Clinical and genetic contributions to medical comorbidity in bipolar disorder: a study using electronic health records-linked biobank data.

Bipolar disorder is a chronic and complex polygenic disease with high rates of comorbidity. However, the independent contribution of either diagnosis or genetic risk of bipolar disorder to the medical comorbidity profile of individuals with the disease remains unresolved. Here, we conducted a multi-step phenome-wide association study (PheWAS) of bipolar disorder using phenomes derived from the electronic health records of participants enrolled in the Mayo Clinic Biobank and the Mayo Clinic Bipolar Disorder Biobank. First, we explored the conditions associated with a diagnosis of bipolar disorder by conducting a phenotype-based PheWAS followed by LASSO-penalized regression to account for correlations within the phenome. Then, we explored the conditions associated with bipolar disorder polygenic risk score (BD-PRS) using a PRS-based PheWAS with a sequential exclusion approach to account for the possibility that diagnosis, instead of genetic risk, may drive such associations. 53,386 participants (58.7% women) with a mean age at analysis of 67.8 years (SD = 15.6) were included. A bipolar disorder diagnosis (n = 1479) was associated with higher rates of psychiatric conditions, injuries and poisonings, endocrine/metabolic and neurological conditions, viral hepatitis C, and asthma. BD-PRS was associated with psychiatric comorbidities but, in contrast, had no positive associations with general medical conditions. While our findings warrant confirmation with longitudinal-prospective studies, the limited associations between bipolar disorder genetics and medical conditions suggest that shared environmental effects or environmental consequences of diagnosis may have a greater impact on the general medical comorbidity profile of individuals with bipolar disorder than its genetic risk.

Phenotypic distinctions in depression and anxiety: a comparative analysis of comorbid and isolated cases.

BACKGROUND: Anxiety and depression are frequently comorbid yet phenotypically distinct. This study identifies differences in the clinically observable phenome across a wide variety of physical and mental disorders comparing patients with diagnoses of depression without anxiety, anxiety without depression, or both depression and anxiety. METHODS: Using electronic health records for 14 994 participants with depression and/or anxiety in the Mayo Clinic Biobank, a phenotype-based phenome-wide association study (Phe2WAS) was performed to test for differences between these groups across a broad range of clinical diagnoses observed in the electronic health record. Additional analyses were performed to determine the temporal sequencing of diagnoses. RESULTS: Compared to patients diagnosed only with anxiety, those diagnosed only with depression were more likely to have diagnoses of obesity (OR 1.75; p = 1 × 10-27), sleep apnea (OR 1.71; p = 1 × 10-22), and type II diabetes (OR 1.74; p = 9 × 10-18). Compared to those diagnosed only with depression, those diagnosed only with anxiety were more likely to have diagnoses of palpitations (OR 1.91; p = 2 × 10-25), benign skin neoplasms (OR 1.61; p = 2 × 10-17), and cardiac dysrhythmias (OR 1.45; p = 2 × 10-12). Patients with comorbid depression and anxiety were more likely to have diagnoses of other mental health disorders, substance use disorders, sleep problems, and gastroesophageal reflux relative to isolated depression. CONCLUSIONS: While depression and anxiety are closely related, this study suggests that phenotypic distinctions exist between depression and anxiety. Improving phenotypic characterization within the broad categories of depression and anxiety could improve the clinical assessment of depression and anxiety.

Real-World Clinical Practice Among Patients With Bipolar Disorder and Chronic Kidney Disease on Long-term Lithium Therapy.

PURPOSE: Long-term lithium therapy (LTLT) has been associated with chronic kidney disease (CKD). We investigated changes in clinical characteristics, pharmacotherapeutic treatments for medical/psychiatric disorders, and outcomes among patients with bipolar disorder (BD) and CKD on LTLT in a 2-year mirror-image study design. METHODS: Adult BD patients on LTLT for ≥1 year who enrolled in the Mayo Clinic Bipolar Disorder Biobank and developed CKD (stage 3) were included, and our study was approved by the Mayo Clinic Institutional Review Board. The primary outcome was the time to the first mood episode after CKD diagnosis among the lithium (Li) continuers and discontinuers. Cox proportional hazards models were used to estimate the time to the first mood episode. We tested for differences in other medication changes between the Li continuers and discontinuers group using Mantel-Haenszel χ2 tests (linear associations). RESULTS: Of 38 BD patients who developed CKD, 18 (47%) discontinued Li, and the remainder continued (n = 20). The median age of the cohort was 56 years (interquartile range [IQR], 48-67 years), 63.2% were female, and 97.4% were White. As compared with continuers, discontinuers had more psychotropic medication trials (6 [IQR, 4-6] vs 3 [IQR, 2-5], P = 0.02), a higher rate of 1 or more mood episodes (61% vs 10%, P = 0.002), and a higher risk of a mood episode after CKD diagnoses (Hazard Ratio, 8.38; 95% confidence interval, 1.85-38.0 [log-rank P = 0.001]]. CONCLUSIONS: Bipolar disorder patients on LTLT who discontinued Li had a higher risk for relapse and a shorter time to the first mood episode, suggesting a need for more thorough discussion before Li discontinuation after the CKD diagnosis.

The Interaction Between Brain-Derived Neurotrophic Factor Levels and Alcohol Consumption, Sleep Disturbance and Sex-Hormones in Alcohol Use Disorders.

AIMS: Brain-derived neurotrophic factor (BDNF) levels may be associated with alcohol use disorders (AUD) and alcohol consumption, correlate with sleep disturbance and be influenced by sex differences and sex hormones. These associations have not been examined in a single sample accounting for all these factors. METHODS: Data from 190 participants (29.4% female) with AUD were utilized. Sleep quality, craving intensity, depression, anxiety and alcohol consumption were assessed using the Pittsburgh Sleep Quality Index (PSQI), Penn Alcohol Craving Scale (PACS), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7) and Timeline Follow Back for 90 days(TLFB 90). Inventory of Drug Taking Situations (IDTS) assessed the tendency to drink in positive/negative emotional states. Serum BDNF (sBDNF) and plasma sex hormones (estrogen, progesterone, testosterone, FSH and SHBG) were measured. Pearson correlation analyses were used to examine the association between sBDNF and these measures in the entire sample and in men and women separately. Higher order interaction effects between these factors were evaluated for their association with sBDNF using a backward selection model. RESULTS: No significant correlations between sBDNF levels and sex hormones, PSQI, PHQ-9, PACS, IDTS scores and alcohol consumption were found (all P-values > 0.05). sBDNF levels were negatively correlated with GAD-7 scores in men (r = -0.1841; P = 0.03). When considering all quadratic and two-way interactions among PSQI, PHQ-9, GAD-7, mean and max drinks/day, number of drinking days, heavy drinking days, and sex no higher order moderating effects of sBDNF levels were found. CONCLUSION: Our study revealed no significant associations between sBDNF and alcohol measures, sleep, depression and sex hormones suggesting limited utility as a biomarker.

Association of socio-demographic characteristics with alcohol use initiation among never users during the COVID-19 pandemic: a longitudinal study.

BACKGROUND: In this longitudinal cohort study, we examined the socio-demographic and psychological predictors of alcohol use initiation during the COVID-19 pandemic in a sample of never alcohol users aged ≥21 prior to COVID-19. METHODS: Our study population consisted of 56 930 patients aged ≥21, as of 30 March 2019 were collected from a pre-COVID period of 1 year before 31 March 2020, and during-COVID, a period between 1 April 2020 and 30 March 2021. Univariable and multivariable logistic regression models were utilized to examine the roles of socio-demographic variables (gender, age, education, Area Deprivation Index and rural residence) changes in anxiety and depression severity as predictors of alcohol use initiation. RESULTS: Age, gender, race, ethnicity, education and rural status were significant predictors in multivariable analysis. A subgroup analysis showed neither anxiety nor depression had a significant association with alcohol use initiation. CONCLUSION: Women, younger individuals, those living in a rural area and people who smoke cigarettes were more likely to initiate alcohol use during the pandemic. Our study has public health and clinical implications such as the need for targeted alcohol use screening and intervention for vulnerable individuals.

Longitudinal factors associated with increased alcohol consumption in adults during the COVID-19 pandemic.

Background: Alcohol is the most abused substance among adults in the United States. The COVID-19 pandemic impacted patterns of alcohol use, but data are conflicting, and previous studies are largely limited to cross-sectional analyses.Objective: This study aimed to longitudinally assess sociodemographic and psychological correlates of changes in three patterns of alcohol use (number of alcoholic drinks, drinking regularity, and binge drinking) during COVID-19.Methods: We studied changes in self-reported drinking behaviors in 222,195 Mayo Clinic patients over 21 years of age (58.1% female and 41.9% male) between April 1, 2019, and March 30, 2021. Logistic regression models were used to estimate associations between patient characteristics and change in alcohol consumption.Results: Sociodemographically younger age, White race, having a college degree, and living in a rural area were associated with increased alcohol use regularity (all p < .05). Younger age, male, White, high-school education or less, living in a more deprived neighborhood, smoking, and living in a rural area were associated with increases in number of alcohol drinks (all p ≤ .04) and binge drinking (all p ≤ .01). Increased anxiety scores were associated with increased number of drinks, while depression severity was associated with both increased drinking regularity and increased number of drinks (all p ≤ .02) independent of sociodemographic characteristics.Conclusion: Our study showed that both sociodemographic and psychological characteristics were associated with increased alcohol consumption patterns during the COVID-19 pandemic. Our study highlights specific target groups previously not described in the literature for alcohol interventions based on sociodemographic and psychological characteristics.

Development of Hands-On Skills in Diagnostics of Lung Diseases Using Ultrasonography in Undergraduate Medical Education.

This study evaluated advanced pulmonary ultrasonography training for COVID-19 lung examination. Students completed identical pretests and post-tests and a survey. Changes were found for individual questions and overall scores (all P≤.02), specifically image identification, previous material, and COVID-19 questions. Students were receptive to the training for education and future practice (P<.001), and they felt capable using ultrasound for diagnosis and management of COVID-19 patients. Pulmonary ultrasonography training should be considered for the medical school curriculum.

Longitudinal Correlates of Increased Alcohol Use Among Adolescents and Young Adults During the COVID-19 Pandemic.

AIMS: The objective of this study is to longitudinally assess sociodemographic and psychological correlates of increased alcohol use during the coronavirus disease of 2019 (COVID-19) period among adolescents and young adults. METHODS: Pre-COVID period is defined as the 1-year period on or before 31 March 2020, and during-COVID period is defined as the period from 1st April 2020 to 30 March 2021. Univariable logistic regression models are used to evaluate the association of demographic characteristics, Area Deprivation Index (ADI), rurality, changes in Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder (GAD-7) scale severity, and the risk of increased alcohol consumption (binge drinking, number of drinks and drinking regularity) from pre-COVID to during-COVID period. RESULTS AND CONCLUSION: Our study found that worsened anxiety symptoms, older age, being in college and current cigarette smoking status were associated with increased alcohol use among youth during the pandemic year. Socioeconomic position (measured by ADI) and rural status were not found to be associated with increased alcohol use among adolescents and young adults.

Effect of Bone Graft on the Correlation between Clinical Bone Quality and CBCT-determined Bone Density: A Pilot Study.

AIM AND OBJECTIVE: The aim of this pilot study is to explore the possible correlation between radiographic bone density and clinical bone quality in edentulous implant sites with and without a history of bone grafting. MATERIALS AND METHODS: A retrospective evaluation of 273 surgically placed dental implants with adequate preoperative cone-beam computed tomography (CBCT) between 2017 and 2019. Misch classification was used to assess the bone quality, and CBCT grayscale values, utilizing Hounsfield units (HU), were used for radiographic bone density assessment. RESULTS: Sixty-six patients (mean age, 58 years; 43 [65%] female and 23 [35%] male) with 118 implant sites were included. A total of 38 sites with bone grafts were evaluated. Controlling for location, sites with previous bone graft had softer bone quality (p = 0.003) and greater bone density (p <0.001) compared to sites without previous bone grafts. A significant correlation existed between radiographic bone density and clinical bone quality (p ≤0.01). The magnitude of the relationship increased in the absence of bone graft (p <0.001) and became nonsignificant in sites with previous grafting. In sites with allograft, the relationship was not statistically different than those without bone graft (both p ≥0.07), while it was statistically different in sites with xenograft when sites assumed independent (p = 0.02). CONCLUSION: CBCT-determined radiographic bone density was correlated to clinical bone quality in the absence of previous bone grafting, while in the presence of previous bone graft, the radiographic bone density of the edentulous sites seemed to be not associated with the clinical bone density, especially in sites with history of xenograft bone grafting. CLINICAL SIGNIFICANCE: CBCT could be utilized to predict preoperative clinical bone quality in sites without previous bone grafting. When assessing sites with history of bone grafting, the CBCT should be interpreted with caution, especially if xenografts were used.

Interprofessional Approach to Learning Vascular Access with Ultrasonography by Medical Students and Nurses.

The current study evaluated an interprofessional approach involving medical students and nurses for learning vascular access with ultrasonography. Vascular access laboratories included needle-guidance training and provided an efficient way to master technically difficult venipuncture cases. Most agreed ultrasound technology was useful for these venipuncture cases. Participants felt prepared to perform venipuncture using ultrasonography in a clinical setting after training. Such laboratories should be considered for interprofessional learning of difficult procedures in the medical school curriculum.

Development of Competency in Needle-Guided Procedures Through the Use of Soft-Embalmed Cadavers.

This study evaluated soft-embalmed human cadavers for ultrasound needle-guidance training. Second-year medical students used peripherally inserted central catheter (PICC) line and central line models and a Thiel-embalmed cadaver for training and provided feedback. Most (85%) agreed the cadaver was useful. There were positive correlations between performing the PICC line (r=0.44, P=.11) and central line (r=0.63, P=.03) procedures on a cadaver and in a clinical setting. Thiel-embalmed cadavers may provide important hands-on training.

Does posttreatment thymoquinone reverse high-dose atorvastatin-induced hepatic oxidative injury in rats?

Atorvastatin (ATO) was commonly used to lower blood cholesterol, but it caused harmful effects to organs, including the liver. Thymoquinone (TQ), a prominent constituent of Nigella sativa, has antioxidant, antiinflammatory, antiapoptotic, antimicrobial, and anticancer activity. The current study investigated the mechanism of ATO-induced hepatotoxicity, whether posttreatment TQ could reverse ATO-induced hepatic injury, and the mechanism of action of TQ as a hepatoprotective agent. Forty adult male Sprague Dawley rats were divided into four equal groups: control, TQ-treated, ATO-treated, and combined ATO/TQ-treated. Rats were treated for 8 weeks and 10 days and euthanized by cervical dislocation 3 days after the last treatment. Blood samples and livers were tested for liver enzymes, oxidative stress, and apoptosis markers and used for histopathological and ultrastructural examination. The ATO-treated group showed an increase in liver enzymes, decreases in reduced glutathione and catalase, and increases in the malondialdehyde lipid peroxidation marker, protein carbonylation, and caspase 3 activity. Posttreatment TQ in the ATO/TQ-treated group seemed to reverse these changes. Histopathological and ultrastructural examination supported these data. Results from the current study suggested that posttreatment TQ may reverse oxidative stress injury in rat liver produced by ATO, suggesting a potential clinical application of using TQ to prevent ATO-induced hepatic injury.

Four-year review of presenteeism data among employees of a large United States health care system: a retrospective prevalence study.

BACKGROUND: Historically, in an effort to evaluate and manage the rising cost of healthcare employers assess the direct cost burden via medical health claims and measures that yield clear data. Health related indirect costs are harder to measure and are often left out of the comprehensive overview of health expenses to an employer. Presenteeism, which is commonly referred to as an employee at work who has impaired productivity due to health considerations, has been identified as an indirect but relevant factor influencing productivity and human capitol. The current study evaluated presenteeism among employees of a large United States health care system that operates in six locations over a four-year period and estimated loss productivity due to poor health and its potential economic burden. METHODS: The Health-Related Productivity Loss Instrument (HPLI) was included as part of an online Health Risk Appraisal (HRA) administered to employees of a large United States health care system across six locations. A total of 58 299 HRAs from 22 893 employees were completed and analyzed; 7959 employees completed the HRA each year for 4 years. The prevalence of 22 specific health conditions and their effects on productivity areas (quantity of work, quality of work, work not done, and concentration) were measured. The estimated daily productivity loss per person, annual cost per person, and annual company costs were calculated for each condition by fitting marginal models using generalized estimating equations. Intra-participant agreement in reported productivity loss across time was evaluated using κ statistics for each condition. RESULTS: The health conditions rated highest in prevalence were allergies and hypertension (high blood pressure). The conditions with the highest estimated daily productivity loss and annual cost per person were chronic back pain, mental illness, general anxiety, migraines or severe headaches, neck pain, and depression. Allergies and migraines or severe headaches had the highest estimated annual company cost. Most health conditions had at least fair intra-participant agreement (κ ≥ 0.40) on reported daily productivity loss. CONCLUSIONS: Results from the current study suggested a variety of health conditions contributed to daily productivity loss and resulted in additional annual estimated costs for the health care system. To improve the productivity and well-being of their workforce, employers should consider presenteeism data when planning comprehensive wellness initiatives to curb productivity loss and increase employee health and well-being during working hours.

Treatment-resistant depression patients with baseline suicidal ideation required more treatments to achieve therapeutic response with ketamine/esketamine.

BACKGROUND: There is an urgent need to identify interventions to reduce suicidality. We investigated the antisuicidal effects of intravenous (IV) ketamine and intranasal (IN) esketamine among patients with treatment-resistant depression (TRD) in a historical cohort study. METHODS: The Quick Inventory of Depressive Symptomatology self-report (QIDS-SR) question 12 was used to measure suicidal ideation (SI). Cox proportional hazards models were used to evaluate associations between the number of treatments to response and baseline SI (yes, Q12 > 0 versus no, Q12 = 0), adjusting for covariates and modified baseline QIDS-SR score. We evaluated associations between the number of treatments to a 50 % reduction in SI score between IV and IN treatment. RESULTS: Fifty-two adults (62.5 % female, median age 49.1 years) received IV ketamine (71 %, n = 37) or IN esketamine (29 %, n = 15). Eighty-one percent of patients reported SI at baseline. Among those with baseline SI, 60 % had improved SI scores while 38 % did not change, and among those with no SI, 80 % did not change. After adjusting for covariates, the hazard ratios (HR) of response were significantly lower among those with baseline SI (HR = 0.36, 95 % CI, 0.14-0.92, p = 0.03). The number of treatments to achieve a 50 % reduction in SI score did not depend on group (IN esketamine vs. IV ketamine HR = 0.74 [95 % CI, 0.27-2.05]; p = 0.57). LIMITATIONS: Small sample size and lack of a placebo group. CONCLUSIONS: This study suggests that patients with baseline suicidal ideation require more treatments to achieve a response with ketamine or esketamine. The antisuicidal response seemed similar between IV ketamine and IN esketamine.

Hypersomnia as a predictor of response to intravenous ketamine/intranasal esketamine in treatment resistant depression.

BACKGROUND: Sleep disturbances are highly prevalent in depressive episodes and are linked to higher mood severity and suicidal behaviors. Slow wave sleep (SWS) and REM sleep are compromised in depression. Current evidence suggests that rapid antidepressant effects of intravenous (IV) ketamine in patients with treatment-resistant depression (TRD) is mediated by its effects on SWS and REM sleep. Sleep phenotypes may help predict ketamine response. METHOD: In this observational study, we investigated differences in rates of response among sleep phenotypes defined by QIDS-SR in a cohort of patients with TRD (n = 52) treated with IV ketamine or intranasal (IN) esketamine. Also, we explored a neurovegetative symptoms of atypical depression (NVSAD) phenotype and its association between response and change in QIDS-SR following the treatment with IV ketamine/IN esketamine. RESULTS: 94 % of patients reported sleep difficulties and 62 % reported more than one sleep phenotype with middle and early insomnia being the most prevalent. Individuals with baseline hypersomnia showed higher response rates and more pronounced improvements on their QIDS-SR score. Additionally, 15 % of patients presented with NVSAD phenotype; the majority of whom achieved response and had higher reductions on QIDS-SR. A trend towards faster response was identified for hypersomnia and atypical depression phenotypes. LIMITATIONS: Observational study design and lack of a placebo group. CONCLUSIONS: Our data indicate that patients with TRD who have baseline hypersomnia and atypical depression features experienced a more substantial reduction in depressive symptoms and are more likely to achieve response with ketamine/esketamine. This could serve as a future predictor for clinical response.

Differential Serum Levels of CACNA1C, Circadian Rhythm and Stress Response Molecules in Subjects with Bipolar Disorder: Associations with Genetic and Clinical Factors.

Background: Many patients with bipolar disorder (BD) do not respond to or have difficulties tolerating lithium and/or other mood stabilizing agents. There is a need for personalized treatments based on biomarkers in guiding treatment options. The calcium voltage-gated channel CACNA1C is a promising candidate for developing personalized treatments. CACNA1C is implicated in BD by genome-wide association studies and several lines of evidence suggest that targeting L-type calcium channels could be an effective treatment strategy. However, before such individualized treatments can be pursued, biomarkers predicting treatment response need to be developed. Methods: As a first step in testing the hypothesis that CACNA1C genotype is associated with serum levels of CACNA1C, we conducted ELISA measures on serum samples from 100 subjects with BD and 100 control subjects. Results: We observed significantly higher CACNA1C (p<0.01) protein levels in subjects with BD. The risk SNP (rs11062170) showed functional significance as subjects homozygous for the risk allele (CC) had significantly greater CACNA1C protein levels compared to subjects with one (p=0.013) or no copies (p=0.009). We observed higher somatostatin (SST) (p<0.003) protein levels and lower levels of the clock protein ARTNL (p<0.03) and stress signaling factor corticotrophin releasing hormone (CRH) (p<0.001) in BD. SST and PER2 protein levels were associated with both alcohol dependence and lithium response. Conclusions: Our findings represent the first evidence for increased serum levels of CACNA1C in BD. Along with altered levels of SST, ARNTL, and CRH our findings suggest CACNA1C is associated with circadian rhythm and stress response disturbances in BD.

Demographics and Social Factors Associated With Persistent Nonuse of Video Appointments at a Multisite Health Care Institution: Cross-Sectional Study.

BACKGROUND: During the COVID-19 outbreak, video appointments became a popular method for health care delivery, particularly in the early stages of the pandemic. Although Mayo Clinic aimed to reduce face-to-face (F2F) appointments to prevent the spread of the virus, some patients continued seeing their health care providers in person. In the later stages of the pandemic, many patients became comfortable with video appointments, even if they were initially hesitant. However, a subset of patients continued to avoid video appointments. It is not yet clear what sociodemographic factors may be associated with this group of patients. OBJECTIVE: This cross-sectional study aimed to examine demographic and social determinant of health (SDoH) factors associated with persistent nonusers of video appointments among a sample of patients within a multistate health care organization. We also explored patient beliefs about the use of video for health care appointments. METHODS: We conducted a 1-time cross-sectional paper survey, mailed between July and December 2022, of patients matching the eligibility criteria: (1) aged ≥18 years as of April 2020, (2) Mayo Clinic Midwest, Florida, or Arizona patient, (3) did not use video appointment services during April-December 2020 but attended F2F appointments in the departments of primary care and psychiatry/psychology. The survey asked patients, "Have you ever had a video appointment with a healthcare provider?" "Yes" respondents were defined as "users" (adapted to video appointments), and "no" respondents were defined as "persistent nonusers" of video appointments. We analyzed demographics, SDoH, and patient beliefs toward video appointments in 2 groups: persistent nonusers of video appointments and users. We used chi-square and 2-tailed t tests for analysis. RESULTS: Our findings indicate that patients who were older, lived in rural areas, sought care at Mayo Clinic Midwest, and did not have access to the patient portal system were likely to be persistent nonusers of video appointments. Only 1 SDoH factor (not having a disability, handicap, or chronic disease) was associated with persistent nonuse of video appointments. Persistent nonusers of video appointments held personal beliefs such as discomfort with video communication, difficulty interpreting nonverbal cues, and personal preference for F2F appointments over video. CONCLUSIONS: Our study identified demographic (older age and rural residence), sociodemographic factors (not having a disability, handicap, or chronic disease), and personal beliefs associated with patients' decisions to choose between video versus F2F appointments for health care delivery. Health care institutions should assess patients' negative attitudes toward technology prior to introducing them to digital health care services. Failing to do so may result in its restricted usage, negative patient experience, and wasted resources. For patients who hold negative beliefs about technology but are willing to learn, a "digital health coordinator" could be assigned to assist with various digital health solutions.

Change in neurocognitive functioning in patients with treatment-resistant depression with serial intravenous ketamine infusions: The Bio-K multicenter trial.

This nonrandomized, multicenter, open-label clinical trial explored the impact of intravenous (IV) ketamine on cognitive function in adults (n = 74) with treatment-resistant depression (TRD). Patients received three IV ketamine infusions during the acute phase and, if remitted, four additional infusions in the continuation phase (Mayo site). Cognitive assessments using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were conducted at baseline, end of the acute phase, and end of the continuation phase (Mayo site). Results showed a significant 53 % (39/74) remission rate in depression symptoms after the acute phase. In adjusted models, baseline language domain score was associated with a higher odd of remission (Odds Ratio, 1.09, 95 % CI = 1.03-1.17, p = 0.004) and greater improvement in MADRS at the end of the acute phase (ß =-0.97; 95 % CI, -1.74 to -0.20; P = 0.02). The likelihood of remission was not significantly associated with baseline immediate or delayed memory, visuospatial/constructional, or attention scores. In the continuation phase, improvements in immediate and delayed memory and attention persisted, with additional gains in visuospatial and language domains. Limitations included an open-label design, potential practice effects, and ongoing psychotropic medication use. Overall, the study suggests cognitive improvement, not deterioration, associated with serial IV ketamine administrations for TRD. These findings encourage future studies with larger sample sizes and longer follow-up periods to examine any potential for deleterious effect with recurrent ketamine use for TRD. Trial Registration: ClinicalTrials.gov: NCT03156504.

Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes.

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (ncombined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.

Detection of Cadmium and Lead in Kidney Stones. Associations with Patient Demographics, Stone Composition, and Smoking.

BACKGROUND: Kidney stones are a highly prevalent disease worldwide. Additionally, both environmental and occupational exposure to Pb and Cd continue to be prevalent globally and can result in renal toxicity. The objective of this study was to examine the potential presence of Pb and Cd in kidney stones, and to assess for correlation with demographic factors including smoking, gender, age, and kidney stone matrix composition. METHODS: Patient kidney stones (n = 96) were analyzed using Fourier transform infrared spectroscopy to identify the stone constituents. Cd and Pb concentrations (µg/g) were determined by inductively coupled plasma mass spectrometry. Cd and Pb concentrations were correlated using bivariable and multivariable statistical analysis with demographic factors (age, gender, smoking status), and kidney stone composition. RESULTS: Kidney stone Cd (median 0.092 µg/g, range 0.014 to 2.46) and Pb concentrations (median 0.95 µg/g, range 0.060 to 15.4) were moderately correlated (r = 0.56, P < 0.0001). Cd concentrations were positively associated with patient history of smoking, patient age, and calcium oxalate monohydrate levels while negatively associated with struvite and uric acid/uric acid dihydrate. Pb concentrations were positively associated with females and apatite levels while negatively associated with uric acid/uric acid dihydrate. After holding constant other stone type composition levels, smoking status, and age, both Pb and Cd were positively associated with apatite and negatively associated with uric acid/uric acid dihydrate, struvite, and calcium carbonate. CONCLUSIONS: Cd and Pb kidney stone concentrations are associated with specific kidney stone types. Cd and Pb kidney stone concentrations are both associated with smoking.