Ethnic disparities in mortality and group-specific risk factors in the UK Biobank.

Despite a substantial overall decrease in mortality, disparities among ethnic minorities in developed countries persist. This study investigated mortality disparities and their associated risk factors for the three largest ethnic groups in the United Kingdom: Asian, Black, and White. Study participants were sampled from the UK Biobank (UKB), a prospective cohort enrolled between 2006 and 2010. Genetics, biological samples, and health information and outcomes data of UKB participants were downloaded and data-fields were prioritized based on participants with death registry records. Kaplan-Meier method was used to evaluate survival differences among ethnic groups; survival random forest feature selection followed by Cox proportional-hazard modeling was used to identify and estimate the effects of shared and ethnic group-specific mortality risk factors. The White ethnic group showed significantly worse survival probability than the Asian and Black groups. In all three ethnic groups, endoscopy and colonoscopy procedures showed significant protective effects on overall mortality. Asian and Black women show lower relative risk of mortality than men, whereas no significant effect of sex was seen for the White group. The strongest ethnic group-specific mortality associations were ischemic heart disease for Asians, COVID-19 for Blacks, and cancers of respiratory/intrathoracic organs for Whites. Mental health-related diagnoses, including substance abuse, anxiety, and depression, were a major risk factor for overall mortality in the Asian group. The effect of mental health on Asian mortality, particularly for digestive cancers, was exacerbated by an observed hesitance to answer mental health questions, possibly related to cultural stigma. C-reactive protein (CRP) serum levels were associated with both overall and cause-specific mortality due to COVID-19 and digestive cancers in the Black group, where elevated CRP has previously been linked to psychosocial stress due to discrimination. Our results point to mortality risk factors that are group-specific and modifiable, supporting targeted interventions towards greater health equity.

Association of Genetic Ancestry and Molecular Signatures with Cancer Survival Disparities: A Pan-Cancer Analysis.

While overall cancer mortality has steadily decreased in recent decades, cancer health disparities among racial and ethnic population groups persist. Here we studied the relationship between cancer survival disparities (CSD), genetic ancestry (GA), and tumor molecular signatures across 33 cancers in a cohort of 9,818 patients. GA correlated with race and ethnicity but showed observable differences in effects on CSD, with significant associations identified in four cancer types: breast invasive carcinoma (BRCA), head and neck squamous cell carcinoma (HNSCC), kidney renal clear cell carcinoma (KIRC), and skin cutaneous carcinoma (SKCM). Differential gene expression and methylation between ancestry groups associated cancer-related genes with CSD, of which, seven protein-coding genes [progestin and adipoQ receptor family member 6 (PAQR6), Lck-interacting transmembrane adaptor 1 (LIME1), Sin3A-associated protein 25 (SAP25), MAX dimerization protein 3 (MXD3), coiled-coil glutamate rich protein 2 (CCER2), refilin A (RFLNA), and cathepsin W (CTSW)] significantly interacted with GA and exacerbated observed survival disparities. These findings indicated that regulatory changes mediated by epigenetic mechanisms have a greater contribution to CSD than population-specific mutations. Overall, we uncovered various molecular mechanisms through which GA might impact CSD, revealing potential population-specific therapeutic targets for groups disproportionately burdened by cancer. SIGNIFICANCE: This large-cohort, multicancer study identifies four cancer types with cancer survival disparities and seven cancer-related genes that interact with genetic ancestry and contribute to disparities.

Vitamin D and socioeconomic deprivation mediate COVID-19 ethnic health disparities.

Ethnic minorities in developed countries suffer a disproportionately high burden of COVID-19 morbidity and mortality, and COVID-19 ethnic disparities have been attributed to social determinants of health. Vitamin D has been proposed as a modifiable risk factor that could mitigate COVID-19 health disparities. We investigated the relationship between vitamin D and COVID-19 susceptibility and severity using the UK Biobank, a large progressive cohort study of the United Kingdom population. Structural equation modelling was used to evaluate the ability of vitamin D, socioeconomic deprivation, and other known risk factors to mediate COVID-19 ethnic health disparities. Asian ethnicity is associated with higher COVID-19 susceptibility, compared to the majority White population, and Asian and Black ethnicity are both associated with higher COVID-19 severity. Socioeconomic deprivation mediates all three ethnic disparities and shows the highest overall signal of mediation for any COVID-19 risk factor. Vitamin supplements, including vitamin D, mediate the Asian disparity in COVID-19 susceptibility, and serum 25-hydroxyvitamin D (calcifediol) levels mediate Asian and Black COVID-19 severity disparities. Several measures of overall health also mediate COVID-19 ethnic disparities, underscoring the importance of comorbidities. Our results support ethnic minorities' use of vitamin D as both a prophylactic and a supplemental therapeutic for COVID-19.

Optimizing drug inventory management with a web-based information system: The TBTC Study 31/ACTG A5349 experience.

INTRODUCTION: Efficient management of study drug inventory shipments is critical to keep research sites enrolling into multisite clinical treatment trials. A standard manual drug-management process used by the Tuberculosis Trials Consortium (TBTC), did not accommodate import permit approval timelines, shipment transit-times and time-zone differences. We compared a new web-based solution with the manual process, during an international 34-site clinical trial conducted by the TBTC and the AIDS Clinical Trials Group (ACTG); TBTC Study 31/ACTG A5349. MATERIAL AND METHODS: We developed and implemented a technological solution by integrating logistical and regulatory requirements for drug importation with statistical simulations that estimated stock-out times in an online Drug Management Module (DMM). We measured the average shipment-related drug stock-outs and time to drug availability, to assess the efficiency of the DMM compared to the manual approach. RESULTS: An Interrupted Time-Series (ITS) analysis showed a 15.4% [p-value = 0.03; 95% C.I. (-28.8%, -2.0%)] reduction in average shipment-related study drug stock-out after DMM implementation. The DMM streamlined the restocking process at study sites, reducing median transit-time for sites associated with a depot by 2 days [95% C.I. (-3.0, -1.0)]. Under the DMM, study drugs were available for treatment assignment on the day received, compared to one day after receipt under the manual process. DISCUSSION: The DMM provided TBTC's Data and Coordinating Center and site staff with more efficient procedures to manage and consistently maintain study drug inventory at enrolling sites. This DMM framework can improve efficiency in future multicenter clinical trials. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (Identifier: NCT02410772) on April 8, 2015.

Histomorphological and biochemical properties of plantar soft tissue in diabetes.

BACKGROUND: Diabetes results in pathophysiological changes, leading to tissue that is unable to withstand and adapt to the same loads, resulting in breakdown. Certain locations are more susceptible to breakdown, yet differences between locations are largely not well understood. The authors performed a histological and biochemical analysis of isolated plantar adipose tissue at six relevant locations. METHODS: Tissue from six plantar locations (hallux, first, third and fifth metatarsal heads, lateral midfoot and calcaneus) was taken from fresh cadaveric feet of older diabetic and older non-diabetic intact donors. Histomorphological and biochemical analysis of isolated plantar tissue from both diabetic and non-diabetic feet at six relevant locations was performed. RESULTS: The main differences found between diabetic and non-diabetic tissue were in the thickness of the septal walls and the elastin content. Diabetic tissue had significantly thicker septal walls and an increased elastin concentration. When comparing the calcaneus to other locations, although there were no differences found in the thickness of the septal walls of diabetic tissue, elastin content was lower in the calcaneous tissue compared to the non-calcaneus sites. CONCLUSIONS: Modifications in the structural and biochemical properties could translate to changes in the mechanical properties. This information could lead to an understanding of how the structural and biochemical changes result in an increase in susceptibility of tissue to breakdown with load at the different locations of the foot.

Non-invasive brain stimulation and robot-assisted gait training after incomplete spinal cord injury: A randomized pilot study.

BACKGROUND: Locomotor training with a robot-assisted gait orthosis (LT-RGO) and transcranial direct current stimulation (tDCS) are interventions that can significantly enhance motor performance after spinal cord injury (SCI). No studies have investigated whether combining these interventions enhances lower extremity motor function following SCI. OBJECTIVE: Determine whether active tDCS paired with LT-RGO improves lower extremity motor function more than a sham condition, in subjects with motor incomplete SCI. METHODS: Fifteen adults with SCI received 36 sessions of either active (n = 9) or sham (n = 6) tDCS (20 minutes) preceding LT-RGO (1 hour). Outcome measures included manual muscle testing (MMT; primary outcome measure); 6-Minute Walk Test (6MinWT); 10-Meter Walk Test (10MWT); Timed Up and Go Test (TUG); Berg Balance Scale (BBS); and Spinal Cord Independence Measure-III (SCIM-III). RESULTS: MMT showed significant improvements after active tDCS, with the most pronounced improvement in the right lower extremity. 10MWT, 6MinWT, and BBS showed improvement for both groups. TUG and SCIM-III showed improvement only for the sham tDCS group. CONCLUSION: Pairing tDCS with LT-RGO can improve lower extremity motor function more than LT-RGO alone. Future research with a larger sample size is recommended to determine longer-term effects on motor function and activities of daily living.

Brain stimulation paired with novel locomotor training with robotic gait orthosis in chronic stroke: a feasibility study.

OBJECTIVES: 1) To investigate the feasibility of combining transcranial direct current stimulation (tDCS) to the lower extremity (LE) motor cortex with novel locomotor training to facilitate gait in subjects with chronic stroke and low ambulatory status, and 2) to obtain insight from study subjects and their caregivers to inform future trial design. METHODS: Double-blind, randomized controlled study with additional qualitative exploratory descriptive design. One-month follow-up.10 subjects with stroke were recruited and randomized to active tDCS or sham tDCS for 12 sessions. Both groups participated in identical locomotor training with a robotic gait orthosis (RGO) following each tDCS session. RGO training protocol was designed to harness cortical neuroplasticity. Data analysis included assessment of functional and participation outcome measures and qualitative thematic analysis. RESULTS: Eight subjects completed the study. Both groups demonstrated trends toward improvement, but the active tDCS group showed greater improvement than the sham group. Qualitative analyses indicated beneficial effects of this combined intervention. CONCLUSIONS: It is feasible to combine tDCS targeting the LE motor cortex with our novel locomotor training. It appears that tDCS has the potential to enhance the effectiveness of gait training in chronic stroke. Insights from participants provide additional guidance in designing future trials.

Histomorphological evaluation of diabetic and non-diabetic plantar soft tissue.

BACKGROUND: Diabetic foot ulceration has a complex and multifactorial etiology and can involve changes in the pathophysiology of the plantar soft tissue. In the current study, histomorphological analyses of diabetic and non-diabetic plantar tissue were performed. It was hypothesized that the diabetic tissue would have thicker skin (epidermis and dermis), less interdigitation between the dermis and epidermis, thicker elastic septa and decreased adipose cell size. MATERIALS AND METHODS: Two locations of the foot (the heel and the first metatarsal) were examined, both of which have been reported to be locations with a high incidence of ulceration. Stereological methods and quantitative morphological techniques were used to evaluate the skin thickness, interdigitation index, elastic septae thickness and adipocyte cell size. RESULTS: The diabetic donors had a greater body mass index (BMI) than the non-diabetic donors. The diabetic tissue had significantly thicker elastic septae and dermis. However, no significant difference was observed in the interdigitation index or adipocyte size. CONCLUSION: These findings demonstrate that morphological changes can be evaluated histologically to give a better understanding of the pathological changes in the plantar soft tissue with diabetes. These evaluations can then be associated with biomechanical changes that occur in diabetes to provide new insight into how microstructural changes can alter macroscopic properties. CLINICAL RELEVANCE: An understanding of the histomorphological changes in the soft tissue in relationship to the location on the foot could help to explain the biomechanical changes that occur in diabetes and the subsequent increase in susceptibility to breakdown.

Crustacean hyperglycemic hormone from the tropical land crab, Gecarcinus lateralis: cloning, isoforms, and tissue expression.

Crustacean hyperglycemic hormone (CHH) regulates carbohydrate metabolism, molting, and ion and water transport. cDNAs encoding four CHH isoforms (designated EG-CHH-A, -B, -C, and -D) were cloned from eyestalk ganglia (EG) from land crab, Gecarcinus lateralis. The isoforms differed in the 3' region of the open reading frame and/or the length of the 3' untranslated region. All encoded essentially identical preprohormones containing a 28-amino acid (aa) signal peptide, a 42-aa precursor related peptide and a 72-aa mature CHH. All deduced aa sequences had the six cysteines, two arginines, one aspartate, one phenylalanine, and one arginine originally identified as characteristic of this neuropeptide family. There was a single aa difference between the EG-CHH-D mature hormone and the other three isoforms. The EG-CHH isoforms were expressed in EG, hindgut, and thoracic ganglion. A fifth CHH isoform, designated pericardial organ (PO)-CHH, was similar to the PO-CHH isoform described in green crab, Carcinus maenas. It was expressed in hindgut and testis, but not in eyestalk ganglia; its expression in PO was not determined. The deduced aa sequence of the PO-CHH was identical to that of the EG-CHH isoforms through aa #40 of the mature peptide. The divergent aa sequence between positions #41 and #73 was encoded by an insertion of a 111-bp sequence absent in EG-CHH cDNAs. The data suggest that EG-CHH and PO-CHH isoforms are generated by alternative splicing of at least two CHH genes.

Molt-inhibiting hormone from the tropical land crab, Gecarcinus lateralis: cloning, tissue expression, and expression of biologically active recombinant peptide in yeast.

Molt-inhibiting hormone (MIH), a member of the crustacean hyperglycemic neuropeptide hormone family, inhibits ecdysteroidogenesis in the molting gland or Y-organ (YO). A cDNA encoding MIH of the land crab (Gel-MIH) was cloned from eyestalk ganglia (EG) by a combination of reverse transcriptase polymerase chain reaction (RT-PCR) and 3'- and 5'-rapid amplification of cDNA ends (RACE). The cDNA (1.4 kb) encoded MIH prohormone containing a 35 amino acid signal peptide and a 78 amino acid mature peptide. The mature peptide had the six cysteines, one glycine, two arginines, one aspartate, one phenylalanine, and one asparagine in identical positions in the highly conserved sequence characteristic of other crustacean MIHs. Gel-MIH was expressed only in the EG, as determined by RT-PCR; it was not detected in Y-organ, heart, integument, gill, testis, ovary, hepatopancreas, thoracic ganglion, or skeletal muscle. A cDNA encoding the mature peptide was used to express recombinant MIH (rMIH) using a yeast (Pichia pastoris) expression system. Two constructs were designed to yield either a mature MIH fusion protein with a c-myc epitope and histidine (His) tag at the carboxyl terminus or an untagged mature protein without the c-myc and His sequences. Immunoreactive peptides were detected in Western blots of the cell culture media with both MIH constructs, indicating secretion of the processed rMIH into the medium. Culture media containing the untagged mature peptide significantly inhibited ecdysteroid secretion by YOs from land crab and green crab (Carcinus maenas) cultured in vitro, indicating that the Gel-rMIH was biologically active.

A crustacean nitric oxide synthase expressed in nerve ganglia, Y-organ, gill and gonad of the tropical land crab, Gecarcinus lateralis.

NO signaling is involved in many physiological processes in invertebrates. In crustaceans, it plays a role in the regulation of the nervous system and muscle contraction. Nested reverse transcription-polymerase chain reaction (RT-PCR) and 5' and 3' rapid amplification of cDNA ends (RACE) PCR generated a full-length cDNA sequence (3982 bp) of land crab NO synthase (Gl-NOS) from molting gland (Y-organ) and thoracic ganglion mRNA. The open reading frame encoded a protein of 1199 amino acids with an estimated mass of 135 624 Da. Gl-NOS had the highest sequence identity with insect NOS. The amino acid sequences for binding heme and tetrahydrobiopterin in the oxygenase domain, binding calmodulin and binding FMN, FAD and NADPH in the reductase domain were highly conserved. Gl-NOS had single amino acid differences in all three highly conserved FAD-binding sequences, which distinguished it from other NOS sequences. RT-PCR showed that the Gl-NOS mRNA was present in testis, ovary, gill, eyestalk neural ganglia, thoracic ganglion and Y-organ. NOS mRNA varied between preparations of Y-organ, thoracic ganglion and gill, while NOS mRNA was at consistently high levels in the ovary, testis and eyestalk ganglia. Immunohistochemistry confirmed that the Gl-NOS protein was expressed in Y-organ, ovary and gill. These results suggest that NOS has functions in addition to neuromodulation in adults, such as regulating or modulating ecdysteroid synthesis in the Y-organ.

Classifying children with heavy prenatal alcohol exposure using measures of attention.

Deficits in attention are a hallmark of the effects of heavy prenatal alcohol exposure but although such deficits have been described in the literature, no attempt to use measures of attention to classify children with such exposure has been described. Thus, the current study attempted to classify children with heavy prenatal alcohol exposure (ALC) and non-exposed controls (CON), using four measures of attentional functioning: the Freedom from Distractibility index from the Wechsler Intelligence Scale for Children-Third Edition (WISC-III), the Attention Problems scale from the Child Behavior Checklist (CBCL), and omission and commission error scores from the Test of Variables of Attention (TOVA). Data from two groups of children were analyzed: children with heavy prenatal alcohol exposure and non-exposed controls. Children in the alcohol-exposed group included both children with or without fetal alcohol syndrome. Groups were matched on age, sex, ethnicity, and social class. Data were analyzed using backward logistic regression. The final model included the Freedom from Distractibility index from the WISC-III and the Attention Problems scale from the CBCL. The TOVA variables were not retained in the final model. Classification accuracy was 91.7% overall. Specifically, 93.3% of the alcohol-exposed children and 90% of the control children were accurately classified. These data indicate that children with heavy prenatal alcohol exposure can be distinguished from non-exposed controls with a high degree of accuracy using 2 commonly used measures of attention.

Antipeptide antibodies for detecting crab (Callinectes sapidus) molt-inhibiting hormone.

In crustaceans, the synthesis of ecdysteroid molting hormones is regulated by molt-inhibiting hormone (MIH), a neuropeptide produced by an eyestalk neuroendocrine system, the X-organ/sinus gland complex. Using sequence analysis software, two regions of the blue crab (Callinectes sapidus) MIH peptide were selected for antibody production. Two 14-mer peptides were commercially synthesized and used to generate polyclonal antisera. Western blot analysis revealed that each antiserum bound to proteins of the predicted size in extracts of C. sapidus sinus glands, and lysates of insect cells containing recombinant MIH. Thin section immunocytochemistry using either antiserum showed specific immunoreactivity in X-organ neurosecretory cell bodies, their associated axons and collaterals, and their axon terminals in the sinus gland.

Expression of crustacean (Callinectes sapidus) molt-inhibiting hormone in insect cells using recombinant baculovirus.

Molt-inhibiting hormone (MIH) negatively regulates the synthesis of ecdysteroid molting hormones by crustacean Y-organs. We report here the expression of blue crab (Callinectes sapidus) MIH in insect cells using recombinant baculovirus. Insect Sf9 cells were transfected with recombinant baculovirus containing a DNA insert encoding the C. sapidus MIH prohormone (signal sequence plus mature hormone). The construct was designed to yield a mature, fully processed recombinant MIH (recMIH). Several baculovirus recombinants showing no contamination with wild-type viral DNA were subsequently analyzed for their ability to direct expression of recMIH. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of proteins from infected cells revealed time-dependent expression of two proteins of approximately the predicted size for the C. sapidus MIH prohormone and mature hormone. Western blot results (using antiserum against MIH of Carcinus maenas) indicated that the proteins were MIH-immunoreactive. N-Terminal amino acid sequence data and mass spectral analysis indicated the expressed proteins were of the correct sequence and molecular mass. Cell lysates containing the recombinant protein dose-dependently suppressed the synthesis of ecdysteroids by Y-organs in vitro. We anticipate the recombinant peptide will prove useful for studies of the structure and function of MIH.