Peripheral-derived regulatory T cells contribute to tumor-mediated immune suppression in a nonredundant manner.

Identifying tumor-mediated mechanisms that impair immunity is instrumental for the design of new cancer therapies. Regulatory T cells (Tregs) are a key component of cancer-derived immune suppression; however, these lymphocytes are necessary to prevent systemic autoimmunity in mice and humans, and thus, direct targeting of Tregs is not a clinical option for cancer patients. We have previously demonstrated that excising transcription factor Kruppel-like factor 2 (Klf2) within the T cell lineage blocks the generation of peripheral-derived Tregs (pTregs) without impairing production of thymic-derived Tregs. Using this mouse model, we have now demonstrated that eliminating pTregs is sufficient to delay/prevent tumor malignancy without causing autoimmunity. Cancer-bearing mice that expressed KLF2 converted tumor-specific CD4+ T cells into pTregs, which accumulated in secondary lymphoid organs and impaired further T cell effector activity. In contrast, pTreg-deficient mice retained cancer-specific immunity, including improved T cell infiltration into "cold" tumors, reduced T cell exhaustion in tumor beds, restricted generation of tumor-associated myeloid-derived suppressor cells, and the continued production of circulating effector T cells that arose in a cancer-dependent manner. Results indicate that tumor-specific pTregs are critical for early stages of cancer progression and blocking the generation of these inhibitory lymphocytes safely delays/prevents malignancy in preclinical models of melanoma and prostate cancer.

Properties of the iron-sulfur cluster electron transfer relay in an [FeFe]-hydrogenase that is tuned for H2 oxidation catalysis.

[FeFe]-hydrogenases catalyze the reversible oxidation of H2 from electrons and protons at an organometallic active site cofactor named the H-cluster. In addition to the H-cluster, most [FeFe]-hydrogenases possess accessory FeS cluster (F-cluster) relays that function in mediating electron transfer with catalysis. There is significant variation in the structural properties of F-cluster relays among the [FeFe]-hydrogenases; however, it is unknown how this variation relates to the electronic and thermodynamic properties, and thus the electron transfer properties, of enzymes. Clostridium pasteurianum [FeFe]-hydrogenase II (CpII) exhibits a large catalytic bias for H2 oxidation (compared to H2 production), making it a notable system for examining if F-cluster properties contribute to the overall function and efficiency of the enzyme. By applying a combination of multifrequency and potentiometric electron paramagnetic resonance, we resolved two electron paramagnetic resonance signals with distinct power- and temperature-dependent properties at g = 2.058 1.931 1.891 (F2.058) and g = 2.061 1.920 1.887 (F2.061), with assigned midpoint potentials of -140 ± 18 mV and -406 ± 12 mV versus normal hydrogen electrode, respectively. Spectral analysis revealed features consistent with spin-spin coupling between the two [4Fe-4S] F-clusters, and possible functional models are discussed that account for the contribution of coupling to the electron transfer landscape. The results signify the interplay of electronic coupling and free energy properties and parameters of the FeS clusters to the electron transfer mechanism through the relay and provide new insight as to how relays functionally complement the catalytic directionality of active sites to achieve highly efficient catalysis.

An uncharacteristically low-potential flavin governs the energy landscape of electron bifurcation.

Electron bifurcation, an energy-conserving process utilized extensively throughout all domains of life, represents an elegant means of generating high-energy products from substrates with less reducing potential. The coordinated coupling of exergonic and endergonic reactions has been shown to operate over an electrochemical potential of ∼1.3 V through the activity of a unique flavin cofactor in the enzyme NADH-dependent ferredoxin-NADP+ oxidoreductase I. The inferred energy landscape has features unprecedented in biochemistry and presents novel energetic challenges, the most intriguing being a large thermodynamically uphill step for the first electron transfer of the bifurcation reaction. However, ambiguities in the energy landscape at the bifurcating site deriving from overlapping flavin spectral signatures have impeded a comprehensive understanding of the specific mechanistic contributions afforded by thermodynamic and kinetic factors. Here, we elucidate an uncharacteristically low two-electron potential of the bifurcating flavin, resolving the energetic challenge of the first bifurcation event.

Cross-talk between IL-6 trans-signaling and AIM2 inflammasome/IL-1ß axes bridge innate immunity and epithelial apoptosis to promote emphysema.

Pulmonary emphysema is associated with dysregulated innate immune responses that promote chronic pulmonary inflammation and alveolar apoptosis, culminating in lung destruction. However, the molecular regulators of innate immunity that promote emphysema are ill-defined. Here, we investigated whether innate immune inflammasome complexes, comprising the adaptor ASC, Caspase-1 and specific pattern recognition receptors (PRRs), promote the pathogenesis of emphysema. In the lungs of emphysematous patients, as well as spontaneous gp130F/F and cigarette smoke (CS)-induced mouse models of emphysema, the expression (messenger RNA and protein) and activation of ASC, Caspase-1, and the inflammasome-associated PRR and DNA sensor AIM2 were up-regulated. AIM2 up-regulation in emphysema coincided with the biased production of the mature downstream inflammasome effector cytokine IL-1ß but not IL-18. These observations were supported by the genetic blockade of ASC, AIM2, and the IL-1 receptor and therapy with AIM2 antagonistic suppressor oligonucleotides, which ameliorated emphysema in gp130F/F mice by preventing elevated alveolar cell apoptosis. The functional requirement for AIM2 in driving apoptosis in the lung epithelium was independent of its expression in hematopoietic-derived immune cells and the recruitment of infiltrating immune cells in the lung. Genetic and inhibitor-based blockade of AIM2 also protected CS-exposed mice from pulmonary alveolar cell apoptosis. Intriguingly, IL-6 trans-signaling via the soluble IL-6 receptor, facilitated by elevated levels of IL-6, acted upstream of the AIM2 inflammasome to augment AIM2 expression in emphysema. Collectively, we reveal cross-talk between the AIM2 inflammasome/IL-1ß and IL-6 trans-signaling axes for potential exploitation as a therapeutic strategy for emphysema.

The Use of Tranexamic Acid for Primary Prophylaxis of Heterotopic Ossification Following Total Hip Arthroplasty.

BACKGROUND: Heterotopic ossification (HO) is a relatively common complication after total hip arthroplasty (THA) and can range from a radiographic observation only to severely disabling and requiring revision surgery. Prophylaxis is recommended for high-risk patients, though the ideal method and targeted population are open to debate. Tranexamic acid (TXA) is a medication increasingly being used to reduce blood loss associated with orthopaedic surgeries, including THA. METHODS: A retrospective review of 357 patients undergoing THA from November 2020 through December 2023 was conducted. The patients were grouped based on whether they received intravenous TXA perioperatively or not, and their propensity score matched 2:1 TXA to no TXA on age, body mass index, sex, Charlson Comorbidity Index, and perioperative celecoxib use. Univariate and multivariate analyses were performed. RESULTS: After propensity score matching, the only significant differences between groups were American Society of Anesthesiologists (ASA) scores and preoperative celecoxib use between groups, as the TXA group had fewer patients who had an ASA of 3 or more (38.9 versus 58.5%, P < 0.001) and more patients who had taken celecoxib preoperatively (16.3 versus 5.9%, P = 0.010). Perioperatively, patients were more likely to undergo THA using the anterior approach (74.5 versus 57.6%, P = 0.002) and were more likely to receive postoperative celecoxib prescriptions (44.8 versus 31.4%, P = 0.021), but there was no difference in other nonsteroidal anti-inflammatory drug (NSAID) usage postoperatively. Postoperatively, patients who received TXA had a lower rate of HO on the last postoperative x-ray (20.1 versus 33.9%, P = 0.007). Multivariable logistic regression, to assess predictors of HO, found that patients who had TXA were 42% less likely to have visible HO (OR [odds ratio] = 0.58, P = 0.047), while holding surgical approach, American Society of Anesthesiologists score, preoperative and postoperative celecoxib use, and postoperative other nonsteroidal anti-inflammatory drug use constant. CONCLUSIONS: The use of TXA in patients undergoing primary THA results in a decreased likelihood ofHO formation on postoperative x-rays.

Same-Day Discharge Does Not Increase Resource Utilization Within One Year of Total Joint Arthroplasty.

BACKGROUND: While the safety of rapid recovery total joint arthroplasty is well established, less is known about its impact on postoperative care utilization patterns. We wished to examine whether same-day discharge-and its associated presumed reduction in hospital-based postoperative care and education-translates to the need for more postoperative support during the 1-year recovery period. METHODS: A retrospective review of 1,237 total hip arthroplasty (THA) and 1,710 total knee arthroplasty (TKA) patients who had 0- or 1-day length of stay (LOS) from January 2020 to October 2023 was conducted. The primary outcome was the number of follow-up visits with total joint arthroplasty providers at our institution during the 1-year postoperative period. Secondary outcomes included 30-day emergency department returns, readmissions, 1-year physical therapy utilization, and improvement in Patient-Reported Outcomes Measurement Information System Physical Function scores at 6 to 12 months postoperatively. Bivariate and multivariable analyses were performed to compare outcomes between 0-day and 1-day LOS THA and TKA patients. RESULTS: In both the THA and TKA populations, 0-day LOS patients were younger, had a lower average body mass index, were more likely to be White, men, and had an American Society of Anesthesiologists score < 3 than 1-day LOS patients. After controlling for differences between groups, no significant differences in the number of one-year follow-up visits, physical therapy visits, emergency department returns, or readmissions were seen between 0 and 1-day THA or TKA patients. In TKA patients, 1-day LOS was associated with lower improvements in Patient-Reported Outcomes Measurement Information System Physical Function scores. CONCLUSIONS: After risk adjustment, same-day discharge of THA and TKA patients did not result in increased resource utilization during the one-year postoperative period. In the setting of a coordinated joint arthroplasty program with nurse navigator support, same-day discharge can be safely performed without increasing the need for postoperative care in appropriately selected patients undergoing both THA and TKA.

Non-White Race and Concomitant Orthopedic Conditions Are Risk Factors for Failure to Achieve Clinically Relevant Improvement After Total Knee Arthroplasty.

BACKGROUND: Data from the American Joint Replacement Registry demonstrate that 1-year minimal clinically important difference (MCID) achievement rates after total knee arthroplasty (TKA) are substantially lower when using general patient reported outcome measures, such as Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS-PF), than joint specific measures. The purpose of this study was to evaluate patient characteristics and outcomes associated with MCID achievement after TKA using the PROMIS-PF measure. METHODS: A retrospective review of 263 patients undergoing TKA with preoperative and 1-year postoperative PROMIS-PF scores from March 12, 2020 to February 8, 2022 was performed. Three multivariate models were built to evaluate predictors of MCID achievement. Preoperative predictors evaluated included demographics, comorbidities, history of spine and knee surgery, and baseline PROMIS-PF. Postoperative clinical outcomes evaluated included lengths of stay, discharge statuses, complications, and utilizations of other orthopaedic services. RESULTS: There were 109 patients (41%) who achieved an MCID at 1-year postoperatively. Non-white patients had 2.17 times lower odds of achieving MCID. No clinical outcomes assessed were independently predictive of MCID achievement. During the 1-year postoperative period, 63% of patients sought care for another orthopaedic condition. Patients requiring postoperative injections on another joint had a 2.27 times lower odds of achieving MCID. Those seen for spine conditions postoperatively had a 2.44 lower odds of achieving MCID. CONCLUSIONS: Race, postoperative injections, and treatment for spine conditions after TKA were independent predictors of failure to achieve MCID. These results may guide preoperative patient consultation and risk-adjustment in future studies using PROMIS-PF as an endpoint for evaluation of TKA outcomes.

High Affinity Electrostatic Interactions Support the Formation of CdS Quantum Dot:Nitrogenase MoFe Protein Complexes.

Nitrogenase MoFe protein can be coupled with CdS nanocrystals (NCs) to enable photocatalytic N2 reduction. The nature of interactions that support complex formation is of paramount importance in intermolecular electron transfer that supports catalysis. In this work we have employed microscale thermophoresis to examine binding interactions between 3-mercaptopropionate capped CdS quantum dots (QDs) and MoFe protein over a range of QD diameters (3.4-4.3 nm). The results indicate that the interactions are largely electrostatic, with the strength of interactions similar to that observed for the physiological electron donor. In addition, the strength of interactions is sensitive to the QD diameter, and the binding interactions are significantly stronger for QDs with smaller diameters. The ability to quantitatively assess NC protein interactions in biohybrid systems supports strategies for understanding properties and reaction parameters that are important for obtaining optimal rates of catalysis in biohybrid systems.

Examining the Temporal Relation between Posttraumatic Stress Symptoms and Heavy Drinking among Veterans Receiving Mental Health Treatment in Primary Care.

OBJECTIVE: Evidence for the use of integrated treatments targeting co-occurring posttraumatic stress disorder (PTSD) and alcohol use disorders is steadily growing. However, limited work has evaluated the temporal association between posttraumatic stress symptoms (PTSS) and alcohol misuse over the course of integrated treatment, with no studies examining such interventions in primary care (PC). The current study examined temporal changes in PTSS and heavy drinking among individuals who received a brief treatment for co-occurring PTSD and alcohol misuse in PC (Primary Care Treatment Integrating Motivation and Exposure; PC-TIME) compared with those who received PC treatment as usual (PC-TAU). METHOD: A total of 63 veterans (33 randomized to PC-TIME and 30 randomized to PC-TAU) presenting to PC with co-occurring PTSD and alcohol misuse were included in this study. PTSS and heavy drinking were examined at each treatment session for those in PC-TIME. Veterans in both conditions provided reports of PTSS and heavy drinking at baseline, 8-weeks (post-treatment), 14-weeks, and 20-week follow-ups. RESULTS: Session-by-session findings for PC-TIME demonstrated that PTSS at Session 1 predicted a greater decrease in heavy drinking from Session 1 to Session 2. Moreover, heavy drinking at baseline predicted greater decreases in PTSS at 8-weeks for those in PC-TIME, whereas the reverse association was found for those randomized to PC-TAU. Additionally, heavy drinking at 8-weeks predicted decreased PTSS at 14-weeks for those randomized to PC-TAU. CONCLUSIONS: The current study evidenced mixed support for the temporal precedence of PTSS and alcohol misuse. Relations between PTSS and heavy drinking appeared to be linked to treatment targets within PC-TIME and varied between treatment condition (PC-TIME versus PC-TAU). Notably, those with greater than average heavy drinking at the initiation of integrated treatment appeared to have greater reductions in PTSS at post-treatment. Results suggest a mutual maintenance model may best characterize the association between co-occurring PTSS and heavy drinking among treatment-seeking individuals.

The Inhibition of Serine Proteases by Serpins Is Augmented by Negatively Charged Heparin: A Concise Review of Some Clinically Relevant Interactions.

Serine proteases are members of a large family of hydrolytic enzymes in which a particular serine residue in the active site performs an essential role as a nucleophile, which is required for their proteolytic cleavage function. The array of functions performed by serine proteases is vast and includes, among others, the following: (i) the ability to fight infections; (ii) the activation of blood coagulation or blood clot lysis systems; (iii) the activation of digestive enzymes; and (iv) reproduction. Serine protease activity is highly regulated by multiple families of protease inhibitors, known collectively as the SERine Protease INhibitor (SERPIN). The serpins use a conformational change mechanism to inhibit proteases in an irreversible way. The unusual conformational change required for serpin function provides an elegant opportunity for allosteric regulation by the binding of cofactors, of which the most well-studied is heparin. The goal of this review is to discuss some of the clinically relevant serine protease-serpin interactions that may be enhanced by heparin or other negatively charged polysaccharides. The paired serine protease-serpin in the framework of heparin that we review includes the following: thrombin-antithrombin III, plasmin-anti-plasmin, C1 esterase/kallikrein-C1 esterase inhibitor, and furin/TMPRSS2 (serine protease Transmembrane Protease 2)-alpha-1-antitrypsin, with the latter in the context of COVID-19 and prostate cancer.

Managing an epidemic within a pandemic: orthopedic opioid prescribing trends during COVID-19.

INTRODUCTION: In response to the opioid epidemic, a multitude of policy and clinical-guideline based interventions were launched to combat physician overprescribing. However, the sudden rise of the Covid-19 pandemic disrupted all aspects of healthcare delivery. The purpose of this study was to evaluate how opioid prescribing patterns changed during the Covid-19 pandemic within a large multispecialty orthopedic practice. MATERIALS AND METHODS: A retrospective review of 1,048,559 patient encounters from January 1, 2015 to December 31, 2022 at a single orthopedic practice was performed. Primary outcomes were the percent of encounters with opioids prescribed and total morphine milligram equivalents (MMEs) per opioid prescription. Differences in outcomes were assessed by calendar year. Encounters were then divided into two groups: pre-Covid (1/1/2019-2/29/2020) and Covid (3/1/2020-12/31/2022). Univariate analyses were used to evaluate differences in diagnoses and outcomes between periods. Multivariate analysis was performed to assess changes in outcomes during Covid after controlling for differences in diagnoses. Statistical significance was assessed at p < 0.05. RESULTS: The percentage of encounters with opioids prescribed decreased from a high of 4.0% in 2015 to a low of 1.6% in 2021 and 2022 (p < 0.001). MMEs per prescription decreased from 283.6 ± 213.2 in 2015 to a low of 138.6 ± 100.4 in 2019 (p < 0.001). After adjusting for diagnoses, no significant differences in either opioid prescribing rates (post-COVID OR = 0.997, p = 0.893) or MMEs (post-COVID ß = 2.726, p = 0.206) were observed between the pre- and post-COVID periods. CONCLUSION: During the Covid-19 pandemic opioid prescribing levels remained below historical averages. While continued efforts are needed to minimize opioid overprescribing, it appears that the significant progress made toward this goal was not lost during the pandemic era.

Social vulnerability adversely affects emergency-department utilization but not patient-reported outcomes after total joint arthroplasty.

INTRODUCTION: Multiple studies demonstrate social deprivation is associated with inferior outcomes after total hip (THA) and total knee (TKA) arthroplasty; its effect on patient-reported outcomes is debated. The primary objective of this study evaluated the relationship between social vulnerability and the PROMIS-PF measure in patients undergoing THA and TKA. A secondary aim compared social vulnerability between patients who required increased resource utilization or experienced complications and those who didn't. MATERIALS AND METHODS: A retrospective review of 537 patients from March 2020 to February 2022 was performed. The Centers for Disease Control Social Vulnerability Index (SVI) were used to quantify socioeconomic disadvantage. The cohort was split into THA and TKA populations; univariate and multivariate analyses were performed to evaluate primary and secondary outcomes. Statistical significance was assessed at p < 0.05. RESULTS: 48.6% of patients achieved PROMIS-PF MCID at 1-year postoperatively. Higher levels of overall social vulnerability (0.40 vs. 0.28, p = 0.03) were observed in TKA patients returning to the ED within 90-days of discharge. Increased overall SVI (OR = 9.18, p = 0.027) and household characteristics SVI (OR = 9.57, p = 0.015) were independent risk factors for 90-day ED returns after TKA. In THA patients, increased vulnerability in the household type and transportation dimension was observed in patients requiring 90-day ED returns (0.51 vs. 0.37, p = 0.04). CONCLUSION: Despite an increased risk for 90-day ED returns, patients with increased social vulnerability still obtain good 1-year functional outcomes. Initiatives seeking to mitigate the effect of social deprivation on TJA outcomes should aim to provide safe alternatives to ED care during early recovery.

Scoping review of the role of social support in women veterans' psychosocial and health outcomes.

Women veterans are a steadily growing population and have unique military experiences (e.g., report high rates of sexual harassment and assault) that are impactful across the lifespan. High levels of positive social support have been linked to a range of positive outcomes in both civilian and military populations. However, research has not consistently explored social support and interpersonal functioning in women veterans, or as potential mechanisms of change within interventions for women veterans. This is a scoping review of peer-reviewed articles that evaluated social support. Articles with at least 10% women or formally evaluated sex or gender in reference to social support were included. A total of 69 studies evaluated social support in relation to women veterans' health outcomes. From a biopsychosocial perspective, social support is an important construct to examine relative to health care engagement and response. Limited research considered aging women veterans needs or focused on the intersectional identities of women veterans. Positive social support can have major physical and mental health benefits, yet limited research and disparate methodological approaches minimize the ability to draw conclusions on how social support can best be leveraged to support women veterans. Women veterans' roles and military experiences (e.g., increased likelihood of combat exposure) are changing and this population is aging. Research is needed to inform best practices for this growing segment of the veteran population.

Women veterans are a growing population with unique military experiences and post-service health needs. Positive social support can have major physical and mental health benefits, however unique effects of women veterans' social support have been understudied particularly with regards to the impact over the lifespan. This review summarizes the state of literature on social support in women veterans, describes relationships among social support and mental and physical health outcomes, and highlights implications for future research, intervention, and prevention work.

Relationships among age, motivation, and exercise among women Veterans.

Physical activity (PA) and exercise are central to maintaining health, however research has shown steep declines in PA and exercise among women Veterans as they age. Though motivation may be an important contributor to initiating and sustaining exercise that may change across the lifespan, little is known about exercise motivation and its relation to age and exercise behavior among women Veterans. This cross-sectional study sought to describe exercise motivations, examine relationships among exercise motivations and age, and explore the degree to which age and motivation predict self-reported exercise behavior among women Veterans. We conducted a secondary data analysis from a regional mail survey of 197 women Veterans (mean age = 51; SD = 10.5) enrolled in Veterans Health Administration primary care in a northeastern region (N = 180 in analysis). Measures included demographics (age, body mass index), self-reported exercise motivation, and an estimate of average weekly exercise. Participants endorsed multiple motivators for exercise, most prominently fitness and health management. Age was significantly negatively related to amount of exercise and with socializing as an exercise motivation. After accounting for body mass index, age was a significant predictor of exercise behavior, and exercise motivations accounted for an additional 7.3% of variance in self-reported weekly exercise. Our results suggest that although motivation is a potentially important predictor of exercise, factors beyond motivation may better predict exercise in women Veterans. Further research is needed on personal and practical facilitators and barriers to exercise in this population.

Cryo-annealing of Photoreduced CdS Quantum Dot-Nitrogenase MoFe Protein Complexes Reveals the Kinetic Stability of the E4(2N2H) Intermediate.

A critical step in the mechanism of N2 reduction to 2NH3 catalyzed by the enzyme nitrogenase is the reaction of the four-electron/four-proton reduced intermediate state of the active-site FeMo-cofactor (E4(4H)). This state is a junction in the catalytic mechanism, either relaxing by the reaction of a metal bound Fe-hydride with a proton forming H2 or going forward with N2 binding coupled to the reductive elimination (re) of two Fe-hydrides as H2 to form the E4(2N2H) state. E4(2N2H) can relax to E4(4H) by the oxidative addition (oa) of H2 and release of N2 or can be further reduced in a series of catalytic steps to release 2NH3. If the H2 re/oa mechanism is correct, it requires that oa of H2 be associative with E4(2N2H). In this report, we have taken advantage of CdS quantum dots in complex with MoFe protein to achieve photodriven electron delivery in the frozen state, with cryo-annealing in the dark, to reveal details of the E-state species and to test the stability of E4(2N2H). Illumination of frozen CdS:MoFe protein complexes led to formation of a population of reduced intermediates. Electron paramagnetic resonance spectroscopy identified E-state signals including E2 and E4(2N2H), as well as signals suggesting the formation of E6 or E8. It is shown that in the frozen state when pN2 is much greater than pH2, the E4(2N2H) state is kinetically stable, with very limited forward or reverse reaction rates. These results establish that the oa of H2 to the E4(2N2H) state follows an associative reaction mechanism.

Health service utilization among women veterans who report eating disorder symptoms.

OBJECTIVE: Describe health service utilization in women veterans with eating disorder symptoms and characterize the nature of mental health services received. METHOD: Women veterans (N = 191) in a northeastern Veterans Health Administration region completed the Eating Disorders Examination Questionnaire. Health service utilization was then observed for 5 years across multiple domains (i.e., mental health, primary care, telephone consultations, emergency services); negative binomial or zero-inflated negative binomial regression models (mental health) estimated the relative impact of reported eating disorder symptoms on health service utilization. RESULTS: After adjusting for the effects of age and body mass index, higher eating disorder symptoms were associated with higher primary care, mental health services, and telephone consultations. Eating disorder diagnoses were infrequent across the sample. DISCUSSION: Women veterans with higher self-reported eating disorder symptoms evidence higher health service utilization across common healthcare domains. Encounter data suggest that eating disorder symptoms are rarely identified or clinically addressed by providers. Existing mental health visits may represent an opportunity for selective screening for eating disorder symptoms, particularly among women who evidence known risk factors. PUBLIC SIGNIFICANCE: This study reveals that women veterans with higher levels of eating disorder symptoms (e.g., dietary restriction, poor body image) use more primary care, mental health, and telephone consultations than others, but may not receive services that target disordered eating. Opportunities may exist to better identify eating disorder symptoms in the context of existing mental health visits, or potentially to combine treatment for eating disorder symptoms into their mental health care.

Elevated blood lactate in COPD exacerbations associates with adverse clinical outcomes and signals excessive treatment with ß2 -agonists.

BACKGROUND AND OBJECTIVE: Raised blood lactate secondary to high dose ß2 -agonist treatment has been reported in asthma exacerbations but has not been investigated during acute exacerbations of COPD (AECOPD). We explored associations of blood lactate measurements with disease outcomes and ß2 -agonist treatments during AECOPD. METHODS: Retrospective (n = 199) and prospective studies (n = 142) of patients hospitalized with AECOPD were conducted. The retrospective cohort was identified via medical records and the prospective cohort was recruited during hospitalization for AECOPD. Baseline demographics, comorbidities, ß2 -agonist treatment, biochemical measurements and clinical outcomes were compared between patients with normal (≤2.0 mmol/L) versus elevated lactate (>2.0 mmol/L). Regression analyses examined associations of lactate measurements with ß2 -agonist dosages. RESULTS: Demographic data and comorbidities were similar between high versus normal lactate groups in both cohorts. The populations were elderly (mean >70 years), predominantly male (>60%) with reduced FEV1 (%) 48.2 ± 19 (prospective cohort). Lactate was elevated in approximately 50% of patients during AECOPD and not related to evidence of sepsis. In the prospective cohort, patients with high lactate had more tachypnoea, tachycardia, acidosis and hyperglycaemia (p < 0.05) and received more non-invasive ventilation (37% vs. 9.7%, p < 0.001, prospective cohort). There was a trend to longer hospitalization (6 vs. 5 days, p = 0.06, prospective cohort). Higher cumulative ß2 -agonist dosages were linked to elevated lactate levels (OR 1.04, p = 0.01). CONCLUSION: Elevated lactate during AECOPD was common, unrelated to sepsis and correlated with high cumulative doses of ß2 -agonists. Raised lactate may indicate excessive ß2 -agonist treatment and should now be investigated as a possible biomarker.

Thoracic Society of Australia and New Zealand (TSANZ) position statement on chronic suppurative lung disease and bronchiectasis in children, adolescents and adults in Australia and New Zealand.

This position statement, updated from the 2015 guidelines for managing Australian and New Zealand children/adolescents and adults with chronic suppurative lung disease (CSLD) and bronchiectasis, resulted from systematic literature searches by a multi-disciplinary team that included consumers. The main statements are: Diagnose CSLD and bronchiectasis early; this requires awareness of bronchiectasis symptoms and its co-existence with other respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease). Confirm bronchiectasis with a chest computed-tomography scan, using age-appropriate protocols and criteria in children. Undertake a baseline panel of investigations. Assess baseline severity, and health impact, and develop individualized management plans that include a multi-disciplinary approach and coordinated care between healthcare providers. Employ intensive treatment to improve symptom control, reduce exacerbation frequency, preserve lung function, optimize quality-of-life and enhance survival. In children, treatment also aims to optimize lung growth and, when possible, reverse bronchiectasis. Individualize airway clearance techniques (ACTs) taught by respiratory physiotherapists, encourage regular exercise, optimize nutrition, avoid air pollutants and administer vaccines following national schedules. Treat exacerbations with 14-day antibiotic courses based upon lower airway culture results, local antibiotic susceptibility patterns, clinical severity and patient tolerance. Patients with severe exacerbations and/or not responding to outpatient therapy are hospitalized for further treatments, including intravenous antibiotics and intensive ACTs. Eradicate Pseudomonas aeruginosa when newly detected in lower airway cultures. Individualize therapy for long-term antibiotics, inhaled corticosteroids, bronchodilators and mucoactive agents. Ensure ongoing care with 6-monthly monitoring for complications and co-morbidities. Undertake optimal care of under-served peoples, and despite its challenges, delivering best-practice treatment remains the overriding aim.

Low-temperature trapping of N2 reduction reaction intermediates in nitrogenase MoFe protein-CdS quantum dot complexes.

The biological reduction of N2 to ammonia requires the ATP-dependent, sequential delivery of electrons from the Fe protein to the MoFe protein of nitrogenase. It has been demonstrated that CdS nanocrystals can replace the Fe protein to deliver photoexcited electrons to the MoFe protein. Herein, light-activated electron delivery within the CdS:MoFe protein complex was achieved in the frozen state, revealing that all the electron paramagnetic resonance (EPR) active E-state intermediates in the catalytic cycle can be trapped and characterized by EPR spectroscopy. Prior to illumination, the CdS:MoFe protein complex EPR spectrum was composed of a S = 3/2 rhombic signal (g = 4.33, 3.63, and 2.01) consistent with the FeMo-cofactor in the resting state, E0. Illumination for sequential 1-h periods at 233 K under 1 atm of N2 led to a cumulative attenuation of E0 by 75%. This coincided with the appearance of S = 3/2 and S = 1/2 signals assigned to two-electron (E2) and four-electron (E4) reduced states of the FeMo-cofactor, together with additional S = 1/2 signals consistent with the formation of E6 and E8 states. Simulations of EPR spectra allowed quantification of the different E-state populations, along with mapping of these populations onto the Lowe-Thorneley kinetic scheme. The outcome of this work demonstrates that the photochemical delivery of electrons to the MoFe protein can be used to populate all of the EPR active E-state intermediates of the nitrogenase MoFe protein cycle.

Effect of COVID-19 lockdown on body weight in chronic obstructive pulmonary disease.

A series of studies has reported weight gain in association with COVID-19 lockdowns; typically, this research has had short-term follow-up in populations that tended to gain weight. In this study, the effect of prolonged lockdowns on weight was assessed in a population of patients with chronic obstructive pulmonary disease. Before lockdown subjects gained an average of 0.022 kg per month; after lockdown this trend reversed with subjects losing weight at 0.032 kg per month, a trend that was highly significant (P < 0.001).