The use of semaglutide in patients with renal failure- a retrospective cohort study.

OBJECTIVE: Semaglutide, a glucagon-like peptide-1 receptor agonist is approved for weight loss and diabetes treatment, but limited literature exists regarding semaglutide use in patients with advanced chronic kidney disease (CKD). Therefore, this project assessed the safety and efficacy of semaglutide among patients with eGFR (estimated glomerular filtration rate) 15-29 mL/min/1.73m2 (CKD stage 4), eGFR<15 mL/min/1.73m2 (CKD stage 5) or on dialysis. METHODS: This is a retrospective Electronic Medical Record based analysis of consecutive patients with advanced CKD (defined as CKD 4 or greater) who were started on semaglutide (injectable or oral). Data was collected between Jan 2018 and Jan 2023. Investigators verified CKD diagnosis and manually extracted data. Data were analyzed using Fisher's exact test, paired T-test, linear mixed effects models and Wilcoxon signed rank test. RESULTS: Seventy-six patients with CKD 4 or greater who initiated semaglutide were included. Most patients had a history of T2DM (96.0%), and most were male (53.9%). The mean age was 66.8 y (SD 11.5) with the mean BMI was 36.2 (SD 7.5). The initial doses were 3 mg orally and 0.25 mg by injection. Maximum prescribed dose was 1mg (injectable) in 28 (45.2%) patients and 14 mg (orally) in 2 (14.2%) patients. Patients received semaglutide for a median duration of 17.4 (IQR 0.43, 48.8) months. Forty-eight (63.1%) patients reported no adverse effects associated with the therapy. Mean weight decreased from 106.2(SD 24.2) to 101.3 (SD 27.3) kg (p<0.001). Eight patients (16%) with type 2 diabetes (T2DM) discontinued insulin after starting semaglutide. Mean HbA1c decreased from 8.0 % (SD 1.7) to 7.1 % (SD 1.3) (p<0.001). Adverse effects were the primary reason for semaglutide discontinuation (37.0%), with nausea, vomiting, and abdominal pain being the most common complaints. CONCLUSIONS: Based on this retrospective study semaglutide appears to be tolerated by most individuals with CKD 4 or greater despite associated gastrointestinal side effects similar to those observed in patients with better kidney function and leads to an improvement of glycemic control and insulin discontinuation in patients with T2DM. Modest weight loss (approximately 4.6 % of the total body weight) was observed on the prescribed doses. Larger prospective randomized studies are needed to comprehensively assess the risks and benefits of semaglutide in patients with CKD 4 or greater and obesity.

Negative mood is associated with sociobehavioral factors contributing to cardiovascular risk in an immigrant population.

BACKGROUND: After settling in the United States (US), immigrants often accumulate obesity and cardiovascular risk factors. As mood is often associated with health behaviors in the US population, mood may be an important mediating factor in immigrant populations. METHODS: The Healthy Immigrant Community (HIC) study, set in southeast Minnesota, enrolled 475 adult participants in a weight loss intervention designed to reduce cardiovascular risk. Baseline questionnaires assessed mood, nutrition, physical activity, self-efficacy for healthy eating and physical activity, social support, and cohesion. A single-item mood rating of poor or fair was considered "negative", while ratings of good, very good, or excellent were considered "positive". RESULTS: Hispanic/Latino (n = 268) and Somali (n = 181) adults enrolled in HIC completed baseline measures and were included in this analysis. Participants endorsing negative mood compared to positive mood had lower healthy eating scores (p = 0.02), lower physical activity levels (p = 0.03), lower confidence in eating a healthy diet (p = 0.001), and felt less of a sense of belonging to their community (p = 0.01). Those endorsing negative mood reported receiving less social support to eat healthy (p = < 0.001) and be physically active (p = 0.01). They also accessed community resources for healthy eating (p = 0.001) and physical activity (p = < 0.01) less frequently than participants endorsing positive mood. CONCLUSIONS: On self-report, negative mood was associated with less healthy nutrition, lower confidence in eating healthy, sedentary lifestyle, and perceived lack of belonging to the community. Integrating mood management and self-efficacy strategies may enhance the effectiveness of lifestyle interventions to reduce obesity and cardiovascular risk among immigrants who report negative mood. TRIAL REGISTRATION: ClinicalTrials.gov registration: NCT05136339; April 23, 2022.

Impact of a Participatory Wellness Continuing Medical Education Program on Physician Burnout and Well-Being.

OBJECTIVE: Examine the impact of a participatory wellness continuing medical education (CME) program on physician burnout, wellness, and well-being. METHODS: Physicians attending a three-day wellness CME program. Self-reported questionnaires at baseline with paired analyses at 26-week follow-up. RESULTS: Compared to baseline, at 26 weeks there were decreases in burnout (P < .001, ES -0.68), red meat consumption (P = .02, ES -0.29), and current stress levels (P < .001, ES -0.50). There were increases in fruit/vegetable consumption (P < .001, ES 0.55), energy levels at work (P < .001, ES 0.60) and at home (P < .001, ES 0.66), quality of life (P < .001, ES 0.53), and confidence (P < .001, ES 0.89) and frequency (P = .01, ES 0.32) of counseling patients on wellness. CONCLUSION: Attendance at this participatory wellness CME program was associated with improved physician burnout, health behaviors in diet, stress, energy, quality of life, and wellness counseling.

The Frequency and Impact of Adverse Childhood Experiences on Mood, Alcohol Relapse, and Outcomes in Liver Transplantation: A Retrospective Cohort Study.

BACKGROUND: Adverse childhood experiences (ACEs) are associated with the development of negative health behaviors and medical illnesses. ACE's association with poor health outcomes has been well documented in the general population; however, this relationship remains less clear in liver transplant (LT) recipients. OBJECTIVE: The aims of this study were to determine the prevalence of ACE and the influence of ACE on LT outcomes. METHODS: A retrospective electronic medical record review of all LT recipients over 11 years at an academic LT center. Demographic, diagnostic, and disease characteristics were extracted and compared for a history of ACE. Associations between a history of ACE and extracted variables were statistically tested using Student's t-test, chi-square tests, or Fisher's exact test, where appropriate. Graft and patient survival were tested using log-rank tests. RESULTS: Of the 1172 LT recipients, 24.1% endorsed a history of ACE. Females (P = 0.017) and recipients with lower levels of education (P < 0.001) had a higher frequency of ACE. Those with a history of ACE had a higher prevalence of hepatitis C virus (P < 0.001) and higher pretransplant body mass index (P < 0.001). Recipients with a history of ACE had higher prevalence of mood (P < 0.001), anxiety (P < 0.001), post traumatic stress disorder (P < 0.001), alcohol use (P < 0.001), and cannabis use (P < 0.001) disorders, as well as higher Patient Health Questionnaire-9 (P < 0.001) and General Anxiety Disorder-7 (P < 0.001) scores pre- and post-transplant. Those with ACE had a higher incidence of recorded relapses to alcohol by 3 years post-transplant (P = 0.027). Mean lab values, graft survival, and patient survival were not significantly different between those with and without a history of ACE except for total bilirubin at 6 months (P = 0.021). CONCLUSIONS: One-quarter of LT recipients have experienced ACE. ACE was associated with a history of psychiatric diagnoses, substance use disorders, elevated Patient Health Questionnaire-9 and General Anxiety Disorder-7 scores, and a higher prevalence of relapse to alcohol use after transplant. This population may benefit from increased/improved access to appropriate mental health and substance use services and support in the peri- and post-transplant period.

Frequency-Domain Low-Wavenumber Hyperspectral Stimulated Raman Scattering Microscopy.

In recent years, stimulated Raman scattering (SRS) microscopy has experienced rapid technological advancements and has found widespread applications in chemical analysis. Hyperspectral SRS (hSRS) microscopy further enhances the chemical selectivity in imaging by providing a Raman spectrum for each pixel. Time-domain hSRS techniques often require interferometry and ultrashort femtosecond laser pulses. They are especially suited to measuring low-wavenumber Raman transitions but are susceptible to scattering-induced distortions. Frequency-domain hSRS microscopy, on the other hand, offers a simpler optical configuration and demonstrates high tolerance to sample scattering but typically operates within the spectral range of 400-4000 cm-1. Conventional frequency-domain hSRS microscopy is widely employed in biological applications but falls short in detecting chemical bonds with a weaker vibrational energy. In this work, we extend the spectral coverage of picosecond spectral-focusing hSRS microscopy to below 100 cm-1. This frequency-domain low-wavenumber hSRS approach can measure the weaker vibrational energy from the sample and has a strong tolerance to sample scattering. By expanding spectral coverage to 100-4000 cm-1, this development enhances the capability of spectral-domain SRS microscopy for chemical imaging.

Genomics-informed captive breeding can reduce inbreeding depression and the genetic load in zoo populations.

Zoo populations of threatened species are a valuable resource for the restoration of wild populations. However, their small effective population size poses a risk to long-term viability, especially in species with high genetic load. Recent bioinformatic developments can identify harmful genetic variants in genome data. Here, we advance this approach, analysing the genetic load in the threatened pink pigeon (Nesoenas mayeri). We lifted the mutation-impact scores that had been calculated for the chicken (Gallus gallus) to estimate the genetic load in six pink pigeons. Additionally, we perform in silico crossings to predict the genetic load and realized load of potential offspring. We thus identify the optimal mate pairs that are theoretically expected to produce offspring with the least inbreeding depression. We use computer simulations to show how genomics-informed conservation can reduce the genetic load whilst reducing the loss of genome-wide diversity. Genomics-informed management is likely to become instrumental in maintaining the long-term viability of zoo populations.

Weight Loss Surgery Increases Kidney Transplant Rates in Patients With Renal Failure and Obesity.

OBJECTIVE: To describe the outcomes of kidney transplant (KT) candidates with obesity undergoing sleeve gastrectomy (SG) to meet the criteria for KT. METHODS: Retrospective analysis was conducted of electronic medical records of KT candidates with obesity (body mass index >35 kg/m2) who underwent SG in our institution. Weight loss, adverse health events, and the listing and transplant rates were abstracted and compared with the nonsurgical cohort. RESULTS: The SG was performed in 54 patients; 50 patients did not have surgery. Baseline demographic characteristics were comparable at the time of evaluation. Mean body mass index ± SD of the SG group was 41.7±3.6 kg/m2 at baseline (vs 41.5±4.3 kg/m2 for nonsurgical controls); at 2 and 12 months after SG, it was 36.4±4.1 kg/m2 and 32.6±4.0 kg/m2 (P<.01 for both). In the median follow-up time of 15.5 months (interquartile range, 6.4 to 23.9 months), SG was followed by active listing (37/54 people), and 20 of 54 received KT during a median follow-up time of 20.9 months (interquartile range, 14.7 to 28.3 months) after SG. In contrast, 14 of 50 patients in the nonsurgical cohort were listed, and 5 received a KT (P<.01). Three patients (5.6%) experienced surgical complications. There was no difference in overall hospitalization rates and adverse health outcomes, but the SG cohort experienced a higher risk of clinically significant functional decline. CONCLUSION: In KT candidates with obesity, SG appears to be effective, with 37% of patients undergoing KT during the next 18 months (P<.01). Further research is needed to confirm and to improve the safety and efficacy of SG for patients with obesity seeking a KT.

Prospective validation of clinical deterioration predictive models prior to intensive care unit transfer among patients admitted to acute care cardiology wards.

Objective. Very few predictive models have been externally validated in a prospective cohort following the implementation of an artificial intelligence analytic system. This type of real-world validation is critically important due to the risk of data drift, or changes in data definitions or clinical practices over time, that could impact model performance in contemporaneous real-world cohorts. In this work, we report the model performance of a predictive analytics tool developed before COVID-19 and demonstrate model performance during the COVID-19 pandemic.Approach. The analytic system (CoMETⓇ, Nihon Kohden Digital Health Solutions LLC, Irvine, CA) was implemented in a randomized controlled trial that enrolled 10 422 patient visits in a 1:1 display-on display-off design. The CoMET scores were calculated for all patients but only displayed in the display-on arm. Only the control/display-off group is reported here because the scores could not alter care patterns.Main results.Of the 5184 visits in the display-off arm, 311 experienced clinical deterioration and care escalation, resulting in transfer to the intensive care unit, primarily due to respiratory distress. The model performance of CoMET was assessed based on areas under the receiver operating characteristic curve, which ranged from 0.725 to 0.737.Significance.The models were well-calibrated, and there were dynamic increases in the model scores in the hours preceding the clinical deterioration events. A hypothetical alerting strategy based on a rise in score and duration of the rise would have had good performance, with a positive predictive value more than 10-fold the event rate. We conclude that predictive statistical models developed five years before study initiation had good model performance despite the passage of time and the impact of the COVID-19 pandemic.

Negative Mood is Associated with Sociobehavioral Factors Contributing to Cardiovascular Risk in an Immigrant Population.

Background: Immigrants to the United States, on average, accumulate cardiovascular risk after resettlement, including obesity. There is a need to co-create interventions to address these disparities, and mood may be an important mediating factor. Methods: The Healthy Immigrant Community (HIC) study, set in southeast Minnesota, enrolled 475 adult participants in a weight loss intervention to reduce cardiovascular risk. Baseline questionnaires assessed mood, nutrition, physical activity, self-efficacy for healthy eating and physical activity, social support, and cohesion. A single-item mood rating of poor or fair was considered "negative", while ratings of good, very good, or excellent were considered "positive". Results: A total of 449 HIC participants (268 Hispanic/Latino and 181 Somali) with complete baseline measures and were included in this analysis. Participants endorsing negative mood compared to those endorsing positive mood had lower scores for healthy eating (p = 0.02) and physical activity levels (p = 0.03), lower confidence in eating a healthy diet (p = 0.001), and felt less of a sense of belonging to their community (p = 0.01). Those endorsing negative mood also reported receiving less social support from their family and friends to eat healthy (p = < 0.001) and be physically active (p = 0.01), and less often accessed community resources for healthy eating (p = 0.001) and physical activity (p = < 0.01) compared to participants reporting positive mood. Conclusions: Negative mood was associated with less healthy nutrition, lower confidence in eating healthy, sedentary lifestyle, and perceived lack of belonging to the community. Integrating mood management and self-efficacy strategies may enhance the effectiveness of lifestyle interventions among immigrants who report negative mood. ClinicalTrialsgov registration: NCT05136339; April 23, 2022.

Patient Engagement in Health Coaching and Self-Management Abilities in Chronic Obstructive Pulmonary Disease.

Objective: Health coaching has the potential to improve self-management abilities (SM) in patients with Chronic Obstructive Pulmonary Disease (COPD). Patient engagement with health care providers has a beneficial effect on patient outcomes. We examined the association of patient engagement with the health coach on SM abilities in patients with COPD. Methods: We analyzed the association between the degree of engagement measured by the Working Alliance Inventory (WAI-SR) and the SM measured by the Self-Management-Ability-Scale-30 (SMAS-30) at the end of a COPD health coaching intervention. Results: The cohort included 146 moderate to severe COPD patients. The WAI-SR total score was 85% of the maximum possible scores indicating a high degree of engagement between the health coach and the patients. The WAI-SR Task and Bond domains were positively associated with SM abilities after adjusting for lung function (FEV1 %) and depression symptoms (PHQ-2). Conclusion: The degree of engagement between a health coach and patients is associated with the perception of SM abilities in patients with COPD. Our results may inform self-management intervention and clinical practice.

Overview of U.S. COVID-19 vaccine safety surveillance systems.

The U.S. COVID-19 vaccination program, which commenced in December 2020, has been instrumental in preventing morbidity and mortality from COVID-19 disease. Safety monitoring has been an essential component of the program. The federal government undertook a comprehensive and coordinated approach to implement complementary safety monitoring systems and to communicate findings in a timely and transparent way to healthcare providers, policymakers, and the public. Monitoring involved both well-established and newly developed systems that relied on both spontaneous (passive) and active surveillance methods. Clinical consultation for individual cases of adverse events following vaccination was performed, and monitoring of special populations, such as pregnant persons, was conducted. This report describes the U.S. government's COVID-19 vaccine safety monitoring systems and programs used by the Centers for Disease Control and Prevention, the U.S. Food and Drug Administration, the Department of Defense, the Department of Veterans Affairs, and the Indian Health Service. Using the adverse event of myocarditis following mRNA COVID-19 vaccination as a model, we demonstrate how the multiple, complementary monitoring systems worked to rapidly detect, assess, and verify a vaccine safety signal. In addition, longer-term follow-up was conducted to evaluate the recovery status of myocarditis cases following vaccination. Finally, the process for timely and transparent communication and dissemination of COVID-19 vaccine safety data is described, highlighting the responsiveness and robustness of the U.S. vaccine safety monitoring infrastructure during the national COVID-19 vaccination program.

Inpatient Transition from Methadone to Buprenorphine-Naloxone Using a Microdosing Strategy in a Postoperative Cancer Patient: A Case Report.

Background: Buprenorphine initiation in opioid-tolerant patients usually requires decreasing the total opioid intake per day due to its potential for precipitating withdrawal. However, this strategy may not be tolerated in patients who require higher amounts of opioids, such as those with cancer pain. Case Presentation: We utilized a buprenorphine microdosing strategy for a postoperative cancer patient who was previously taking buprenorphine-naloxone for chronic noncancer pain, then initiated on methadone for uncontrolled cancer-related pain. He had a planned cancer resection in the hospital. He subsequently underwent a successful transition from methadone to buprenorphine-naloxone through microdosing in one week with close monitoring in the inpatient setting. Conclusions: Using a microdosing strategy to transition from methadone to buprenorphine-naloxone in a span of days was achieved in this case report. More research regarding the feasibility and tolerability of microinductions is needed, especially in the setting of chronic pain or cancer-related pain.

Management of Patients With Kidney Disease Undergoing Bariatric Surgery: A Multidisciplinary Approach.

Bariatric surgery is increasingly recognized as a safe and effective treatment for obesity in patients with chronic kidney disease (CKD), including stages 4, 5, and 5D (on dialysis). Among the available surgical methods, sleeve gastrectomy (SG) is the most commonly performed weight loss procedure and is mainly done to facilitate kidney transplantation (KT). However, many KT candidates treated with SG remain on the transplant waiting list for months to years, with some never receiving a transplant. Therefore, appropriate candidates for SG must be selected, and post-SG management should address the unique needs of this population, with a focus on sustaining the metabolic benefits of surgery while minimizing potential side effects related to rapid weight loss which may inadvertently lead to muscle and bone catabolism. Multidisciplinary post-SG care in this population may lead to overall better health on the transplant waiting list, resulting in a higher percentage of post-SG patients ultimately receiving KT. To tailor the effective treatment for these patients, clinicians should acknowledge that patients with CKD stage 4-5D have different nutritional needs and are metabolically and psychosocially distinct from the general bariatric surgery population. Sarcopenia is highly prevalent and may be exacerbated by muscle catabolism following SG if not adequately addressed. Blood pressure, glucose, and bone metabolism are all affected by the CKD stage 4-5D, and therefore require distinct diagnostic and management approaches. Long-standing chronic disease, associated comorbidities, and low adherence to medical therapies require ongoing comprehensive psychosocial assessment and support. This paper aims to review and consolidate the existing literature concerning the intersection of CKD stage 4-5D and the consequences of SG. We also suggest future clinical outcome studies examining novel treatment approaches for this medically complex population.

Healthy immigrant community study protocol: A randomized controlled trial of a social network intervention for cardiovascular risk reduction among Hispanic and Somali adults.

BACKGROUND: Immigrants to the United States face structural barriers that contribute to rising cardiovascular risk factors and obesity after immigration. This manuscript describes the development of the Healthy Immigrant Community protocol and baseline measures for a stepped wedge cluster randomized trial to test the effectiveness of a social network intervention for cardiovascular risk reduction among two immigrant populations. METHODS: We developed a social network-informed, community-based, participatory research-derived health promotion intervention with Hispanic and Somali immigrant communities in Minnesota consisting of mentoring, educational and motivational sessions, group activities, and a community toolkit for healthy weight loss delivered by culturally concordant health promoters (HPs) to their social networks. Using a stepped wedge cluster randomized design, social network-based groups were randomly assigned to receive the intervention either immediately or after a delay of one year. Outcomes, measured at baseline, 6 months, 12 months, and 24 months, were derived from the American Heart Association's "Life's Simple 7": BMI and waist circumference, blood pressure, fasting blood glucose, total cholesterol, physical activity level, and dietary quality. RESULTS: A total of 51 HPs were enrolled and randomized (29 Hispanic; 22 Somali). There were 475 participants enrolled in the study, representing a mean social network group size of 8 (range, 5-12). The mean BMI of the sample (32.2) was in the "obese" range. CONCLUSION: Processes and products from this Healthy Immigrant Community protocol are relevant to other communities seeking to reduce cardiovascular risk factors and negative health behaviors among immigrant populations by leveraging the influence of their social networks.

COVID-19 Vaccine Safety Technical (VaST) Work Group: Enhancing vaccine safety monitoring during the pandemic.

During the COVID-19 pandemic, candidate COVID-19 vaccines were being developed for potential use in the United States on an unprecedented, accelerated schedule. It was anticipated that once available, under U.S. Food and Drug Administration (FDA) Emergency Use Authorization (EUA) or FDA approval, COVID-19 vaccines would be broadly used and potentially administered to millions of individuals in a short period of time. Intensive monitoring in the post-EUA/licensure period would be necessary for timely detection and assessment of potential safety concerns. To address this, the Centers for Disease Control and Prevention (CDC) convened an Advisory Committee on Immunization Practices (ACIP) work group focused solely on COVID-19 vaccine safety, consisting of independent vaccine safety experts and representatives from federal agencies - the ACIP COVID-19 Vaccine Safety Technical Work Group (VaST). This report provides an overview of the organization and activities of VaST, summarizes data reviewed as part of the comprehensive effort to monitor vaccine safety during the COVID-19 pandemic, and highlights selected actions taken by CDC, ACIP, and FDA in response to accumulating post-authorization safety data. VaST convened regular meetings over the course of 29 months, from November 2020 through April 2023; through March 2023 FDA issued EUAs for six COVID-19 vaccines from four different manufacturers and subsequently licensed two of these COVID-19 vaccines. The independent vaccine safety experts collaborated with federal agencies to ensure timely assessment of vaccine safety data during this time. VaST worked closely with the ACIP COVID-19 Vaccines Work Group; that work group used safety data and VaST's assessments for benefit-risk assessments and guidance for COVID-19 vaccination policy. Safety topics reviewed by VaST included those identified in safety monitoring systems and other topics of scientific or public interest. VaST provided guidance to CDC's COVID-19 vaccine safety monitoring efforts, provided a forum for review of data from several U.S. government vaccine safety systems, and assured that a diverse group of scientists and clinicians, external to the federal government, promptly reviewed vaccine safety data. In the event of a future pandemic or other biological public health emergency, the VaST model could be used to strengthen vaccine safety monitoring, enhance public confidence, and increase transparency through incorporation of independent, non-government safety experts into the monitoring process, and through strong collaboration among federal and other partners.

Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen.

Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein-protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitro potency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57/59 with a balanced profile, which are suitable for future development toward therapeutic use.

Transfer Learning for Mortality Prediction in Non-Small Cell Lung Cancer with Low-Resolution Histopathology Slide Snapshots.

High-resolution whole slide image scans of histopathology slides have been widely used in recent years for prediction in cancer. However, in some cases, clinical informatics practitioners may only have access to low-resolution snapshots of histopathology slides, not high-resolution scans. We evaluated strategies for training neural network prognostic models in non-small cell lung cancer (NSCLC) based on low-resolution snapshots, using data from the Veterans Affairs Precision Oncology Data Repository. We compared strategies without transfer learning, with transfer learning from general domain images, and with transfer learning from publicly available high-resolution histopathology scans. We found transfer learning from high-resolution scans achieved significantly better performance than other strategies. Our contribution provides a foundation for future development of prognostic models in NSCLC that incorporate data from low-resolution pathology slide snapshots alongside known clinical predictors.