Effects of state opioid prescribing cap laws on providers' opioid prescribing patterns among patients with chronic non-cancer pain.

Prior work suggests opioid prescribing cap laws are not associated with changes in opioid prescribing among patients with chronic pain. It is unknown how these effects differ by provider specialty, provider opioid prescribing volume, or patient insurer. This study assessed effects of state opioid prescribing cap laws on opioid prescribing among providers of patients with chronic non-cancer pain, by high volume prescribing, provider specialty, and patient insurer. We identified 224,290 providers of patients with low back pain, fibromyalgia, or headache from the IQVIA administrative database. Using a difference-in-differences approach, we examined impacts of opioid prescribing cap laws implemented between 2016 and 2018 on the annual proportion of a provider's patient panel who received any opioid prescription, as well as on dose and duration of opioid prescriptions. For providers overall, high volume prescribers, all specialties, and patient insurance categories, prescribing cap laws were associated with non-significant changes of <1.0, 1.5, and 3.5 percentage points in the proportion of chronic non-cancer patients receiving any opioid prescription, a prescription with 7 days' supply, or with >50 morphine milligram equivalents (MME)/day, per year, respectively. There were two exceptions with high dose prescribing: prescribing cap laws were associated with a 1.5 percentage point increase in the proportion of high-volume prescribers' patient panel receiving an opioid prescription with ≥50 MME/day, and a 3.0 percentage point decrease in the same measure among surgeons. Among nearly all measured subgroups of providers and patient insurers, opioid prescribing cap laws were not associated with changes in opioid prescribing.

Smoking Cessation Medication Prescribing for Smokers With and Without Mental Illness.

OBJECTIVE: This study examined trends in receipt of smoking cessation medications among smokers with and without mental illness, including serious mental illness, from 2005 to 2019 and characterized physician attitudes and practices related to tobacco screening and cessation treatment. METHODS: Medical Expenditure Panel Survey (MEPS) data (2005-2019) were examined for receipt of cessation medication prescriptions for bupropion, varenicline, and nicotine replacement therapy (NRT) among 55,662 smokers-18,353 with any mental illness and 7,421 with serious mental illness. Qualitative interviews with 40 general internists and psychiatrists between October and November 2017 used a semistructured guide. MEPS data were analyzed with descriptive statistics, and interviews were analyzed with hybrid inductive-deductive coding. RESULTS: From 2005 to 2019, at least 83% of smokers with or without mental illness did not receive varenicline, NRT, or bupropion. Over 14 years, the proportion of smokers receiving varenicline peaked at 2.1% among those with no mental illness, 2.9% among those with any mental illness, and 2.4% among those with serious mental illness. The respective peak proportions for NRT were 0.4%, 1.1%, and 1.6%; for bupropion, they were 1.2%, 8.4%, and 16.7%. Qualitative themes were consistent across general internists and psychiatrists; providers viewed cessation treatment as challenging because of the perception of smoking as a coping mechanism and agreed on barriers to treatment, including lack of insurance coverage and contraindications for people with mental illness. CONCLUSIONS: System- and provider-level strategies to support evidence-based smoking cessation treatment for people with and without mental illness are needed.

Developing and implementing a self-monitoring toolkit for a coordinated multinational randomized acupuncture trial.

BACKGROUND: In 2019, investigators from China, South Korea and the United States of America initiated a coordinated multinational trial. The trial included three parallel randomized studies with a planned pooled analysis of individual patient data, to test the effectiveness of acupuncture on hot flash-related symptoms in hormone receptor-positive breast cancer patients prescribed adjuvant endocrine therapy. Given the study's approach, there was no central coordinating center or data monitoring committee for the study, so a site performance self-monitoring toolkit was developed and implemented to support study teams in collecting and maintaining high-quality regulatory information, and consistent review of study data and documentation. METHODS: The site performance self-monitoring toolkit was created based on best practices related to post-approval quality assurance/quality improvement (QA/QI) procedures that support data quality. The toolkit included: (1) a binder of essential study management documents and related monitoring logs for sites to complete and maintain (herein called regulator binder), (2) a study start-up checklist, (3) a self-assessment study conduct and oversight checklist to be completed regularly, and (4) a study close-out checklist. In addition, a process of regular virtual meetings to discuss documentation progress coupled with periodic external remote review of completed logs and checklists provided accountability checks. RESULTS: Over the course of the study, the sites in China and South Korea completed the entirety of the site performance self-monitoring toolkit, and successfully submitted their completed materials for review. The process of implementing a self-monitoring toolkit in a multinational integrative medicine study is described qualitatively. Periodic external review of the completed toolkit materials revealed categories of findings. Written follow-up reports were provided to sites and discussion of the documents occurred via separate virtual meetings. CONCLUSIONS: Site study team self-monitoring provides a feasible, consistent, and effective way to review the collection and maintenance of data and regulatory documentation for quality assessment in minimal risk clinical research studies and can augment formal study monitoring activities in higher risk studies. Iterative feedback and support appeared to drive a disciplined approach to maintaining regulatory document compliance and helped sustain investigator and study team engagement in the process. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03783546 (21/12/2018).

Long-Term Outcome of Horses Undergoing Unilateral Mandibular Condylectomy and Meniscectomy for Temporomandibular Joint Disease.

Background: There are no reports describing the long-term outcome of sport horses undergoing unilateral mandibular condylectomy with meniscectomy (UMC) for treatment for severe temporomandibular joint (TMJ) disease (TMD). Whether horses undergoing UMC require a specialized diet, can return to riding with a bit, or return to intended function after surgery is unknown. Objective: To determine the long-term outcome of horses undergoing UMC for treatment of severe TMD. Study Design: A multi-institutional, retrospective study. Methods: Medical records obtained from seven equine referral hospitals of horses with severe TMD that underwent UMC were reviewed. Details regarding the presenting complaints, results of clinical examination, findings of diagnostic imaging, surgical technique, and outcome (including long-term follow-up with an owner questionnaire) were recorded. Results: Eleven horses fit the inclusion criteria. Three had severe idiopathic osteoarthritis, and eight had confirmed septic osteoarthritis of the TMJ. The most common post-operative complications were drainage and peri-incisional swelling (n = 5). One horse developed a hematoma at the surgical site because the facial artery was inadvertently transected during the approach, causing the condylectomy to be postponed. All horses were discharged alive from the hospital, and 10 returned to their previous or intended use. All had complete resolution of clinical signs of TMD. One mare was retired from athletic use due to her genetic value as a broodmare. One horse was euthanized 2 years after UMC due to progressively worsening of clinical signs of temporohyoid osteoarthropathy (THO), which were not present before surgery. When available, owner satisfaction of the results of the procedure was excellent. Main Limitations: Sample size; multiple institutions; owner bias. Conclusions: Unilateral mandibular condylectomy should not be considered a salvage procedure. Horses treated for severe TMD by UMC can return to their previous or intended level of athletic performance and do not require a specialized diet.

Iron supplementation in HIV-infected Malawian children with anemia: a double-blind, randomized, controlled trial.

BACKGROUND: It is unknown whether iron supplementation in human immunodeficiency virus (HIV)-infected children living in regions with high infection pressure is safe or beneficial. A 2-arm, double-blind, randomized, controlled trial was conducted to examine the effects of iron supplementation on hemoglobin, HIV disease progression, and morbidity. METHODS: HIV-infected Malawian children aged 6-59 months with moderate anemia (hemoglobin level, 7.0-9.9 g/dL) were randomly assigned to receive 3 mg/kg/day of elemental iron and multivitamins (vitamins A, C, and D) or multivitamins alone for 3 months. Participants were followed for 6 months. RESULTS: A total of 209 children were randomly assigned to treatment, and 196 (93.8%) completed 6 months of follow-up. Iron supplementation was associated with greater increases in hemoglobin concentrations (adjusted mean difference [aMD], 0.60; 95% confidence interval [CI], .06-1.13; P = .03) and reduced the risk of anemia persisting for up to 6 months follow-up (adjusted prevalence ratio, 0.59; 95% CI, .38-.92; P = .02). Children who received iron had a better CD4 percentage response at 3 months (aMD, 6.00; 95% CI, 1.84-10.16; P = .005) but an increased incidence of malaria at 6 months (incidence rate, 120.2 vs 71.7; adjusted incidence rate ratio [aIRR], 1.81 [95% CI, 1.04-3.16]; P = .04), especially during the first 3 months (incidence rate, 78.1 vs 36.0; aIRR, 2.68 [95% CI, 1.08-6.63]; P = .03). CONCLUSIONS: Iron supplementation in anemic HIV-infected children has beneficial effects on hemoglobin, anemia, and immunity but increases the risk of malaria. Thus, iron supplementation in HIV-infected children living in malaria-endemic areas should only be provided in combination with adequate protection from malaria. CLINICAL TRIALS REGISTRATION: ISRCTN-62947977.

Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic ß-cells.

B-cell lymphoma 2 (Bcl-2) family proteins are established regulators of cell survival, but their involvement in the normal function of primary cells has only recently begun to receive attention. In this study, we demonstrate that chemical and genetic loss-of-function of antiapoptotic Bcl-2 and Bcl-x(L) significantly augments glucose-dependent metabolic and Ca(2+) signals in primary pancreatic ß-cells. Antagonism of Bcl-2/Bcl-x(L) by two distinct small-molecule compounds rapidly hyperpolarized ß-cell mitochondria, increased cytosolic Ca(2+), and stimulated insulin release via the ATP-dependent pathway in ß-cell under substimulatory glucose conditions. Experiments with single and double Bax-Bak knockout ß-cells established that this occurred independently of these proapoptotic binding partners. Pancreatic ß-cells from Bcl-2(-/-) mice responded to glucose with significantly increased NAD(P)H levels and cytosolic Ca(2+) signals, as well as significantly augmented insulin secretion. Inducible deletion of Bcl-x(L) in adult mouse ß-cells also increased glucose-stimulated NAD(P)H and Ca(2+) responses and resulted in an improvement of in vivo glucose tolerance in the conditional Bcl-x(L) knockout animals. Our work suggests that prosurvival Bcl proteins normally dampen the ß-cell response to glucose and thus reveals these core apoptosis proteins as integrators of cell death and physiology in pancreatic ß-cells.

Early deaths during tuberculosis treatment are associated with depressed innate responses, bacterial infection, and tuberculosis progression.

Up to 14% of Malawian adults die during the intensive phase of tuberculosis treatment. In a prospective cohort of 199 Malawian adults with microbiologically confirmed pulmonary tuberculosis, clinical and laboratory parameters were compared between those who died or deteriorated with those who had an uneventful recovery. Baseline tumor necrosis factor alpha responses to stimulation with heat-killed Mycobacterium tuberculosis and lipopolysaccharide were reduced among the 22 patients with poor outcome (P = .017). Low body mass index (P = .002) and elevated respiratory rate (P = .01) at tuberculosis diagnosis independently predicted poor outcome. Validation of a clinical score identifying high-risk individuals is warranted, together with further investigation of immunological derangements.

Alveolar macrophages from HIV-infected patients with pulmonary tuberculosis retain the capacity to respond to stimulation by lipopolysaccharide.

The functional capacity of alveolar macrophages (AM) in human immunodeficiency virus (HIV)-infected patients with pulmonary tuberculosis (TB) is not completely understood. To investigate the capacity of AM to mediate inflammatory responses, we obtained AM from human subjects by bronchoalveolar lavage (BAL) and studied the cells ex vivo. We compared AM from HIV-infected patients with suspected pulmonary TB to AM from healthy, HIV-negative controls for their capacity to produce TNF-alpha or IL-6 spontaneously and upon stimulation with lipopolysaccharide (LPS). Cytokine-producing cells were identified by macrophage markers and intracellular cytokine staining and flow cytometry. A higher proportion of AM from patients with microbiologically confirmed pulmonary TB than patients with probable TB or controls spontaneously expressed TNF-alpha shortly after isolation (geometric means: 38.5%, 23.7% and 15.8%, respectively), suggesting endogenous cytokine production. The proportions of AM spontaneously expressing TNF-alpha positively correlated with peripheral blood CD4(+) T-lymphocyte counts in patients (partial r=0.60, p=0.003) but not controls. Stimulation with LPS resulted in a significant increase in the proportions of TNF-alpha- and IL-6-positive AM from patients and controls (p<0.01). Bronchoalveolar lavage fluid (BALF) from confirmed TB patients also contained higher concentrations of the inflammatory cytokines predominantly produced by macrophages, IL-6 and IL-8, than controls (geometric mean cytokine concentrations per gram of BALF albumin were 1291 pg/g vs. 115 pg/g, p=0.03 for IL-6 and 4739 pg/g vs. 704 pg/g, p=0.03 for IL-8). We concluded that AM from HIV-infected patients with pulmonary TB produced and released inflammatory cytokines in vivo and retained their innate ability to respond to stimulation by LPS.

High pneumococcal DNA loads are associated with mortality in Malawian children with invasive pneumococcal disease.

BACKGROUND: In bacteremia owing to Streptococcus pneumoniae, high bacterial counts at presentation have been shown to be predictive of the development of serious invasive disease. Using real-time PCR, we aimed to determine pneumococcal DNA loads in blood and CSF, and their relationship to cytokine concentrations, clinical presentation and outcome. METHODS: Children with confirmed meningitis (n = 82) or pneumonia (n = 13) were prospectively recruited, and blood and CSF samples taken for pneumococcal bacterial DNA loads and cytokine determination. RESULTS: At the time of admission, the median bacterial load in blood was 1.6 x 10 DNA copies/mL (range 0.00-1.54 x 10) and in CSF it was 5.77 x 10 DNA copies/mL (range 4.42 x 10 to 6.15 x 10). Median blood and CSF bacterial loads (log DNA copies/mL) were significantly higher in nonsurvivors than in survivors; blood (3.80 vs. 2.97, P = 0.003), CSF (8.17 vs. 7.50, P = 0.03). In HIV-infected children (n = 59), blood and CSF loads and plasma tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), IL-6 and IL-10 were all significantly higher in nonsurvivors than in survivors, but in HIV-uninfected children (n = 36) this difference was not significant. Blood bacterial loads and plasma cytokine concentrations were significantly associated, and were all significantly higher in children with meningitis than in those with pneumonia. In children with meningitis, median CSF cytokine concentrations were significantly higher than median plasma cytokine concentrations (P < 0.001) and CSF bacterial loads were significantly associated with CSF IL-1beta (P = 0.002) and IL-10 (P = 0.001) concentrations. CONCLUSIONS: Pneumococcal DNA loads are associated with plasma cytokine concentrations, and are higher in meningitis than in pneumonia. High blood and CSF pneumococcal DNA loads are associated with a fatal outcome.