Cigarette smoke augments CSF3 expression in neutrophils to compromise alveolar-capillary barrier function during influenza infection.

BACKGROUND: Cigarette smokers are at increased risk of acquiring influenza, developing severe disease and requiring hospitalisation/intensive care unit admission following infection. However, immune mechanisms underlying this predisposition are incompletely understood, and therapeutic strategies for influenza are limited. METHODS: We used a mouse model of concurrent cigarette smoke exposure and H1N1 influenza infection, colony-stimulating factor (CSF)3 supplementation/receptor (CSF3R) blockade and single-cell RNA sequencing (scRNAseq) to investigate this relationship. RESULTS: Cigarette smoke exposure exacerbated features of viral pneumonia such as oedema, hypoxaemia and pulmonary neutrophilia. Smoke-exposed infected mice demonstrated an increase in viral (v)RNA, but not replication-competent viral particles, relative to infection-only controls. Interstitial rather than airspace neutrophilia positively predicted morbidity in smoke-exposed infected mice. Screening of pulmonary cytokines using a novel dysregulation score identified an exacerbated expression of CSF3 and interleukin-6 in the context of smoke exposure and influenza. Recombinant (r)CSF3 supplementation during influenza aggravated morbidity, hypothermia and oedema, while anti-CSF3R treatment of smoke-exposed infected mice improved alveolar-capillary barrier function. scRNAseq delineated a shift in the distribution of Csf3 + cells towards neutrophils in the context of cigarette smoke and influenza. However, although smoke-exposed lungs were enriched for infected, highly activated neutrophils, gene signatures of these cells largely reflected an exacerbated form of typical influenza with select unique regulatory features. CONCLUSION: This work provides novel insight into the mechanisms by which cigarette smoke exacerbates influenza infection, unveiling potential therapeutic targets (e.g. excess vRNA accumulation, oedematous CSF3R signalling) for use in this context, and potential limitations for clinical rCSF3 therapy during viral infectious disease.

The psychopharmacology algorithm project at the Harvard South Shore Program: An algorithm for adults with obsessive-compulsive disorder.

A previous algorithm for the pharmacological treatment of obsessive-compulsive disorder was published in 2012. Developments over the past 7 years suggest an update is needed. The authors conducted searches in PubMed, focusing on new studies and reviews since 2012 that would support or change previous recommendations. We identified exceptions to the main algorithm, including pregnant women and women of child-bearing potential, the elderly, and patients with common medical and psychiatric co-morbidities. Selective serotonin reuptake inhibitors (SSRIs) are still first-line. An adequate trial requires a period at typical antidepressant doses and dose adjustments guided by a plasma level to evaluate for poor adherence or ultra-rapid metabolism. If the response is inadequate, consider a trial of another SSRI this time possibly taken to a very high dose. Clomipramine could be an alternative. If the response to the second trial remains inadequate, the next recommendation is to augment with aripiprazole or risperidone. Alternatively, augmentation with novel agents could be selected, including glutamatergic (memantine, riluzole, topiramate, n-acetylcysteine, lamotrigine), serotonergic (ondansetron), and anti-inflammatory (minocycline, celecoxib) agents. A third option could be transcranial magnetic stimulation. Lastly, after several of these trials, deep brain stimulation and cingulotomy have evidence for a role in the most treatment-refractory patients.

Seeing is believing: an exploration of what residents value when they receive feedback.

OBJECTIVE: The primary purpose of this paper is to report on psychiatry residents' perceptions of what is important when receiving feedback from evaluators. METHODS: In January 2018, as part of the Harvard South Shore Psychiatry Residency Training Program's (HSS) ongoing local quality improvement efforts to enhance the delivery and effectiveness of feedback that residents receive from faculty during training, the authors disseminated a survey to psychiatry residents (n = 31) at HSS. Residents rated the level of importance of 17 statements pertaining to the way feedback is delivered. Two open-ended prompts also allowed respondents to share examples of growth-oriented and unhelpful feedback they have received during residency. RESULTS: Twenty-seven residents responded (87% response rate). Eighty-one percent rated "the evaluator models the same behavior they're encouraging" as "extremely important" when receiving feedback. Many residents also rated the following survey items as "extremely important": "confidence in the evaluator's clinical and interpersonal skills" (63.0%), "amount of time the evaluator observed the resident" (51.9%), "there is a way to fix a performance deficit" (51.8%), and "specific feedback based off the resident's work" (48.1%). Conversely, only 11.1% of residents rated the feedback sandwich as "extremely important." CONCLUSIONS: Despite a small sample size, this project demonstrated that, when receiving feedback, the majority of psychiatry residents strongly value when evaluators model the targeted behavior. The feedback sandwich was least important to residents. This project underscores the importance of evaluators serving as role models in the context of feedback, and findings can be used in faculty development activities focused on feedback delivery best practices.

A placebo-controlled trial of acetyl-L-carnitine and α-lipoic acid in the treatment of bipolar depression.

BACKGROUND: Bipolar disorder may be associated with mitochondrial dysfunction. Therefore, agents that enhance mitochondrial functioning may be efficacious in bipolar disorder. We performed a randomized placebo-controlled trial of the mitochondrial enhancers acetyl-L-carnitine (ALCAR) and α-lipoic acid (ALA) in patients with bipolar depression, and assessed markers of cerebral energy metabolism using phosphorus magnetic resonance spectroscopy. METHODS: We administered ALCAR (1000-3000 mg daily) plus ALA (600-1800 mg daily) or placebo for 12 weeks to 40 patients with bipolar depression and obtained imaging data at baseline, week 1, and week 12 of treatment in 20 patients using phosphorus 3-dimensional chemical-shift imaging at 4 T. Statistical analysis used random effects mixed models. RESULTS: We found no significant difference between ALCAR/ALA and placebo on change from baseline in the Montgomery-Asberg Depression Rating Scale in both the longitudinal (mean difference [95% confidence interval], -1.4 [-6.2 to 3.4], P = 0.58) and last-observation-carried-forward (-3.2 [-7.2 to 0.9], P = 0.12) analyses. ALCAR/ALA treatment significantly reduced phosphocreatine levels in the parieto-occipital cortex at week 12 (P = 0.002). Reduction in whole brain total nucleoside triphosphate levels from baseline to week 1 was associated with reduction in Montgomery-Asberg Depression Rating Scale scores (P = 0.02) in patients treated with ALCAR/ALA. However, this was likely a chance finding attributable to multiple statistical comparisons. CONCLUSIONS: Treatment with ALCAR and ALA at the dose and duration used in this study does not have antidepressant effects in depressed bipolar patients and does not significantly enhance mitochondrial functioning in this patient group.