Bone Fragility in Hereditary Connective Tissue Disorders: A Systematic Review and Meta-Analysis.

OBJECTIVE: To investigate bone fragility in patients with hereditary connective tissue disorders (HCTD), including Ehlers-Danlos syndrome (EDS), Marfan's syndrome (MFS) and Loeys-Dietz syndrome (LDS). METHODS: From inception to June 2022, potentially eligible studies were identified in the Medline and EMBASE databases using search strategy that included terms for "HCTD", "Fracture" and "Osteoporosis". Eligible studies must consist of a group of patients with HCTD and report prevalence/incidence of fracture/osteoporosis in their participants, with or without comparison with healthy individuals. Point estimates with standard errors were obtained from each study and combined using the generic inverse variance method. RESULTS: Among the 4206 articles identified, 19 studies were included. The pooled prevalence of fracture in EDS, MFS, and LDS were 44% (95% confidence interval [CI], 25% to 65%, I2 88%), 17% (95% CI, 11% to 26%, I2 68%), 69% (95% CI, 47% to 85%, I2 83%), respectively. The pooled prevalence of osteoporosis in EDS was 17% (95% CI, 8% to 34%, I2 96%). EDS was associated with fracture [pooled odds ratio {OR} 4.90 (95% CI, 1.49 - 16.08, I2 86%)], but not osteoporosis [pooled OR 1.34 (95% CI, 0.28 - 6.36, I2 87%). One study reported a 5% (95% CI, 3% to 8%) prevalence of osteoporosis in MFS, which was associated with fracture [incidence rate ratio 1.35 (95% CI, 1.18 - 1.55)] and osteoporosis [subhazard ratio 3.97 (95% CI, 2.53 - 6.25)]. CONCLUSION: EDS was associated with fracture, which could be independent of osteoporosis status. MFS had a milder degree of increased risk of fracture and osteoporosis. Despite no data from cohort studies, there was a significantly higher rate of fracture in LDS.

Potassium Concentrations in Transgender Women Using Spironolactone: A Retrospective Chart Review.

OBJECTIVE: To assess the incidence of hyperkalemia in transgender women using spironolactone. METHODS: This was a retrospective chart review of transgender women who received gender-affirming hormone therapy that included spironolactone between January 2000 and September 2018. Forty-four participants who had paired potassium concentrations documented and were on spironolactone were included and analyzed. Study outcomes included the incidence of hyperkalemia (serum potassium concentrations > 5.0 mmol/L), the relationship between the duration of treatment and degree of hyperkalemia, and difference between serum potassium concentrations at the beginning of spironolactone treatment versus last serum potassium concentrations. RESULTS: The median age of the participants was 36.5 years. The cohort was predominantly non-Hispanic White (32/44). No serum potassium concentration was >5.5 mmol/L, and all participants had serum creatinine level of <2 mg/dL. Median duration of treatment was 25 months (range 2-92 months) and 140 potassium measurements were available. The mean potassium concentration (3.87 mmol/L) before the initiation of spironolactone was lower than the mean potassium concentration (4.03 mmol/L) while on spironolactone (mean difference, 0.16 mmol/L, P = .013). The regression ß, that is, the average change in potassium concentration per 1 additional month of treatment duration, was -.001 (95% CI [-.004, .001]; P = .255) signifying no relation between treatment duration and spironolactone use. CONCLUSION: No participant had laboratory evidence of significant hyperkalemia (K > 5.5 mmol/L) after initiation of spironolactone. Frequent measurement of potassium concentrations might be unnecessary in transgender women taking spironolactone in patients with serum creatinine levels of <2 mg/dL.

Vitamin D-Related Genetic Variations and Nonalcoholic Fatty Liver Disease: A Systematic Review.

BACKGROUND: Studies have demonstrated the link between vitamin-D-related genetic variations and nonskeletal outcomes. We aimed to identify all available data on the association of vitamin-D-related genetic variations with nonalcoholic fatty liver disease (NAFLD). METHODS: Potentially eligible studies were identified from Embase and Medline databases from inception to June 2022 using a search strategy that comprised terms for "Vitamin D" and "NAFLD". Eligible studies must report the association between vitamin D-related genetic variations and presence, severity or response to treatment of NAFLD. Data were extracted from each eligible study. RESULTS: A total of 3495 articles were identified. After a systematic review, twelve studies were included. A total of 26 genetic variations were identified. Presence of NAFLD was associated with variations of GC (rs222054, rs222020, rs10011000, rs7041), VDR (rs2228570, rs11168287, rs10783219, rs4752), CYP24A1 (rs3787557, rs6068816, rs2296241, rs2248359) and CYP27B1 (rs4646536). Severity of NAFLD was associated with variations of GC (rs4588), VDR (rs2228570, rs4334089), CYP2R1 (rs10741657), DHCR7 (rs1544410, rs3829251, rs12785878) and CYP24A1 (rs3787557, rs6068816, rs6097809, rs6127119, rs2248359, rs3787554, rs4809960, rs6022999). Response to calcitriol treatment was associated with variation of VDR (rs10735810). CONCLUSIONS: Multiple vitamin D-related genetic variations were associated with NAFLD, indicating the role of vitamin D in the pathogenesis of NAFLD.

SERUM HORMONE CONCENTRATIONS IN TRANSGENDER INDIVIDUALS RECEIVING GENDER-AFFIRMING HORMONE THERAPY: A LONGITUDINAL RETROSPECTIVE COHORT STUDY.

OBJECTIVE: To examine the association of various gender-affirming hormone therapy regimens with blood sex hormone concentrations in transgender individuals. METHODS: This retrospective study included transgender people receiving gender-affirming hormone therapy between January 2000 and September 2018. Data on patient demographics, laboratory values, and hormone dose and frequency were collected. Nonparametric tests and linear regression analyses were used to identify factors associated with serum hormone concentrations. RESULTS: Overall, 196 subjects (134 transgender women and 62 transgender men), with a total of 941 clinical visits, were included in this study. Transgender men receiving transdermal testosterone had a significantly lower median concentration of serum total testosterone when compared with those receiving injectable preparations (326.0 ng/dL vs 524.5 ng/dL, respectively, P = .018). Serum total estradiol concentrations in the transgender women were higher in those receiving intramuscular estrogen compared with those receiving oral and transdermal estrogen (366.0 pg/mL vs 102.0 pg/mL vs 70.8 pg/mL, respectively, P < .001). A dose-dependent increase in the hormone levels was observed for oral estradiol (P < .001) and injectable testosterone (P = .018) but not for intramuscular and transdermal estradiol. Older age and a history of gonadectomy in both the transgender men and women were associated with significantly higher concentrations of serum gender-affirming sex hormones. CONCLUSION: In the transgender men, all routes and formulations of testosterone appeared to be equally effective in achieving concentrations in the male range. The intramuscular injections of estradiol resulted in the highest serum concentrations of estradiol, whereas transdermal estradiol resulted in the lowest concentration. There was positive relationship between both oral estradiol and injectable testosterone dose and serum sex hormone concentrations in transgender people receiving GAHT.

Frequent premature atrial complexes as a predictor of atrial fibrillation: Systematic review and meta-analysis.

BACKGROUND: Frequent premature atrial complexes (PACs) are associated with higher morbidity and mortality. Recent studies suggest that frequent PACs are associated with new onset atrial fibrillation (AF). However, a systematic review and meta-analysis of the literature has not been done. We assessed the association between frequent PACs and new onset AF by a systematic review and a meta-analysis. METHODS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to September 2017. Included studies were published cohort (prospective or retrospective) that compared new onset AF among patients with and without frequent PACs documented by Holter monitoring or 12-lead electrocardiogram. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate risk ratios and 95% confidence intervals. RESULTS: Twelve studies from 2009 to 2017 were included in this meta-analysis involving 109,689 subjects (9217frequent and 100,472 non-frequent PACs). Frequent PACs were associated with increased risk of new onset AF (pooled risk ratio = 2.76, 95% confidence interval: 2.05-3.73, p < 0.000, I2 = 90.6%). CONCLUSION: Frequent PACs are associated with up to three-fold increased risk of new onset AF. Our study suggests that frequent PACs in general population is an independent predictor of new onset AF.

EBV-associated CNS infection in an immunocompetent adult: A case report and literature review.

EBV infections rarely cause CNS involvement. For young adult patients with suspected CNS infection, bacterial and other common viral infections should be excluded first and treated empirically until proven otherwise. Challenges in diagnosing EBV-associated CNS infection, emphasizing the role of CSF PCR in confirming the diagnosis.

Vitamin D and prebiotics for intestinal health in cystic fibrosis: Rationale and design for a randomized, placebo-controlled, double-blind, 2 x 2 trial of administration of prebiotics and cholecalciferol (vitamin D3) (Pre-D trial) in adults with cystic fibrosis.

Individuals with cystic fibrosis (CF) have dysfunctional intestinal microbiota and increased gastrointestinal (GI) inflammation also known as GI dysbiosis. It is hypothesized that administration of high-dose cholecalciferol (vitamin D3) together with a prebiotic (inulin) will be effective, and possibly additive or synergistic, in reducing CF-related GI and airway dysbiosis. Thus, a 2 x 2 factorial design, placebo-controlled, double-blinded, pilot and feasibility, clinical trial was proposed to test this hypothesis. Forty adult participants with CF were block-randomized into one of four groups: 1) high-dose oral vitamin D3 (50,000 IU weekly) plus oral prebiotic placebo daily; 2) oral prebiotic (12 g inulin daily) plus oral placebo vitamin D3 weekly; 3) combined oral vitamin D3 weekly and oral prebiotic inulin daily; and 4) oral vitamin D3 placebo weekly and oral prebiotic placebo. The primary endpoints included 12-week changes in the microbial bacterial communities, gut and airway microbiota richness and diversity before and after the intervention. This pilot study examined whether vitamin D3 with or without prebiotics supplementation was feasible, changed airway and gut microbiota, and reduced dysbiosis, which in turn, may improve health outcomes and quality of life of patients with CF.

Vitamin D and Prebiotics for Intestinal Health in Cystic Fibrosis: Rationale and design for a randomized, placebo-controlled, double-blind, 2 × 2 trial of administration of prebiotics and cholecalciferol (vitamin D3) (Pre-D Trial) in adults with cystic fibrosis.

Individuals with cystic fibrosis (CF) have dysfunctional intestinal microbiota and increased gastrointestinal (GI) inflammation also known as GI dysbiosis. It is hypothesized that administration of high-dose cholecalciferol (vitamin D3) together with a prebiotic (inulin) will be effective, and possibly additive or synergistic, in reducing CF-related GI dysbiosis and improving intestinal functions. Thus, a 2 × 2 factorial design, placebo-controlled, double-blind, clinical trial was proposed to test this hypothesis. Forty adult participants with CF will be block-randomized into one of four groups: 1) high-dose oral vitamin D3 (50,000 IU weekly) plus oral prebiotic placebo daily; 2) oral prebiotic (12 g inulin daily) plus oral placebo vitamin D3 weekly; 3) combined oral vitamin D3 weekly and oral prebiotic inulin daily; and 4) oral vitamin D3 placebo weekly and oral prebiotic placebo. The primary endpoints will include 12-week changes in the reduced relative abundance of gammaproteobacteria, and gut microbiota richness and diversity before and after the intervention. This clinical study will examine whether vitamin D3 with or without prebiotics will improve intestinal health and reduce GI dysbiosis, which in turn, should improve health outcomes and quality of life of patients with CF.

Predicting glycemic control status and high blood glucose levels through voice characteristic analysis in patients with cystic fibrosis-related diabetes (CFRD).

Cystic fibrosis-related diabetes (CFRD) is associated with reduced life expectancy in adults with cystic fibrosis (CF). Voice analysis may be a convenient method for diagnosing and monitoring CFRD. This study aims to determine the relationship between voice characteristics and markers of glucose and glycemic control and to identify if voice analysis can predict high blood glucose levels and glycemic control in adults with CFRD. We conducted a prospective cross-sectional study in adults with CF from March to December 2021. We recorded 3-second voice samples of a sustained /a/ vowel and analyzed voice characteristic using the Computerized Speech Lab with the Multi-Dimensional Voice Program. In female participants with CFRD, the noise-to-harmonic ratio was significantly lower in those with HbA1c ≥ 7. Furthermore, fundamental frequency variation was significantly lower in both male and female participants with CFRD who had a glucose level of 200 mg/dL or higher at the time of collection. This finding was also associated with a high level of point-of-care glucose. The human voice has potential as a non-invasive tool for measuring glucose levels and glycemic control status in CFRD patients in the future.

Instrumental Acoustic Voice Characteristics in Adults with Type 2 Diabetes.

OBJECTIVE: The objective of this study was to investigate if there are differences in acoustic parameters between diabetic patients and normal controls. METHODS: A prospective cross-sectional study was performed in 83 diabetic patients and 70 healthy controls. Voice parameters including fundamental frequency (F0), jitter, shimmer, amplitude perturbation quotient, noise-to-harmonic ratio, smoothed amplitude perturbation quotient, and relative average perturbation were analyzed using Computerized Speech Lab with the Multi-Dimensional Voice Program. RESULTS: F0 in female diabetic patients was significantly lower than controls (222.23 ± 27.89 Hz versus 241.08 ± 28.21 Hz, P< 0.01). In female diabetic subgroups with disease duration more than 10 years, poor glycemic control, or neuropathy, the F0 was still significantly lower. Multivariate analysis showed that F0 was significantly associated with diabetes after controlled for age, body mass index, presence of hypertension, and dyslipidemia. (P= 0.022). However, F0 was not able to predict the presence of diabetes as shown by logistic regression analysis (P= 0.243). CONCLUSIONS: Voice fundamental frequency is lower in females with diabetes. However, voice fundamental frequency cannot adequately predict the presence of diabetes.

Identifying individuals with recent COVID-19 through voice classification using deep learning.

Recently deep learning has attained a breakthrough in model accuracy for the classification of images due mainly to convolutional neural networks. In the present study, we attempted to investigate the presence of subclinical voice feature alteration in COVID-19 patients after the recent resolution of disease using deep learning. The study was a prospective study of 76 post COVID-19 patients and 40 healthy individuals. The diagnoses of post COVID-19 patients were based on more than the eighth week after onset of symptoms. Voice samples of an 'ah' sound, coughing sound and a polysyllabic sentence were collected and preprocessed to log-mel spectrogram. Transfer learning using the VGG19 pre-trained convolutional neural network was performed with all voice samples. The performance of the model using the polysyllabic sentence yielded the highest classification performance of all models. The coughing sound produced the lowest classification performance while the ability of the monosyllabic 'ah' sound to predict the recent COVID-19 fell between the other two vocalizations. The model using the polysyllabic sentence achieved 85% accuracy, 89% sensitivity, and 77% specificity. In conclusion, deep learning is able to detect the subtle change in voice features of COVID-19 patients after recent resolution of the disease.

Effects of gender affirming hormone therapy on body mass index in transgender individuals: A longitudinal cohort study.

INTRODUCTION: Many transgender people take hormone therapy to affirm their gender identity. One potential long-term consequence of gender affirming hormone therapy is increased body mass index (BMI), which may be associated with metabolic syndrome, cardiovascular disease and higher mortality. Only a few published studies explored changes in BMI in transgender people taking gender affirming hormone therapy (GAHT). OBJECTIVE: To examine the changes in BMI longitudinally in response to GAHT in transgender women and men. METHODS: We conducted a retrospective cohort study of transgender individuals who received GAHT from the endocrinology clinic between January 1, 2000 and September 6, 2018. Subjects who sought GAHT were included if they had two separate measurements of BMI and were excluded if they had a BMI greater than 35 kg/m2 or were missing demographic data at entry. We used a linear mixed model to analyze the longitudinal change in BMI. RESULTS: There were a total of 227 subjects included in this cohort. Among subjects already on GAHT, transgender women were receiving GAHT longer than transgender men (6.59 ± 9.35 vs 3.67 ± 3.43 years, p-value = 0.04). Over the period of 7 years, there was a significant increase in BMI in transwomen who newly initiated GAHT (p-value 0.004). There were no changes in BMI in transgender men and women already on GAHT or in transgender men who newly initiated GAHT in the study. CONCLUSION: We conclude that BMI significantly increases in transwomen but not in transmen after initiation of GAHT in a single center based in the United States. In transwomen and transmen, BMI appears to be stable following 3 to 6 years of GAHT. Future investigations should examine the causes for increased BMI in transgender women including type of GAHT, diet and lifestyle, and association with risk of metabolic syndrome and cardiovascular disease.