Stigma Against Patients With Substance Use Disorders Among Health Care Professionals and Trainees and Stigma-Reducing Interventions: A Systematic Review.

PURPOSE: In this systematic review, the authors examine the prevalence and extent of stigmatizing attitudes among health care professionals (HCPs) and trainees against patients with substance use disorders (SUDs), including research on interventions to reduce stigma. METHOD: The authors searched 7 databases for articles published from January 1, 2011, through February 15, 2023, that quantified SUD stigma among HCPs or trainees. Inclusion criteria allowed both observational and intervention studies from the United States or Canada to be included in this review. Quality assessment was applied to all included studies; studies were not excluded based on quality. RESULTS: A total of 1,992 unique articles were identified of which 32 articles (17 observational studies and 15 intervention studies), all conducted in the United States, met the inclusion criteria. Half of the included studies (16 of 32) were published in 2020 or later. Most of the intervention studies (13 of 15) used a single-group pre-post design; interventions involved didactics and/or interactions with persons with SUDs. The 32 included studies used a total of 19 different measures of stigma. All 17 observational studies showed some degree of HCP or trainee stigma against patients with SUDs. Most intervention studies (12 of 15) found small but statistically significant reductions in stigma after intervention. CONCLUSIONS: SUD stigma exists among HCPs and trainees. Some interventions to reduce this stigma had positive impacts, but future studies with larger, diverse participants and comparison groups are needed. Heterogeneity among studies and stigma measures limits the ability to interpret results across studies. Future rigorous research is needed to determine validated, consensus measures of SUD stigma among HCPs and trainees, identify stigma scores that are associated with clinical outcomes, and develop effective antistigma interventions for HCPs and trainees.

Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial.

BACKGROUND: We hypothesised that combining zanubrutinib with obinutuzumab and venetoclax (BOVen) as an initial therapy for chronic lymphocytic leukaemia and small lymphocytic lymphoma would lead to high rates of undetectable minimal residual disease (MRD), and we explored MRD as a biomarker for directing treatment duration. METHODS: This multicenter, investigator-initiated, single-arm, phase 2 trial took place at two two academic medical centres in the USA. Patients were eligible for the primary cohort if they had treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, required therapy, and were at least 18 years of age with an Eastern Cooperative Oncology Group performance status up to 2. BOVen was administered in 28 day cycles (oral zanubrutinib at 160 mg twice per day starting in cycle 1 on day 1; intravenous obinutuzumab at 1000 mg on day 1 [split over day 1 with 100 mg and day 2 with 900 mg for an absolute lymphocyte count >25 000 cells per µL or lymph nodes >5 cm in diameter], day 8, and day 15 of cycle 1, and day 1 of cycles 2-8; and oral venetoclax ramp up to 400 mg per day starting in cycle 3 on day 1) and discontinued after 8-24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow. The primary endpoint was the proportion of patients that reached undetectable MRD in both the peripheral blood and bone marrow (flow cytometry cutoff less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes [<10-4]) assessed per protocol. This trial is registered at clinicaltrials.gov (NCT03824483). The primary cohort is closed to recruitment, and recruitment continues in the TP53-mutated mantle cell lymphoma cohort. FINDINGS: Between March 14, 2019, and Oct 10, 2019, 47 patients were screened for eligibility, and 39 patients were enrolled and treated. Median age was 62 years (IQR 52-70) with 30 (77%) of 39 male participants and nine (23%) of 39 female participants. 28 (72%) of 39 patients had unmutated immunoglobulin heavy-chain variable-region and five (13%) of 39 had 17p deletion or TP53 mutation. After a median follow-up of 25·8 months (IQR 24·0-27·3), 33 (89%) of 37 patients (95% CI 75-97) had undetectable MRD in both blood and bone marrow, meeting the prespecified undetectable MRD criteria to stop therapy after a median of ten cycles (IQR 8-12), which includes two cycles of zanubrutinib and obinutuzumab before starting venetoclax. After median surveillance after treatment of 15·8 months (IQR 13·0-18·6), 31 (94%) of 33 patients had undetectable MRD. The most common adverse events were thrombocytopenia (23 [59%] of 39), fatigue (21 [54%]), neutropenia (20 [51%]), and bruising (20 [51%]), and the most common adverse event at grade 3 or worse was neutropenia (seven [18%]) in the intention-to-treat population. One death occurred in a patient with intracranial haemorrhage on day 1 of cycle 1 after initiating intravenous heparin for pulmonary emboli. INTERPRETATION: BOVen was well tolerated and met its primary endpoint, with 33 (89%) of 37 previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma reaching undetectable MRD in both peripheral blood and bone marrow despite a median treatment duration of only 10 months, owing to our undetectable MRD-driven treatment discontinuation design. These data support further evaluation of the BOVen regimen in chronic lymphocytic leukaemia and small lymphocytic lymphoma with treatment duration guided by early MRD response kinetics. FUNDING: Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute.

Positive Expiratory Pressure Therapy With And Without Oscillation And Hospital Length Of Stay For Acute Exacerbation Of Chronic Obstructive Pulmonary Disease.

Introduction: Pharmacologic management of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is well-established. Our aim in the current study is to determine if therapy with a positive expiratory pressure (PEP) device with or without an oscillatory mechanism (OM) in addition to standard care results in a reduction in hospital length of stay (LOS) among patients hospitalized for AECOPD. Methods: Two studies were performed and are reported here. Study 1: Patients admitted with AECOPD and sputum production were enrolled in a prospective trial comparing PEP therapy versus Oscillatory PEP (OPEP) therapy. Study 2: A retrospective historical cohort, matched in a 2 to 1 manner by age, gender, and season of admission, was compared with the prospectively collected data to determine the effect of PEP ± OM versus standard care on hospital LOS. Results: In the prospective trial (Study 1; 91 subjects), median hospital LOS was 3.2 (95% CI 3.0-4.3) days in the OPEP group and 4.8 (95% CI 3.9-6.1) days in the PEP group (p=0.16). In fully adjusted models comparing the prospective trial data with the retrospective cohort (Study 2; 182 subjects), cases had a median hospital LOS of 4.2 days (95% CI 3.8-5.1) versus 5.2 days (95% CI 4.4-6.0) in controls, consistent with a shorter hospital LOS with adjunctive PEP±OM therapy versus standard care (p=0.04). Conclusion: Adjunctive therapy with a PEP device versus standard care may reduce hospital LOS in patients admitted for AECOPD. Although the addition of an OM component to PEP therapy suggests a further reduction in hospital LOS, comprehensive multicenter randomized controlled trials are needed to confirm these findings. Clinical trial registration number: NCT03094806.

The association of NOV/CCN3 with obstructive sleep apnea (OSA): preliminary evidence of a novel biomarker in OSA.

Obstructive sleep apnea (OSA) has a strong association with cardiovascular and metabolic abnormalities, although the mechanism driving this association is not well established. NOV/CCN3, a multifunctional extracellular matrix protein, may play a mechanistic and/or prognostic role in these associations. We hypothesized that patients with OSA, which primarily affects obese individuals, will have increased levels of NOV, and that NOV can serve as a biomarker in patients to predict OSA as well as metabolic and cardiac risk. Ten morbidly obese and 10 healthy lean subjects underwent overnight polysomnography (PSG) and clinical evaluation. Blood samples were analyzed for NOV levels, adiponectin and IL-6. OSA was found in nine obese subjects and three lean subjects. NOV levels were significantly higher in the OSA vs. no OSA group (2.1 ± 0.9 vs. 1.3 ± 0.8, p < 0.03). NOV levels were significantly higher in the obese vs. lean group (2.2 ± 0.3 vs. 1.4 ± 0.2-fold change, p < 0.03). Among lean subjects, NOV levels were significantly higher in the OSA vs. no OSA group (2.1 ± 0.9 vs. 1.0 ± 0.4, p < 0.05). NOV and AHI were positively correlated (ρ = 0.49, p = 0.033). IL-6 and adiponectin differences in obese vs. lean and OSA vs. no OSA were consistent with an inflammatory phenotype in obese subjects and OSA subjects. NOV is a novel biomarker of the presence and severity of OSA and a potential marker of future cardiovascular and metabolic disease in OSA patients.

Differential effects of alcohol upon gluconeogenesis from lactate in young and old hepatocytes.

The purpose of this study was to determine the effect of age upon hepatic gluconeogenesis (HGN) from lactate in the presence of various concentrations of alcohol from young (3 months) and old (24 months) male rats. After a 24-hour fast, livers were perfused with collagenase and the hepatocytes were isolated. Aliquots of the cell suspension were placed in Krebs-Henseleit buffer and incubated with lactate, [U-(14)C]lactate, and nine different concentrations of ethanol (EtOH) for 30 min. Dose-effect curves were generated for the determination of maximal and half-maximal alcohol-induced inhibition on gluconeogenesis. There were no significant differences in basal HGN (lactate only and no EtOH) between young and old hepatocytes, 86.9+/-6.3 nmol/mg protein/30 min. The addition of ethanol significantly reduced HGN from lactate in both groups. At the highest ethanol concentration (15 mM), the glucose production was inhibited more from old, 46.1+/-1.2 nmol/mg protein/30 min, compared to young hepatocytes, 56.0+/-1.6 nmol/mg protein/30 min. The greater age-related reduction in HGN was confirmed by the minimal glycogenolysis, and the concomitant decline in [U-(14)C]glucose production, lactate uptake, and [U-(14)C]lactate uptake. The results suggest that alcohol elicits a greater inhibition upon HGN from lactate in old compared to young liver cells.

Hepatic gluconeogenic capacity from various precursors in young versus old rats.

Hepatic gluconeogenic capacity was studied in young (4 months of age) and old (24 months of age) male Fischer 344 rats fasted for 24 hours using the isolated hepatocyte technique. Following the isolation of liver cells, the following precursors were added to the cell suspensions and incubated for 30 minutes: lactate (5 mmol/L), pyruvate (5 mmol/L), alanine (5 mmol/L), glutamine (5 mmol/L), oxaloacetate (5 mmol/L), glycerol (5 mmol/L), dihydroxyacetone (10 mmol/L), fructose (10 mmol/L), or saline (no precursor addition). To confirm that glucose production reflects gluconeogenic capacity, there was significant depletion of hepatic glycogen after the 24-hour fast and minimal alterations in glycogen content once substrates were added. Adjusting the gluconeogenic rates to reflect 100% cell viability resulted in no difference between young and old animals for any substrate used with the sole exception of fructose. The hepatic glucose production from fructose was 34% greater for young versus old animals. The results suggest that following a period of starvation the basal glucose production rates from hepatocytes, incubated with precursors entering the gluconeogenic pathway prior to fructose-6-phosphate, are equivalent in young and old rats.