Citations

PURPOSE: This study aimed to analyze organ system-based causes and non-organ system-based mechanisms of death (COD, MOD) in people with myelomeningocele (MMC), comparing urological to other COD. METHODS: A retrospective review was performed of 16 institutions in Canada/United States of non-random convenience sample of people with MMC (born > = 1972) using non-parametric statistics. RESULTS: Of 293 deaths (89% shunted hydrocephalus), 12% occurred in infancy, 35% in childhood, and 53% in adulthood (documented COD: 74%). For 261 shunted individuals, leading COD were neurological (21%) and pulmonary (17%), and leading MOD were infections (34%, including shunt infections: 4%) and non-infectious shunt malfunctions (14%). For 32 unshunted individuals, leading COD were pulmonary (34%) and cardiovascular (13%), and leading MOD were infections (38%) and non-infectious pulmonary (16%). COD and MOD varied by shunt status and age (p < = 0.04), not ambulation or birthyear (p > = 0.16). Urology-related deaths (urosepsis, renal failure, hematuria, bladder perforation/cancer: 10%) were more likely in females (p = 0.01), independent of age, shunt, or ambulatory status (p > = 0.40). COD/MOD were independent of bladder augmentation (p = >0.11). Unexplained deaths while asleep (4%) were independent of age, shunt status, and epilepsy (p >= 0.47). CONCLUSION: COD varied by shunt status. Leading MOD were infectious. Urology-related deaths (10%) were independent of shunt status; 26% of COD were unknown. Life-long multidisciplinary care and accurate mortality documentation are needed.

Abstract Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Steatotic hepatocytes accumulate profound numbers of large neutral lipid‐storage organelles called lipid droplets (LDs). The process by which the formation or utilization of these organelles are perturbed during NAFLD and NASH is poorly defined. EtOH consumption can also exacerbate these conditions markedly by yet unknown mechanisms. Thus, there is a critical need to understand lipolytic mechanisms for LD catabolism in hepatocytes. In adipocytes, catecholamines induce lipolysis through a β‐adrenergic/cAMP pathway that activates cytosolic lipases ATGL and HSL to catabolize LD triglycerides. Importantly, β‐adrenergic induction of LD catabolism has not been demonstrated in hepatocytes. Thus, the GOAL of this study was to determine whether hepatocytes, like adipocytes, also undergo cAMP‐mediated lipolysis in response to β‐adrenergic (β‐AR) stimulation. First, treatment of primary rat hepatocytes or Hep3B human hepatoma cells with the β‐AR agonist isoproterenol caused a 20–40% reduction in total cellular LD content within 24 hours. β‐AR induced LD loss was mimicked by the cAMP agonist forskolin/IBMX and was abrogated by the cAMP‐dependent protein kinase (PKA) inhibitor H89. In correlation, PKA activation following β‐AR stimulation was confirmed by FRET biosensors and biochemical analysis. β‐AR stimulation directly activated the lipolytic pathway, as evidenced by cAMP/PKA‐mediated phosphorylation of hormone sensitive lipase (HSL) and adipose triglyceide lipase (ATGL). In addition, pharmacological inhibitors against ATGL or HSL each blocked β‐AR induced LD loss, suggesting that lipase activation is critical for this process in stimulated cells. To examine whether β‐AR/cAMP stimulation triggered lipase recruitment directly to the LD, live‐cell imaging of Hep3B cells expressing either ATGL‐EGFP or HSL‐sfGFP showed that within 60 min of stimulation, each lipase was significantly displaced from the cytosol and recruited to the LD surface. This recruitment was blocked by the PKA inhibitor H89. Finally, to test if EtOH exposure attenuates the activation of lipolysis in hepatocytes, we isolated primary hepatocytes from rats fed a 6‐week ethanol‐containing Lieber‐DeCarli diet. Compared with controls, ethanol‐exposed hepatocytes showed a drastic inhibition in lipase activation and LD breakdown following β‐AR/cAMP stimulation. Remarkably, in ethanol‐metabolizing VA13 hepatocytes, ethanol insult completely prevented isoproterenol‐induced translocation of ATGL‐EGFP to the LD. In summary , these results show that β‐adrenergic stimulation mobilizes cytosolic lipases for LD breakdown in hepatocytes, and perturbation of this pathway could be a major consequence of chronic ethanol insult leading to fatty liver. Manipulation of this regulatory cascade could be useful in developing new therapies to attenuate fatty liver disease. Support or Funding Information This study was generously supported by funding from NIAAA 5R01AA020735 (MAM and CAC) and NIDDK 5R37DK044650 (MAM), T32DK007352‐36 (MBS), and P30DK084567 (Mayo Clinic Center for Cell Signaling in Gastroenterology).

Introduction Several common and functional genes are known to contribute to renal, blood vessel, and cardiac functional characteristics associated with sodium (Na + ) handling, vascular reactivity, and cardiac output, respectively. Many of these same genes are suggested to contribute to differential responsiveness to blood pressure (BP) therapy. Few studies have explored the simultaneous phenotypic consequence of multiple genes critical for BP control. Despite a significant impulse of the medical community towards personalized medicine, BP therapy is typically guided by algorithms that do not include a patient's genetic information. Purpose The purpose of this study was to determine the impact of 14 genes on time to BP control in response to common BP therapy, with a specific focus on genes associated with drug metabolism and protein function in the kidney, the blood vessels, and the heart. Methods Eighty‐six patients completed one study visit consisting of a buccal swab for DNA extraction and genotyping, measurement of ambulatory BP, and a medical chart review for objective BP history. Genes in the analysis included those that encode for one drug metabolizing enzyme (CYP2D6), renal Na + handling (SCNN1A, WNK1, SLC12A3, and Alpha Adducin), vascular function (angiotensin, ACE, angiotensin‐II receptor type‐I, and renin), and cardiac function (the β 1 and β 2 adrenergic receptors ADRB1 and ADRB2, respectively). Results Genetic variation of WNK1 (rs1159744) demonstrated differential responses to diuretic therapy (determined as those with blood pressure under 140/90 vs. those above 140/90 according to genotype)(WNK1=GG>CG/CC, P<0.05). Genes that encode ADRB1 (rs1801252), ADRB2 (rs1042713), and CYP2D6 (rs3892097) demonstrated differential response to β‐blocker therapy (ADRB1=Ser/Ser>SerThr/ThrThr, ADRB2=GG>AG/AA, CYP2D6=CC>CT/TT, P<0.05). Genes that encode angiotensin (rs699), ACE (rs1799752), and renin (rs12750834) demonstrated differential response to ACE‐inhibition and angiotensin receptor blockade (angiotensin=CT/TT>CC, ACE=Ins/Ins>InsDel/DelDel, renin=AG/AA>GG, p<0.05). Conclusion These results demonstrate that genetic variants encoding proteins involved in renal Na + handling, vascular function, and cardiac output influence response to BP therapy for their respective drug classes. Support or Funding Information Funded by Geneticure

Introduction Hypertension is one of the most important preventable contributors to disease and death worldwide and represents the most common condition seen in the primary care setting. Approximately one in three adults living in the US has hypertension. Despite the prevalence and impact of hypertension, little data exists on the average time to blood pressure (BP) control in US patients and time to control according to common BP medication classes. Purpose Therefore, the purpose of this study was to assess the average time to BP control in adults with controlled hypertension, according to drug class. Methods For this study we assessed how long (in months) and how many clinic visits were needed in order to control BP according to common medication classes in patients with existing hypertension. The study was performed at two clinical sites where patients came in for one visit for an in‐clinic assessment of BP and for completion of a patient survey regarding their history of BP. The primary care physician performed a chart review for a detailed objective BP history. Results Ninety‐nine patients completed all aspects of the study (age=58±0.8yrs., %female=46, height=169±1.0cm, weight=86±1.4kg, BMI=29.9±0.4m/kg 2 ). The average initial BP was 151±2mmHg systolic (SBP), 91±1mmHg diastolic, and 111±1mmHg mean arterial (MAP). Patients demonstrated a significant drop in BP with therapy (SBP=16mmHg, DBP=10mmHg, MAP=12mmHg). Patients were prescribed an average of 1.8 BP medications (62% on ACE‐inhibitor, 42% on diuretic, 33% on β‐blocker, 27% on angiotensin receptor blocker, and 16% on Ca + channel blocker). The average time to BP control was 14.9 months or 3.6 clinic visits. Patients on a diuretic had the longest time to BP control, while patients on a Ca + channel blocker had the shortest time to control (diuretic=19.5±10.4, angiotensin receptor blocker=22.8±13.1, ACE‐inhibitor=22.2±11.4, β‐blocker=24.5±16.9, Ca + channel blocker=9.9±4.5 months, pANOVA<0.05). In contrast, patients on a Ca + channel blocker had significantly more clinic visits to attain BP control (diuretic=4.5±0.6, ACE‐inhibitor=3.1±0.4, angiotensin receptor blocker=3.9±0.6, β‐blocker=4.9±0.7, Ca + channel blocker=5.1±0.7 visits). Conclusion These results suggest important differences in the time to BP control, and the number of office visits necessary for BP control according to common classes of hypertension therapies. Funding was provided by Geneticure, LLC Support or Funding Information Funded by Geneticure

Purpose To develop a machine learning model capable of identifying subscapularis tears before surgery based on imaging and physical examination findings. Methods Between 2010 and 2020, 202 consecutive shoulders underwent arthroscopic rotator cuff repair by a single surgeon. Patient demographics, physical examination findings (including range of motion, weakness with internal rotation, lift/push‐off test, belly press test, and bear hug test), and imaging (including direct and indirect signs of tearing, biceps status, fatty atrophy, cystic changes, and other similar findings) were included for model creation. Results Sixty percent of the shoulders had partial or full thickness tears of the subscapularis verified during surgery (83% of these were upper third). Using only preoperative imaging‐related parameters, the XGBoost model demonstrated excellent performance at predicting subscapularis tears (c‐statistic, 0.84; accuracy, 0.85; F1 score, 0.87). The top 5 features included direct signs related to the presence of tearing as evidenced on magnetic resonance imaging (MRI) (changes in tendon morphology and signal), as well as the quality of the MRI and biceps pathology. Conclusions In this study, machine learning was successful in predicting subscapularis tears by MRI alone in 85% of patients, and this accuracy did not decrease by isolating the model to the top features. The top five features included direct signs related to the presence of tearing as evidenced on MRI (changes in tendon morphology and signal), as well as the quality of the MRI and biceps pathology. Last, in advanced modeling, the addition of physical examination or patient characteristics did not make a significant difference in the predictive ability of this model. Level of Evidence Level III, diagnostic case‐control study.