Citations

AbstractBackgroundLithium is regarded as a first‐line treatment for bipolar disorder (BD), but partial response and non‐response commonly occurs. There exists a need to identify lithium non‐responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response.MethodsThe PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse.ResultsA total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness.ConclusionsIn this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

Abstract Context Hypoparathyroidism is characterized by low serum calcium, increased serum phosphorus, and inappropriately low or decreased serum parathyroid hormone, which may be associated with soft tissue calcification in the basal ganglia of the brain. Objective To assess the prevalence and factors involved in the pathophysiology of basal ganglia calcification (BGC) in the brain in chronic hypoparathyroidism and to evaluate proposed pathophysiologic mechanisms. Design Case-control study with retrospective review of medical records over 20 years. Setting Single academic medical center. Patients 142 patients with chronic hypoparathyroidism and computed tomography (CT) head scans followed between January 1, 2000 and July 9, 2020, and 426 age- and sex-matched controls with CT head scans over the same interval. Interventions None. Main Outcome Measures Demographic, biochemical, and CT head imaging findings, with semiquantitative assessment of volumetric BGC. Results The study found that 25.4% of 142 patients followed for a median of 17 years after diagnosis of chronic hypoparathyroidism had BGC, which developed at a younger age than in controls. BGC was 5.1-fold more common in nonsurgical patients and less common in postsurgical patients. Low serum calcium and low calcium/phosphate ratio correlated with BGC. Neither serum phosphorus nor calcium × phosphate product predicted BGC. Lower serum calcium was associated with greater volume of BGC. The extent of BGC varied widely, with nonsurgical patients generally having a greater volume and distribution of calcification. Conclusions BGC is associated with low serum calcium and low serum calcium/phosphate ratio, which may be related to severity of the disease, its etiology, or duration of treatment.

ObjectiveTo determine the incidence of psoriatic arthritis (PsA) in a US population and describe trends in incidence and mortality over 5 decades.MethodsThe previously identified population‐based cohort that included Olmsted County, Minnesota residents ≥18 years of age who fulfilled PsA criteria during 1970–1999 was extended to include patients with incident PsA during 2000–2017. Age‐ and sex‐specific incidence rates and point prevalence, adjusted to the 2010 US White population, were reported.ResultsThere were 164 incident cases of PsA in 2000–2017 (mean ± SD age 46.4 ± 12.0 years; 47% female). The overall age‐ and sex‐adjusted annual incidence of PsA per 100,000 population was 8.5 (95% confidence interval [95% CI] 7.2–9.8) and was higher in men (9.3 [95% CI 7.4–11.3]) than women (7.7 [95% CI 5.9–9.4]) in 2000–2017. Overall incidence was highest in the 40–59 years age group. The incidence rate was relatively stable during 2000–2017, with no evidence of an overall increase or an increase in men only (but a modest increase of 3% per year in women), compared to 1970–1999 when a 4%‐per‐year increase in incidence was observed. Point prevalence was 181.8 per 100,000 population (95% CI 156.5–207.1) in 2015. The percentage of women among those with PsA increased from 39% in 1970–1999 and 41% in 2000–2009 to 54% in 2010–2017 (P = 0.08). Overall survival in PsA did not differ from the general population (standardized mortality ratio 0.85 [95% CI 0.61–1.15]).ConclusionThe incidence of PsA in this predominantly White US population was stable in 2000–2017, in contrast to previous years. However, an increasing proportion of women with PsA was found in this study.

Purpose Parental leave for new parents is essential as they adjust to the physical and psychological changes that accompany childbirth and caring for a newborn. This study sought to determine the current state of parental leave policies for medical students at medical schools in the United States. Method From November to December 2019, 2 researchers independently reviewed the websites of 199 U.S. MD-granting and DO-granting medical schools (including in U.S. territories). Online student handbooks and school webpages were searched for the following keywords: “pregnant” OR “pregnancy” OR “maternity” OR “parent” OR “family” OR “child” OR “birth.” Data were analyzed using descriptive statistics. Fisher’s exact tests evaluated differences in proportion by group. Results Of 199 schools, 65 (32.66%) had parental leave policies available online or in the handbook: 39 of 155 (25.16%) MD-granting and 26 of 44 (59.09%) DO-granting schools. Of those policies, 59 (90.77%) were included in the student handbook. Most policies (28, 43.08%) were included as an option within the school’s general leave of absence policy. Both parents were included in 38 (58.46%) policies; 23 (35.38%) policies mentioned only mothers; and 4 (6.15%) were unknown. An option to maintain original graduation date was offered in 21 (32.1%) schools’ policies. Three schools (4.62%) included adoption as qualifying for parental leave. When comparing MD and DO programs, DO programs were statistically more likely to have a parental leave policy: 39 (25.16%) vs 26 (59.09%); P < .001. Conclusions Balancing medical school with pregnancy and childbirth necessitates administrative support to address the inherent scheduling challenges. Currently, many schools lack parental leave policies for medical students that are easily accessible, are separate from formal leaves of absence, allow for at least 12 weeks, and are tailored to the student academic year to ensure on-time completion of medical education.

Objectives To describe the percentile distribution of multimorbidity across age by sex, race and ethnicity, and to demonstrate the utility of multimorbidity percentiles to predict mortality. Design Population-based descriptive study and cohort study. Setting Olmsted County, Minnesota (USA). Participants We used the medical records-linkage system of the Rochester Epidemiology Project (REP; http://www.rochesterproject.org ) to identify all residents of Olmsted County, Minnesota who reached one or more birthdays between 1 January 2005 and 31 December 2014 (10 years). Methods For each person, we obtained the count of chronic conditions (out of 20 conditions) present on each birthday by extracting all of the diagnostic codes received in the 5 years before the index birthday from the electronic indexes of the REP. To compare each person’s count to peers of same age, the counts were transformed into percentiles of the total population and displayed graphically across age by sex, race and ethnicity. In addition, quintiles 1, 2, 4 and 5 were compared with quintile 3 (reference) to predict the risk of death at 1 year, 5 years and through end of follow-up using time-to-event analyses. Follow-up was passive using the REP. Results We identified 238 010 persons who experienced a total of 1 458 094 birthdays during the study period (median of 6 birthdays per person; IQR 3–10). The percentiles of multimorbidity across age did not vary noticeably by sex, race or ethnicity. In general, there was an increased risk of mortality at 1 and 5 years for quintiles 4 and 5 of multimorbidity. The risk of mortality for quintile 5 was greater for younger age groups and for women. Conclusions The assignment of multimorbidity percentiles to persons in a population may be a simple and intuitive tool to assess relative health status, and to predict short-term mortality, especially in younger persons and in women.

Background: Besides their other roles, brain imaging and other biomarkers of Alzheimer’s disease (AD) have the potential to inform a cognitively unimpaired (CU) person’s likelihood of progression to mild cognitive impairment (MCI) and benefit subject selection when evaluating promising prevention therapies. We previously described that among baseline FDG-PET and MRI measures known to be preferentially affected in the preclinical and clinical stages of AD, hippocampal volume was the best predictor of incident MCI within 2 years (79%sensitivity/78%specificity), using standard automated MRI volumetric algorithmic programs, binary logistic regression, and leave-one-out procedures. Objective: To improve the same prediction by using different hippocampal features and machine learning methods, cross-validated via two independent and prospective cohorts (Arizona and ADNI). Methods: Patch-based sparse coding algorithms were applied to hippocampal surface features of baseline TI-MRIs from 78 CU adults who subsequently progressed to amnestic MCI in approximately 2 years (“progressors”) and 80 matched adults who remained CU for at least 4 years (“nonprogressors”). Nonprogressors and progressors were matched for age, sex, education, and apolipoprotein E4 allele dose. We did not include amyloid or tau biomarkers in defining MCI. Results: We achieved 92%prediction accuracy in the Arizona cohort, 92%prediction accuracy in the ADNI cohort, and 90%prediction accuracy when combining the two demographically distinct cohorts, as compared to 79%(Arizona) and 72%(ADNI) prediction accuracy using hippocampal volume. Conclusion: Surface multivariate morphometry and sparse coding, applied to individual MRIs, may accurately predict imminent progression to MCI even in the absence of other AD biomarkers.

Objective: To compare language and audiological outcomes among infants (<9 and <12 mo) and older children receiving cochlear implantation (CI). Study design: Retrospective chart review. Setting: Tertiary academic referral center. Patients: Pediatric patients receiving CI between October 1995 and October 2019. Intervention: Cochlear implantation Main Outcome Measures: Most recent language and audiological assessment scores were evaluated by age group. Results: A total of 118 children were studied, including 19 who were implanted <9 months of age, 19 implanted 9 to <12 months of age, and 80 implanted 12 to <36 months of age. The mean duration of follow-up was 7.4 ± 5.0 years. Most recent REEL-3 receptive (88 ± 12 vs. 73 ± 15; p = 0.020) and expressive (95 ± 13 vs. 79 ± 12; p = 0.013) communication scores were significantly higher in the <9 months group compared to the 9 to <12 months group. PLS and OWLS auditory comprehension and oral expression scores were significantly higher in the <12 months group compared to the 12 to <36 months group. The difference in NU-CHIPS scores between <12 and 12 to <36 months was statistically significant (89% ± 6 vs. 83% ± 12; p = 0.009). LNT scores differed significantly between <9 and 9 to <12 months (94% ± 4 vs. 86% ± 10; p = 0.028). Conclusions: The recent FDA expansion of pediatric CI eligibility criteria to include infants as young as 9 months of age should not serve as a strict clinical cutoff. Rather, CI can be pursued in appropriately selected younger infants to optimize language and audiological outcomes.

Objective: To compare the prevalence of surgical, anesthetic, and device-related complications among infants and older children receiving cochlear implantation (CI). Study Design: Retrospective chart review. Setting: Tertiary academic referral center. Patients: Pediatric patients who underwent CI from November 1990 to January 2020. Intervention: CI. Main Outcome Measures: Surgical, anesthetic, and device-related complication rates were compared by age group (<12 versus 12–23 versus 24+ months with subset analysis of <9 versus 9–11 months). Results: A total of 406 primary pediatric CI surgeries encompassing 482 ears were analyzed, including 45 ears in 23 patients implanted less than 9 months and 89 ears in 49 patients less than 12 months. No anesthetic complications occurred. Postoperative surgical and device-related complication rates were not significantly different among the less than 12, 12 to 23, and 24+ month groups (16% versus 16% versus 12%; p = 0.23) or between the less than 9 and 9 to 11 month groups (22% versus 9%; p = 0.09). Thirty-day readmission was significantly higher for patients less than 12 months compared with patients 24+ months (6% versus <1%; p = 0.011), but was not significantly higher compared with patients 12 to 23 months (6% versus 3%; p = 0.65). Reoperation rates did not differ significantly among the less than 12, 12 to 23, and 24+ month groups (10% versus 7% versus 6%; p = 0.31). Conclusions: The prevalence of surgical, anesthetic, and device related complications was not significantly different among infants implanted less than 9 or less than 12 months of age when compared with older children. These data provide evidence for the continued expansion of pediatric cochlear implant candidacy criteria to include appropriately selected infants less than 9 months of age.

AbstractBackground and aimOff‐label use of fibrates in patients with cholestatic liver diseases results in improved biochemical parameters and pruritus; however, their safety in this population has been a concern. This study summarizes safety data for fibrates when used for treatment of cholestatic liver diseases.MethodsA systematic review of published studies evaluating the use of fibrates for treatment of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) was performed. Electronic databases were searched up to December 2019 for published studies evaluating treatment outcomes associated to fibrates for these 2 diseases.ResultsA total of 37 studies were identified, including 31 for PBC and 6 for PSC, with a total of 1107 unique patients treated with fibrates ± ursodeoxycholic acid (UDCA). Most studies evaluated fenofibrate and bezafibrate, and only 1 study evaluated pemafibrate. There were no studies evaluating gemfibrozil or clofibrate. The most commonly reported adverse events (AEs) were gastrointestinal and musculoskeletal. Elevations of aminotransferases and serum creatinine were reported more commonly in patients treated with UDCA plus fibrates versus UDCA monotherapy.ConclusionsFibrates appear to be safe and well tolerated in patients with PBC, with a low frequency of AEs. There are scarce data about the safety of these agents for treatment of PSC.

Aim To explore the feasibility and possible effects of low‐frequency repetitive transcranial magnetic stimulation (rTMS) delivered to the supplementary motor area (SMA) on tic severity and motor system neurophysiology in children with Tourette syndrome. Method Ten children with Tourette syndrome (eight males, two females; 9–15y) participated in this open‐label, phase 1 clinical trial. Treatment consisted of 1800 low‐frequency (1Hz) neuronavigated robotic rTMS (100% resting motor threshold) to the SMA, bilaterally for 15 sessions. The primary outcome was a change in Yale Global Tic Severity Scale (YGTSS) total score from baseline to posttreatment. Secondary outcome measures included changes in magnetic resonance spectroscopy metabolite concentrations, TMS neurophysiology measures, TMS motor maps, and clinical assessments (anxiety, depression) from baseline to the end of treatment. Results The YGTSS score decreased from baseline after treatment ( p <0.001; Cohen's d =2.9). All procedures were well‐tolerated. Interpretation Robot‐driven, neuronavigated bilateral rTMS of the SMA is feasible in children with Tourette syndrome and appears to reduce tic severity. What this paper adds Repetitive transcranial magnetic stimulation (rTMS) is feasible to use in children with Tourette syndrome. rTMS is tolerated by children with Tourette syndrome. Precise targeting of the supplementary motor area using functional magnetic resonance imaging is also feasible in these children.