Molecular mechanisms underlying adverse effects of dexamethasone and betamethasone in the developing cardiovascular system.

Antenatal glucocorticoids accelerate fetal lung maturation and reduce mortality in preterm babies but can trigger adverse effects on the cardiovascular system. The mechanisms underlying off-target effects of the synthetic glucocorticoids mostly used, Dexamethasone (Dex) and Betamethasone (Beta), are unknown. We investigated effects of Dex and Beta on cardiovascular structure and function, and underlying molecular mechanism using the chicken embryo, an established model system to isolate effects of therapy on the developing heart and vasculature, independent of effects on the mother or placenta. Fertilized eggs were treated with Dex (0.1 mg kg-1 ), Beta (0.1 mg kg-1 ), or water vehicle (Control) on embryonic day 14 (E14, term = 21 days). At E19, biometry, cardiovascular function, stereological, and molecular analyses were determined. Both glucocorticoids promoted growth restriction, with Beta being more severe. Beta compared with Dex induced greater cardiac diastolic dysfunction and also impaired systolic function. While Dex triggered cardiomyocyte hypertrophy, Beta promoted a decrease in cardiomyocyte number. Molecular changes of Dex on the developing heart included oxidative stress, activation of p38, and cleaved caspase 3. In contrast, impaired GR downregulation, activation of p53, p16, and MKK3 coupled with CDK2 transcriptional repression linked the effects of Beta on cardiomyocyte senescence. Beta but not Dex impaired NO-dependent relaxation of peripheral resistance arteries. Beta diminished contractile responses to potassium and phenylephrine, but Dex enhanced peripheral constrictor reactivity to endothelin-1. We conclude that Dex and Beta have direct differential detrimental effects on the developing cardiovascular system.

Assessment of heavy metals accumulation by vegetables irrigated with different stages of textile wastewater for evaluation of food and health risk.

Wastewater irrigation for vegetable cultivation is greatly concerned about the presence of toxic metals in irrigated soil and vegetables which causes possible threats to human health. This study aimed to ascertain the accumulation of heavy metals (HMs) in edible parts of vegetables irrigated with different stages of textile dyeing wastewater (TDW). Bio-concentration factor (BCF), Estimated daily intake (EDI), and target hazard quotient (THQ) were computed to estimate human health risks and speculate the hazard index (HI) of adults and children with the consumption of HMs contaminated vegetables at recommended doses. Five vegetables (red amaranth, Indian spinach, cauliflower, tomato, and radish) in a pot experiment were irrigated with groundwater (T1) and seven stages of TDW (T2∼T8) following a randomized complete block design (RCBD) with three replications. Among the TDW stages, T8, T7, T4, and T5 exhibited elevated BCF, EDI, THQ, and HI due to a rising trend in the accumulation of Pb, Cd, Cr, and Ni heavy metals in the edible portion of the red amaranth, followed by radish, Indian spinach, cauliflower, and tomato. The general patterns of heavy metal (HM) accumulation, regarded as vital nutrients for plants, were detected in the following sequence: Zn > Mn/Cu > Fe. Conversely, toxic metals were found to be Cd/Cr > Ni > Pb, regardless of the type of vegetables. Principal Component Analysis (PCA) identified T8, T7, and T4 of TDW as the primary contributors to the accumulation of heavy metals in the vegetables examined. Furthermore, the analysis of the heavy metals revealed that the BCF, THQ, and HI values for all studied metals were below 1, except for Pb. This suggests that the present consumption rates of different leafy and non-leafy vegetables, whether consumed individually or together, provide a low risk in terms of heavy metal exposure. Nevertheless, the consumption of T8, T7, and T4 irrigated vegetables, specifically Indian spinach alone or in combination with red amaranth and radish, by both adults and children, at the recommended rate, was found to pose potential health risks. On the other hand, T2, T3, and T6 irrigated vegetables were deemed safe for consumption. These findings indicated that the practice of irrigating the vegetables with T8, T7, and T4 stages of TDW has resulted in a significant buildup of heavy metals in the soils and edible parts of vegetables which are posing health risks to adults and children. Hence, it is imperative to discharge the T8, T7, and T4 stages of TDW after ETP to prevent the contamination of vegetables and mitigate potential health risks.

The Modulation of Euglycemic Endocrine and Exocrine Pancreatic Secretions in Iron Deficiency.

OBJECTIVES: The contribution of pancreatic secretions in iron metabolism has been elucidated, but the clinical outcomes of iron deficiency on pancreatic function are debatable. This study aimed to investigate the modulation of euglycemic endocrine and exocrine pancreatic excretions in response to variations in iron availability. SUBJECTS AND METHODS: Serum levels of insulin, glucagon, insulin-to-glucagon ratio (IGR), and amylase were determined in 170 adult subjects with variable levels of serum iron. RESULTS: Control (n = 46) and iron-deficient (n = 124) subjects had significant differences (p < 0.001) in their average levels of insulin (68.7 ± 0.5 vs. 100.0 ± 2.0 pmol/dL), glucagon (17.9 ± 0.6 vs. 10.8 ± 0.8 pmol/dL), IGR (4.0 ± 0.1 vs. 19.5 ± 2.1), and amylase (29.7 ± 0.9 vs. 17.5 ± 0.2). The upregulation of serum insulin levels increases proportionally and gradually to the extent of iron deficiency as compared to an abrupt downregulation of serum levels of glucagon and amylase. A significant association was observed between serum iron and IGR (r = -0.645, p < 0.001) and amylase levels (r = 0.653, p < 0.001). The receiver operating characteristic curve analysis defines an excellent predictivity of the reduced serum iron level to discriminate subjects with upregulated IGR and amylase levels with area under curves of 0.938 and 0.905, respectively. CONCLUSION: Iron deficiency is associated with an adaptive modulation of euglycemic endocrine and exocrine secretions that is consistent with a status of insulin resistance.

Childhood outcomes after induction of labor or expectant management for preterm prelabor rupture of membranes: a 10-year follow-up of the PPROMEXIL trials.

BACKGROUND: Management of late preterm prelabor rupture of membranes between 34+0 and 36+6 weeks' gestation balances the risks of preterm birth with the risks of infection for both the mother and the neonate. Expectant management to prolong pregnancy showed similar risks of neonatal sepsis, but children at 2 years of age showed more neurodevelopmental delay when compared with induction of labor. Long-term outcomes on child development after 2 years of age are unknown. OBJECTIVE: This study aimed to assess the long-term outcomes of children born after singleton pregnancies complicated by late preterm prelabor rupture of membranes managed by induction of labor in comparison with expectant management. STUDY DESIGN: This was a follow-up study of the Preterm Prelabor Rupture of Membranes Expectant Management Versus Induction of Labor (PPROMEXIL) trials (randomized controlled trials between 2007 to 2011) evaluating children at 10 to 12 years of age (Netherlands Trial Register 6953). The primary outcomes were cognition, motor function, and behavior as assessed by the Wechsler Intelligence Scale for Children-V-NL, Movement Assessment Battery for Children-2, and Child Behavior Checklist, respectively. The secondary outcomes were sensory processing, respiratory problems, educational attainment, and general health. Mild delay was defined as -1 standard deviation or corresponding percentile. The relative risk and confidence intervals were calculated using standard methods. RESULTS: This follow-up study invited 711 surviving children of the 714 singleton pregnancies randomized in the original trials. In total, 248 (35%) children participated (127 induction of labor, 121 expectant management). Children born after induction of labor had no significant differences in the primary outcomes when compared with those born after expectant management. Mild cognitive delay was observed in 7 of 122 (5.7%) children born after induction of labor in comparison with in 12 of 120 (10.0%) children born after expectant management (relative risk, 0.57; 95% confidence interval, 0.23-1.41). A mild delay in motor function was observed in 42 of 122 (34.4%) children born after induction of labor vs in 55 of 120 (45.8%) children born after expectant management (relative risk, 0.75; 95% confidence interval, 0.55-1.03). Mild abnormal behavior was observed in 37 of 125 (29.6%) children born after induction of labor compared with in 33 of 118 (28.0%) children born after expectant management (relative risk, 1.05; 95% confidence interval, 0.71-1.57). Secondary outcomes were also comparable between the induction of labor and the expectant management groups except that more children born after expectant management had a hospital admission (relative risk, 0.68; 95% confidence interval, 0.52-0.89) or a surgery (relative risk, 0.58; 95% confidence interval, 0.41-0.82). CONCLUSION: In children born after pregnancies with late preterm prelabor rupture of membranes, expectant management did not improve long-term outcomes at 10 to 12 years when compared with induction of labor.

Evaluation of Asymmetries in Speech-in Noise Abilities in Audiologic Screening for Vestibular Schwannoma.

OBJECTIVES: Measures of speech-in-noise, such as the QuickSIN, are increasingly common tests of speech perception in audiologic practice. However, the effect of vestibular schwannoma (VS) on speech-in-noise abilities is unclear. Here, we compare the predictive ability of interaural QuickSIN asymmetry for detecting VS against other measures of audiologic asymmetry. METHODS: A retrospective review of patients in our institution who received QuickSIN testing in addition to a regular audiologic battery between September 2015 and February 2019 was conducted. Records for patients with radiographically confirmed, unilateral, pretreatment VSs were identified. The remaining records excluding conductive pathologies were used as controls. The predictive abilities of various measures of audiologic asymmetry to detect VS were statistically compared. RESULTS: Our search yielded 73 unique VS patients and 2423 controls. Receiver operating characteristic curve analysis showed that QuickSIN asymmetry was more sensitive and specific than pure-tone average asymmetry and word-recognition-in-quiet asymmetry for detecting VS. Multiple logistic regression analysis revealed that QuickSIN asymmetry was more predictive of VS (odds ratio [OR] = 1.23, 95% confidence interval [CI] [1.10, 1.38], p < 0.001) than pure-tone average asymmetry (OR = 1.04, 95% CI [1.00, 1.07], p = 0.025) and word-recognition-in-quiet asymmetry (OR = 1.03, 95% CI [0.99, 1.06], p = 0.064). CONCLUSION: Between-ear asymmetries in the QuickSIN appear to be more efficient than traditional measures of audiologic asymmetry for identifying patients with VS. These results suggest that speech-in noise testing could be integrated into clinical practice without hindering the ability to identify retrocochlear pathology.

Treatment Experiences for Patients Receiving Buprenorphine/Naloxone for Opioid Use Disorder: A Qualitative Study of Patients' Perceptions and Attitudes.

Background: Although buprenorphine/naloxone has been demonstrated to be an effective treatment for patients with opioid use disorder (OUD), treatment retention has been a challenge. This study extends what is presently a limited literature regarding patients' experiences with this medication and the implications for treatment retention. Methods: The study was conducted as a qualitative investigation of patients in treatment for OUD at the time of the study. Forty-three patients (27 men, 15 women, mean age 34.7) were recruited from three clinical settings, a community health center, an academically-based treatment site, and an independent substance abuse treatment facility. Most patients had returned to use in the past after attempts to become abstinent. Results: Patients generally reported positive experiences with this medication noting it helped to reduce opioid cravings quickly. As important considerations for treatment retention, patients emphasized a firm commitment to achieving abstinence when beginning treatment and a prescriber who is informed about and attentive to their emotional state. Diverging attitudes did exist regarding treatment duration as some patients were accepting of long-term treatment while others desired a relatively brief option. Among patients who had returned to use, potentially important issues emerged pertaining to the absence of patient outreach for missed medication appointments and inadequate discharge planning following stays at rehabilitation facilities. Conclusions: While results regarding the importance of patient motivation and strong patient-prescriber relationships have been noted in previous studies, other findings regarding opportunities to improve patient outreach and coordination of care have received relatively less attention and warrant further consideration.

Investigation of Simulated Adherence in Long-Term Buprenorphine/Naloxone Treatment Patients.

BACKGROUND: Buprenorphine is a medication that is used to treat opioid use disorder by reducing withdrawal symptoms and cravings for opioids. Patients with poor adherence are at higher risk of relapse and overdose. Providers often test adherence through urine testing but are not aware of simulated adherence, where patients may directly add buprenorphine to the urine samples. As of now, there exists no literature on the simulated adherence practices for patients who stayed in the treatment for more than three months. METHODS: This study is a cross-sectional analysis of simulated adherence through urine toxicology results of 3950 patients undergoing buprenorphine/naloxone treatment. Simulated adherence was measured by the ratio of norbuprenorphine and buprenorphine <0.02 in the urine sample. Descriptive statistics as well as multivariate analysis was conducted to examine the relationship between patient information and outcomes. RESULTS: Out of 3950 patients, 411 (10.4%) had a history of one or more simulated adherence. On average, patients with multiple simulated adherences had 48.1% of their tests simulated, while on the contrary, patients with a single occurrence of simulated adherence had 17.6% of their tests simulated. Weekly testing and visit number of over 15 were associated with a higher likelihood of simulated adherence. CONCLUSION: The study demonstrates that simulated adherence is a recurring phenomenon among buprenorphine/naloxone treatment patients regardless of the duration in the treatment. Utilization of quantitative urine toxicology to identify simulated adherence will enable healthcare providers to formulate a more precise and effective treatment plan tailored to support individual patient needs.

Loxhd1 Mutations Cause Mechanotransduction Defects in Cochlear Hair Cells.

Sound detection happens in the inner ear via the mechanical deflection of the hair bundle of cochlear hair cells. The hair bundle is an apical specialization consisting of actin-filled membrane protrusions (called stereocilia) connected by tip links (TLs) that transfer the deflection force to gate the mechanotransduction channels. Here, we identified the hearing loss-associated Loxhd1/DFNB77 gene as being required for the mechanotransduction process. LOXHD1 consists of 15 polycystin lipoxygenase α-toxin (PLAT) repeats, which in other proteins can bind lipids and proteins. LOXHD1 was distributed along the length of the stereocilia. Two LOXHD1 mouse models with mutations in the 10th PLAT repeat exhibited mechanotransduction defects (in both sexes). While mechanotransduction currents in mutant inner hair cells (IHCs) were similar to wild-type levels in the first postnatal week, they were severely affected by postnatal day 11. The onset of the mechanotransduction phenotype was consistent with the temporal progression of postnatal LOXHD1 expression/localization in the hair bundle. The mechanotransduction defect observed in Loxhd1-mutant IHCs was not accompanied by a morphologic defect of the hair bundle or a reduction in TL number. Using immunolocalization, we found that two proteins of the upper and lower TL protein complexes (Harmonin and LHFPL5) were maintained in the mutants, suggesting that the mechanotransduction machinery was present but not activatable. This work identified a novel LOXHD1-dependent step in hair bundle development that is critical for mechanotransduction in mature hair cells as well as for normal hearing function in mice and humans.SIGNIFICANCE STATEMENT Hair cells detect sound-induced forces via the hair bundle, which consists of membrane protrusions connected by tip links. The mechanotransduction machinery forms protein complexes at the tip-link ends. The current study showed that LOXHD1, a multirepeat protein responsible for hearing loss in humans and mice when mutated, was required for hair-cell mechanotransduction, but only after the first postnatal week. Using immunochemistry, we demonstrated that this defect was not caused by the mislocalization of the tip-link complex proteins Harmonin or LHFPL5, suggesting that the mechanotransduction protein complexes were maintained. This work identified a new step in hair bundle development, which is critical for both hair-cell mechanotransduction and hearing.

Genetic evidence for the most common risk factors for chronic axonal polyneuropathy in the general population.

BACKGROUND AND PURPOSE: Chronic axonal polyneuropathy is a common disease, but the etiology remains only partially understood. Previous etiologic studies have identified clinical risk factors, but genetic evidence supporting causality between these factors and polyneuropathy are largely lacking. In this study, we investigate whether there is a genetic association of clinically established important risk factors (diabetes, body mass index [BMI], vitamin B12 levels, and alcohol intake) with chronic axonal polyneuropathy. METHODS: This study was performed within the population-based Rotterdam Study and included 1565 participants (median age = 73.6 years, interquartile range = 64.6-78.8, 53.5% female), of whom 215 participants (13.7%) had polyneuropathy. Polygenic scores (PGSs) for diabetes, BMI, vitamin B12 levels, and alcohol intake were calculated at multiple significance thresholds based on published genome-wide association studies. RESULTS: Higher PGSs of diabetes, BMI, and alcohol intake were associated with higher prevalence of chronic axonal polyneuropathy, whereas higher PGS of vitamin B12 levels was associated with lower prevalence of polyneuropathy. These effects were most pronounced for PGSs with lenient significance thresholds for diabetes and BMI (odds ratio [OR]diabetes, p < 1.0  = 1.21, 95% confidence interval [CI] = 1.05-1.39 and ORBMI, p < 1.0  = 1.21, 95% CI = 1.04-1.41) and for the strictest significance thresholds for vitamin B12 level and alcohol intake (OR vitamin B12, p < 5e-6  = 0.79, 95% CI = 0.68-0.92 and ORalcohol, p < 5e-8  = 1.17, 95% CI = 1.02-1.35). We did not find an association between different PGSs and sural sensory nerve action potential amplitude, nor between individual lead variants of PGSp < 5e-8 and polyneuropathy. CONCLUSIONS: This study provides evidence for polygenic associations of diabetes, BMI, vitamin B12 level, and alcohol intake with chronic axonal polyneuropathy. This supports the hypothesis of causal associations between well-known clinical risk factors and polyneuropathy.

Long-term patient outcomes following buprenorphine/naloxone treatment for opioid use disorder: a retrospective analysis in a commercially insured population.

Background: While buprenorphine/naloxone (buprenorphine) has been demonstrated to be an effective medication for treating opioid use disorder (OUD), an important question exists about how long patients should remain in treatment.Objective: To examine the relationship between treatment duration and patient outcomes for individuals with OUD who have been prescribed buprenorphine.Methods: We conducted a retrospective, longitudinal study using the Massachusetts All Payer Claims Database, 2013 to 2017. The study comprised over 2,500 patients, approximately one-third of whom were female, who had been prescribed buprenorphine for OUD. The outcomes were hospitalizations and emergency room (ER) visits at 36 months following treatment initiation and 12 months following treatment discontinuation. Patients were classified into four groups based on treatment duration and medication adherence: poor adherence, duration <12 months; good adherence, duration <6 months; good adherence, duration 6 to 12 months, and good adherence, duration >12 months. We conducted analyses at the patient level of the relationship between duration and outcomes.Results: Better outcomes were observed for patients whose duration was greater than 12 months. Patients in the other groups had higher odds of hospitalization at 36 months following treatment initiation: poor adherence (2.71), <6 months (1.53), and 6 to 12 months (1.42). They also had higher odds of ER visits: poor adherence (1.69), <6 months (1.51), and 6 to 12 months (1.30). Similar results were observed following treatment discontinuation.Conclusions: OUD treatment with buprenorphine should be continued for at least 12 months to reduce hospitalizations and ED visits.

Amnioinfusion versus Usual Care in Women with Prelabor Rupture of Membranes in Midtrimester: A Systematic Review and Meta-Analysis of Short- and Long-Term Outcomes.

INTRODUCTION: Midtrimester prelabor rupture of membranes (PROM) between 16 and 24 weeks of gestational age is a major obstetric complication with high rates of perinatal morbidity and mortality. Amnioinfusion has been proposed in women with midtrimester PROM to target oligohydramnios and subsequently enhance pulmonary development and perinatal outcomes. MATERIAL AND METHODS: The purpose of this study was to perform a systematic review and meta-analysis including all randomized clinical trials investigating amnioinfusion versus no intervention in women with PROM between 16+0 and 24+0 weeks of gestational age. Databases Central, Embase, Medline, ClinicalTrials.gov and references of identified articles were searched from inception of database to December 2021. The primary outcome was perinatal mortality. Secondary outcomes included neonatal, maternal, and long-term developmental outcomes as defined in the core outcome set for preterm birth studies. Summary measures were reported as pooled relative risk (RR) or mean difference with corresponding 95% confidence interval (CI). RESULTS: Two studies (112 patients, 56 in the amnioinfusion group and 56 in the no intervention group) were included in this review. Pooled perinatal mortality was 66.1% (37/56) in the amnioinfusion group compared with 71.4% (40/56) in no intervention group (RR 0.92, 95% CI: 0.72-1.19). Other neonatal and maternal core outcomes were similar in both groups, although due to the relatively small number of events and wide CIs, there is a possibility that amnioinfusion can be associated with clinically important benefits and harms. Long-term healthy survival was seen in 35.7% (10/28) of children assessed for follow-up and treated with amnioinfusion versus 28.6% (8/28) after no intervention (RR 1.30, 95% CI: 0.47-3.60, "best case scenario"). CONCLUSIONS: Based on these findings, the benefits of amnioinfusion for midtrimester PROM <24 weeks of gestational age are unproven, and the potential harms remain undetermined.

Isolating adverse effects of glucocorticoids on the embryonic cardiovascular system.

Antenatal glucocorticoid therapy reduces mortality in the preterm infant, but evidence suggests off-target adverse effects on the developing cardiovascular system. Whether deleterious effects are direct on the offspring or secondary to alterations in uteroplacental physiology is unclear. Here, we isolated direct effects of glucocorticoids using the chicken embryo, a model system in which the effects on the developing heart and circulation of therapy can be investigated, independent of effects on the mother and/or the placenta. Fertilized chicken eggs were incubated and divided randomly into control (C) or dexamethasone (Dex) treatment at day 14 out of the 21-day incubation period. Combining functional experiments at the isolated organ, cellular and molecular levels, embryos were then studied close to term. Chicken embryos exposed to dexamethasone were growth restricted and showed systolic and diastolic dysfunction, with an increase in cardiomyocyte volume but decreased cardiomyocyte nuclear density in the left ventricle. Underlying mechanisms included a premature switch from tissue accretion to differentiation, increased oxidative stress, and activated signaling of cellular senescence. These findings, therefore, demonstrate that dexamethasone treatment can have direct detrimental off-target effects on the cardiovascular system in the developing embryo, which are independent of effects on the mother and/or placenta.

Cardiovascular health and chronic axonal polyneuropathy: A population-based study.

BACKGROUND AND PURPOSE: Chronic axonal polyneuropathy is a common, usually multifactorial, disease for which there is no treatment yet available. We investigated the association between cardiovascular health, defined by the health score of the American Heart Association, and chronic axonal polyneuropathy. METHODS: Between June 2013 and January 2017, we investigated participants of the Rotterdam Study, a population-based cohort study. Participants were screened for polyneuropathy and categorized as having no, possible, probable or definite polyneuropathy. The cardiovascular health score (range 0-14; higher score reflecting better health) consisted of four health behaviours (diet, physical activity, smoking and body mass index) and three health factors (blood pressure, serum cholesterol and fasting glucose level). RESULTS: We included 1919 participants, of whom 120 (6.3%) had definite polyneuropathy. The median (interquartile range [IQR]) age was 69.0 (58.6-73.7) years and 53.4% were women. A higher cardiovascular health score was associated with a lower prevalence of definite polyneuropathy (per point increase: odds ratio [OR] 0.90, 95% confidence interval [CI] 0.84-0.96). Optimal cardiovascular health (score≥10) was strongly associated with a lower prevalence of definite polyneuropathy (OR 0.55, 95% CI 0.32-0.90). An increase in health factors and health behaviour scores separately was associated with a lower prevalence of polyneuropathy (per point increase: OR 0.82, 95% CI 0.71-0.95 and OR 0.86, 95% CI 0.78-0.96, respectively). The association between a lower cardiovascular health score and lower sural nerve amplitude was not significant after correction for covariates (difference 0.07µV, 95% CI -0.02-0.17). CONCLUSIONS: Better cardiovascular health, consisting of both modifiable health behaviours and health factors, is associated with a lower prevalence of chronic axonal polyneuropathy.

A machine learning based two-stage clinical decision support system for predicting patients' discontinuation from opioid use disorder treatment: retrospective observational study.

BACKGROUND: Buprenorphine is a widely used treatment option for patients with opioid use disorder (OUD). Premature discontinuation from this treatment has many negative health and societal consequences. OBJECTIVE: To develop and evaluate a machine learning based two-stage clinical decision-making framework for predicting which patients will discontinue OUD treatment within less than a year. The proposed framework performs such prediction in two stages: (i) at the time of initiating the treatment, and (ii) after two/three months following treatment initiation. METHODS: For this retrospective observational analysis, we utilized Massachusetts All Payer Claims Data (MA APCD) from the year 2013 to 2015. Study sample included 5190 patients who were commercially insured, initiated buprenorphine treatment between January and December 2014, and did not have any buprenorphine prescription at least one year prior to the date of treatment initiation in 2014. Treatment discontinuation was defined as at least two consecutive months without a prescription for buprenorphine. Six machine learning models (i.e., logistic regression, decision tree, random forest, extreme-gradient boosting, support vector machine, and artificial neural network) were tested using a five-fold cross validation on the input data. The first-stage models used patients' demographic information. The second-stage models included information on medication adherence during the early phase of treatment based on the proportion of days covered (PDC) measure. RESULTS: A substantial percentage of patients (48.7%) who started on buprenorphine discontinued the treatment within one year. The area under receiving operating characteristic curve (C-statistic) for the first stage models varied within a range of 0.55 to 0.59. The inclusion of knowledge regarding patients' adherence at the early treatment phase in terms of two-months and three-months PDC resulted in a statistically significant increase in the models' discriminative power (p-value < 0.001) based on the C-statistic. We also constructed interpretable decision classification rules using the decision tree model. CONCLUSION: Machine learning models can predict which patients are most at-risk of premature treatment discontinuation with reasonable discriminative power. The proposed machine learning framework can be used as a tool to help inform a clinical decision support system following further validation. This can potentially help prescribers allocate limited healthcare resources optimally among different groups of patients based on their vulnerability to treatment discontinuation and design personalized support systems for improving patients' long-term adherence to OUD treatment.

Independent influences of maternal obesity and fetal sex on maternal cardiovascular adaptation to pregnancy: a prospective cohort study.

BACKGROUND/OBJECTIVES: Successful pregnancy requires the de novo creation of low-resistance utero-placental and feto-placental circulations and incomplete remodeling of this vasculature can lead to maternal or fetal compromise. Maternal BMI and fetal sex are known to influence vascular compliance and placental development, but it is unknown if these are independent or synergistic effects. Here we aim to investigate the impact of maternal obesity, fetal sex, and any interaction thereof on maternal cardiovascular adaptation to pregnancy, by assessing the physiological drop of uterine artery doppler pulsatility (UtA-PI) and umbilical artery doppler pulsatility index (UA-PI) over gestation. SUBJECTS/METHODS: Nulliparous women with a singleton pregnancy participating in a prospective cohort study (n = 4212) underwent serial UtA-PI and UA-PI measurements at 20-, 28- and 36-weeks gestation. Linear mixed regression models were employed to investigate the influence of maternal BMI, fetal sex and interactions thereof on the magnitude of change in UtA-PI and UA-PI. RESULTS: Throughout gestation, UtA-PI was higher for male fetuses and UA-PI was higher for female fetuses. The physiological drop of UtA-PI was significantly smaller in overweight (change -24.3% [95%CI -22.3, -26.2]) and obese women (change -21.3% [-18.3, -24.3]), compared to normal-weight women (change -25.7% [-24.3, -27.0]) but did not differ by fetal sex. The physiological drop in UA-PI was greater for female than male fetuses (-32.5% [-31.5, -33.5] vs. -30.7% [-29.8, -31.7]) but did not differ by maternal BMI. No interactions between maternal BMI and fetal sex were found. CONCLUSIONS: Maternal cardiovascular adaptation to pregnancy is independently associated with maternal BMI and fetal sex. Our results imply sexual dimorphism in both maternal cardiovascular adaptation and feto-placental resistance.

Sleep surgery in syndromic and neurologically impaired children.

PURPOSE: To examine surgery performed for obstructive sleep apnea (OSA) in children with syndromic or neurologic comorbidities. MATERIAL AND METHODS: Medical records of 375 children with OSA were retrospectively reviewed, including 142 patients with trisomy 21, 105 with cerebral palsy, 53 with muscular dystrophy, 32 with spinal muscular atrophy, 18 with mucopolysaccharidoses, 14 with achondroplasia, and 11 with Prader-Willi. OUTCOME MEASURES: Apnea-hypopnea index (AHI), complications, length of postoperative stay, and endoscopic findings. RESULTS: 228 patients received 297 surgical interventions, with the remainder undergoing observation or positive pressure ventilation. Adenoidectomy was the most common procedure performed (92.1% of patients), followed by tonsillectomy (91.6%). Average AHI decreased following tonsillectomy, from 12.4 to 5.7 (p = 0.002). The most common DISE finding was the tongue base causing epiglottic retroflexion. Lingual tonsillectomy also resulted in an insignificant decrease in the AHI. CONCLUSIONS: Adenotonsillectomy, when there is hypertrophy, remains the mainstay of management of syndromic and neurologically-impaired children with OSA. However, additional interventions are often required, due to incomplete resolution of the OSA. DISE is valuable in identifying remaining sites of obstruction and guiding future management.

Patterns of buprenorphine/naloxone prescribing: an analysis of claims data from Massachusetts.

Background: The brand name Suboxone and its generic formulation buprenorphine/naloxone is a medication for treating opioid use disorder. While this medication has been shown to be effective, little research has examined the extent to which it is being prescribed and under what circumstances.Objective: This study examined patterns of prescription claims for buprenorphine/naloxone in terms of volume and associated clinical conditions.Methods: The study was conducted using a statewide database comprising pharmacy and medical claims that were covered by commercial health insurance plans in Massachusetts between 2011 and 2015. Trends in prescription volume for buprenorphine/naloxone were assessed based on the annual number of patients with a prescription for buprenorphine/naloxone. To examine clinical conditions associated with buprenorphine/naloxone prescriptions, patients' pharmacy claims were linked to their medical claims within the prior three months. For patients with common pain-related conditions, the odds they were prescribed buprenorphine/naloxone rather than oxycodone, a widely used opioid for pain management, were also examined.Results: The number of patients with a buprenorphine/naloxone prescription increased substantially during the study period, from approximately 25,000 in 2011 to over 39,000 in 2015. The most common clinical condition associated with buprenorphine/naloxone prescribing was opioid use disorder, but a substantial percentage of prescriptions were preceded by diagnoses that included pain or were for pain alone.Conclusion: A substantial increase in the number of patients with a prescription for buprenorphine/naloxone was observed. While buprenorphine/naloxone is most frequently prescribed for opioid use disorder, clinicians also appear to prescribe it for pain, particularly for patients who may be at elevated risk for opioid use disorder.

Muscle percentage index as a marker of disease severity in golden retriever muscular dystrophy.

INTRODUCTION: Golden retriever muscular dystrophy (GRMD) is a spontaneous X-linked canine model of Duchenne muscular dystrophy that resembles the human condition. Muscle percentage index (MPI) is proposed as an imaging biomarker of disease severity in GRMD. METHODS: To assess MPI, we used MRI data acquired from nine GRMD samples using a 4.7 T small-bore scanner. A machine learning approach was used with eight raw quantitative mapping of MRI data images (T1m, T2m, two Dixon maps, and four diffusion tensor imaging maps), three types of texture descriptors (local binary pattern, gray-level co-occurrence matrix, gray-level run-length matrix), and a gradient descriptor (histogram of oriented gradients). RESULTS: The confusion matrix, averaged over all samples, showed 93.5% of muscle pixels classified correctly. The classification, optimized in a leave-one-out cross-validation, provided an average accuracy of 80% with a discrepancy in overestimation for young (8%) and old (20%) dogs. DISCUSSION: MPI could be useful for quantifying GRMD severity, but careful interpretation is needed for severe cases.

Diagnostic value of symptoms in chronic polyneuropathy: The Erasmus Polyneuropathy Symptom Score.

In this study, we evaluated the diagnostic value of symptoms of chronic polyneuropathy and to construct and validate a simple questionnaire that can help diagnose chronic polyneuropathy. In a multi-step procedure, we initially compiled a 12-item questionnaire concerning polyneuropathy symptoms. The questionnaire was completed by 117 polyneuropathy patients and 188 controls (headache, transient ischemic attack, multiple sclerosis). First, we calculated sensitivity, specificity and likelihood ratios of each symptom. Next, we used multi-variable logistic regression to create a model that could discriminate patients from controls, using only the most informative symptoms and their frequency of occurrence. Based on the regression coefficients, we developed a simple scoring system (Erasmus Polyneuropathy Symptom Score, E-PSS), which was externally validated in 140 cases with chronic idiopathic axonal polyneuropathy and 96 controls without polyneuropathy. We assessed performance with discrimination (area under the curve, AUC) and calibration analyses. Numb and tingling feet were most frequently reported by polyneuropathy patients and had the highest sensitivity. Walking on cotton wool and allodynia had the highest specificity. Logistic regression yielded a model that contained these four symptoms, complemented with balance problems and tingling hands. Based on this analysis, the E-PSS was created, ranging from 0 to 14. The E-PSS had a good performance (AUC = 0.92) in the derivation set and proved to be valid in the external population (AUC = 0.95). In conclusion, the Erasmus Polyneuropathy Symptom Score (E-PSS) is a simple, validated six-item score that takes the presence and frequency of six different symptoms into account and it may be a helpful tool to screen individuals for the presence of chronic polyneuropathy.

Effect of interpregnancy weight change on perinatal outcomes: systematic review and meta-analysis.

BACKGROUND: Although obesity is a well-known risk factor for adverse pregnancy outcomes, evidence is sparse about the effects of interpregnancy weight change on the risk of adverse perinatal complications in a subsequent pregnancy. The current study aims to assess the effect of interpregnancy weight change on the risk of developing gestational diabetes, pre-eclampsia, pregnancy induced hypertension, preterm birth, or delivering a large- or small-for-gestational age neonate. METHODS: Pubmed, Ovid Embase, ClinicalTrial.gov and the Cochrane library were systematically searched up until July 24th, 2019. Interpregnancy weight change was defined as the difference between pre-pregnancy weight of an index pregnancy and a consecutive pregnancy. Inclusion criteria included full text original articles reporting quantitative data about interpregnancy weight change in multiparous women with any time interval between consecutive births and the risk of any perinatal complication of interest. Studies reporting adjusted odds ratios and a reference group of - 1 to + 1 BMI unit change between pregnancies were harmonised by meta-analysis. RESULTS: Twenty-three cohort studies identified a total of 671,906 women with two or more consecutive pregnancies. Seven of these studies were included in the meta-analysis (280,672 women). Interpregnancy weight gain was consistently associated with a higher risk of gestational diabetes, pre-eclampsia, pregnancy induced hypertension and large-for-gestational age births. In contrast, interpregnancy weight loss was associated with a lower risk of delivering a large-for-gestational age neonate. The effect magnitude (relative risk) of interpregnancy weight gain on pregnancy induced hypertension or delivering a large-for-gestational age neonate was greater among women with a normal BMI in the index pregnancy compared to women with a starting BMI ≥25 kg/m2. CONCLUSION: These findings confirm that interpregnancy weight change impacts the risk of developing perinatal complications in a subsequent pregnancy. This provides evidence in support of guidelines encouraging women to achieve post-partum weight loss, as their risk of perinatal complications might be minimised if they return to their pre-pregnancy weight before conceiving again. Prospectively registered with PROSPERO (CRD42017067326).