. The effects of nitrite in human conduit arteries have not been investigated. In contrast to nitrite, organic nitrates are established selective dilators of conduit arteries. METHODS AND RESULTS: We examined the effects of local and systemic administration of sodium nitrite on the radial artery (a muscular conduit artery), forearm resistance vessels (forearm blood flow), and systemic hemodynamics in healthy male volunteers (n=43). Intrabrachial sodium nitrite (8.7 µmol/min) increased radial artery diameter by a median of 28.0% (25th and 75th percentiles, 25.7% and 40.1%; P<0.001). Nitrite (0.087-87 µmol/min) displayed conduit artery selectivity similar to that of glyceryl trinitrate (0.013-4.4 nmol/min) over resistance arterioles. Nitrite dose-dependently increased local cGMP production at the dose of 2.6 µmol/min by 1.1 pmol·min(-1)·100 mL(-1) tissue (95% confidence interval, 0.5-1.8). Nitrite-induced radial artery dilation was enhanced by administration of acetazolamide (oral or intra-arterial) and oral raloxifene (P=0.0248, P<0.0001, and P=0.0006, respectively) but was inhibited under hypoxia (P<0.0001) and hyperoxia (P=0.0006) compared with normoxia. Systemic intravenous administration of sodium nitrite (8.7 µmol/min) dilated the radial artery by 10.7% (95% confidence interval, 6.8-14.7) and reduced central systolic blood pressure by 11.6 mm Hg (95% confidence interval, 2.4-20.7), augmentation index, and pulse wave velocity without changing peripheral blood pressure. CONCLUSIONS: Nitrite selectively dilates conduit arteries at supraphysiological and near-physiological concentrations via a normoxia-dependent mechanism that is associated with cGMP production and is enhanced by acetazolamide and raloxifene. The selective central blood pressure-lowering effects of nitrite have therapeutic potential to reduce cardiovascular events.

Arterial injury and endothelial repair: rapid recovery of function after mechanical injury in healthy volunteers.

Objective. Previous studies suggest a protracted course of recovery after mechanical endothelial injury; confounders may include degree of injury and concomitant endothelial dysfunction. We sought to define the time course of endothelial function recovery using flow-mediated dilation (FMD), after ischaemia-reperfusion (IR) and mechanical injury in patients and healthy volunteers. The contribution of circulating CD133(+)/CD34(+)/VEGFR2(+) "endothelial progenitor" (EPC) or repair cells to endothelial repair was also examined. Methods. 28 healthy volunteers aged 18-35 years underwent transient forearm ischaemia induced by cuff inflation around the proximal biceps and radial artery mechanical injury induced by inserting a wire through a cannula. A more severe mechanical injury was induced using an arterial sheath and catheter inserted into the radial artery of 18 patients undergoing angiography. Results. IR and mechanical injury produced immediate impairment of FMD (from 6.5 ± 1.2% to 2.9 ± 2.2% and from 7.4 ± 2.3% to 1.5 ± 1.6% for IR and injury, resp., each P < 0.001) but recovered within 6 hours and 2 days, respectively. FMD took up to 4 months to recover in patients. Circulating EPC did not change significantly during the injury/recovery period in all subjects. Conclusions. Recovery of endothelial function after IR and mechanical injury is rapid and not associated with a change in circulating EPC.

An intervention for sensory difficulties in children with autism: a randomized trial.

This study evaluated a manualized intervention for sensory difficulties for children with autism, ages 4-8 years, using a randomized trial design. Diagnosis of autism was confirmed using gold standard measures. Results show that the children in the treatment group (n = 17) who received 30 sessions of the occupational therapy intervention scored significantly higher (p = 0.003, d = 1.2) on Goal Attainment Scales (primary outcome), and also scored significantly better on measures of caregiver assistance in self-care (p = 0.008 d = 0.9) and socialization (p = 0.04, d = 0.7) than the Usual Care control group (n = 15). The study shows high rigor in its measurement of treatment fidelity and use of a manualized protocol, and provides support for the use of this intervention for children with autism. Findings are discussed in terms of their implications for practice and future research.

Endothelial function does not relate to haemoglobin or serum erythropoietin concentrations and these do not explain the gender difference in endothelial function in healthy middle-aged men and women.

BACKGROUND: Haemoglobin scavenges nitric oxide, and a previous study has shown a negative association between flow-mediated vasodilation (FMD), a measure of nitric oxide (NO)-dependent vasomotor function and haemoglobin concentrations [Hb]. Circulating erythropoietin (EPO) is also negatively associated with [Hb] and could influence availability of NO. The purpose of this study was to examine the association of FMD with [Hb] and EPO concentrations and to determine whether these contribute to the sex difference in FMD. FMD (by high-resolution ultrasound), [Hb], circulating immunoreactive EPO and cardiovascular risk factors were measured in 317 healthy middle-aged men and women (183 women, 33 premenopausal, mean age ± SD, 55 ± 6·8 years) participating in a dietary study. RESULTS: In the whole mixed-sex group, FMD was negatively correlated with [Hb] (R = -0·23, P < 0·001). However, in a multivariable model, incorporating sex and other confounding factors, FMD was independently negatively correlated only with age, male sex and systolic blood pressure: standardized regression coefficients -0·21 (P < 0·01), -0·17 (P < 0·05) and -0·20 (P < 0·05) respectively and not with [Hb]. Similarly, when the analysis was restricted to men or to postmenopausal women, there was no significant relationship between FMD and Hb. There was no significant correlation between FMD and EPO on either univariate analysis in the whole group, in each sex, or in multivariate analysis. CONCLUSION: These results suggest that in healthy middle-aged subjects, FMD is not influenced by [Hb] or EPO and these do not contribute to the gender difference in FMD.