Genomic and computational analysis of four novel variants of MPL gene in Congenital Amegakaryocytic Thrombocytopenia.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, genetic, autosomal recessive disorder characterized by severe thrombocytopenia, due to inefficient bone marrow megakaryopoiesis eventually leading to aplasia. Majority of the cases are due to homozygous or compound heterozygous mutations in MPL gene encoding for thrombopoietin (THPO) receptor protein. CAMT can be diagnosed at early phase of life, with major complication of transfusion dependency and hematopoietic transplantation as only curative treatment. We have investigated the sequence variations in MPL gene of 7 bone marrow failure (BMF) subjects, who presented with clinically diverse phenotypes, through next generation sequencing (NGS). Plasma THPO levels were estimated using ELISA. Insilico sequence and structure-based analyses were performed to understand the structural and functional implications of mutations, identified through NGS. We studied 7 CAMT subjects suspected of BMF, who presented with severe thrombocytopenia followed by pancytopenia, bleeding manifestation and physical anomalies. The plasma THPO levels were significantly elevated (p<0.05) in all the cases. Molecular analysis by NGS identified 9 genomic mutations in MPL gene. These included 7 non-synonymous substitution, 1 nonsense substitution and 1 in-del mutations, of which 4 are novel mutations. Insilico analysis predicted damaging effects on THPO-R and its reduced affinity for THPO for all the identified mutations. CAMT is a rare disorder with diverse clinical phenotypes and diagnosis is challenging. The elevated plasma THPO levels should be considered for the primary diagnosis and prognosis of the disease. However, molecular analysis of MPL gene is important for the diagnosis and management of the disease through genetic counselling. Though the cytokines, THPO-R agonist are used for the treatment of CAMT, HSCT is the only curative therapy.

Orange peel-derived Cu2O/RGO nanocomposite: Mesoporous binary system for degradation of doxycycline in water.

In recent times, there is a mammoth challenge for the world and mankind to deal with the frequent use and misuse of antibiotics and its casual discard to the water bodies. The scavenging degradation of antibiotics which are no longer in use from the environment is a growing concern and compulsively needs to be addressed. Herein, we have devised a novel and green protocol for the synthesis of Cu2O decorated on reduced graphene oxide (Cu2O/RGO) nanocomposite (NCs) using agro-waste, i.e., orange pomace extract (OPE) as a reducing and stabilizing agent for the degradation of antibiotic. The biogenically synthesized Cu2O/RGO NCs proved to emerge as an excellent degradation catalyst exhibiting efficiency of 98.68% within 15 min and 86.38% within 30 min for 10 mg/L DC concentration assisted by ultrasound waves and solar light respectively in separate reactions. The complete degradation process followed a pseudo-first-order kinetics with a rate constant of 0.29 min- 1 and 0.0542 min- 1 for sonocatalytic and photocatalytic degradation process, respectively. Surface area analysis showed that with the increase in the GO amount, the doxycycline degradation increases. An in-depth mechanistic account of sonocatalytic and photocatalytic process has been discussed followed by a radical scavenging test which validated the major role of the synthesized NCs in the degradation of DC. The extraordinary catalytic indulgence of biogenically synthesized graphene-based nanocatalyst opens newer avenues for future research in green chemistry and catalytic field. Supplementary Information: The online version contains supplementary material available at 10.1007/s10668-022-02895-2.

The influence of mode of anaesthesia on perioperative outcomes in people with hip fracture: a prospective cohort study from the National Hip Fracture Database for England, Wales and Northern Ireland.

BACKGROUND: Delirium is common after hip fracture surgery, affecting up to 50% of patients. The incidence of delirium may be influenced by mode and conduct of anaesthesia. We examined the effect of spinal anaesthesia (with and without sedation) compared with general anaesthesia on early outcomes following hip fracture surgery, including delirium. METHODS: We used prospective data on 107,028 patients (2018 to 2019) from the National Hip Fracture Database, which records all hip fractures in patients aged 60 years and over in England, Wales and Northern Ireland. Patients were grouped by anaesthesia: general (58,727; 55%), spinal without sedation (31,484; 29%), and spinal with sedation (16,817; 16%). Outcomes (4AT score on post-operative delirium screening; mobilisation day one post-operatively; length of hospital stay; discharge destination; 30-day mortality) were compared between anaesthetic groups using multivariable logistic and linear regression models. RESULTS: Compared with general anaesthesia, spinal anaesthesia without sedation (but not spinal with sedation) was associated with a significantly reduced risk of delirium (odds ratio (OR)=0.95, 95% confidence interval (CI)=0.92-0.98), increased likelihood of day one mobilisation (OR=1.06, CI=1.02-1.10) and return to original residence (OR=1.04, CI=1.00-1.07). Spinal without sedation (p<0.001) and spinal with sedation (p=0.001) were both associated with shorter hospital stays compared with general anaesthesia. No differences in mortality were observed between anaesthetic groups. CONCLUSIONS: Spinal and general anaesthesia achieve similar outcomes for patients with hip fracture. However, this equivalence appears to reflect improved perioperative outcomes (including a reduced risk of delirium, increased likelihood of mobilisation day one post-operatively, shorter length of hospital stay and improved likelihood of returning to previous residence on discharge) among the sub-set of patients who received spinal anaesthesia without sedation. The role and effect of sedation should be studied in future trials of hip fracture patients undergoing spinal anaesthesia.

Assessment of Long-Term in vitro Multiplied Human Wharton's Jelly-Derived Mesenchymal Stem Cells prior to Their Use in Clinical Administration.

The quantity of mesenchymal stem/stromal cells (MSCs) required for a particular therapy demands their subsequent expansion through ex vivo culture. During in vitro multiplication, they undergo replicative senescence which may alter their genetic stability. Therefore, this study was aimed to analyze cellular, molecular, and chromosomal alterations in Wharton's jelly-derived MSCs (WJ-MSCs) during their in vitro sequential passages, where WJ-MSCs were sequentially passaged up to P14 and cells were evaluated at an interval of P2, P6, P10, and P14. They were examined for their morphology, tumorigenicity, surface markers, stemness markers, DNA damage, chromosomal aberration, and telomere length. We have processed five full-term delivered human umbilical cord samples to obtain WJ-MSCs. Morphological appearance observed at initial stages was small fine spindle-shaped WJ-MSCs which were transformed to flat, long, and broader cells in later passages. The cell proliferation rate was gradually decreased after the 10th passage. WJ-MSCs have expressed stemness markers OCT-4 and NANOG, while they showed high expression of positive surface markers CD90 and CD105 and lower expression of CD34 and CD45. They were non-tumorigenic with slow cellular aging during subsequent passages. There was no chromosomal abnormality up to the 14th passage, while increase in comet score and decrease in telomere length were observed in later passages. Hence, our study suggests that early and middle passaged (less than P10) WJ-MSCs are good candidates for clinical administration for treatment.

Severe telomere shortening in Fanconi anemia complementation group L.

Fanconi Anemia (FA) is a rare genetic disease with the incidence of 1 in 360,000 and is characterised by bone marrow failure, physical abnormalities, pancytopenia, and high frequency of chromosomal breakage and increased risk of evolving into malignancy. Telomere plays an important role in genomic stability, ageing process and cancers. Telomere shortening has been reported in FA. We studied telomere length in FA subjects and compared with complementation groups. Chromosomal breakage analysis from PHA stimulated, MMC induced peripheral blood culture was carried out in 37 clinically diagnosed FA. Molecular study of FANCA, G, and L was done through Sanger sequencing and next generation sequencing. Telomere length was estimated using real time quantitative polymerase chain reaction (qPCR) method. Student t-test was applied to test the significance. A high frequency of chromosomal breakage was observed in all the patients compared to healthy controls. We found significantly shorter telomere length in all the three complementation groups compare to age matched healthy controls. Among all complementation groups, FANCL showed severe telomere shortening (P value 0.0001). A negative correlation was observed between telomere length and chromosomal breakage frequency (R = -0.3116). Telomere shortening is not uncommon in FA subjects. However the telomere length shortening is different in complementation groups as FANCL showed severe telomere shortening in FA subjects. Though BM transplantation is essential for the management of the FA subjects, the telomere length can be considered as biological marker to understand the prognosis of the disease as FA subjects primarily treated with androgens.

Superusers' Engagement in Asthma Online Communities: Asynchronous Web-Based Interview Study.

BACKGROUND: Superusers, defined as the 1% of users who write a large number of posts, play critical roles in online health communities (OHCs), catalyzing engagement and influencing other users' self-care. Their unique online behavior is key to sustaining activity in OHCs and making them flourish. Our previous work showed the presence of 20 to 30 superusers active on a weekly basis among 3345 users in the nationwide Asthma UK OHC and that the community would disintegrate if superusers were removed. Recruiting these highly skilled individuals for research purposes can be challenging, and little is known about superusers. OBJECTIVE: This study aimed to explore superusers' motivation to actively engage in OHCs, the difficulties they may face, and their interactions with health care professionals (HCPs). METHODS: An asynchronous web-based structured interview study was conducted. Superusers of the Asthma UK OHC and Facebook groups were recruited through Asthma UK staff to pilot and subsequently complete the questionnaire. Open-ended questions were analyzed using content analysis. RESULTS: There were 17 superusers recruited for the study (14 patients with asthma and 3 carers); the majority were female (15/17). The age range of participants was 18 to 75 years. They were active in OHCs for 1 to 6 years and spent between 1 and 20 hours per week reading and 1 and 3 hours per week writing posts. Superusers' participation in OHCs was prompted by curiosity about asthma and its medical treatment and by the availability of spare time when they were off work due to asthma exacerbations or retired. Their engagement increased over time as participants furthered their familiarity with the OHCs and their knowledge of asthma and its self-management. Financial or social recognition of the superuser role was not important; their reward came from helping and interacting with others. According to the replies provided, they showed careful judgment to distinguish what can be dealt with through peer advice and what needs input from HCPs. Difficulties were encountered when dealing with misunderstandings about asthma and its treatment, patients not seeking advice from HCPs when needed, and miracle cures or dangerous ideas. Out of 17 participants, only 3 stated that their HCPs were aware of their engagement with OHCs. All superusers thought that HCPs should direct patients to OHCs, provided they are trusted and moderated. In addition, 9 users felt that HCPs themselves should take part in OHCs. CONCLUSIONS: Superusers from a UK-wide online community are highly motivated, altruistic, and mostly female individuals who exhibit judgment about the complexity of coping with asthma and the limits of their advice. Engagement with OHCs satisfies their psychosocial needs. Future research should explore how to address their unmet needs, their interactions with HCPs, and the potential integration of OHCs in traditional healthcare.

Hydroxychloroquine: balancing the need to maintain therapeutic levels with ocular safety: an update.

PURPOSE OF REVIEW: Antimalarial drugs including chloroquine, its less toxic quinolone-derivative hydroxychloroquine (HCQ), and quinacrine have become cornerstones in the treatment of autoimmune diseases including systemic lupus, rheumatoid arthritis, sarcoidosis, and Sjogren syndrome; cutaneous disorders, antiphospholipid syndrome, and have recently been employed at higher dioses in oncology. Benefits include anti-inflammatory effects, protection against thrombosis, and improved control of hyperglycemia and hyperlipidemia. In general, both the therapeutic advantages and the toxic effects of the drugs correlate with the dose and the duration of therapy. Here we summarize the current literature regarding the administration and the safety profile of HCQ in management of rheumatologic disease and focus on the most recent revised American Academy of Ophthalmology (AAO) guidelines for prevention and detection of hydroxychloroquine retinopathy to help guide therapeutic decision-making for patients. RECENT FINDINGS: The risk of antimalarial-induced retinal toxicity is better predicted by calculating the daily dosage based on 5 mg/kg total body weight rather than 6.5 mg/kg lean body weight and reducing dosage in patients with risk factors such as renal failure. The risk of retinal toxicity after 5 years is substantially increased even when these guidelines are followed; hence dose reduction is appropriate with long-term use. Newer techniques provide improved detection of early signs of retinal damage. These advances are reflected in the revised AAO guidelines 2016, which are in part based on the retrospective study by Melles and Marmor of HCQ toxicity. SUMMARY: The most important changes in practice guidelines include dose calculation based on total body weight, dose reduction after long-term use, and intensified screening with techniques including optical coherence tomography (OCT) after 5 years.

Postoperative Hemorrhagic Occlusive Retinal Vasculitis: Expanding the Clinical Spectrum and Possible Association with Vancomycin.

PURPOSE: To describe a syndrome of hemorrhagic occlusive retinal vasculitis (HORV) that developed after seemingly uncomplicated cataract surgery. DESIGN: Retrospective case series. SUBJECTS: Eleven eyes of 6 patients from 6 different institutions. METHODS: Cases were identified after discussion among retina specialists. The findings on presentation, clinical course, and outcome of a series of 7 eyes of 4 patients were compared with a previous report of 4 eyes of 2 patients, and data from both series were combined for a comprehensive analysis. MAIN OUTCOME MEASURES: Historical data, examination findings, imaging results, systemic evaluation findings, treatment regimens, and visual outcomes. RESULTS: Eleven eyes of 6 patients underwent otherwise uncomplicated cataract surgery, receiving viscoelastic and prophylactic intracameral vancomycin during the procedure. Despite good initial vision on postoperative day 1, between 1 to 14 days after surgery, all eyes demonstrated painless vision loss resulting from HORV. Extensive ocular and systemic evaluations were unrevealing in all patients. All patients were treated with aggressive systemic and topical corticosteroids. Additional treatments included systemic antiviral medication in 4 patients, intravitreal antibiotics in 4 eyes, and pars plana vitrectomy in 4 eyes. Skin testing for vancomycin sensitivity showed negative results in 3 patients and was not performed in the others. Neovascular glaucoma developed in 7 eyes, and all eyes received intravitreal anti-vascular endothelial growth factor (VEGF) injection, panretinal photocoagulation, or both for retinal ischemia. Final visual acuity was less than 20/100 in 8 of 11 eyes. CONCLUSIONS: Postoperative HORV is an exceedingly rare and potentially devastating condition that can occur after otherwise uncomplicated cataract surgery. Although the precise cause remains unknown, this disease may represent a delayed immune reaction similar to vancomycin-induced leukocytoclastic vasculitis. Despite treatment with high-dose corticosteroids, antiviral medication, and early vitrectomy in many patients, visual outcomes typically were poor in this series. Early intervention with intravitreal anti-VEGF medication and panretinal photocoagulation may help to prevent additional vision loss resulting from neovascular glaucoma.

Incident reviews in UK maternity units: a systematic appraisal of the quality of local guidelines.

BACKGROUND: Maternity care is recognised as a particularly high-risk speciality that is subject to investigation and inquiry, and improvements in risk management have been recommended. However, the quality of guidelines for local reviews of maternity incidents is unknown. The aim of the study is to appraise the quality of local guidance on conducting reviews of severe maternity incidents in the National Health Service. METHODS: Guidelines for incident reviews were requested from all 211 consultant-led maternity units in the UK during 2012. The Appraisal of Guidelines for Research and Evaluation Instrument (AGREE II) was used to evaluate the quality of guidelines. The methods used for reviewing an incident, the people involved in the review and the methods for disseminating the outcomes of the reviews were also examined. RESULTS: Guidelines covering 148 (70%) of all NHS maternity units in the UK were received for evaluation. Most guidelines (55%) received were of good or high quality. The median score on 'scope and purpose' (86%), concerned with the aims and target population of the guideline, was higher than for other domains. Median scores were: 'stakeholder involvement' (representation of users' views) 56%, 'rigour of development' (process used to develop guideline) 34%, 'clarity of presentation' 78%, 'applicability' (organisational and cost implications of applying guideline) 56% and 'editorial independence' 0%. Most guidelines (81%) recommended a range of health professionals review serious maternity incidents using root cause analysis. Findings were most often disseminated at meetings, in reports and in newsletters. Many guidelines (69%) stated lessons learnt from incidents would be audited. CONCLUSIONS: Overall, local guidance for the review of maternity incidents was mostly of good or high quality. Stakeholder participation in guideline development could be widened, and editorial independence more clearly stated. It was unclear in over a quarter of guidelines whether changes in practice in response to review recommendations were audited or monitored; such auditing should be mandatory. Further research is required to examine the translation of guidance into practice by evaluating the quality of local reviews of maternity incidents.

Survival and cure of acute myeloid leukaemia in England, 1971-2006: a population-based study.

The 5-year relative survival of adults diagnosed with acute myeloid leukaemia (AML) was less than 10% during the 1970s and 1980s in England. This population-based study estimated the 5-year relative survival and 'cure' for 48 380 adult patients diagnosed with AML in England during 1971-2006. Relative survival and cure mixture models were used to produce estimates of 5-year relative survival and the percentage 'cured'. 'Cure' was defined as the proportion of a group of survivors for whom there is no excess mortality compared with the general population. The 5-year relative survival and the percentage 'cured' increased for patients aged under 70 years at diagnosis during 1971-2006, but advancing age was associated with poorer outcome. During the study period a dramatic increase in 5-year relative survival occurred in those aged 15-24 years, from 7% to 53%. The percentage 'cured' was less than 10% for all ages in 1975, but increased to 45% for those aged 15-24 years in 2000. Cure could not be estimated for patients over 70 years, because survival was consistently low (<5%). The long-term outcome of patients with AML has improved substantially, particularly in younger patients. The potential exists for further increasing levels of 'cure'.

Floaters in Mohs micrographic surgery.

BACKGROUND: Floaters are dislodged pieces of tumor tissue than can obscure Mohs micrographic surgery (MMS) frozen sections and confound their interpretation. OBJECTIVE: To understand the common causes of floaters and identify management strategies. METHODS: An initial virtual consensus conference of Mohs surgeons based on a 60-item questionnaire. Data were validated in interviews with randomly selected Mohs surgeons. RESULTS: Based on retrospective reporting of 230 surgeon-years and 170,404 cases of MMS by 26 surgeons, the mean rate of floaters per tumor treated was 1.8%, and the rate of floaters per tissue block was 0.70%. Not wiping blades between cuts when a stage is separated into subunits can predispose to floaters. There was also strong consensus that basal cell carcinomas, ulcerated tumors, and tissue from the first stage were more likely to yield floaters. There is little consensus on how to manage floaters, with possibilities including taking additional sections, taking an additional stage, or simply noting the floater. CONCLUSION: Floaters are not rare and can complicate MMS margin assessment. There is significant expert consensus regarding the causes of floaters and the tissue features that may predispose to them. Floaters may be prevented by minimizing their likely causes. There is less consensus on what to do with a floater.

Psychosocial Effects of Remote Reading with Telephone Support versus In-Person Health Education for Diverse, Older Adults.

This study evaluated initial information about psychosocial differences of 130 diverse, older adults (M age: 70.8 ± 9.2 years) who received a "low-tech" remote (independent reading with telephone support) or in-person education through DREAMS (Developing a Research Participation Enhancement and Advocacy Training Program for Diverse Seniors) health seminar series. Outcomes on measures of depression, quality of life, and spatial extent of lifestyle of 115 completers were analyzed at baseline, immediately post-intervention, and 8-week follow-up. Adjusted at baseline, psychosocial outcomes were compared between groups at post-test and 8-week follow-up using adjusted mean differences. Post-participation, compared to remote participants, in-person participants had significantly lower depression on Beck Depression Inventory-II, Geriatric Depression Scale, and significantly higher mental quality of life on Short Form-12. This study links knowledge acquisition via in-person learning with decreased stress, depression, and increased quality of life among seniors. Identifying effective educational delivery methods may increase clinical research involvement for aging communities.

Remote versus In-Person Health Education: Feasibility, Satisfaction, and Health Literacy for Diverse Older Adults.

OBJECTIVES: Health education may improve health in geriatric patients. To evaluate differences between remote and in-person education, the DREAMS (Developing a Research Participation Enhancement and Advocacy Training Program for Diverse Seniors) health seminar series compared in-person and remote learning groups to assess feasibility, satisfaction, adherence, health literacy, and cognitive outcomes. RESEARCH DESIGN: Nonrandomized two-arm interventions occurred remotely or in-person. About 130 diverse, older adults (M age: 70.8 ± 9.2 years; in-person n = 95; remote, n = 35) enrolled. Data from 115 completers (In-person n = 80; Remote n = 35) were analyzed for performance outcomes. Feasibility, adherence, and satisfaction benchmarks were evaluated at baseline, immediately post intervention, and 8 weeks post intervention. Adjusting for baseline performances, outcomes on health literacy and cognitive measures were compared between groups after intervention (at posttest and at 8-week follow-up) using adjusted mean differences (ß coefficients). RESULTS: Eighty in-person and all remote participants completed at least six modules. Both programs had high satisfaction, feasibility, and strong adherence. After adjusting for demographic covariates and baseline values, cognitive and motor cognitive measures between groups were domain specific (e.g., global cognition, executive function, spatial memory, mental tracking capacity, and cognitive integration). DISCUSSION AND IMPLICATIONS: This work explores feasible measures of knowledge acquisition and its link to health literacy and cognitive outcomes. Identifying effective delivery methods may increase involvement in clinical research. Future studies may encourage remote learning for increased accessibility.

Incidence and quality of care for open fractures in England between 2008 and 2019 : a cohort study using data collected by the Trauma Audit and Research Network.

AIMS: This study estimated trends in incidence of open fractures and the adherence to clinical standards for open fracture care in England. METHODS: Longitudinal data collected by the Trauma Audit and Research Network were used to identify 38,347 patients with open fractures, and a subgroup of 12,170 with severe open fractures of the tibia, between 2008 and 2019 in England. Incidence rates per 100,000 person-years and 95% confidence intervals were calculated. Clinical care was compared with the British Orthopaedic Association Standards for Trauma and National Major Trauma Centre audit standards. RESULTS: In total, 60% of all open fractures occurred in males; the median age was 48 years (interquartile range (IQR) 29 to 68). Between 2012 and 2019, the overall incidence in England was 6.94 per 100,000 person-years. In males, the highest incidence observed was in those aged 20 to 29 years (11.50 per 100,000 person-years); in females, incidence increased with age, peaking at 32.11/100,000 person-years at 90 years of age and over. Among those with severe open fractures of the tibia, there was a bimodal distribution in males, peaking at 20 to 29 years (3.71/100,000 person-years) and greater than 90 years of age (2.84/100,000 person-years) respectively; among females, incidence increased with age to a peak of 9.91/100,000 person years at 90 years of age and over. There has been variable improvement with time in the clinical care standards for patients with severe open fractures of the tibia. The median time to debridement was 13.0 hours (IQR 6.4 to 20.9); almost two-thirds of patients underwent definitive soft-tissue coverage within 72 hours from 2016 to 2019. CONCLUSION: This is the first time the incidence of all open fractures has been studied using data from a national audit in England. While most open fractures occurred in young males, the incidence increased with age in females to a much greater level than observed in older males. The degree of missing data in the national audit is startling, and limits the certainty of inferences drawn concerning open fracture care. Cite this article: Bone Joint J 2022;104-B(6):736-746.

Variation in timely surgery for severe open tibial fractures by time and place of presentation in England from 2012 to 2019 : a cohort study using data collected nationally by the Trauma Audit and Research Network.

AIMS: Several studies have reported that patients presenting during the evening or weekend have poorer quality healthcare. Our objective was to examine how timely surgery for patients with severe open tibial fracture varies by day and time of presentation and by type of hospital. This cohort study included patients with severe open tibial fractures from the Trauma Audit and Research Network (TARN). METHODS: Provision of prompt surgery (debridement within 12 hours and soft-tissue coverage in 72 hours) was examined, using multivariate logistic regression to derive adjusted risk ratios (RRs). Time was categorized into three eight-hour intervals for each day of the week. The models were adjusted for treatment in a major trauma centre (MTC), sex, age, year of presentation, injury severity score, injury mechanism, and number of operations each patient received. RESULTS: We studied 8,258 patients from 175 hospitals. Patients presenting during the day (08:00 to 15:59; risk ratio (RR) 1.11, 95% confidence interval (CI) 1.02 to 1.20) were more likely to receive debridement within 12 hours, and patients presenting at night (16:00 to 23:59; RR 0.56, 95% CI 0.51 to 0.62) were less likely to achieve the target; triage to a MTC had no effect. Day of presentation was associated with soft-tissue coverage within 72 hours; patients presenting on a Thursday or Friday being less likely to receive this surgery within 72 hours (Thursday RR 0.88, 95% CI 0.81 to 0.97; Friday RR 0.89, 95% CI 0.81 to 0.98), and the standard less likely to be achieved for those treated in 'non-MTC' hospitals (RR 0.76, 95% CI 0.70 to 0.82). CONCLUSION: Variations in care were observed for timely surgery for severe open tibial fractures with debridement surgery affected by time of presentation and soft-tissue coverage affected by day of presentation and type of hospital. The variation is unwarranted and highlights that there are opportunities to substantially improve the delivery and quality of care for patients with severe open tibial fracture.Cite this article: Bone Jt Open 2022;3(12):941-952.

Sociodemographic variables associated with risk for diabetic retinopathy.

BACKGROUND: Several systemic and sociodemographic factors have been associated with the development and progression of diabetic retinopathy (DR). However, there is limited investigation of the potential role sociodemographic factors may play in augmenting systemic risk factors of DR. We hypothesize that age, sex, race, ethnicity, income, and insurance payor have an impact on hemoglobin A1c (HbA1c), body mass index, and systolic blood pressure, and therefore an upstream effect on the development of DR and vision-threatening forms of DR (VTDR). METHODS: Multivariable analysis of longitudinal electronic health record data at a large academic retina clinic was performed. Sociodemographic factors included race, ethnicity, income, and insurance payor. Systemic risk factors for DR included hemoglobin A1c (HbA1c), systolic blood pressure (SBP), and body mass index (BMI). VTDR was identified from encounter diagnostic codes indicating proliferative retinopathy or diabetic macular edema. Patient-reported primary address zip codes were used to approximate income level, stratified into quartiles. RESULTS: From 2016 to 2018, 3,470 patients with diabetes totaled 11,437 visits were identified. Black patients had higher HbA1c and SBP compared to White patients. White patients had higher BMI and SBP compared to patients of unknown/other race and greater odds of VTDR than the latter. Patients of Hispanic ethnicity had significantly higher SBP than non-Hispanic patients. Low-income patients had higher BMI and SBP than high-income patients and greater odds of VTDR than the latter. Medicaid recipients had greater odds of VTDR than those with Blue Care Network (BCN) and Blue Cross Blue Shield (BCBS) insurance. Medicaid and Medicare recipients had higher SBP compared to BCBS recipients. Finally, both higher HbA1c and SBP had greater odds of VTDR. There were no differences in odds of VTDR between White and Black patients or between Hispanic and non-Hispanic patients. CONCLUSION: Significant associations exist between certain sociodemographic factors and well-known risk factors for DR. Income and payor were associated with increased severity of systemic risk factors and presence of VTDR. These results warrant further investigation of how risk factor optimization and disease prevention may be further improved by targeted intervention of these modifiable sociodemographic factors.

Novel deletion of exon 3 in TYR gene causing Oculocutaneous albinism 1B in an Indian family along with intellectual disability associated with chromosomal copy number variations.

BACKGROUND: Oculocutaneous albinism (OCA) is an autosomal recessive disorder characterized by hypo-pigmentation of skin, hair, and eyes. The OCA clinical presentation is due to a deficiency of melanin biosynthesis. Intellectual disability (ID) in OCA cases is a rare clinical presentation and appropriate diagnosis of ID is challenging through clinical examination. We report an Indian family with a rare co-inheritance of OCA1B and ID due to a novel TYR gene variant and chromosomal copy number variations. METHODS: We have done a study on three siblings (2 males and 1 female) of a family where all of them presented with hypopigmented skin, hair and eyes. The male children and their father was affected with ID. Targeted exome sequencing and multiplex ligation-dependent probe amplification analysis were carried out to identify the OCA1B and ID associated genomic changes. Further Array-CGH was performed using SurePrint G3 Human CGH + SNP, 8*60 K array. RESULTS: A rare homozygous deletion of exon 3 in TYR gene causing OCA1B was identified in all three children. The parents were found to be heterozygous carriers. The Array-CGH analysis revealed paternally inherited heterozygous deletion(1.9 MB) of 15q11.1-> 15q11.2 region in all three children. Additionally, paternally inherited heterozygous deletion(2.6 MB)of 10q23.2-> 10q23.31 region was identified in the first male child; this may be associated with ID as the father and the child both presented with ID. While the 2nd male child had a denovo duplication of 13q31.1-> 13q31.3 chromosomal region. CONCLUSION: A rare homozygous TYR gene exon 3 deletion in the present study is the cause of OCA1B in all three children, and the additional copy number variations are associated with the ID. The study highlights the importance of combinational genetic approaches for diagnosing two different co-inherited disorders (OCA and ID). Hence, OCA cases with additional clinical presentation need to be studied in-depth forthe appropriate management of the disease.

The Relationship Between Attitudes about Research and Health Literacy among African American and White (Non-Hispanic) Community Dwelling Older Adults.

BACKGROUND: Ethnic minority representation lacks in research. Understanding factors that promote minorities in research helps address this participation gap. Minorities often face representation disparities, including health education, socioeconomic status, and race. Compared to other races in the USA, over 50% of African Americans (AA) over age 65 face obstacles towards achieving basic health literacy skills. This study aims to investigate differences in beliefs regarding research and health literacy between White and AA participants. METHODS: This cross-sectional study compared 46 AA vs. 60 White healthy older adults (n = 106; age = 73.97 ± 10.6 years). Participants were assessed once with the Participant Attitudes and Beliefs towards Research Questionnaire (PABRQ) and two validated health literacy measures, the Rapid Estimate of Adult Literacy in Medicine (REALM) and the Short Test of Functional Health Literacy for Adults (S-TOFHLA). RESULTS: Controlling for age, sex, and education, AA performed significantly worse on REALM. Compared to White participants, AA more likely believed that researchers were motivated to perform studies to increase their general knowledge. Participants with lower health literacy scores more likely believed that scientists were motivated to conduct research to minimize treatment expenses. About 83-85% of participants reported not being familiar with the informed consent process, 90-95% had positive attitudes towards research involvement, and 38-52% believed researchers performed to promote their own careers. CONCLUSION: This work helps link older adults' beliefs towards research, health literacy, and their participation in research. Future research is needed to remove barriers to participation in research for underserved, older adults.

Transcriptional dysregulation of TrkA associates with neurodegeneration in spinocerebellar ataxia type 17.

TATA binding protein (TBP), a universal transcription factor, is broadly required by nuclear RNA polymerases for the initiation of transcription. TBP contains a polymorphic polyglutamine tract in its N-terminal region, and expansion of this tract leads to spinocerebellar ataxia type 17 (SCA17), one of nine dominantly inherited neurodegenerative diseases caused by polyglutamine expansion in the affected proteins. The expanded polyglutamine proteins are ubiquitously expressed, but cause selective and characteristic neurodegeneration in distinct brain regions in each disease. Unlike many other polyglutamine proteins, whose functions are not yet fully understood, TBP is a well-characterized transcription factor that is restricted to the nucleus. Thus, investigating how mutant TBP mediates neuropathology should help elucidate the mechanisms by which transcriptional dysregulation contributes to neuronal dysfunction and/or neurodegeneration in polyglutamine diseases. To this end, we characterized cellular and mouse models expressing polyQ-expanded TBP. The cell model exhibits characteristic features of neuronal dysfunction, including decreased cell viability and defective neurite outgrowth. We found that the high-affinity nerve growth factor receptor, TrkA, is down-regulated by mutant TBP in cells. Down-regulation of TrkA also occurs in the cerebellum of SCA17 transgenic mice prior to Purkinje cell degeneration. Mutant TBP binds more Sp1, reduces its occupancy of the TrkA promoter and inhibits the activity of the TrkA promoter. These findings suggest that the transcriptional down-regulation of TrkA by mutant TBP contributes to SCA17 pathogenesis.