Treatment resistant late-life depression: A narrative review of psychosocial risk factors, non-pharmacological interventions, and the role of clinical phenotyping.

BACKGROUND: Treatment resistant depression (TRD) is a subset of major depressive disorder (MDD) in which symptoms do not respond to front line therapies. In older adults, the assessment and treatment of TRD is complicated by psychosocial risk factors unique to this population, as well as a relative paucity of research. METHODS: Narrative review aimed at (1) defining TRLLD for clinical practice and research; (2) describing psychosocial risk factors; (3) reviewing psychological and non-pharmacological treatments; (4) discussing the role of clinical phenotyping for personalized treatment; and (5) outlining research priorities. RESULTS: Our definition of TRLLD centers on response to medication and neuromodulation in primary depressive disorders. Psychosocial risk factors include trauma and early life adversity, chronic physical illness, social isolation, personality, and barriers to care. Promising non-pharmacological treatments include cognitive training, psychotherapy, and lifestyle interventions. The utility of clinical phenotyping is highlighted by studies examining the impact of comorbidities, symptom dimensions (e.g., apathy), and structural/functional brain changes. LIMITATIONS: There is a relative paucity of TRLLD research. This limits the scope of empirical data from which to derive reliable patterns and complicates efforts to evaluate the literature quantitatively. CONCLUSIONS: TRLLD is a complex disorder that demands further investigation given our aging population. While this review highlights the promising breadth of TRLLD research to date, more research is needed to help elucidate, for example, the optimal timing for implementing risk mitigation strategies, the value of collaborative care approaches, specific treatment components associated with more robust response, and phenotyping to help inform treatment decisions.

Digital Collateral Information Through Electronic and Social Media in Psychotherapy: Comparing Clinician-reported Trends Before and During the COVID-19 Pandemic.

BACKGROUND: Patient clinical collateral information is critical for providing psychiatric and psychotherapeutic care. With the shift to primarily virtual care triggered by the COVID-19 pandemic, psychotherapists may have received less clinical information than they did when they were providing in-person care. This study assesses whether the shift to virtual care had an impact on therapists' use of patients' electronic and social media to augment clinical information that may inform psychotherapy. METHODS: In 2018, we conducted a survey of a cohort of psychotherapists affiliated with McLean Hospital. We then reapproached the same cohort of providers for the current study, gathering survey responses from August 10, 2020, to September 1, 2020, for this analysis. We asked clinicians whether they viewed patients' electronic and social media in the context of their psychotherapeutic relationship, what they viewed, how much they viewed it, and their attitudes about doing so. RESULTS: Of the 99 respondents, 64 (64.6%) had viewed at least 1 patient's social media and 8 (8.1%) had viewed a patient's electronic media. Of those who reported viewing patients' media, 70 (97.2%) indicated they believed this information helped them provide more effective treatment. Compared with the 2018 prepandemic data, there were significantly more clinicians with>10 years of experience reporting media use in therapy. There was also a significant increase during the pandemic in the viewing of media of adult patients and a trend toward an increase in viewing of media of older adult patients. CONCLUSIONS: Review of patients' electronic and social media in therapy became more common among clinicians at a large psychiatric teaching hospital during the COVID-19 pandemic. These findings support continuing research about how reviewing patients' media can inform and improve clinical care.

Nonoperative Treatment of Rotator Cuff Tears.

Rotator cuff tears are common with prevalence increasing with age. Diagnosis by physical examination may require a cluster of tests. Although radiographs can be helpful, MRI, MRI arthrography, and ultrasound represent the most used imaging technique to identify rotator cuff tears. Although surgery is sometimes necessary, a large portion of patients may respond to conservative treatment including physical therapy and injections. Physical therapy should include restoring the range of motion, addressing any pectoralis minor or posterior capsule stiffness, and restoring motor control/strength to the scapula and rotator cuff. Other conservative treatments may include nonsteroidal anti-inflammatory drugs, corticosteroid injects, and platelet-rich plasma.

Are unmet needs driving requests for Medical Assistance in Dying (MAiD)? A qualitative study of Canadian MAiD providers.

In this study, 20 medical assistance in dying (MAiD) providers were interviewed about their experience when assessing patients with unmet needs, including medical, financial or social needs. Collectively they had experience with over 3700 MAiD assessments and found that unmet needs were rare. In the cases where patients had unmet needs, these were usually related to loneliness and poverty. This led to the ethical dilemma of providers deciding to honor their wishes for MAiD, knowing that some of their suffering was due to society's failure to provide for them.

Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation.

Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS.

The Stress-Active Cell Division Protein ZapE Alters FtsZ Filament Architecture to Facilitate Division in Escherichia coli.

During pathogenic infections, bacterial cells experience environmental stress conditions, including low oxygen and thermal stress. Bacterial cells proliferate during infection and divide by a mechanism characterized by the assembly of a large cytoskeletal structure at the division site called the Z-ring. The major protein constituting the Z-ring is FtsZ, a tubulin homolog and GTPase that utilizes the nucleotide to assemble into dynamic polymers. In Escherichia coli, many cell division proteins interact with FtsZ and modulate Z-ring assembly, while others direct cell wall insertion and peptidoglycan remodeling. Here, we show that ZapE, an ATPase that accumulates during late constriction, directly interacts with FtsZ and phospholipids in vitro. In the presence of adenosine triphosphate (ATP), ZapE induces bundling of GTP-induced FtsZ polymers; however, ZapE also binds FtsZ in the absence of GTP. The ZapE mutant protein ZapE(K84A), which is defective for ATP hydrolysis, also interacts with FtsZ and induces FtsZ filament bundling. In vivo, cultures of zapE deletion cells contain a low percentage of filamentous cells, suggesting that they have a modest division defect; however, they are able to grow when exposed to stress, such as high temperature and limited oxygen. When combined with the chromosomal deletion of minC, which encodes an FtsZ disassembly factor, ΔzapE ΔminC cells experience growth delays that slow proliferation at high temperature and prevent recovery. This synthetic slow growth phenotype after exposure to stress suggests that ZapE may function to ensure proliferation during and after stress, and this is exacerbated when cells are also deleted for minC. Expression of either ZapE or ZapE(K84A) complements the aberrant growth phenotypes in vivo suggesting that the division-associated role of ZapE does not require ZapE ATP hydrolysis. These results support that ZapE is a stress-regulated cell division protein that interacts directly with FtsZ and phospholipids, promoting growth and division after exposure to environmental stress.

Pulmonary embolism severity before and during the COVID-19 pandemic.

OBJECTIVES: Early in the coronavirus 2019 (COVID-19) pandemic, a high frequency of pulmonary embolism was identified. This audit aims to assess the frequency and severity of pulmonary embolism in 2020 compared to 2019. METHODS: In this retrospective audit, we compared computed tomography pulmonary angiography (CTPA) frequency and pulmonary embolism severity in April and May 2020, compared to 2019. Pulmonary embolism severity was assessed with the Modified Miller score and the presence of right heart strain was assessed. Demographic information and 30-day mortality was identified from electronic health records. RESULTS: In April 2020, there was a 17% reduction in the number of CTPA performed and an increase in the proportion identifying pulmonary embolism (26%, n = 68/265 vs 15%, n = 47/320, p < 0.001), compared to April 2019. Patients with pulmonary embolism in 2020 had more comorbidities (p = 0.026), but similar age and sex compared to 2019. There was no difference in pulmonary embolism severity in 2020 compared to 2019, but there was an increased frequency of right heart strain in May 2020 (29 vs 12%, p = 0.029). Amongst 18 patients with COVID-19 and pulmonary embolism, there was a larger proportion of males and an increased 30 day mortality (28% vs 6%, p = 0.008). CONCLUSION: During the COVID-19 pandemic, there was a reduction in the number of CTPA scans performed and an increase in the frequency of CTPA scans positive for pulmonary embolism. Patients with both COVID-19 and pulmonary embolism had an increased risk of 30-day mortality compared to those without COVID-19. ADVANCES IN KNOWLEDGE: During the COVID-19 pandemic, the number of CTPA performed decreased and the proportion of positive CTPA increased. Patients with both pulmonary embolism and COVID-19 had worse outcomes compared to those with pulmonary embolism alone.

Hypoxia drives murine neutrophil protein scavenging to maintain central carbon metabolism.

Limiting dysfunctional neutrophilic inflammation while preserving effective immunity requires a better understanding of the processes that dictate neutrophil function in the tissues. Quantitative mass-spectrometry identified how inflammatory murine neutrophils regulated expression of cell surface receptors, signal transduction networks, and metabolic machinery to shape neutrophil phenotypes in response to hypoxia. Through the tracing of labeled amino acids into metabolic enzymes, proinflammatory mediators, and granule proteins, we demonstrated that ongoing protein synthesis shapes the neutrophil proteome. To maintain energy supplies in the tissues, neutrophils consumed extracellular proteins to fuel central carbon metabolism. The physiological stresses of hypoxia and hypoglycemia, characteristic of inflamed tissues, promoted this extracellular protein scavenging with activation of the lysosomal compartment, further driving exploitation of the protein-rich inflammatory milieu. This study provides a comprehensive map of neutrophil proteomes, analysis of which has led to the identification of active catabolic and anabolic pathways that enable neutrophils to sustain synthetic and effector functions in the tissues.

Implementation of Safety Standards for Youth Sports Leagues: The "Safe Stars" Example in Tennessee.

OBJECTIVE: Discuss the implementation of the nation's first statewide standardized youth sports safety program and review the current culture and status of youth sports which led to its development. DESIGN: Descriptive. SETTING: State of Tennessee. INTERVENTIONS: The "Safe Stars" Initiative. MAIN OUTCOME MEASURES: Provide a summary of the process of devising, developing, and deploying a set of evidence-based and best practice criteria to improve the health, safety, and well-being of youth athletes. CONCLUSIONS: Safe Stars provides a structured opportunity for every child to play sports and develop successful habits and skills for life while safely doing so. We intend for this to serve as a roadmap for others to adopt and institute a statewide philosophy that emphasizes the importance of a safe, positive, and high-quality experience for children while holding their respective youth sports communities accountable for its achievement. Currently, very few leagues meet the recommended minimum standards of safety. Continued advancement of strategic partnerships as well as research into the program's impact on sports participation, health, and safety will be some of the critical next steps in realizing the full value of this program.

Operative vs Nonoperative Treatment for Atraumatic Rotator Cuff Tears: A Trial Protocol for the Arthroscopic Rotator Cuff Pragmatic Randomized Clinical Trial.

Importance: Rotator cuff disorders remain the most common cause of shoulder pain and are among the most common reasons for patients to seek care in primary and specialty settings. Although operative and nonoperative treatments are offered to patients with atraumatic rotator cuff tears, there is a lack of evidence to support operative vs nonoperative treatment. This paucity of evidence has been highlighted by several professional agencies and experts. Objective: To perform a pragmatic randomized clinical trial, the Arthroscopic Rotator Cuff trial, comparing pain and functional outcomes in patients undergoing operative vs nonoperative treatment for atraumatic rotator cuff tears, and assessing heterogeneity of treatment effects by age and tear size. Design, Setting, and Participants: Trial protocol of the Arthroscopic Rotator Cuff trial. This pragmatic randomized clinical trial of an estimated 700 patients is adequately powered to accomplish its aims with 488 patients. Primary analysis will be conducted on an intent-to-treat population in the context of a mixed model. The multicenter trial started recruitment in 2018 with a 1-year follow-up duration. Patients aged 50 years or older to younger than 85 years with magnetic resonance imaging-confirmed atraumatic rotator cuff tears that are suitable for either operative or nonoperative treatment will be enrolled. Block randomization will be performed and stratified by site, age, and tear size. Intervention: Nonoperative treatment consists of an approximately 3-month standardized physical therapy program, whereas operative treatment consists of rotator cuff surgery followed by approximately 4 months of postoperative rehabilitation. Main Outcomes and Measures: The primary outcome is patient-reported Shoulder Pain and Disability Index score, and the secondary outcome is American Shoulder and Elbow Surgeons Standardized Shoulder Form score measured at 1 year of follow-up. Discussion: The Arthroscopic Rotator Cuff trial is ongoing, and 12 sites with more than 40 physicians are currently recruiting patients. Although there is variation by site, as of May 2, 2019, 13% of all patients screened (787 of 6293) were eligible for the trial, and 9% of eligible patients (74 of 787) were recruited. Results of this study may help patients, clinicians, and policy makers assess the comparative effectiveness of operative vs nonoperative treatment for atraumatic rotator cuff tears. Trial Registration: ClinicalTrials.gov identifier: NCT03295994.

'If you can't see a dilemma in this situation you should probably regard it as a warning': a metasynthesis and theoretical modelling of general practitioners' opioid prescription experiences in primary care.

INTRODUCTION: The prescribing of opioids has increased internationally in developed countries in recent decades within primary and secondary care. The majority of patients with chronic non-malignant pain (CNMP) are managed by their general practitioner (GP). Recent qualitative studies have examined the issue of opioid prescribing for CNMP from a GP viewpoint. The aim of this study is to identify and synthesise the qualitative literature describing the factors influencing the nature and extent of opioid prescribing by GPs for patients with CNMP in primary care. METHODS: MEDLINE, Embase, PsycINFO, Cochrane Database, International Pharmaceutical Abstracts, Database of Abstracts of Reviews of Effects, CINAHL and Web of Science were systematically searched from January 1986 to February 2018. The full text of included articles was reviewed using the Critical Appraisal Skills Programme (CASP) tool for qualitative research. The papers were coded by two researchers and themes organised using Thematic Network Analysis. Themes were constructed in a hierarchical manner, basic themes informed organising themes which informed global themes. A theoretical model was derived using global themes to explain the interplay between factors influencing opioid prescribing decisions. RESULTS: From 7020 records, 21 full text papers were assessed, and 13 studies included in the synthesis; 9 were from the United States, 3 from the United Kingdom and 1 from Canada. Four global themes emerged: suspicion, risk, agreement and encompassing systems level factors. These global themes are inter-related and capture the complex decision-making processes underlying opioid prescribing whereby the physician both consciously and unconsciously quantifies the risk-benefit relationship associated with initiating or continuing an opioid prescription. CONCLUSION: Recognising the inherent complexity of opioid prescribing and the limitations of healthcare systems is crucial to developing opioid stewardship strategies to combat the rise in opioid prescription morbidity and mortality.

IL4Rα Signaling Abrogates Hypoxic Neutrophil Survival and Limits Acute Lung Injury Responses In Vivo.

Rationale: Acute respiratory distress syndrome is defined by the presence of systemic hypoxia and consequent on disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood. Objectives: To test the hypothesis that during acute lung inflammation tissue production of proresolution type 2 cytokines (IL-4 and IL-13) dampens the proinflammatory effects of hypoxia through suppression of HIF-1α (hypoxia-inducible factor-1α)-mediated neutrophil adaptation, resulting in resolution of lung injury. Methods: Neutrophil activation of IL4Ra (IL-4 receptor α) signaling pathways was explored ex vivo in human acute respiratory distress syndrome patient samples, in vitro after the culture of human peripheral blood neutrophils with recombinant IL-4 under conditions of hypoxia, and in vivo through the study of IL4Ra-deficient neutrophils in competitive chimera models and wild-type mice treated with IL-4. Measurements and Main Results: IL-4 was elevated in human BAL from patients with acute respiratory distress syndrome, and its receptor was identified on patient blood neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1α-dependent hypoxic survival and limited proinflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent on expression of the oxygen-sensing prolyl hydroxylase PHD2. In vivo, IL-4Ra-deficient neutrophils had a survival advantage within a hypoxic inflamed niche; in contrast, inflamed lung treatment with IL-4 accelerated resolution through increased neutrophil apoptosis. Conclusions: We describe an important interaction whereby IL4Rα-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil-mediated acute lung injury.

Physical therapy versus natural history in outcomes of rotator cuff tears: the Rotator Cuff Outcomes Workgroup (ROW) cohort study.

BACKGROUND: We compared the outcomes of patients who performed physical therapy versus those who did not in a longitudinal cohort of patients undergoing nonoperative treatment of rotator cuff tears. We also assessed whether there was a dose effect in which the pain and functional outcomes in patients performing physical therapy plateaued. METHODS: From February 2011 to June 2015, a multicenter cohort of patients with rotator cuff tears undergoing nonoperative treatment completed a detailed health and demographic questionnaire and the Shoulder Pain and Disability Index (SPADI) at baseline and 3, 6, 12, and 18 months. Longitudinal mixed models were used to assess whether physical therapy in the first 3 months predicted SPADI scores and dose effect. RESULTS: Among the 55 patients in our cohort, the performance of physical therapy within the first 3 months predicted better SPADI scores versus nonperformance of physical therapy at 3 months (P = .02). Scores were similar between groups at 6, 12, and 18 months. A threshold of 16 physical therapy sessions was observed for pain and functional improvement during follow-up, after which significant improvement was not seen. CONCLUSIONS: Patients who performed physical therapy within the first 3 months had statistically significant improvements in pain and function as measured by the SPADI score at 3 months compared with patients who did not report performing physical therapy. Depending on the minimal clinically important difference used for the SPADI score, our results could be interpreted as meeting the minimal clinically important difference threshold or not. Improvement in outcomes was observed up to 16 sessions of physical therapy, after which outcomes plateaued.

The effect of counseling on willingness to use a hypothetical medication and perceptions of medication safety.

BACKGROUND: Poor medication adherence is an ongoing issue, and contributes to increased hospitalizations and healthcare costs. Although most adverse effects are rare, the perceived risk of adverse effects may contribute to low adherence rates. OBJECTIVES: The objective of this study was to determine how adverse effect likelihood and pharmacist counseling on adverse effect prevention affects individuals': (1) willingness to use a hypothetical medication and (2) perceptions of medication safety. METHODS: This study used a 3 × 3 experimental design. Participants (n = 601) viewed a hypothetical scenario asking them to imagine being prescribed an anti-asthma medication that could cause fungal infections of the throat. Participants were randomized to 1 of 9 scenarios that differed on: probability of developing an infection (5%, 20%, no probability mentioned) and whether they were told how to reduce the risk of infection (no prevention strategy discussed, prevention strategy discussed, prevention strategy discussed with explanation for how it works). Participants were recruited through Amazon Mechanical Turk. RESULTS: Participants were less willing to take the medication (F = 12.86, p < 0.0001) and considered it less safe (F = 13.11, p < 0.0001) when the probability of fungal infection was presented as 20% compared to 5% or when no probability information was given. Participants were more willing to take the medication (F = 11.78, p < 0.0001) and considered it safer (F = 11.17, p < 0.0001) when a prevention strategy was given. Finally, there was a non-statistically significant interaction between the probability and prevention strategy information such that provision of prevention information reduced the effect of variation in the probability of infection on both willingness to use the medication and perceived medication safety. CONCLUSIONS: Optimal risk communication involves more than informing patients about possible adverse effects. Pharmacists could potentially improve patient acceptance of therapeutic recommendations, and allay medication safety concerns, by counseling about strategies patients can implement to reduce the perceived risk of adverse effects.

Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses.

Fully activated innate immune cells are required for effective responses to infection, but their prompt deactivation and removal are essential for limiting tissue damage. Here, we have identified a critical role for the prolyl hydroxylase enzyme Phd2 in maintaining the balance between appropriate, predominantly neutrophil-mediated pathogen clearance and resolution of the innate immune response. We demonstrate that myeloid-specific loss of Phd2 resulted in an exaggerated inflammatory response to Streptococcus pneumonia, with increases in neutrophil motility, functional capacity, and survival. These enhanced neutrophil responses were dependent upon increases in glycolytic flux and glycogen stores. Systemic administration of a HIF-prolyl hydroxylase inhibitor replicated the Phd2-deficient phenotype of delayed inflammation resolution. Together, these data identify Phd2 as the dominant HIF-hydroxylase in neutrophils under normoxic conditions and link intrinsic regulation of glycolysis and glycogen stores to the resolution of neutrophil-mediated inflammatory responses. These results demonstrate the therapeutic potential of targeting metabolic pathways in the treatment of inflammatory disease.

A systematic review of cost-effective treatment of postoperative rotator cuff repairs.

OBJECTIVE: The Bundled Payments for Care Improvement initiative combines payment of multiple services for episodes of care into 1 bundle. Rotator cuff repair is a likely candidate for future inclusion. The objective of this study was to determine cost-effective, high-quality postoperative rehabilitation dosing and cryotherapy for patients undergoing rotator cuff repair based on systematic review of the literature. METHODS: Systematic review of level I and level II articles was performed in PubMed, Cochrane Databases, and PEDro. Conference references and bibliographies were also reviewed. For postoperative therapy, keywords included rotator cuff, rotator cuff repair, exercise therapy, exercise, unsupervised, self-care, postoperative period, physical therapy, and physiotherapy; for cryotherapy, keywords included rotator cuff repair, shoulder, cryotherapy, and ice. RESULTS: Five studies compared postoperative outcomes in participants assigned to supervised therapy vs. unsupervised therapy. Three found no difference between groups. One found improved outcomes in supervised therapy. Limitations included that therapies were not consistently defined and significant methodologic issues were present, decreasing the applicability and validity of the results. Five articles examined cryotherapy outcomes in the postoperative shoulder. Two studies showed improved patient outcomes with cryotherapy vs. no cryotherapy; 2 studies showed no decrease in joint space temperatures at 90 minutes but decrease in temperature at 4 to 23 hours postoperatively. One study indicated that an ice bag and Ace bandage might be as effective as continuous, compressive cryotherapy units using patient-reported outcomes. CONCLUSION: Further studies are needed to determine effective dosing of physical therapy after rotator cuff repair. Cryotherapy is favorable and cost-effective using simple methods for delivery.

How much information about the benefits of medicines is included in patient leaflets in the European Union? - A survey.

INTRODUCTION: Patient information leaflets (PILs) are required with all licensed medicines throughout the European Union (EU) and they must include information about all side effects and their likelihood. This has led to criticism of a lack of balance, with little information included about potential benefits. Recent European Medicines Agency guidance proposed the inclusion of benefit information, and this study examined the current prevalence and type of such information in PILs in the EU. METHODS: A survey and content analysis of the English translation of PILs in the EUwas carried out. Random quota sampling was used on the most frequently dispensed (n = 50) and newly licensed medicines (n = 50) in 2011/2. Leaflets were searched for benefit information meeting predefined criteria, and data synthesised and categorised into 10 categories. RESULTS: Eighty-five (85%) leaflets described how the medicine works, with 45 providing information about the rationale for treatment (more commonly for newly licensed (32/50) than most commonly dispensed medicines (13/50; P < 0.001). Nearly half (47) did not describe whether the medicine was curative, symptomatic or preventative. The terms used to communicate uncertainty were imprecise (such as 'may help'). None communicated numerical benefit information. CONCLUSION: Current PILs do not appropriately communicate information about benefit. At the basic level, around a half did not include information about treatment rationale or whether the treatment was to treat symptoms, curative or preventative. However, for true informed decision making, patients need quantitative information about benefits and none of the leaflets provided this.