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Context No consensus exists about the optimal duration of the low-iodine diet (LID) in the preparation of 131I therapy in differentiated thyroid cancer (DTC) patients. Objective This work aimed to investigate if a LID of 4 days is enough to achieve adequate iodine depletion in preparation for 131I therapy. In addition, the nutritional status of the LID was evaluated. Methods In this prospective study, 65 DTC patients treated at 2 university medical centers were included between 2018 and 2021. The patients collected 24-hour urine on days 4 and 7 of the LID and kept a food diary before and during the LID. The primary outcome was the difference between the 24-hour urinary iodine excretion (UIE) on both days. Results The median 24-hour UIE on days 4 and 7 of the LID were not significantly different (36.1 mcg [interquartile range, 25.4-51.2 mcg] and 36.5 mcg [interquartile range, 23.9-47.7 mcg], respectively, P = .43). On day 4 of the LID, 72.1% of the DTC patients were adequately prepared (24-hour UIE Conclusion The 24-hour UIE on day 4 of the LID did not differ from day 7, and therefore shortening the LID from 7 to 4 days seems justified to prepare DTC patients for 131I therapy in areas with sufficient iodine intake and may be beneficial to maintain a sufficient nutritional intake during DTC treatment.

Background: Coccygodynia is one of the chronic, refractory painful musculoskeletal disorders. Interventional procedures are applied to patients unresponsive to initial treatment in coccygodynia. This study aims to compare the treatment outcomes of ganglion impar block (GIB) and caudal epidural steroid injection (CESI) in patients with chronic coccygodynia. Methods: This study was a prospective randomized comparison study conducted between June 2019 and January 2021. Patients diagnosed with chronic coccygodynia were randomly divided into two groups: the GIB group and the CESI group. The severity of pain, presence of neuropathic pain, and quality of life were evaluated using the Numeric Rating Scale, Leeds Assessment of the Neuropathic Symptoms and Signs Scale, and Short Form-12 Health Survey (SF-12), respectively. Results: A total of 34 patients in each group were included in the final analyses. While there was a significant decrease in pain intensity in both groups in the 3-month follow-up, this decrease was more significant in the GIB group at the 3rd week. There was a significant improvement in the SF-12 physical score and the number of patients with neuropathic pain in both groups in the 3rd week, but this improvement was not observed in the 3rd month. Conclusions: Although GIB may provide more pain relief in short term, both GIB and CESI are useful treatment methods in coccygodynia unresponsive to more conservative treatments.

Context Maternal prepregnancy body mass index (BMI) has a strong influence on gestational metabolism, but detailed metabolic alterations are unknown. Objective First, to examine the associations of maternal prepregnancy BMI with maternal early-pregnancy metabolite alterations. Second, to identify an early-pregnancy metabolite profile associated with birthweight in women with a higher prepregnancy BMI that improved prediction of birthweight compared to glucose and lipid concentrations. Design, Setting, and Participants Prepregnancy BMI was obtained in a subgroup of 682 Dutch pregnant women from the Generation R prospective cohort study. Main Outcome Measures Maternal nonfasting targeted amino acids, nonesterified fatty acid, phospholipid, and carnitine concentrations measured in blood serum at mean gestational age of 12.8 weeks. Birthweight was obtained from medical records. Results A higher prepregnancy BMI was associated with 72 altered amino acids, nonesterified fatty acid, phospholipid and carnitine concentrations, and 6 metabolite ratios reflecting Krebs cycle, inflammatory, oxidative stress, and lipid metabolic processes (P-values Conclusions A higher maternal prepregnancy BMI was associated with altered maternal early-pregnancy amino acids, nonesterified fatty acids, phospholipids, and carnitines. Using these metabolites, we identified a maternal metabolite profile that improved prediction of birthweight in women with a higher prepregnancy BMI compared to glucose and lipid concentrations.

Background Percutaneous transforaminal endoscopic discectomy (PTED) has been widely used in the treatment of lumbar degenerative diseases. Epidural injection of steroids can reduce the incidence and duration of postoperative pain in a short period of time. Although steroids are widely believed to reduce the effect of surgical trauma, the observation indicators are not uniform, especially the long-term effects, so the problem remains controversial. Therefore, the purpose of this paper was to evaluate the efficacy of epidural steroids following PTED. Methods We searched PubMed, Embase, and the Cochrane Database from 1980 to June 2021 to identify randomized and non-randomized controlled trials comparing epidural steroids and saline alone following PTED. The primary outcomes included postoperative pain at least 6 months as assessed using a visual analogue scale (VAS) and the Oswestry Disability Index (ODI). The secondary outcomes included length of hospital stay and the time of return to work. Results A total of 451 patients were included in three randomized and two non-randomized controlled trials. The primary outcomes, including VAS and ODI scores, did not differ significantly between epidural steroids following PTED and saline alone. There were no significant intergroup differences in length of hospital stay. Epidural steroids were shown to be superior in terms of the time to return to work (P < 0.001). Conclusions Intraoperative epidural steroids did not provide significant benefits, leg pain control, improvement in ODI scores, and length of stay in the hospital, but it can enable the patient to return to work faster.

Background Different views have been proposed on the radiofrequency treatment modes and parameters of radiofrequency thermocoagulation of the spinal dorsal root ganglion for the treatment of postherpetic neuralgia (PHN). It is urgent to identify a more effective therapy for patients with PHN. Methods Patients who underwent radiofrequency thermocoagulation therapy for PHN were retrospectively reviewed and were divided into a radiofrequency thermocoagulation (CRF) and double neddles radiofrequency thermocoagulation (DCRF). The pain scores (numerical rating scale, NRS) were evaluated at the following time points before the operation, 1 day, 3 months, 6 months, 1 year, and 2 years after operation. The incidence of complications and the degree of pain relief were evaluated. The in vitro ovalbumin experiment was used to indicate the effects of radiofrequency thermocoagulation. Results Compared with the preoperative NRS scores, the postoperative NRS scores decreased significantly; the NRS scores of the DCRF group was lower than that of the CRF group at all time points from 6 months to 2 years following the operation. The total effective rate of the DCRF group was significantly higher than that of the CRF group at 2 years following the operation. The incidence of numbness in the DCRF group was higher than that noted in the CRF group. The ovalbumin experiments in vitro indicated that the effects of radiofrequency thermocoagulation were optimal when the distance between the two needles was 5 mm. Conclusions DCRF with a 5 mm spacing exhibits a longer duration and higher effective rate in the treatment of PHN and is worth promoting.

Context Mutations in type I collagen or collagen-related proteins cause osteogenesis imperfecta (OI). Energy expenditure and body composition in OI could reflect reduced mobility or intrinsic defects in osteoblast differentiation increasing adipocyte development. Objective This study compares adiposity and resting energy expenditure (REE) in OI and healthy controls (HC), for OI genotype- and Type-associated differences. Methods We studied 90 participants, 30 with OI (11 COL1A1 Gly, 8 COL1A2 Gly, 4 COL1A1 non-Gly, 1 COL1A2 non-Gly, 6 non-COL; 8 Type III, 16 Type IV, 4 Type VI, 1 Type VII, 1 Type XIV) and 60 HC with sociodemographic characteristics/BMI/BMIz similar to the OI group. Participants underwent dual-energy x-ray absorptiometry to determine lean mass and fat mass percentage (FM%) and REE. FM% and REE were compared, adjusting for covariates, to examine the relationship of OI genotypes and phenotypic Types. Results FM% did not differ significantly in all patients with OI vs HC (OI: 36.6% ± 1.9%; HC: 32.7% ± 1.2%; P = 0.088). FM% was, however, greater than HC for those with non-COL variants (P = 0.016). FM% did not differ from HC among OI Types (P values > 0.05). Overall, covariate-adjusted REE did not differ significantly between OI and HC (OI: 1376.5 ± 44.7 kcal/d; HC: 1377.0 ± 96 kcal/d; P = 0.345). However, those with non-COL variants (P = 0.016) and Type VI OI (P = 0.04) had significantly lower REE than HC. Conclusion Overall, patients with OI did not significantly differ in either extra-marrow adiposity or REE from BMI-similar HC. However, reduced REE among those with non-COL variants may contribute to greater adiposity.

CONTEXT: Diabetic neuropathy affects 10.5%–32.2% of diabetic population posing clinical burden onto society. AIMS: We aimed to study the efficacy, safety, and tolerability of methylcobalamin, methylcobalamin plus pregabalin, and methylcobalamin plus duloxetine in patients of painful diabetic neuropathy. SETTINGS AND DESIGN: It is a prospective, randomized, open-label, interventional, and parallel-group study done in patients of painful diabetic neuropathy. MATERIALS AND METHODS: A total of 100 patients were recruited and randomized to three study groups A, B, and C on methylcobalamin, methylcobalamin and pregabalin, and methylcobalamin and duloxetine, respectively. Patients were assessed at day 0 and 4, 8, and 12 weeks. The tuning fork test, monofilament test, Thermal Sensitivity testing, and Visual Analog Scale (VAS) were used to analyze vibration, pressure, thermal sensitivity, and pain. STATISTICAL ANALYSIS USED: The results are expressed as mean ± standard deviation. Appropriate statistical methods were used to calculate P value (

OBJECTIVES AND METHODS: In September 2018, the government of India banned 328 fixed dose combinations (FDCs), 24 of which are combinations containing topical steroids. To assess what impact can be expected from this regulatory action, we analyzed reports of adverse drug events due to topical corticosteroids at a hospital-based pharmacovigilance center between January 2017 and August 2018. RESULTS: Among 34 different steroid-containing FDCs responsible for 485 reports of ADEs with topical steroids, only three preparations, accounting for 50.10% of ADEs, come under the umbrella of the recent ban. Clobetasone propionate (68.87%) and betamethasone (28.45%) were the corticosteroids most frequently associated with adverse events. Most of the steroid preparations (87.84%) had been bought without a prescription for the treatment of dermatophytoses (76.70%). Males (77.73%) were predominantly affected, and nearly half (47.43%) of the patients were between 21 and 30 years of age. Skin atrophy (50.10%), striae (25.54%), and hypopigmentation (19.79%) were the major ADEs. CONCLUSION: Nearly half of the cutaneous adverse effects were due to topical steroid combinations which are still widely available over the counter.

Context Familial partial lipodystrophy (FPL), Dunnigan variety is characterized by skeletal muscle hypertrophy and insulin resistance besides fat loss from the extremities. The cause for the muscle hypertrophy and its functional consequences is not known. Objective To compare muscle strength and endurance, besides muscle protein synthesis rate between subjects with FPL and matched controls (n = 6 in each group). In addition, we studied skeletal muscle mitochondrial function and gene expression pattern to help understand the mechanisms for the observed differences. Methods Body composition by dual-energy X-ray absorptiometry, insulin sensitivity by minimal modelling, assessment of peak muscle strength and fatigue, skeletal muscle biopsy and calculation of muscle protein synthesis rate, mitochondrial respirometry, skeletal muscle transcriptome, proteome, and gene set enrichment analysis. Results Despite increased muscularity, FPL subjects did not demonstrate increased muscle strength but had earlier fatigue on chest press exercise. Decreased mitochondrial state 3 respiration in the presence of fatty acid substrate was noted, concurrent to elevated muscle lactate and decreased long-chain acylcarnitine. Based on gene transcriptome, there was significant downregulation of many critical metabolic pathways involved in mitochondrial biogenesis and function. Moreover, the overall pattern of gene expression was indicative of accelerated aging in FPL subjects. A lower muscle protein synthesis and downregulation of gene transcripts involved in muscle protein catabolism was observed. Conclusion Increased muscularity in FPL is not due to increased muscle protein synthesis and is likely due to reduced muscle protein degradation. Impaired mitochondrial function and altered gene expression likely explain the metabolic abnormalities and skeletal muscle dysfunction in FPL subjects.

Background The effect of lumbar spinal stenosis (LSS) and peripheral vascular disease (PVD), which occurs with similar degenerative conditions, when seen together, has not been studied. The aim of this study is to examine and compare the relationship between pain, balance, disability, fear of falling, and kinesiophobia in LSS patients with intermittent vascular claudication (IVC). Methods Seventy-two patients diagnosed with LSS using magnetic resonance imaging participated in this study. Thirty-five patients with IVC symptoms and showing vascular lesions by lower extremity venous and arterial Doppler ultrasonography imaging were included in the IVC-LSS group. The pain, static balance, dynamic balance, disability, fear of falling, and kinesiophobia were evaluated using the numeric rating scale, single leg stance test, Time Up and Go (TUG), the Oswestry Disability Index (ODI), Fall Efficacy Scale-International (FES-I), and Tampa Scale for Kinesiophobia (TSK), respectively. Results Age and female sex were found to be higher in the IVC-LSS group (P = 0.024; P = 0.012). The IVC-LSS group had a shorter single leg stance time and TUG test duration, pain intensity, ODI, FES-I, and TSK scores were higher than patients with LSS (P = 0.001). Pain, fear of falling, and kinesiophobia were moderately correlated with disability in the IVC-LSS group. No relationship was found between pain and dynamic balance. Also, the pain was not related to kinesiophobia. Conclusions The findings indicated that IVC causes loss of balance and an increase in pain, disability, fear of falling, and kinesophobia in patients with LSS.

Background Prior studies have reported that 40%-90% of the patients with celiac plexus-mediated visceral pain benefit from the neurolytic celiac plexus block (NCPB), but the predictive factors of response to NCPB have not been evaluated extensively. This study aimed to identify the factors associated with the immediate analgesic effectiveness of NCPB in patients with intractable upper abdominal cancer-related pain. Methods A retrospective review was performed of 513 patients who underwent NCPB for upper abdominal cancer-related pain. Response to the procedure was defined as (1) a decrease of ≥ 50% or ≥ 4 points on the numerical rating scale (NRS) in pain intensity from the baseline without an increase in opioid requirement, or (2) a decrease of ≥ 30% or ≥ 2 points on the NRS from the baseline with simultaneously reduced opioid consumption after NCPB. Logistic regression analysis was performed to determine the factors associated with successful responses to NCPB. Results Among the 513 patients included in the analysis, 255 (49.8%) and 258 (50.2%) patients were in the non-responder and responder group after NCPB, respectively. Multivariable logistic regression analysis showed that diabetes (odds ratio [OR] = 0.644, P = 0.035), history of upper abdominal surgery (OR = 0.691, P = 0.040), and celiac metastasis (OR = 1.496, P = 0.039) were the independent factors associated with response to NCPB. Conclusions Celiac plexus metastases, absence of diabetes, and absence of prior upper abdominal surgery may be independently associated with better response to NCPB for upper abdominal cancer-related pain.

Context Low bone mineral density has been reported in individuals with congenital adrenal hyperplasia (CAH), but the prevalence of fractures is unclear. Objective To study the prevalence of fractures in CAH. Design, Setting, and Participants Patients with CAH (n = 714, all 21-hydroxylase deficiency) were compared with controls matched for sex and year and place of birth (n = 71 400). Data were derived by linking National Population-Based Registers. Main Outcome Measures Number and type of fractures. Results Mean age was 29.8 ± 18.4 years. Individuals with CAH had more fractures compared to controls [23.5% vs 16.1%, odds ratio (OR) 1.61, 95% CI 1.35-1.91], and this was found in both sexes (females: 19.6% vs 13.3%, OR 1.57, 95% CI 1.23-2.02; males: 28.7% vs 19.6%, OR 1.65, 95% CI 1.29-2.12). Fractures were significantly increased in patients born before the introduction of neonatal screening but not in those born afterwards. Any major fracture associated with osteoporosis (spine, forearm, hip, or shoulder) was increased in all individuals with CAH (9.8% vs 7.5%, OR 1.34, 95% CI 1.05-1.72). The highest prevalence of fractures was seen in SV phenotype and I172N genotype while nonclassic phenotype and I2 splice genotype did not show increased prevalence. A transport accident as a car occupant and fall on the same level were more common in patients with CAH, both sexes, than in controls. Conclusions Patients with CAH had an increased prevalence of both any fracture and fractures associated with osteoporosis (both sexes) but not for patients neonatally screened. We conclude that fracture risk assessment and glucocorticoid optimization should be performed regularly.

Background Yellow flags are psychosocial factors shown to be indicative of long-term chronicity and disability. The purpose of the study was to evaluate the psychometric properties of the Turkish Yellow Flag Questionnaire (YFQ) in patients with chronic musculoskeletal pain (CMP). Methods The cross-cultural adaptation was conducted with translation and back-translation of the original version. Reliability (internal consistency and test-retest) was examined for 231 patients with CMP. Construct validity was assessed by correlating the YFQ with the Hospital Anxiety and Depression Scale (HADS), Orebro Musculoskeletal Pain Questionnaire (OMPQ), and Tampa Kinesiophobia Scale (TKS). Factorial validity was examined with both exploratory and confirmatory factorial analysis. Results The YFQ showed excellent test/retest reliability with an Intraclass correlation coefficient of 0.82. The internal consistency was moderate (Cronbach’s alpha of 0.797). As a result of the exploratory factor analysis, there were 7 domains compatible with the original version. As a result of confirmatory factor analysis, the seven-factor structure of YFQ was confirmed. There was a statistically significant correlation between YFQ-total score and OMPQ (r = 0.57, P < 0.001), HADS-anxiety (r = 0.32, P < 0.001), HADS-depression (r = 0.44, P < 0.001), and TKS (r = 0.37, P < 0.001). Conclusions This study’s results provide considerable evidence that the Turkish version of the YFQ has appropriate psychometric properties, including test-retest reliability, internal consistency, construct validity and factorial validity. It can be used for evaluating psychosocial impact in patients with CMP.

Background Although neuropathic pain is a severe and common pain, its pathophysiology has not been elucidated yet. Studies in recent years have focused on the immune system's role in the pathogenesis of neuropathic pain. The aim of this study was to investigate the role of immunological mechanisms in neuropathic pain and the effect of pregabalin by measuring immunological marker levels in peripheral blood before and after pregabalin treatment in postherpetic neuralgia (PHN) patients with neuropathic pain. Methods Forty patients diagnosed with PHN were included in the study. CD4, T follicular cells (Tfh: CD4+CXCR5+PD1+), Th17 (CD4+CCR6+ and CD4+IL17A+), regulatory T cells (Treg: CD4+ CD25+foxp3+), Th1 (CD4+ CXCR3+ and CD4+ IFN-γ+) and Th2 (CD4+ IL-4+) cell ratios were measured in peripheral blood samples before treatment and after 3 months of treatment. Results When immunological marker and inflammation parameter levels were compared before and after treatment, the helper T cell ratio (CD3+, CD4+) was 30.28 ± 12.27% before treatment and 34.93 ± 11.70% after treatment, so there was a statistically significant increase (P = 0.028). Th17 was 4.75 ± 5.02% before treatment and 5.80 ± 3.13% after treatment, and there was a statistically significant increase (P = 0.036). Conclusions Immunological mechanisms play an essential role in the pathogenesis of neuropathic pain, immunologically based treatment approach will be the critical point of treatment.

Background Non-invasive painless signaling therapy (NPST) is an electro-cutaneous treatment that converts endogenous pain information into synthetic non-pain information. This study explored whether pain improvement by NPST in failed back surgery syndrome (FBSS) patients is related to cerebral modulation. Methods Electroencephalography (EEG) analysis was performed in 11 patients with FBSS. Subjects received daily NPST for 5 days. Before the first treatment, patients completed the Brief Pain Inventory (BPI) and Beck Depression Inventory and underwent baseline EEG. After the final treatment, they responded again to the BPI, reported the percent pain improvement (PPI), and then underwent post-treatment EEG. If the PPI grade was zero, they were assigned to the ineffective group, while all others were assigned to the effective group. We used standardized low-resolution brain electromagnetic tomography (sLORETA) to explore the EEG current-source distribution (CSD) associated with pain improvement by NPST. Results The 11 participants had a median age of 67.0 years, and 63.6% were female. The sLORETA images revealed a beta-2 CSD increment in 12 voxels of the right anterior cingulate gyrus (ACG) and the right medial frontal area. The point of maximal CSD changes was in the right ACG. The alpha band CSD increased in 2 voxels of the left transverse gyrus. Conclusions Pain improvement by NPST in FBSS patients was associated with increased cerebral activity, mainly in the right ACG. The change in afferent information induced by NPST seems to be associated with cerebral pain perception.

Aims Prior studies have reported inconsistent results for the association between sex hormone-binding globulin (SHBG) and cardiovascular disease among men and women. Although it is suggested that SHBG levels change with aging, the exact trend of SHBG across age and cardiovascular risk and the underlying mechanisms of these changes remain to be elucidated. Methods Using data of 3264 men and women from a large population-based cohort study, we first visualized the distribution of serum SHBG levels across age. Second, we computed a cardiovascular risk factor sum score and investigated the mean SHBG levels across categories of the risk factor sum score and stratified per age-category. Next, linear regression models were used to investigate the associations between serum SHBG levels and age and potential regulators of SHBG, including body mass index (BMI), fasting insulin, sex steroids, thyroxine, and triglycerides. Results Among men, a linear increase in SHBG levels with age and among women a U-shaped pattern was observed. Participants with larger number of cardiovascular risk factors had lower SHBG levels. When stratified by age, older participants had higher SHBG levels. A multivariate model including total testosterone and triglyceride levels in men and total testosterone, triglycerides, BMI, and fasting insulin in women explained, respectively, 46.2% and 31.8% of the variance in SHBG levels. Conclusion We observed a clear sex-specific pattern for SHBG levels with age. Our findings highlight the importance of taking into account the age-related changes in SHBG levels to avoid controversial results in the assessment of the cardiovascular risk associated with SHBG.

Background Postherpetic neuralgia (PHN) is a refractory complication of herpes zoster (HZ). To prevent PHN, various strategies have been aggressively adopted. However, the efficacy of these strategies remains controversial. Therefore, we aimed to estimate the relative efficacy of various strategies used in clinical practice for preventing PHN using a network meta-analysis (NMA). Methods We performed a systematic and comprehensive search to identify all randomized controlled trials. The primary outcome was the incidence of PHN at 3 months after acute HZ. We performed both frequentist and Bayesian NMA and used the surface under the cumulative ranking curve (SUCRA) values to rank the interventions evaluated. Results In total, 39 studies were included in the systematic review and NMA. According to the SUCRA value, the incidence of PHN was lower in the order of continuous epidural block with local anesthetics and steroids (EPI-LSE), antiviral agents with subcutaneous injection of local anesthetics and steroids (AV + sLS), antiviral agents with intracutaenous injection of local anesthetics and steroids (AV + iLS) at 3 months after acute HZ. EPI-LSE, AV + sLS and AV + iLS were also effective in preventing PHN at 1 month after acute HZ. And paravertebral block combined with antiviral and antiepileptic agents was effective in preventing PHN at 1, 3, and 6 months. Conclusions The continuous epidural block with local anesthetics and steroid, antiviral agents with intracutaneous or subcutaneous injection of local anesthetics and a steroid, and paravertebral block combined with antiviral and antiepileptic agents are effective in preventing PHN.

Background This study was performed to reveal the relationships between the cross-sectional areas (CSAs) of the paraspinal muscles and the severity of low back pain (LBP), including the level of disability. Methods This single-center cross-sectional study was conducted on 164 patients with chronic LBP. The effects of demographic characteristics, posture, level of physical activity, disc herniation type, and sarcopenia risk on the CSAs of paraspinal muscles were evaluated along with the relationship between the CSAs and severity of pain and disability in all patients. The CSAs of paraspinal muscles were evaluated using the software program Image J 1.53. Results A negative significant correlation was found between age and the paraspinal muscle’s CSA (P < 0.05), whereas a positive correlation was present between the level of physical activity and the CSA of the paraspinal muscle at the L2-3 and L3-4 levels. The CSAs of paraspinal muscles in patients with sarcopenia risk was significantly lower than those in patients without sarcopenia risk (P < 0.05). The CSAs of paraspinal muscles at the L2-3 and L3-4 levels in obese patients were significantly higher than those in overweight patients (P = 0.028, P = 0.026, respectively). There was no relationship between the CSAs of paraspinal muscles and pain intensity or disability. Conclusions Although this study did not find a relationship between paraspinal CSAs and pain or disability, treatment regimens for preventing paraspinal muscles from atrophy may aid pain physicians in relieving pain, restoring function, and preventing recurrence in patients with chronic LBP.

Background Although the erector spinae plane block has been used in various truncal surgical procedures, its clinical benefits in patients undergoing spinal surgery remain controversial. The aim of this meta-analysis was to evaluate the clinical benefits of erector spinae plane block in patients undergoing spinal surgery. Methods We searched the Cochrane Library, PubMed, EMBASE, and China National Knowledge Infrastructure for randomized controlled trials comparing the erector spinae plane block with a nonblocked control for spinal surgery. Results Twelve studies encompassing 696 subjects were included in our systematic review and meta-analysis. We found that the erector spinae plane block decreased postoperative pain scores and opioid consumption in the postoperative and intraoperative periods. Moreover, it prolonged the time to the first rescue analgesic, reduced the number of patients who required rescue analgesia, and lowered the incidence of postoperative nausea and vomiting. However, it did not exhibit efficacy in decreasing the incidence of urinary retention and itching or shortening the length of hospital stays, or the time to first ambulation. Conclusions Erector spinae plane block improves analgesic efficacy among patients undergoing spinal surgery compared with nonblocked controls; however, there is insufficient evidence regarding the benefits of erector spinae plane block for rapid recovery.

Context Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; also known as autoimmune polyendocrine syndrome type 1) has a severe, unpredictable course. Autoimmunity and disease components may affect fertility and predispose to maternal and fetal complications, but pregnancy outcomes remain unknown. Objective To assess fetal and maternal outcomes and course of clinical APECED manifestations during pregnancy in women with APECED. Design and Setting A multicenter registry-based study including 5 national patient cohorts. Patients 321 females with APECED. Main Outcome Measure Number of pregnancies, miscarriages, and deliveries. Results Forty-three patients had altogether 83 pregnancies at median age of 27 years (range, 17–39). Sixty (72%) pregnancies led to a delivery, including 2 stillbirths (2.4%) and 5 (6.0%) preterm livebirths. Miscarriages, induced abortions, and ectopic pregnancies were observed in 14 (17%), 8 (10%), and 1 (1.2%) pregnancies, respectively. Ovum donation resulted in 5 (6.0%) pregnancies. High maternal age, premature ovarian insufficiency, primary adrenal insufficiency, or hypoparathyroidism did not associate with miscarriages. Women with livebirth had, on average, 4 APECED manifestations (range 0-10); 78% had hypoparathyroidism, and 36% had primary adrenal insufficiency. APECED manifestations remained mostly stable during pregnancy, but in 1 case, development of primary adrenal insufficiency led to adrenal crisis and stillbirth. Birth weights were normal in >80% and apart from 1 neonatal death of a preterm baby, no serious perinatal complications occurred. Conclusions Outcome of pregnancy in women with APECED was generally favorable. However, APECED warrants careful maternal multidisciplinary follow-up from preconceptual care until puerperium.

Context Systematic investigations into the cognitive impact of estradiol and insulin in male individuals are sparse, and it is unclear whether the 2 hormones interact to benefit specific cognitive functions in humans. Objective We investigated the acute effect of estradiol and insulin and of their combined administration on divergent (creative) and convergent (arithmetical) thinking as well as short-term and working verbal memory in healthy young men. Methods According to a 2 × 2 design, 2 groups of men (each n = 16) received a 3-day transdermal estradiol (100 µg/24 h) or placebo pretreatment and on 2 separate mornings were intranasally administered 160 IU regular human insulin and, respectively, placebo before completing a battery of cognitive tests; we also determined relevant blood parameters. Results Estrogen compared with placebo treatment induced a 3.5-fold increase in serum estradiol and suppressed serum testosterone concentrations by 70%. Estrogen in comparison to placebo improved creative performance, that is, verbal fluency and flexibility, but not arithmetical thinking, as well as verbal short-term memory, but not visuospatial memory. The combination of estrogen and insulin enhanced recognition discriminability at delayed verbal memory recall; insulin alone remained without effect. Conclusion Estrogen specifically enhances core aspects of creativity and verbal memory in young male individuals; delayed recognition memory benefits from the combined administration of estradiol and insulin. Our results indicate that insulin’s acute cognitive impact in young men is limited and not robustly potentiated by estradiol. Estradiol per se exerts a beneficial acute effect on creative and verbal performance in healthy young men.

Context Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with low-grade inflammation and increased incidence of pregnancy complications, but its influence on the maternal immune system in pregnancy is unknown. Longitudinal serum cytokine profiling is a sensitive measure of the complex immunological dynamics of pregnancy. Objective This work aimed to determine the immunological dynamics of serum cytokines throughout pregnancy in women with PCOS and compare it to pregnancy in women without PCOS. Methods A post hoc analysis was conducted of longitudinal serum samples from 2 randomized, placebo-controlled multicenter studies of pregnant women with PCOS and 2 studies of pregnant women without PCOS. Pregnant women with PCOS (n = 358) and without PCOS (n = 258, controls) provided 1752 serum samples from 4 time points in pregnancy (weeks 10, 19, 32, and 36). Main outcome measures included maternal serum levels of 22 cytokines and C-reactive protein (CRP) at 4 time points in pregnancy. Results Women with PCOS showed marked immunological changes in serum cytokines throughout pregnancy. Compared to controls, women with PCOS showed higher levels of 17 cytokines and CRP at week 10 of pregnancy and a distinct cytokine development throughout pregnancy. The immunological dynamics in women with PCOS was significantly affected by maternal body mass index, smoking, and fetal sex. Conclusion Pregnancy in women with PCOS was associated with a strong early mobilization of inflammatory and other serum cytokines persisting throughout pregnancy, indicating a more activated immune status. These findings provide a novel basis for further study of PCOS and pregnancy complications.

Context Vitamin D regulates glucose homeostasis pathways, but effects of vitamin D supplementation on β-cell function remain unclear. Objective To investigate the effects of vitamin D3 supplementation on insulin sensitivity and β-cell function. Methods This is a prespecified secondary analysis of the Vitamin D and Type 2 Diabetes study. Overweight/obese adults at high risk for type 2 diabetes (prediabetes) were randomly treated with vitamin D3 4000 IU or matching placebo daily for 24 months. Main Outcome Disposition index (DI), as an estimate of β-cell function, was calculated as the product of Homeostasis Model Assessment 2 indices derived from C-peptide values (HOMA2%Scpep) and C-peptide response during the first 30 minutes of a 75-g oral glucose tolerance test (OGTT). Results Mean age was 60.5 ± 9.8 years and body mass index was 31.9 ± 4.4 kg/m2. Mean serum 25(OH)D level increased from 27.9 ± 10.3 ng/mL at baseline to 54.9 ng/mL at 2 years in the vitamin D group and was unchanged (28.5 ± 10.0 ng/mL) in the placebo group. The baseline DI predicted incident diabetes independent of the intervention. In the entire cohort, there were no significant differences in changes in DI, HOMA2%Scpep, or C-peptide response between the 2 groups. Among participants with baseline 25(OH)D level Conclusions Supplementation with vitamin D3 for 24 months did not improve an OGTT-derived index of β-cell function in people with prediabetes not selected based on baseline vitamin D status; however, there was benefit among those with very low baseline vitamin D status.

Context Peptide receptor radionuclide therapy (PRRT) with [Lutetium-177-DOTA0-Tyr3]octreotate (177Lu-DOTATATE) results in an increase of progression-free survival and quality of life in patients with progressive, well-differentiated neuroendocrine neoplasms (NENs). Objective To study the effect of 177Lu-DOTATATE in patients with carcinoid syndrome and radiologically stable or newly diagnosed disease treated solely for the purpose of symptom reduction. Design Retrospective cohort study. Setting Tertiary care hospital. Patients Twenty-two patients with a metastatic midgut NEN, elevated urinary 5-hydroxyindolacetic acid excretion, and flushing and/or diarrhea despite treatment with a somatostatin analog, without documented disease progression. Intervention PRRT with 177Lu-DOTATATE (intended cumulative dose: 29.6 GBq) with a primary aim to reduce symptoms. Results After PRRT, mean bowel movement frequency (BMF) decreased from 6.1 ± 3.4 to 4.6 ± 3.6 per day (P = 0.009). Flushes decreased from 4.3 ± 2.9 to 2.4 ± 2.7 flushes per day (P = 0.002). A decrease of BMF of more than 30% occurred in 47% of patients with baseline BMF of 4 or more (n = 17). In patients with ≥2 episodes of flushing a day (n = 15), 67% of patients had more than 50% decrease of daily flushing. A decrease in urinary 5-hydroxyindolacetic acid excretion of more than 30% was seen in 56% of patients. The European Organization for Research and Treatment of Cancer–Core Module diarrhea subscale score showed a trend toward improvement by an average of 16.7 ± 33.3 points (P = 0.11). Conclusion PRRT with 177Lu-DOTATATE effectively reduced diarrhea and flushing in patients with carcinoid syndrome and can be considered for symptomatic treatment of carcinoid syndrome insufficiently controlled with somatostatin analogs.

Context Thyroid hormone (TH) is crucial for the adaptation to cold. Objective To evaluate the effect of hyperthyroidism on resting energy expenditure (REE), cold-induced thermogenesis (CIT) and changes in body composition and weight. Methods This was a prospective cohort study at the endocrine outpatient clinic of a tertiary referral center. Eighteen patients with overt hyperthyroidism were included. We measured REE during hyperthyroidism, after restoring euthyroid TH levels and after 3 months of normal thyroid function. In 14 of the 18 patients, energy expenditure (EE) was measured before and after a mild cold exposure of 2 hours and CIT was the difference between EEcold and EEwarm. Skin temperatures at 8 positions were recorded during the study visits. Body composition was assessed by dual X-ray absorption. Results Free thyroxine (fT4) and free triiodothyronine (fT3) decreased significantly over time (fT4, P = .0003; fT3, P = .0001). REE corrected for lean body mass (LBM) decreased from 42 ± 6.7 kcal/24 hour/kg LBM in the hyperthyroid to 33 ± 4.4 kcal/24 hour/kg LBM (–21%, P Conclusion CIT is not increased in patients with overt hyperthyroidism.

Context The identification and biological actions of pituitary-derived exosomes remain elusive. Objective This work aimed to validate production of exosomes derived from human and rat pituitary and elucidate their actions. Methods Isolated extracellular vesicles (EVs) were analyzed by Nanoparticle Tracking Analysis (NTA) and expressed exosomal markers detected by Western blot, using nonpituitary fibroblast FR and myoblast H9C2 cells as controls. Exosome inhibitor GW4869 was employed to detect attenuated EV release. Exosomal RNA contents were characterized by RNA sequencing. In vitro and in vivo hepatocyte signaling alterations responding to GH1-derived exosomes (GH1-exo) were delineated by mRNA sequencing. GH1-exo actions on protein synthesis, cAMP (3′,5′-cyclic adenosine 5′-monophosphate) response, cell motility, and metastases were assessed. Results NTA, exosomal marker detection, and GW4869 attenuated EV release, confirming the exosomal identity of pituitary EVs. Hydrocortisone increased exosome secretion in GH1 and GH3 cells, suggesting a stress-associated response. Exosomal RNA contents showed profiles distinct for pituitary cells, and rat primary hepatocytes exposed to GH1-exo exhibited transcriptomic alterations distinct from those elicited by growth hormone or prolactin. Intravenous GH1-exo injection into rats attenuated hepatic Eif2ak2 and Atf4 mRNA expression, both involved in cAMP responses and amino acid biosynthesis. GH1-exo suppressed protein synthesis and forskolin-induced cAMP levels in hepatocytes. GH1-exo–treated HCT116 cells showed dysregulated p53 and mitogen-activated protein kinase (MAPK) pathways and attenuated motility of malignant HCT116 cells, and decreased tumor metastases in nude mice harboring splenic HCT116 implants. Conclusion Our findings elucidate biological actions of somatotroph-derived exosomes and implicate exosomes as nonhormonal pituitary-derived messengers.

Context Daily variation in the thermic effect of food (TEF) is commonly reported and proposed as a contributing factor to weight gain with late eating. However, underlying circadian variability in resting metabolic rate (RMR) is an overlooked factor when calculating TEF associated with eating at different times of the day. Objective This work aimed to determine whether methodological approaches to calculating TEF contribute to the reported phenomena of daily variation in TEF. Methods Fourteen overweight to obese but otherwise healthy individuals had their resting and postprandial energy expenditure (EE) measured over 15.5 hours at a clinical research unit. TEF was calculated for breakfast, lunch, and dinner using standard methods (above a baseline and premeal RMR measure) and compared to a method incorporating a circadian RMR by which RMR was derived from a sinusoid curve model and TEF was calculated over and above the continuously changing RMR. Main outcome measures were TEF at breakfast, lunch, and dinner calculated by different methods. Results Standard methods of calculating TEF above a premeal measured RMR showed that morning TEF (60.8 kcal ± 5.6) (mean ± SEM) was 1.6 times greater than TEF at lunch (36.3 kcal ± 8.4) and 2.4 times greater than dinner TEF (25.2 kcal ± 9.6) (P = .022). However, adjusting for modeled circadian RMR nullified any differences between breakfast (54.1 kcal ± 30.8), lunch (49.5 kcal ± 29.4), and dinner (49.1 kcal ± 25.7) (P = .680). Conclusion Differences in TEF between morning and evening can be explained by the underlying circadian resting EE, which is independent of an acute effect of eating.

Context Confirming a diagnosis of Cushing disease (CD) remains challenging, yet is critically important before recommending transsphenoidal surgery for adenoma resection. Objective To describe predictive performance of preoperative biochemical and imaging data relative to post-operative remission and clinical characteristics in patients with presumed CD. Design, Setting, Patients, Interventions Patients (n = 105; 86% female) who underwent surgery from 2007 through 2020 were classified into 3 groups: group A (n = 84) pathology-proven ACTH adenoma; group B (n = 6) pathology-unproven but with postoperative hypocortisolemia consistent with CD; and group C (n = 15) pathology-unproven, without postoperative hypocortisolemia. Group A + B were combined as confirmed CD and group C as unconfirmed CD. Main outcomes Group A + B was compared with group C regarding predictive performance of preoperative 24-hour urinary free cortisol (UFC), late night salivary cortisol (LNSC), 1-mg dexamethasone suppression test (DST), plasma ACTH, and pituitary magnetic resonance imaging (MRI). Results All groups had a similar clinical phenotype. Compared with group C, group A + B had higher mean UFC (P Conclusions Use of strict biochemical thresholds may help avoid offering transsphenoidal surgery to presumed CD patients with equivocal data and improve surgical remission rates. Patients with Cushingoid phenotype but equivocal biochemical data warrant additional rigorous testing.

Context In 2020, the terminology of metabolic dysfunction–associated fatty liver disease (MAFLD) was proposed to replace nonalcoholic fatty liver disease (NAFLD). Objectives This work aimed to investigate the prevalence and incidence of MAFLD and evaluate its effects on incident extrahepatic diseases. Methods A total of 6873 individuals, with a 4.6-year follow-up, were included in this study. Associations of MAFLD and NAFLD with diabetes, chronic kidney disease (CKD), and cardiovascular disease (CVD) were examined using logistic regression and Cox proportional hazards models. Results The prevalence of NAFLD and MAFLD was 40.3% (95% CI, 39.2%-41.5%) and 46.7% (95% CI, 45.6%-47.9%), respectively. Additionally, 321 (4.7%) and 156 (2.3%) participants had MAFLD with excessive alcohol consumption and hepatitis B virus (HBV) infection. During the follow-up period, the incidence of NAFLD and MAFLD was 22.7% (95% CI, 21.3%-24.0%) and 27.0% (95% CI, 25.5%-28.4%). MAFLD was associated with higher risks of incident diabetes (risk ratio [RR] 2.08; 95% CI, 1.72-2.52), CKD (RR 1.64; 95% CI, 1.39-1.94), and CVD (hazard ratio 1.44; 95% CI, 1.15-1.81). Similar associations for NAFLD were observed. Furthermore, the MAFLD subgroups with excessive alcohol consumption (RR 2.49; 95% CI, 1.64-3.78) and HBV infection (RR 1.98; 95% CI, 1.11-3.52) were associated with higher risks of incident diabetes. Conclusion The change from NAFLD to MAFLD did not greatly affect the associations with diabetes, CKD, and CVD. MAFLD further identified those patients of metabolically fatty liver combined with excessive alcohol consumption and HBV infection, who had increased risks of incident diabetes compared with those of non–fatty liver.

Context Adrenal vein sampling (AVS) represents the current diagnostic gold standard for differentiation between unilateral and bilateral primary aldosteronism (PA). Postural stimulation testing (PST) has been used to provide additional diagnostic information. Objective This work aimed to evaluate the diagnostic utility of PST in the differential diagnosis of PA. Methods This cohort study was conducted at a single tertiary reference center. We analyzed 106 PST performed between 2008 and 2020. Diagnosis of PA and cause of PA were determined according to the Endocrine Society Clinical Practice Guideline, taking into account results of saline infusion testing, AVS, preoperative imaging, and outcome after medical or surgical treatment. The suggested cutoffs for the diagnosis of unilateral PA were revisited and optimized for high specificity using receiver operating characteristics (ROC) analysis. Results A total of 106 patients had confirmed PA (unilateral PA: n = 55, bilateral PA: n = 29, AVS unsuccessful/declined by patients: n = 22). Based on decreased aldosterone plasma concentration of 28% or more after 4 hours in the upright position, the PST showed a sensitivity of 36.4% at a specificity of 100% to identify unilateral disease (area under the curve [AUC] = 0.72; 95% CI, 0.62-0.83; P = .001). In patients with valid testing (drop of cortisol of 10% or more after 4 hours, n = 53) the sensitivity of PST rose to 51.4% at a specificity of 100% (AUC = 0.77; 95% CI, 0.65-0.90; P = .001). Conclusion The high specificity of 100% for the detection of unilateral PA in patients with decreased aldosterone by at least 28% after 4 hours makes PST a simple, noninvasive contribution to subtype differentiation in PA.

Introduction:/Aims Patients with neuromuscular disorders (NMDs), including many elderly, immunosuppressed, and disabled individuals, may have been particularly affected during the coronavirus disease 2019 (COVID‐19) pandemic in Lombardy, a COVID‐19 high‐incidence area between February and May 2020. We aimed to evaluate the effects of the COVID‐19 pandemic on the quality of life (QoL) and perceived disease burden of this group of patients. Methods We conducted a cross‐sectional phone‐based survey study between June 1 and June 14, 2020, on a sample of 240 NMD patients followed at our clinic in Milan, Italy. We asked about perceived NMD burden and QoL before and during the COVID‐19 pandemic. We collected responses on access to outpatient care and ancillary services. We investigated the presence of symptoms suggestive of COVID‐19 infection and confirmed cases. Results We collected 205 responses: 53 patients (25.9%) reported a subjective worsening of the underlying NMD. QoL measures showed a significant worsening between pre and pandemic time frames (odds ratio, 2.14 95%; confidence interval, 1.82–2.51). Outpatient visits were postponed in more than half of cases (57.1%), with 104 patients (50.7%) experiencing a cancellation of scheduled diagnostic tests. 79 patients (38.5%) reported at least one symptom attributable to COVID‐19 infection. Among the 10 patients tested with nasopharyngeal swabs, 6 tested positive and 3 died from respiratory failure, including 2 patients on corticosteroid/ immunosuppressive therapy. Discussion The COVID‐19 pandemic affected QoL and limited access to outpatient care and ancillary services of NMD patients in Lombardy between February and May 2020.

BackgroundThe risk of developing gestational diabetes mellitus (GDM) is higher in women undergoing assisted reproductive treatment than in women conceiving spontaneously.ObjectivesTo determine whether the GDM risk after day-3 embryo transfer differs from the GDM risk after day-5 blastocyst transfer.MethodsProspective observational study in women becoming pregnant after first fresh embryo or blastocyst transfer.ResultsA total of 1579 women got pregnant and had live birth; 1300 women got day-3 embryo transfer only, whereas 279 women received at least 1 blastocyst. Of 1579 women, 252 developed GDM. Age, body mass index, baseline estradiol, baseline high-density lipoprotein, and progesterone on the day of human chorionic gonadotropin injection were not different in women receiving day-3 embryos only vs women receiving at least 1 blastocyst. The number and quality of retrieved oocytes were not different in women receiving day-3 embryo transfer from those receiving blastocysts. Our study confirmed already established GDM risk factors such as age and body mass index, baseline estradiol, and high-density lipoprotein, as well as progesterone after ovarian stimulation. We furthermore demonstrate that the GDM incidence in women receiving day-5 blastocyst transfer was significantly higher than those who received day-3 embryo transfer (21.15% vs 14.85%; P = 0.009). Considering confounding factors, we likewise saw that blastocyst transfer was an independent procedure-related GDM risk factor [P = 0.009, Exp (B): 1.56, 95% CI: 1.12-2.18].ConclusionBlastocyst transfer after in vitro fertilization/intracytoplasmic sperm injection increases the risk of developing GDM.

Funding: This paper presents independent research supported by the National Funding: Institute for Health Research (NIHR) Clinical Research Facility and the NIHR Biomedical Research Centre based at Imperial College Healthcare NHS Trust. AA is supported by an NIHR Clinician Scientist award (CS‐2018‐18‐ST2‐002). MAM is funded by the Tommy’s National Centre for Miscarriage Research. MP is supported by an NIHR Academic Clinical Lectureship. CI-E is supported by an Imperial College-BRC IPPRF Fellowship. SAC is supported by an NIHR Academic Clinical Lectureship. EGM is supported by an MRC clinical training fellowship (MR/T006242/1). LY is supported by an MRC clinical training fellowship (MR/R000484/1). ANC is supported by the NHS and BRC. TB is supported by the NIHR Biomedical Research Centre based at Imperial College Healthcare NHS Trust. WSD is supported by an NIHR Research Professorship (RP-2014-05-001). Context: Antenatal complications such as hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR), gestational diabetes (GDM), and preterm birth (PTB) are associated with placental dysfunction. Kisspeptin has emerged as a putative marker of placental function, but limited data exist describing circulating kisspeptin levels across all three trimesters in women with antenatal complications. Objective: To assess whether kisspeptin levels are altered in women with antenatal complications. Methods: Women with antenatal complications (n = 105) and those with uncomplicated pregnancies (n = 265) underwent serial ultrasound scans and blood sampling at the Early Pregnancy Assessment Unit at Hammersmith Hospital, UK, at least once during each trimester (March 2014 to March 2017). The women with antenatal complications (HDP [n = 32], FGR [n = 17], GDM [n = 35], PTB [n = 11], and multiple complications [n=10]) provided 373 blood samples and the controls provided 930 samples. Differences in circulating kisspeptin levels were assessed. Participants: Women with antenatal complications: HDP (n=32), FGR (n=17), GDM (n=35) and PTB (n=11), and 10 women with multiple complications, provided 373 blood samples, and a further 265 controls provided 930 samples. Results: Third-trimester kisspeptin levels were higher than controls in HDP but lower in FGR. The odds of HDP adjusted for gestational age, maternal age, ethnicity, BMI, smoking, and parity were increased by 30% (95% CI, 16%-47%; P

Context Severe forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies. Objective This work aims to identify the genetic cause of growth failure in 3 “classical” GHI individuals. Methods A novel intronic growth hormone receptor gene (GHR) variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function. Results We identified a novel homozygous intronic GHR variant (g.5:42700940T > G, c.618+836T > G), 44 bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C > T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151-bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a nonfunctional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following GH stimulation. Conclusion Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.

Context The interaction of glycated hemoglobin A1c (HbA1c) and glycemic variability in relation to diabetes-related outcomes remains unknown. Objective To evaluate the relationship between HbA1c and all-cause mortality across varying degrees of glycemic variability in patients with type 2 diabetes. Design, Setting, and Patients This was a prospective study conducted in a single referral center. Data of 6090 hospitalized patients with type 2 diabetes was analyzed. Glucose coefficient of variation [coefficient of variation (CV)] was obtained as the measure of glycemic variability by using continuous glucose monitoring for 3 days. Cox proportional hazards regression models were used to estimate hazard ratios and 95% CIs for all-cause mortality. Results During a median follow-up of 6.8 years, 815 patients died. In patients with the lowest and middle tertiles of glucose CV, HbA1c ≥ 8.0% was associated with 136% (95% CI 1.46-3.81) and 92% (95% CI 1.22-3.03) higher risks of all-cause mortality, respectively, as compared with HbA1c 6.0%-6.9%, after adjusting for confounders. However, a null association of HbA1c with mortality was found in patients with the highest tertile of glucose CV. Conclusions HbA1c may not be a robust marker of all-cause mortality in patients with high degree of glycemic variability. New metrics of glycemic control may be needed in these individuals to achieve better diabetes management.

Context Histone deacetylases (HDACs) and histone acetyltransferases (HAT) have an important role in the regulation of gene transcription as well as in the development and function of CD4+Foxp3+ T regulatory (Treg) cells. Our group and others have reported that patients with autoimmune thyroid disease (AITD) show abnormalities in the levels and function of different Treg cell subsets. Objective We aimed to analyze the levels of expression of several HDACs and the Tip60 HAT in the thyroid gland and immune cells from patients with AITD. Methods The expression of HDAC1-11 and the Tip60 HAT, at RNA and protein levels, were determined in thyroid tissue from 20 patients with AITD and 10 healthy controls and these findings were correlated with clinical data. HDAC9 and Tip60 levels were also analyzed in thyroid cell cultures, stimulated or not with proinflammatory cytokines, as well as in different cell subsets from peripheral blood mononuclear cells. Results Altered expression of different HDACs was observed in thyroid tissue from AITD patients, including a significant increase in HDAC9, at RNA and protein levels. Likewise, HDAC9 expression was increased in peripheral blood mononuclear cells particularly in Treg cells in patients with AITD. In contrast, Tip60 expression was reduced in thyroid gland samples from patients with Hashimoto thyroiditis. Conclusion Our results indicate that HDAC expression is dysregulated in thyroid gland and immune cells from patients with AITD, suggesting involvement in the pathogenesis of this condition.

Context Estradiol is the primary female sex hormone and plays an important role for skeletal health in both sexes. Several enzymes are involved in estradiol metabolism, but few genome-wide association studies (GWAS) have been performed to characterize the genetic contribution to variation in estrogen levels. Objective Identify genetic loci affecting estradiol levels and estimate causal effect of estradiol on bone mineral density (BMD). Design We performed GWAS for estradiol in males (n = 147 690) and females (n = 163 985) from UK Biobank. Estradiol was analyzed as a binary phenotype above/below detection limit (175 pmol/L). We further estimated the causal effect of estradiol on BMD using Mendelian randomization. Results We identified 14 independent loci associated (P Conclusion Our findings further support the importance of the body’s own estrogen to maintain skeletal health in males and in females.

Context There are concerns that a higher fat mass in the early life of preterm infants is associated with adverse cardiometabolic outcomes in young adulthood. Objective To investigate the role of IGF-I and growth in determining body composition of preterm infants at term equivalent age. Methods An observational study was conducted from August 2015 to August 2018. From birth to term equivalent age, IGF-I levels were measured bi-weekly and growth was assessed weekly. At term equivalent age, body composition was assessed through air displacement plethysmography; 65 infants with a gestational age of 24 to 32 weeks were assessed at term equivalent age, of whom 58 completed body composition measurement. The main outcome measures were fat (free) mass (g) and fat (free) mass percentage at term equivalent age. Results In the first month of life, each 0.1 nmol/L per week increase in IGF-I was associated with a 465 g (SE 125 g) increase in fat free mass. A greater increase in weight SDS in the first month of life was associated with a higher fat free mass percentage (B 200.9; 95% CI, 12.1-389.6). A higher head circumference SDS was associated with more fat free mass (r = 0.46; 95% CI, 0.21-0.65). However, a greater increase in weight SDS up to term equivalent age was associated with a lower fat free mass percentage (B −55.7, SE 9.4). Conclusion These findings suggest that impaired growth in the first month of life is associated with a less favorable body composition at term equivalent age.

Background Trigeminal neuralgia (TN) is one of the most painful disorder in the orofacial region, and many patients have suffered from this disease. For the effective management of TN, fundamental epidemiologic data related to the target population group are essential. Thus, this study was performed to clarify the epidemiological characteristics of TN in the Korean population. This is the first national study to investigate the prevalence of TN in Korean patients. Methods From 2014 to 2018, population-based medical data for 51,276,314 subscribers to the National Health Insurance Service of Korea were used for this study. Results The incidence of TN was 100.21 per 100,000 person-years in the year of 2018 in Korea, and the male to female ratio was 1:2.14. The age group of 51-59 years had the highest prevalence of TN. Constant increases in medical cost, regional imbalance, and differences in prescription patterns by the medical specialties were showed in the management of TN. Conclusions The results in this study will not only help to study the characteristics of TN, but also serve as an important basis for the effective management of TN in Korea.

Background: Ultrasound-guided caudal epidural injection (CEI) is limited in that it cannot confirm drug distribution at the target site without fluoroscopy. We hypothesized that visualization of solution flow through the inter-laminar space of the lumbosacral spine using color Doppler ultrasound alone would allow for confirmation of drug distribution. Therefore, we aimed to prospectively evaluate the usefulness of this method by comparing the color Doppler image in the paramedian sagittal oblique view of the lumbosacral spine (LS-PSOV) with the distribution of the contrast medium observed during fluoroscopy. Methods: Sixty-five patients received a 10-mL CEI of solution containing contrast medium under ultrasound guidance. During injection, flow was observed in the LSPSOV using color Doppler ultrasonography, following which it was confirmed using fluoroscopy. The presence of contrast image at L5-S1 on fluoroscopy was defined as “successful CEI.” We then calculated prediction accuracy for successful CEI using color Doppler ultrasonography in the LS-PSOV. We also investigated the correlation between the distribution levels measured via color Doppler and fluoroscopy. Results: Prediction accuracy with color Doppler ultrasonography was 96.9%. The sensitivity, specificity, positive predictive value, and negative predictive value were 96.7%, 100%, 100%, and 60.0%, respectively. In 52 of 65 patients (80%), the highest level at which contrast image was observed was the same for both color Doppler ultrasonography and fluoroscopy. Conclusions: Our findings demonstrate that color Doppler ultrasonography in the LS-PSOV is a new method for determining whether a drug solution reaches the lumbosacral region (i.e. , the main target level) without the need for fluoroscopy.

Background: Pillar pain may develop after carpal tunnel release surgery (CTRS). This prospective double-blinded randomized trial investigated the effectiveness of extracorporeal shock wave therapy (ESWT) in pillar pain relief and hand function improvement. Methods: The sample consisted of 60 patients with post-CTRS pillar pain, randomized into two groups. The ESWT group (experimental) received three sessions of ESWT, while the control group received three sessions of sham ESWT, one session per week. Participants were evaluated before treatment, and three weeks, three months, and six months after treatment. The pain was assessed using the visual analogue scale (VAS). Hand functions were assessed using the Michigan hand outcomes questionnaire (MHQ). Results: The ESWT group showed significant improvement in VAS and MHQ scores after treatment at all time points compared to the control group (P < 0.001). Before treatment, the ESWT and control groups had a VAS score of 6.8 ± 1.3 and 6.7 ± 1.0, respectively. Three weeks after treatment, they had a VAS score of 2.8 ± 1.1 and 6.1 ± 1.0, respectively. Six months after treatment, the VAS score was reduced to 1.9 ± 0.9 and 5.1 ± 1.0, respectively. The ESWT group had a MHQ score of 54.4 ± 7.7 before treatment and 73.3 ± 6.8 six months after. The control group had a MHQ score of 54.2 ± 7.1 before treatment and 57.8 ± 4.4 six months after. Conclusions: ESWT is an effective and a safe non-invasive treatment option for pain management and hand functionality in pillar pain.

Background Recalcitrant disc herniation may result in chronic lumbar radiculopathy or sciatica. Fluoroscopically directed epidural injections and other conservative modalities may provide inadequate improvement in some patients. In these cases, percutaneous neurolysis with targeted delivery of medications is often the next step in pain management. Methods An evidence-based system of methodologic assessment, namely, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was used. Multiple databases were searched from 1966 to January 2021. Principles of the best evidence synthesis were incorporated into qualitative evidence synthesis. The primary outcome measure was the proportion of patients with significant pain relief and functional improvement (≥ 50%). Duration of relief was categorized as short-term (< 6 months) and long-term (≥ 6 months). Results This assessment identified one high-quality randomized controlled trial (RCT) and 5 moderate-quality non-randomized studies with an application of percutaneous neurolysis in disc herniation. Overall, the results were positive, with level II evidence. Conclusions Based on the present systematic review, with one RCT and 5 non-randomized studies, the evidence level is II for percutaneous neurolysis in managing lumbar disc herniation.

ContextContinuous glucose monitoring (CGM) overcomes the limitations of glycated hemoglobin (HbA1c).ObjectiveThis study aimed to investigate the relationship between CGM metrics and laboratory HbA1c in pregnant women with type 1 diabetes.MethodsAn observational study enrolled pregnant women with type 1 diabetes who wore CGM devices during pregnancy and postpartum from 11 hospitals in China from January 2015 to June 2019. CGM data were collected to calculate time in range (TIR), time above range (TAR), time below range (TBR), and glycemic variability parameters. Relationships between the CGM metrics and HbA1c were explored. Linear and curvilinear regressions were conducted to investigate the best-fitting model to clarify the influence of HbA1c on the TIR-HbA1c relationship during pregnancy.ResultsA total of 272 CGM data and corresponding HbA1c from 98 pregnant women with type 1 diabetes and their clinical characteristics were analyzed in this study. Mean HbA1c and TIR were 6.49 ± 1.29% and 76.16 ± 17.97% during pregnancy, respectively. HbA1c was moderately correlated with TIR3.5-7.8(R = –0.429, P = .001), mean glucose (R = 0.405, P = .001) and TAR7.8 (R = 0.435, P = .001), but was weakly correlated with TBR3.5 (R = 0.034, P = .001) during pregnancy. On average, a 1% (11 mmol/mol) decrease in HbA1c corresponded to an 8.5% increase in TIR3.5–7.8. During pregnancy, HbA1c of 6.0%, 6.5%, and 7.0% were equivalent to a TIR3.5–7.8 of 78%, 74%, and 69%, respectively.ConclusionWe found there was a moderate correlation between HbA1c and TIR3.5–7.8 during pregnancy. To achieve the HbA1c target of less than 6.0%, pregnant women with type 1 diabetes should strive for a TIR3.5–7.8 of greater than 78% (18 hours 43 minutes) during pregnancy.

Background: Complex regional pain syndrome (CRPS) is an intractable pain disease with various symptoms. Here, we investigated the disease status, work life, sleep problems, medical insurance, economic status, psychological problems, and quality of life (QOL) of CRPS patients. Methods: CRPS patients from 37 university hospitals in South Korea were surveyed. The survey questionnaire consisted of 24 questions on the following aspects of CRPS patients: sex, age, occupation, cause of injury, activities of daily living (ADL), pain severity, sleep disturbance, level of education, economic status, therapeutic effect, and suicidal ideation. Additionally, the abbreviated World Health Organization Quality of Life (WHOQOL-BREF) questionnaire, consisting of 26 questions, was used to identify the status of QOL. Results: A total of 251 patients completed the questionnaire. According to the survey, 54.2% patients could not perform ADL on their own. Over the previous week, the mean pain score was 7.15 ± 1.78 (out of a total of 10 points); 92.1% of patients had sleep disorders and 80.5% had suicidal ideation, with most patients suffering from psychological problems. The average for each domain of WHOQOL-BREF was as follows: 21.74 ± 14.77 for physical, 25.22 ± 17.66 for psychological, 32.02 ± 22.36 for social relationship, and 30.69 ± 15.83 for environmental (out of a total of 100 points each). Occupation, ADL, sleep time, therapeutic effect, and suicidal ideation were statistically correlated with multiple domains. Conclusions: Most patients had moderate to severe pain, economic problems, limitations of their ADL, sleep problems, psychological problems, and a low QOL score.

Background Postoperative pain management is crucial for patients undergoing total knee arthroplasty (TKA). There have been many recent clinical trials on post-TKA peripheral nerve block; however, they have reported inconsistent findings. In this meta-analysis, we aimed to comprehensively analyze studies on post-TKA analgesia to provide evidence-based clinical suggestions. Methods We performed a computer-based query of PubMed, Embase, the Cochrane Library, and the Web of Science to retrieve related articles using neurothe following search terms: nerve block, nerve blockade, chemodenervation, chemical neurolysis, peridural block, epidural anesthesia, extradural anesthesia, total knee arthroplasty, total knee replacement, partial knee replacement, and others. After quality evaluation and data extraction, we analyzed the complications, visual analogue scale (VAS) score, patient satisfaction, perioperative opioid dosage, and rehabilitation indices. Evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation approach. Results We included 16 randomized controlled trials involving 981 patients (511 receiving peripheral nerve block and 470 receiving epidural block) in the final analysis. Compared with an epidural block, a peripheral nerve block significantly reduced complications. There were no significant between-group differences in the postoperative VAS score, patient satisfaction, perioperative opioid dosage, and rehabilitation indices. Conclusions Our findings demonstrate that the peripheral nerve block is superior to the epidural block in reducing complications without compromising the analgesic effect and patient satisfaction. Therefore, a peripheral nerve block is a safe and effective postoperative analgesic method with encouraging clinical prospects.

Background The present study employed National Health Insurance Data to explore complex regional pain syndrome (CRPS) updated epidemiology in a Korean context. Methods A CRPS cohort for the period 2009-2016 was created based on Korean Standard Classification of Diseases codes alongside the national registry. The general CRPS incidence rate and the yearly incidence rate trend for every CRPS type were respectively the primary and secondary outcomes. Among the analyzed risk factors were age, sex, region, and hospital level for the yearly trend of the incidence rate for every CRPS. Statistical analysis was performed via the chi-square test and the linear and logistic linear regression tests. Results Over the research period, the number of registered patients was 122,210. The general CRPS incidence rate was 15.83 per 100,000, with 19.5 for type 1 and 12.1 for type 2. The condition exhibited a declining trend according to its overall occurrence, particularly in the case of type 2 (P < 0.001). On the other hand, registration was more pervasive among type 1 compared to type 2 patients (61.7% vs. 38.3%), while both types affected female individuals to a greater extent. Regarding age, individuals older than 60 years of age were associated with the highest prevalence in both types, regardless of sex (P < 0.001). Conclusions CRPS displayed an overall incidence of 15.83 per 100,000 in Korea and a declining trend for every age group which showed a negative association with the aging shift phenomenon.

Context Comprehensive assessment of metabolism in maternal obesity and pregnancy disorders can provide information about the shared maternal-fetal milieu and give insight into both maternal long-term health and intergenerational transmission of disease burden. Objective To assess levels, profiles, and change in the levels of metabolic measures during pregnancies complicated by obesity, gestational diabetes (GDM), or hypertensive disorders. Design, Setting and Participants A secondary analysis of 2 study cohorts, PREDO and RADIEL, including 741 pregnant women. Main Outcome Measures We assessed 225 metabolic measures by nuclear magnetic resonance in blood samples collected at median 13 [interquartile range (IQR) 12.4-13.7], 20 (IQR 19.3-23.0), and 28 (27.0-35.0) weeks of gestation. Results Across all 3 time points women with obesity [body mass index (BMI) ≥ 30kg/m2] in comparison to normal weight (BMI 18.5-24.99 kg/m2) had significantly higher levels of most very-low-density lipoprotein-related measures, many fatty and most amino acids, and more adverse metabolic profiles. The change in the levels of most metabolic measures during pregnancy was smaller in obese than in normal weight women. GDM, preeclampsia, and chronic hypertension were associated with metabolic alterations similar to obesity. The associations of obesity held after adjustment for GDM and hypertensive disorders, but many of the associations with GDM and hypertensive disorders were rendered nonsignificant after adjustment for BMI and the other pregnancy disorders. Conclusions This study shows that the pregnancy-related metabolic change is smaller in women with obesity, who display metabolic perturbations already in early pregnancy. Metabolic alterations of obesity and pregnancy disorders resembled each other suggesting a shared metabolic origin.

Introduction/Aims In this study, we examined the social and health impacts of the coronavirus disease 2019 (COVID‐19) pandemic and social guidelines on people with muscular dystrophies. Methods A prospective de‐identified electronic survey was distributed to adults with self‐reported facioscapulohumeral muscular dystrophy (FSHD), myotonic dystrophy (DM), and limb‐girdle muscular dystrophy (LGMD) enrolled in national registries or with patient advocacy groups. The COVID‐19 Impact Survey was developed by muscular dystrophy experts in association with patient collaborators and advocacy groups. The Perceived Stress Scale was used to measure perceived stress. Results Respondents (n = 774: 56% FSHD; 35% DM, and 9% LGMD) were mostly women and middle‐aged (range 19–87 y). Rates of COVID‐19 infections were low (

Context Although gonadotropin-releasing hormone stimulation test (GnRHST) is the gold standard in diagnosing central precocious puberty (CPP), it is invasive, expensive, and time-consuming, requiring multiple blood samples to measure gonadotropin levels. Objective We evaluated whether urinary hormones could be potential biomarkers for prepuberty or postpuberty, aiming to simplify the current diagnosis and prognosis procedure. Methods We performed a cross-sectional study of a total of 355 girls with CPP in National Clinical Research Center for Child Health in China, including 258 girls with positive and 97 girls with negative results from GnRHST. Twenty patients received GnRH analogue (GnRHa) treatment and completed a 6-month follow up. We measured luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, prolactin, progesterone, testosterone, and human chorionic gonadotropin in the first morning voided urine samples. Results Their urinary LH levels and the ratios of LH to FSH increased significantly with the advancement in Tanner stages. uLH levels were positively associated with basal and peak LH levels in the serum after GnRH stimulation. A cutoff value of 1.74 IU/L for uLH reached a sensitivity of 69.4% and a specificity of 75.3% in predicting a positive GnRHST result. For the combined threshold (uLH ≥ 1.74 + uLH-to-uFSH ratio > 0.4), the specificity reached 86.6%. After 3 months of GnRHa therapy, the uLH and uFSH levels decreased accordingly. Conclusion uLH could be a reliable biomarker for initial CPP diagnosis and screening; uLH could also be an effective marker for evaluating the efficacy of clinical treatment.

Context There is evidence demonstrating variation in insulin sensitivity across the menstrual cycle. However, to date, research has yielded inconsistent results. Objective This study investigated variation in insulin sensitivity across the menstrual cycle and associations with body mass index (BMI), physical activity, and cardiorespiratory fitness (CRF). Methods Data from 1906 premenopausal women in NHANES cycles 1999 to 2006 were analyzed. Menstrual cycle day was assessed using questionnaire responses recording days since last period. Rhythmic variation of plasma glucose, triglycerides, and insulin, homeostatic model of insulin resistance (HOMA-IR), and adipose tissue insulin resistance index (ADIPO-IR) across the menstrual cycle were analyzed using cosinor rhythmometry. Participants were assigned low or high categories of BMI, physical activity, and CRF, and category membership included in cosinor models as covariates. Results Rhythmicity was demonstrated by a significant cosine fit for glucose (P = .014) but not triglycerides (P = .369), insulin (P = .470), HOMA-IR (P = .461), and ADIPO-IR (P = .335). When covariates were included, rhythmicity was observed when adjusting for: 1) BMI: glucose (P Conclusion Rhythmicity in insulin sensitivity and associated metabolites across the menstrual cycle are modified by BMI, physical activity, and CRF.