Genetic contributions to pain modulation in sickle cell: A focus on single nucleotide polymorphisms.

Background: Despite recent advances in our knowledge of genetic contributions to the highly variable sickle cell disease (SCD) phenotype, our understanding of genetic factors associated with pain sensitivity in SCD remains limited. Previous studies investigated specific variants in single candidate genes and their association with SCD pain variability. The primary aim of the current study was to expand the genes and polymorphisms tested to discover new risk genes (polymorphisms) associated with central sensitization for individuals with SCD. Methods: Adults with sickle cell disease (n = 59, Mage = 36.8 ± 11.5, 65.8 % female) underwent quantitative sensory testing to examine central sensitization and general pain sensitivity. Participants reported average crisis and non-crisis pain intensities weekly using a 0-100 scale, and provided salivary samples for genotyping. The Hardy-Weinberg equilibrium was verified for controls, and allele distributions were tested with chi-square and odds ratio tests. The Benjamini-Hochberg procedure was used to control for false discovery rate. Regression analyses and Wilcoxon tests were used to test associations for normally distributed and skewed data, respectively. Results: Central sensitization and general pain sensitivity were not associated with hemoglobin genotype (Ps > 0.05). Of 4145 SNPs tested, following false discovery rate adjustments, 11 SNPs (rs11575839, rs12185625, rs12289836, rs1493383, rs2233976, rs3131787, rs3739693, rs4292454, rs4364, rs4678, rs6773307) were significantly associated with central sensitization, and one SNP (rs7778077) was significantly associated with average weekly non-crisis pain. No SNPs were associated with general pain sensitivity. Conclusions: These findings provide insights into genetic variants association with average non-crisis pain and central sensitization for individuals with SCD, and may provide support for genetic predictors of heightened pain experience within SCD.

Trainees' perspectives on sickle cell education: a qualitative needs assessment.

BACKGROUND: Sickle cell disease (SCD) exemplifies many of the social, racial, and healthcare equity issues in the United States. Despite its high morbidity, mortality, and cost of care, SCD has not been prioritized in research and clinical teaching, resulting in under-trained clinicians and a poor evidence base for managing complications of the disease. This study aimed to perform a needs assessment, examining the perspectives of medical trainees pursuing hematology/oncology subspecialty training regarding SCD-focused education and clinical care. METHOD: Inductive, iterative thematic analysis was used to explore qualitative interviews of subspecialty hematology-oncology trainees' attitudes and preferences for education on the management of patients with SCD. Fifteen trainees from six programs in the United States participated in 4 focus groups between April and May 2023. RESULTS: Thematic analysis resulted in 3 themes: 1. Discomfort caring for patients with SCD. 2. Challenges managing complications of SCD, and 3. Desire for SCD specific education. Patient care challenges included the complexity of managing SCD complications, limited evidence to guide practice, and healthcare bias. Skill-building challenges included lack of longitudinal exposure, access to expert clinicians, and didactics. CONCLUSIONS: Variations in exposure, limited formal didactics, and a lack of national standardization for SCD education during training contributes to trainees' discomfort and challenges in managing SCD, which in turn, contribute to decreased interest in entering the SCD workforce. The findings underscore the need for ACGME competency amendments, dedicated SCD rotations, and standardized didactics to address the gaps in SCD education.

The Evolution of the Hive Educator Role.

The evolution of a digitally focused clinical educator in Adult Critical Care Units at Manchester Foundation Trust (MFT), has been pivotal to the success and support of Nursing staff. The role has grown beyond what was initially managed to support services widely.

An Observational Study of Proactive and On-Request Psychiatry Consultation Services: Evidence for Differing Roles and Outcomes.

BACKGROUND: Proactive psychiatric consultation services rapidly identify and assess medical inpatients in need of psychiatric care. In addition to more rapid contact, proactive services may reduce the length of stay and improve staff satisfaction. However, in some settings, it is impractical to integrate a proactive consultation service into every hospital unit; on-request and proactive services are likely to coexist in the future. Prior research has focused on changes in outcomes with the implementation of proactive services. OBJECTIVE AND METHODS: This report describes differences between contemporary proactive and on-request services within the same academic medical center, comparing demographic and clinical data collected retrospectively from a 4-year period from the electronic medical record. RESULTS: The proactive service saw patients over four times as many initial admissions (7592 vs. 1762), but transitions and handoffs between services were common, with 434 admissions involving both services, comprising nearly 20% of the on-request service's total contacts. The proactive service admissions had a shorter length of stay and a faster time to first psychiatric contact, and the patients seen were more likely to be female, of Black race, and to be publicly insured. There were over three times as many admissions to psychiatry from the proactive service. The on-request service's admissions had a longer length of stay, were much more likely to involve intensive care unit services, surgical services, and transfers among units, and the patients seen were more likely to die in the hospital or to be discharged to subacute rehabilitation. CONCLUSIONS: Overall, the results suggest that the two services fulfill complementary roles, with the proactive service's rapid screening and contact providing care to a high volume of patients who might otherwise be unidentified and underserved. Simultaneously, the on-request service's ability to manage patients in response to consult requests over a much larger area of the hospital provided important support and continuity for patients with complex health needs. Institutions revising their consultation services will likely need to consider the best balance of these differing functions to address perceived demand for services.

Psychiatry referral and appointment attendance in a clinic for young adults with sickle cell disease.

Mental illness is a common sickle cell disease (SCD) comorbidity. This observational study evaluated psychiatry appointment attendance among 137 young adults with SCD. In their first year of adult SCD care, 43% of subjects were referred to psychiatry. Referral was associated with chronic transfusion therapy. Twenty-four percent of subjects attended a psychiatry appointment; attendance was associated with the appointment being scheduled within 6 weeks of referral and no subject characteristics. Ninety-one percent of subjects attending psychiatry appointments had a psychiatric disorder. Among young adults with SCD, psychiatric morbidity is high. Psychiatric services are, therefore, essential for this patient population.

Mental health, pain and likelihood of opioid misuse among adults with sickle cell disease.

Depressive symptoms are prevalent in individuals living with sickle cell disease (SCD) and may exacerbate pain. This study examines whether higher depressive symptoms are associated with pain outcomes, pain catastrophizing, interference and potential opioid misuse in a large cohort of adults with SCD. The study utilized baseline data from the 'CaRISMA' trial, which involved 357 SCD adults with chronic pain. Baseline assessments included pain intensity, daily mood, the Patient Health Questionnaire (PHQ), the Generalized Anxiety Disorders scale, PROMIS Pain Interference, Pain Catastrophizing Scale, the Adult Sickle Cell Quality of Life Measurement Information System and the Current Opioid Misuse Measure. Participants were categorized into 'high' or 'low' depression groups based on PHQ scores. Higher depressive symptoms were significantly associated with increased daily pain intensity, negative daily mood, higher pain interference and catastrophizing, poorer quality of life and a higher likelihood of opioid misuse (all p < 0.01). SCD patients with more severe depressive symptoms experienced poorer pain outcomes, lower quality of life and increased risk of opioid misuse. Longitudinal data from this trial will determine whether addressing depressive symptoms may potentially reduce pain frequency and severity in SCD.

"Buprenorphine, It Works so Differently": Adults with Sickle Cell Disease Describe Transitioning to Buprenorphine for Treatment of Chronic Pain.

A growing body of literature describes the use of buprenorphine for the treatment of chronic pain in people with sickle cell disease. The experiences of people with sickle cell disease who have tried buprenorphine have not yet reported. This qualitative descriptive study was conducted to explore perspectives on buprenorphine for chronic pain in sickle cell disease. We interviewed 13 participants with sickle cell disease who had been prescribed buprenorphine and had a clinic visit between December 1, 2020, and April 2022 in our Sickle Cell Center for Adults. Interviews were recorded, transcribed, and analyzed using thematic analysis. Eleven out of 13 participants were taking buprenorphine at the time of the interview, with a mean treatment duration of 33 months (SD 18, range 7-78 months). Five major themes were identified: 1) dissatisfaction with full agonist opioids; 2) navigating uncertainty with autonomy in deciding to try buprenorphine; 3) functional and relational changes after starting buprenorphine, 4) enduring systemic barriers to pain treatment, and 5) trusting treatment relationships are necessary when approaching patients about buprenorphine. The experience of adulthood living with sickle cell disease before and after starting buprenorphine is qualitatively different with significant improvements in social functioning. PERSPECTIVE: This study examined the experience of adults with sickle cell disease and chronic pain transitioning from full agonist opioids to buprenorphine. It is the first qualitative study of buprenorphine in people with sickle cell disease, contributing to a small but growing literature about buprenorphine and sickle cell disease.

Psychiatric comorbidities in adults with sickle cell disease: A narrative review.

Although descriptions of quality of life and patient reports of mood in sickle cell disease (SCD) have become more common in the literature, less is known about psychiatric illness prevalence, presentation, and treatment, particularly for adults. We provide a narrative review of what is known about common and debilitating psychiatric conditions such as depression, anxiety, and cognitive impairment, specifically for adults with SCD. We discuss the limitations of the current evidence, make provisional recommendations, and identify opportunities for research and improved care.

Illness Intrusiveness in Adults with Sickle Cell Disease: The Role of Fatigue.

Chronic illness experiences often interfere with daily functioning (a concept known as illness intrusiveness) and health-related quality of life (HRQoL). However, less is known about the role of specific symptoms in predicting illness intrusiveness in sickle cell disease (SCD). This exploratory study examined associations between common SCD-related symptoms (i.e., pain, fatigue, depression, and anxiety), illness intrusiveness, and HRQoL among adults with SCD (n = 60). Illness intrusiveness significantly correlated with fatigue severity (r = .39, p = .002), depression severity (r = .45, p < .001), anxiety severity (r = .41, p = .001), physical HRQoL (r = - .53, p < .001), and mental HRQoL (r = - .44, p < .001). Multiple regression revealed a significant overall model, (R2 = .28, F(4, 55) = 5.21, p = .001), with fatigue, but not pain, depression, or anxiety, significantly predicting illness intrusiveness (ß = .29, p = .036). Results suggest that fatigue may be a primary factor contributing to illness intrusiveness-a determinant of HRQoL-in individuals with SCD. Given the limited sample size, larger confirmatory studies are warranted.

The Complex Association of Daily Opioid Dose with Visits for Pain in Sickle Cell Disease: Tolerance or Treatment-Refractory Pain?

INTRODUCTION: Opioids are used for acute and chronic pain in patients with sickle cell disease. How outpatient opioid regimens relate to acute care visits is of interest given the risks of high opioid doses and high hospital utilization. A prior study by our group suggested that outpatient opioid treatment for chronic pain could contribute to a vicious cycle of treatment-refractory acute pain, greater acute care utilization, and escalating opioid doses. The present larger naturalistic observational study was undertaken to determine whether the results were reliable across multiple acute care settings. METHODS: One year of clinical data on patients (n = 291) followed in the Sickle Cell Center for Adults (August 2018 to July 2019) were extracted, including visits to the emergency department, visits to the infusion center, and inpatient admissions. Outpatient opioid dosage was used to predict acute care treatment in generalized linear models that were controlled for patient, disease, and treatment characteristics. RESULTS: Outpatient opioid dosage predicted dosage during visits but did not predict visit length or pain relief. Higher outpatient opioid dosage was associated with greater number of visits. However, in post hoc analyses, this relationship was nonlinear, with a clear positive association only for those prescribed the lowest 50% of dosages. DISCUSSION: Higher outpatient opioid dosage predicted higher dosages during acute care visits to achieve the same pain score improvement, which is more consistent with opioid tolerance than with treatment-refractory pain. The relationship of outpatient opioid dosage with number of acute care visits was more complex, which suggests that opioid consumption at lower levels is driven by intermittent acute pain and opioid consumption at higher levels is driven by chronic pain.

Antidepressants Trial in Parkinson's Disease (ADepT-PD): protocol for a randomised placebo-controlled trial on the effectiveness of escitalopram and nortriptyline on depressive symptoms in Parkinson's disease.

BACKGROUND: Depressive symptoms are common in patients with Parkinson's disease and depression is a significant predictor of functional impairment, reduced quality of life and general well-being in Parkinson's disease. Despite the high prevalence of depression, evidence on the effectiveness and tolerability of antidepressants in this population is limited. The primary aim of this trial is to establish the clinical and cost effectiveness of escitalopram and nortriptyline for the treatment of depression in Parkinson's disease. METHODS: This is a multi-centre, double-blind, randomised placebo-controlled trial in 408 people with Parkinson's disease with subsyndromal depression, major depressive disorder or persistent depressive disorder and a Beck Depression Inventory-II (BDI-II) score of 14 or above. Participants will be randomised into one of three groups, receiving either escitalopram, nortriptyline or placebo for 12 months. Trial participation is face-to-face, hybrid or remote. The primary outcome measure is the BDI-II score following 8 weeks of treatment. Secondary outcomes will be collected at baseline, 8, 26 and 52 weeks and following withdrawal, including severity of anxiety and depression scores as well as Parkinson's disease motor severity, and ratings of non-motor symptoms, cognitive function, health-related quality of life, levodopa-equivalence dose, changes in medication, overall clinical effectiveness, capability, health and social care resource use, carer health-related quality of life, adverse effects and number of dropouts. DISCUSSION: This trial aims to determine the effectiveness of escitalopram and nortriptyline for reducing depressive symptoms in Parkinson's disease over 8 weeks, to provide information on the effect of these medications on anxiety and other non-motor symptoms in PD and on impact on patients and caregivers, and to examine their effect on change in motor severity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03652870 Date of registration - 29th August 2018.

Motivations and barriers to exercise among clinicians.

According to Kirk & Rhodes (2011), Nooijen et al. (2018), and Saridi et al. (2019), the motivators and barriers to exercise are influenced by one's occupation, especially among those in the healthcare field. We sought to examine the barriers and motivators to physical activity that are distinctive to clinicians. Community hospital clinicians were surveyed regarding motivators and barriers to exercise that they experience, their burnout levels as described by an adaptation of the Mini-Z single item burnout scale, and average weekly exercise habits. The top barriers and motivators were then correlated to burnout levels, levels of physical activity, and demographics. We received 64 total responses from clinicians. The overall average level of burnout was 2.37 and the median level was 2. Approximately 38% of clinicians reported adhering to American Heart Association (AHA) guidelines of 150 minutes of exercise per week, while 33% of clinicians exercise <75 minutes per week. The top general motivator was for one's own well-being and the top clinician-related motivator was reducing stress. The top two barriers to exercise were COVID-19 concerns at an indoor exercise facility and a lack of time. Higher average levels of burnout were experienced by those who marked being too stressed or too burnt out as barriers to exercise. Because of clinicians' roles in propagating healthy practices in their patients from their own habits, wellness programs should be aimed at capitalizing motivators to combat barriers that this group distinctively experiences. Efforts to improve physical and mental wellness among clinicians will translate into better provider and patient health outcomes.

Converting adults with sickle cell disease from full agonist opioids to buprenorphine: A reliable method with safety and early evidence of reduced acute care utilization.

Buprenorphine, a novel opioid with complex pharmacology, is effective for treating pain and is qualitatively safer than high-dose full agonist opioid therapy; but transitioning to buprenorphine can be technically complex and carries some risk of precipitated withdrawal. We report our clinic's experience converting 36 patients with sickle cell disease (SCD) from full agonist opioids to buprenorphine using a method developed in the past 10 years. Thirty of these patients were induced using a standard outpatient protocol and six were induced during medical admissions. Typically, patients were on high-dose chronic opioid therapy (COT) with inadequate response, and often with very high acute care utilization. Unlike prior case series, the method of induction, dosing, and management of withdrawal are detailed, as are post-induction adverse events. There were seven adverse events in the first 3 days following standard induction, and two of which were judged to be definitely related to the induction but none with any lasting sequelae. At 6 months follow-up, five participants had discontinued buprenorphine (16.67%), and overall acute care visits dropped from a mean of 10.50 (SD 11.35) in the 6 months pre-induction to 2.89 (SD 3.40) in the 6 months post-induction. In an appropriately interdisciplinary care setting, buprenorphine shows promise as a safe alternative to COT with early evidence of benefit for high-utilizing patients with SCD.

Treatment Challenges When Stopping Denosumab.

Introduction Denosumab is commonly used to treat osteoporosis. However, discontinuation results in rebound bone loss and increased vertebral fracture risk. We report a clinical case series, illustrating the dilemma in deciding the best treatment should denosumab be stopped. Cases In eight patients aged 56-89 years, zolendronic acid after stopping denosumab resulted in BTM rises and BMD decline.  In a 68-year-old, two years of oral bisphosphonate after three years of denosumab resulted in elevated bone turnover markers (BTM) and decline in bone mineral density (BMD), necessitating a switch to zoledronic acid.  In a 79-year-old, two annual doses of zolendronic acid after three years of denosumab failed to suppress high BTM, with BMD dropping and denosumab being restarted.  In a 60-year-old, on stopping denosumab after 10 years of oral bisphosphonate, BMD remained stable despite no further therapy. Conclusion Drug holidays are not an option with denosumab, with a risk of bone loss even on transitioning to bisphosphonates. Risk is greater with longer duration of treatment6 and may be mitigated by prior bisphosphonate use. Standard dose zoledronic acid does not prevent bone loss in a significant proportion of patients. BTM may help in monitoring treatment and need for further bisphosphonates.

Unhealthy Food and Beverage Consumption in Children and Risk of Overweight and Obesity: A Systematic Review and Meta-Analysis.

This WHO-commissioned review contributed to the update of complementary feeding recommendations, synthesizing evidence on effects of unhealthy food and beverage consumption in children on overweight and obesity. We searched PubMed (Medline), Cochrane CENTRAL, and Embase for articles, irrespective of language or geography. Inclusion criteria were: 1) randomized controlled trials (RCTs), non-RCTs, cohort studies, and pre/post studies with control; 2) participants aged ≤10.9 y at exposure; 3) studies reporting greater consumption of unhealthy foods/beverages compared with no or low consumption; 4) studies assessing anthropometric and/or body composition; and 5) publication date ≥1971. Unhealthy foods and beverages were defined using nutrient- and food-based approaches. Risk of bias was assessed using the ROBINS-I (risk of bias in nonrandomized studies of interventions version I) and RoB2 [Cochrane RoB (version 2)] tools for nonrandomized and randomized studies, respectively. Narrative synthesis was complemented by meta-analyses where appropriate. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation. Of 26,542 identified citations, 60 studies from 71 articles were included. Most studies were observational (59/60), and no included studies were from low-income countries. The evidence base was low quality, as assessed by ROBINS-I and RoB2 tools. Evidence synthesis was limited by the different interventions and comparators across studies. Evidence indicated that consumption of sugar-sweetened beverages (SSBs) and unhealthy foods in childhood may increase BMI/BMI z-score, percentage body fat, or odds of overweight/obesity (low certainty of evidence). Artificially sweetened beverages and 100% fruit juice consumption make little/no difference to BMI, percentage body fat, or overweight/obesity outcomes (low certainty of evidence). Meta-analyses of a subset of studies indicated a positive association between SSB intake and percentage body fat, but no association with change in BMI and BMI z-score. High-quality epidemiological studies that are designed to assess the effects of unhealthy food consumption during childhood on risk of overweight/obesity are needed to contribute to a more robust evidence base upon which to design policy recommendations. This protocol was registered at https://www.crd.york.ac.uk/PROSPERO as CRD42020218109.

Impact of trauma centre capacity and volume on the mortality risk of incoming new admissions.

INTRODUCTION: Trauma centre capacity and surge volume may affect decisions on where to transport a critically injured patient and whether to bypass the closest facility. Our hypothesis was that overcrowding and high patient acuity would contribute to increase the mortality risk for incoming admissions. METHODS: For a 6-year period, we merged and cross-correlated our institutional trauma registry with a database on Trauma Resuscitation Unit (TRU) patient admissions, movement and discharges, with average capacity of 12 trauma bays. The outcomes of overall hospital and 24 hours mortality for new trauma admissions (NEW) were assessed by multivariate logistic regression. RESULTS: There were 42 003 (mean=7000/year) admissions having complete data sets, with 36 354 (87%) patients who were primary trauma admissions, age ≥18 and survival ≥15 min. In the logistic regression model for the entire cohort, NEW admission hospital mortality was only associated with NEW admission age and prehospital Glasgow Coma Scale (GCS) and Shock Index (SI) (all p<0.05). When TRU occupancy reached ≥16 patients, the factors associated with increased NEW admission hospital mortality were existing patients (TRU >1 hour) with SI ≥0.9, recent admissions (TRU ≤1 hour) with age ≥65, NEW admission age and prehospital GCS and SI (all p<0.05). CONCLUSION: The mortality of incoming patients is not impacted by routine trauma centre overcapacity. In conditions of severe overcrowding, the number of admitted patients with shock physiology and a recent surge of elderly/debilitated patients may influence the mortality risk of a new trauma admission.