Antimicrobial effects of blue light therapy against cutibacterium acnes: optimal dosing and impact of serial treatments.

Background: Blue light therapy (BLT) is a Food and Drug Administration cleared modality used in dermatology as an effective treatment of acne. The primary purpose of this study is to determine if there are dose-dependent antimicrobial effects of BLT against Cutibacterium acnes (C. acnes). Methods: A known strain of C. acnes was grown on chocolate agar in a controlled laboratory environment under anaerobic conditions for 1 week. After 1 week, 2-3 colonies of C. acnes were isolated and transferred to broth medium to incubate for 2 or 7 days. Broth vials (treatment arm) then underwent 1 of 6 different blue light dosing treatment regimens and a duplicate broth vial served as a control left open to the same environment. The BLT regimens were a single treatment of 25 J/cm2, 50 J/cm2, 75 J/cm2, 100 J/cm2, 2 serial treatments of 50 J/cm2 separated by 24 hours, or 2 serial treatments of 75 J/cm2 separated by 24 hours. The Omnilux Blue device (415 nm wavelength) was used for all BLT treatments and delivered, on average, 1.68 ± 0.004 J/min. Following treatment, the control and treatment broth samples were plated on chocolate agar and allowed to grow for 7 days. After 7 days, plates were counted and colony forming units (CFUs) were calculated. Six trials were completed for each BLT dosing regimen based on an a priori power analysis of 6 individual 2-sided t-tests. Comparisons in the primary outcome were made via mixed-effects analysis of variance with replicate as a random effect. Results: All BLT treatment regimens resulted in significantly fewer CFUs than their aggregate control plate CFUs (P < .05 for all). Furthermore, in 2-way comparison of CFUs between BLT treatment groups, a single treatment of 75 J/cm2 did lead to significantly less growth than 25 J/cm2 (P = .017) and 50 J/cm2 (P = .017). There were no improved antimicrobial effects with serial treatments when comparing 2 doses of 50 J/cm2 with a single dose of 100J/cm2, nor were 2 doses of 75 J/cm2 more efficacious than 100 J/cm2. Using the Omnilux Blue device, it took 44.8 minutes to deliver a 75 J/cm2 dose. Conclusion: BLT is an effective antimicrobial agent against this single virulent strain of C. acnes. Treatment dosing of 75 J/cm2 was identified to be the most effective dose per unit time. Serial treatments did not lead to superior antimicrobial effects over a single, high-dose treatment.

Self-managing symptoms of Long COVID: an education and strategies research protocol.

Post-acute sequelae of SARS-COV-2 (PASC) is growing in prevalence, and involves symptoms originating from the central neurological, cardiovascular, respiratory, gastrointestinal, autonomic nervous, or immune systems. There are non-specific symptoms such as fatigue, headaches, and brain fog, which cannot be ascribed to a single system. PASC places a notable strain on our healthcare system, which is already laden with a large number of acute-COVID-19 patients. Furthermore, it impedes social, academic and vocational functioning, and impacts family life, relationships, and work/financial life. The treatment for PASC needs to target this non-specific etiology and wide-ranging sequelae. In conditions similar to PASC, such as "chemo brain," and prolonged symptoms of concussion, the non-specific symptoms have shown to be effectively managed through education and strategies for self-management and Mindfulness interventions. However, such interventions have yet to be empirically evaluated in PASC to our knowledge. In response to this gap, we have developed a virtual education intervention synthesized by psychiatrists and clinical psychologists for the current study. We will undertake a two-phase randomized controlled trial to determine the feasibility (Phase 1; N = 90) and efficacy (Phase 2; sample sized based on phase 1 results) of the novel 8 week Education and Self-Management Strategies group compared to a mindfulness skills program, both delivered virtually. Main outcomes include confidence/ability to self-manage symptoms, quality of life, and healthcare utilization. This study stands to mitigate the deleterious intrusiveness of symptoms on everyday life in patients with PASC, and may also help to reduce the impact of PASC on the healthcare system. Clinical trial registration:https://classic.clinicaltrials.gov/ct2/show/NCT05268523; identifier NCT05268523.

The evolution of cnidarian stinging cells supports a Precambrian radiation of animal predators.

Cnidarians-the phylum including sea anemones, corals, jellyfish, and hydroids-are one of the oldest groups of predatory animals. Nearly all cnidarians are carnivores that use stinging cells called cnidocytes to ensnare and/or envenom their prey. However, there is considerable diversity in cnidocyte form and function. Tracing the evolutionary history of cnidocytes may therefore provide a proxy for early animal feeding strategies. In this study, we generated a time-calibrated molecular clock of cnidarians and performed ancestral state reconstruction on 12 cnidocyte types to test the hypothesis that the original cnidocyte was involved in prey capture. We conclude that the first cnidarians had only the simplest and least specialized cnidocyte type (the isorhiza) which was just as likely to be used for adhesion and/or defense as the capture of prey. A rapid diversification of specialized cnidocytes occurred through the Ediacaran (~654-574 million years ago), with major subgroups developing unique sets of cnidocytes to match their distinct feeding styles. These results are robust to changes in the molecular clock model, and are consistent with growing evidence for an Ediacaran diversification of animals. Our work also provides insight into the evolution of this complex cell type, suggesting that convergence of forms is rare, with the mastigophore being an interesting counterexample.

Genetics re-establish the utility of 2-methylhopanes as cyanobacterial biomarkers before 750 million years ago.

Fossilized lipids offer a rare glimpse into ancient ecosystems. 2-Methylhopanes in sedimentary rocks were once used to infer the importance of cyanobacteria as primary producers throughout geological history. However, the discovery of hopanoid C-2 methyltransferase (HpnP) in Alphaproteobacteria led to the downfall of this molecular proxy. In the present study, we re-examined the distribution of HpnP in a new phylogenetic framework including recently proposed candidate phyla and re-interpreted a revised geological record of 2-methylhopanes based on contamination-free samples. We show that HpnP was probably present in the last common ancestor of cyanobacteria, while the gene appeared in Alphaproteobacteria only around 750 million years ago (Ma). A subsequent rise of sedimentary 2-methylhopanes around 600 Ma probably reflects the expansion of Alphaproteobacteria that coincided with the rise of eukaryotic algae-possibly connected by algal dependency on microbially produced vitamin B12. Our findings re-establish 2-methylhopanes as cyanobacterial biomarkers before 750 Ma and thus as a potential tool to measure the importance of oxygenic cyanobacteria as primary producers on early Earth. Our study illustrates how genetics can improve the diagnostic value of biomarkers and refine the reconstruction of early ecosystems.

Feasibility of a Home-Based Cognitive-Physical Exercise Program in Patients With Chronic Obstructive Pulmonary Disease: Protocol for a Feasibility and Pilot Randomized Controlled Trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive condition associated with physical and cognitive impairments contributing to difficulty in performing activities of daily living (ADLs) that require dual tasking (eg, walking and talking). Despite evidence showing that cognitive decline occurs among patients with COPD and may contribute to functional limitations and decreased health-related quality of life (HRQL), pulmonary rehabilitation continues to focus mainly on physical training (ie, aerobic and strength exercises). An integrated cognitive and physical training program compared to physical training alone may be more effective in increasing dual-tasking ability among people living with COPD, leading to greater improvements in performance of ADLs and HRQL. OBJECTIVE: The aims of this study are to evaluate the feasibility of an 8-week randomized controlled trial of home-based, cognitive-physical training versus physical training for patients with moderate to severe COPD and derive preliminary estimates of cognitive-physical training intervention efficacy on measures of physical and cognitive function, dual task performance, ADLs, and HRQL. METHODS: A total of 24 participants with moderate to severe COPD will be recruited and randomized into cognitive-physical training or physical training. All participants will be prescribed an individualized home physical exercise program comprising 5 days of moderate-intensity aerobic exercise (30-50 minutes/session) and 2 days of whole-body strength training per week. The cognitive-physical training group will also perform cognitive training for approximately 60 minutes, 5 days per week via the BrainHQ platform (Posit Science Corporation). Participants will meet once weekly with an exercise professional (via videoconference) who will provide support by reviewing the progression of their training and addressing any queries. Feasibility will be assessed through the recruitment rate, program adherence, satisfaction, attrition, and safety. The intervention efficacy regarding dual task performance, physical function, ADLs, and HRQL will be evaluated at baseline and at 4 and 8 weeks. Descriptive statistics will be used to summarize intervention feasibility. Paired 2-tailed t tests and 2-tailed t tests will be used to compare the changes in the outcome measures over the 8-week study period within and between the 2 randomized groups, respectively. RESULTS: Enrollment started in January 2022. It is estimated that the enrollment period will be 24 months long, with data collection to be completed by December 2023. CONCLUSIONS: A supervised home-based cognitive-physical training program may be an accessible intervention to improve dual-tasking ability in people living with COPD. Evaluating the feasibility and effect estimates is a critical first step to inform future clinical trials evaluating this approach and its effects on physical and cognitive function, ADL performance, and HRQL. TRIAL REGISTRATION: ClinicalTrials.gov NCT05140226; https://clinicaltrials.gov/ct2/show/NCT05140226. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48666.

Response to comment on 'A conserved strategy for inducing appendage regeneration in moon jellyfish, Drosophila, and mice'.

Previously we reported evidence that a regenerative response in the appendages of moon jellyfish, fruit flies, and mice can be promoted by nutrient modulation (Abrams et al., 2021). Sustar and Tuthill subsequently reported that they had not been able to reproduce the induced regenerative response in flies (Sustar and Tuthill, 2023). Here we discuss that differences in the amputation method, treatment concentrations, age of the animals, and stress management explain why they did not observe a regenerative response in flies. Typically, 30-50% of treated flies showed response in our assay.

Deep resilience: An evolutionary perspective on calcification in an age of ocean acidification.

The success of today's calcifying organisms in tomorrow's oceans depends, in part, on the resilience of their skeletons to ocean acidification. To the extent this statement is true there is reason to have hope. Many marine calcifiers demonstrate resilience when exposed to environments that mimic near-term ocean acidification. The fossil record similarly suggests that resilience in skeletons has increased dramatically over geologic time. This "deep resilience" is seen in the long-term stability of skeletal chemistry, as well as a decreasing correlation between skeletal mineralogy and extinction risk over time. Such resilience over geologic timescales is often attributed to genetic canalization-the hardening of genetic pathways due to the evolution of increasingly complex regulatory systems. But paradoxically, our current knowledge on biomineralization genetics suggests an opposing trend, where genes are co-opted and shuffled at an evolutionarily rapid pace. In this paper we consider two possible mechanisms driving deep resilience in skeletons that fall outside of genetic canalization: microbial co-regulation and macroevolutionary trends in skeleton structure. The mechanisms driving deep resilience should be considered when creating risk assessments for marine organisms facing ocean acidification and provide a wealth of research avenues to explore.

Analysis of Disease Activity Metrics in a Methotrexate Withdrawal Study among Patients with Rheumatoid Arthritis Treated with Tofacitinib plus Methotrexate.

INTRODUCTION: The objective of this analysis was to assess disease activity metrics using a variety of disease outcome measures following methotrexate (MTX) withdrawal in ORAL Shift, a phase 3b/4 study of tofacitinib with/without MTX, in patients with rheumatoid arthritis (RA) achieving Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA). METHODS: Patients aged ≥ 18 years with active RA and an inadequate response to MTX received open-label tofacitinib modified-release 11 mg once daily plus MTX for 24 weeks. In the double-blind MTX withdrawal phase, those who had achieved CDAI LDA (≤ 10) at week 24 were randomised 1:1 to receive tofacitinib monotherapy or continued tofacitinib plus MTX. Efficacy analyses were performed in subgroups defined by whether remission and/or LDA had been achieved at week 24 with: Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)], Routine Assessment of Patient Index Data 3 (RAPID3), CDAI and Simplified Disease Activity Index (SDAI); or DAS28-4[C-reactive protein(CRP)] < 2.4/ < 2.6/ < 2.9/ ≤ 3.2. RESULTS: Five hundred and thirty patients received treatment in the double-blind MTX withdrawal phase. Proportions of patients achieving each disease activity criterion at week 24 varied by metric. Across disease activity metrics [excluding DAS28-4(ESR) remission], 58-89% of patients per group, and numerically more patients receiving tofacitinib plus MTX, achieved the same criterion at week 48 as at week 24. Differences between groups in least squares mean change from baseline (Δ) DAS28-4(ESR) from week 24-48 favoured tofacitinib plus MTX (nominal p values < 0.05). RAPID3 and DAS28-4(CRP) estimated a higher proportion of patients with acceptable disease state versus DAS28-4(ESR), CDAI remission and SDAI remission. CONCLUSION: Response rates at the beginning of the double-blind phase varied across metrics. A consistent trend towards higher response rates with tofacitinib plus MTX was observed across metrics after randomisation, with nominal differences in DAS28-4(ESR) responses. Compared with continued combination therapy, MTX withdrawal did not lead to a clinically meaningful reduction in the response to tofacitinib. DAS28-4(CRP) and RAPID3 were the least stringent metrics. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02831855.

Sirtuin Evolution at the Dawn of Animal Life.

Sirtuins are a family of proteins that protect against cellular injury and aging; understanding their evolution should reveal fundamental mechanisms governing longevity. "Early-branching" animals such as sea sponges and jellyfish have been understudied in previous analyses of sirtuin diversity. These organisms not only hold important positions at the base of the evolutionary tree, but also have unique aging dynamics that defy convention, such as quasi-immortality and high regenerative capacity. In this study, we survey the evolution of sirtuin proteins in animals, with a focus on the oldest living lineages. We describe previously unrecognized expansions of "Class IV" and "Class I" sirtuins around the origin of animals, raising the number of sirtuin families in the last common ancestor to at least nine. Most of these undescribed sirtuins have been lost in vertebrates and other bilaterian animals. Our work also clarifies the evolution of PNC1 and NAMPT enzymes that carry out the rate-limiting step in sirtuin-related NAD+ biosynthesis. The genes for PNC1 and NAMPT enzymes were both present in the first animals, with the genes being lost a minimum of 11 and 13 times, respectively, over the course of animal evolution. We propose that species with these ancestral gene repertoires are ideal model organisms for studying the genetic regulation of animal longevity and will provide clues to increasing longevity in humans.

Infections in patients with rheumatoid arthritis receiving tofacitinib versus tumour necrosis factor inhibitors: results from the open-label, randomised controlled ORAL Surveillance trial.

OBJECTIVES: To characterise infections in patients with rheumatoid arthritis (RA) in ORAL Surveillance. METHODS: In this open-label, randomised controlled trial, patients with RA aged≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 or 10 mg two times per day or a tumour necrosis factor inhibitor (TNFi). Incidence rates (IRs; patients with first events/100 patient-years) and hazard ratios (HRs) were calculated for infections, overall and by age (50-<65 years; ≥65 years). Probabilities of infections were obtained (Kaplan-Meier estimates). Cox modelling identified infection risk factors. RESULTS: IRs/HRs for all infections, serious infection events (SIEs) and non-serious infections (NSIs) were higher with tofacitinib (10>5 mg two times per day) versus TNFi. For SIEs, HR (95% CI) for tofacitinib 5 and 10 mg two times per day versus TNFi, respectively, were 1.17 (0.92 to 1.50) and 1.48 (1.17 to 1.87). Increased IRs/HRs for all infections and SIEs with tofacitinib 10 mg two times per day versus TNFi were more pronounced in patients aged≥65 vs 50-<65 years. SIE probability increased from month 18 and before month 6 with tofacitinib 5 and 10 mg two times per day versus TNFi, respectively. NSI probability increased before month 6 with both tofacitinib doses versus TNFi. Across treatments, the most predictive risk factors for SIEs were increasing age, baseline opioid use, history of chronic lung disease and time-dependent oral corticosteroid use, and, for NSIs, female sex, history of chronic lung disease/infections, past smoking and time-dependent Disease Activity Score in 28 joints, C-reactive protein. CONCLUSIONS: Infections were higher with tofacitinib versus TNFi. Findings may inform future treatment decisions. TRIAL REGISTRATION NUMBER: NCT02092467.

Postoperative outcomes in older surgical patients with preoperative cognitive impairment: A systematic review and meta-analysis.

STUDY OBJECTIVE: To determine the effect of cognitive impairment (CI) and dementia on adverse outcomes in older surgical patients. DESIGN: A systematic review and meta-analysis of observational studies and randomized controlled trials (RCTs). Various databases were searched from their inception dates to March 8, 2021. SETTING: Preoperative assessment. PATIENTS: Older patients (≥ 60 years) undergoing non-cardiac surgery. MEASUREMENTS: Outcomes included postoperative delirium, mortality, discharge to assisted care, 30-day readmissions, postoperative complications, and length of hospital stay. Effect sizes were calculated as Odds Ratio (OR) and Mean Difference (MD) based on random effect model analysis. The quality of included studies was assessed using the Cochrane Risk Bias Tool for RCTs and Newcastle-Ottawa Scale for observational cohort studies. RESULTS: Fifty-three studies (196,491 patients) were included. Preoperative CI was associated with a significant risk of delirium in older patients after non-cardiac surgery (25.1% vs. 10.3%; OR: 3.84; 95%CI: 2.35, 6.26; I2: 76%; p < 0.00001). Cognitive impairment (26.2% vs. 13.2%; OR: 2.28; 95%CI: 1.39, 3.74; I2: 73%; p = 0.001) and dementia (41.6% vs. 25.5%; OR: 1.96; 95%CI: 1.34, 2.88; I2: 99%; p = 0.0006) significantly increased risk for 1-year mortality. In patients with CI, there was an increased risk of discharge to assisted care (44.7% vs. 38.3%; OR 1.74; 95%CI: 1.05, 2.89, p = 0.03), 30-day readmissions (14.3% vs. 10.8%; OR: 1.36; 95%CI: 1.00, 1.84, p = 0.05), and postoperative complications (40.7% vs. 18.8%; OR: 1.85; 95%CI: 1.37, 2.49; p < 0.0001). CONCLUSIONS: Preoperative CI in older surgical patients significantly increases risk of delirium, 1-year mortality, discharge to assisted care, 30-day readmission, and postoperative complications. Dementia increases the risk of 1-year mortality. Cognitive screening in the preoperative assessment for older surgical patients may be helpful for risk stratification so that appropriate management can be implemented to mitigate adverse postoperative outcomes.

The impact of tofacitinib on fatigue, sleep, and health-related quality of life in patients with rheumatoid arthritis: a post hoc analysis of data from Phase 3 trials.

BACKGROUND: Fatigue, a common symptom of rheumatoid arthritis (RA), is detrimental to health-related quality of life (HRQoL). We evaluated the impact of tofacitinib on fatigue, sleep, and HRQoL and explored associations between fatigue, related patient-reported outcomes (PROs), and disease activity in RA patients. METHODS: This post hoc analysis pooled data from three Phase 3 studies of tofacitinib (ORAL Scan; ORAL Standard; ORAL Sync) in RA patients. Patients received tofacitinib 5 or 10 mg twice daily, placebo, or adalimumab (active control; ORAL Standard only, not powered for superiority) with conventional synthetic disease-modifying antirheumatic drugs. Assessed through Month (M)12 were changes from baseline in disease activity, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Medical Outcomes Study Sleep scale (MOS-SS), and Short Form-36 Health Survey (SF-36) composite/domain scores, and proportions of patients reporting improvements from baseline in FACIT-F total and SF-36 domain scores ≥ minimum clinically important differences (MCIDs) or ≥ population normative values. Pearson correlations examined associations among PROs at M6. Treatment comparisons were exploratory, with p < 0.05 considered nominally significant. RESULTS: Generally, active treatment led to significant improvements from baseline in FACIT-F total, and MOS-SS and SF-36 composite/domain scores vs placebo, observed by M1 and maintained through M6 (last placebo-controlled time point). Through M6, more patients achieved improvements from baseline ≥ MCID and achieved scores ≥ population normative values in FACIT-F total and SF-36 domain scores with tofacitinib vs placebo. Through M12, some nominally significant improvements with tofacitinib vs adalimumab were observed. With active treatment at M6, FACIT-F scores were moderately (0.40-0.59) to highly (≥ 0.60) correlated with SF-36 composite/domain scores (particularly vitality), moderately correlated with most MOS-SS domain scores, and highly correlated with MOS-SS Sleep Problems Index I scores. Disease activity correlations were moderate with FACIT-F scores and low (0.20-0.39) to moderate with SF-36 general health domain/composite scores. CONCLUSION: Tofacitinib and adalimumab generally conferred significant, clinically meaningful improvements in fatigue, sleep, and HRQoL (including vitality) vs placebo through M6, with improvements maintained to M12. M6 correlations between FACIT-F, PROs of sleep, HRQoL, and disease activity underscore the interrelatedness of multiple PROs and disease activity in RA. TRIAL REGISTRATION: ClinicalTrials.gov NCT00847613 (registered: February 19, 2009); NCT00853385 (registered: March 2, 2009); NCT00856544 (registered: March 5, 2009).

Sodium molybdate does not inhibit sulfate-reducing bacteria but increases shell growth in the Pacific oyster Magallana gigas.

Recent work on microbe-host interactions has revealed an important nexus between the environment, microbiome, and host fitness. Marine invertebrates that build carbonate skeletons are of particular interest in this regard because of predicted effects of ocean acidification on calcified organisms, and the potential of microbes to buffer these impacts. Here we investigate the role of sulfate-reducing bacteria, a group well known to affect carbonate chemistry, in Pacific oyster (Magallana gigas) shell formation. We reared oyster larvae to 51 days post fertilization and exposed organisms to control and sodium molybdate conditions, the latter of which is thought to inhibit bacterial sulfate reduction. Contrary to expectations, we found that sodium molybdate did not uniformly inhibit sulfate-reducing bacteria in oysters, and oysters exposed to molybdate grew larger shells over the experimental period. Additionally, we show that microbiome composition, host gene expression, and shell size were distinct between treatments earlier in ontogeny, but became more similar by the end of the experiment. Although additional testing is required to fully elucidate the mechanisms, our work provides preliminary evidence that M. gigas is capable of regulating microbiome dysbiosis caused by environmental perturbations, which is reflected in shell development.

Lipid biomarkers: molecular tools for illuminating the history of microbial life.

Fossilized lipids preserved in sedimentary rocks offer singular insights into the Earth's palaeobiology. These 'biomarkers' encode information pertaining to the oxygenation of the atmosphere and oceans, transitions in ocean plankton, the greening of continents, mass extinctions and climate change. Historically, biomarker interpretations relied on inventories of lipids present in extant microorganisms and counterparts in natural environments. However, progress has been impeded because only a small fraction of the Earth's microorganisms can be cultured, many environmentally significant microorganisms from the past no longer exist and there are gaping holes in knowledge concerning lipid biosynthesis. The revolution in genomics and bioinformatics has provided new tools to expand our understanding of lipid biomarkers, their biosynthetic pathways and distributions in nature. In this Review, we explore how preserved organic molecules provide a unique perspective on the history of the Earth's microbial life. We discuss how advances in molecular biology have helped elucidate biomarker origins and afforded more robust interpretations of fossil lipids and how the rock record provides vital calibration points for molecular clocks. Such studies are open to further exploitation with the expansion of sequenced microbial genomes in accessible databases.

Prevalence of preoperative cognitive impairment in older surgical patients.: A systematic review and meta-analysis.

STUDY OBJECTIVE: Older surgical patients with cognitive impairment are at an increased risk for adverse perioperative outcomes, however the prevalence of preoperative cognitive impairment is not well-established within this population. The purpose of this review is to determine the pooled prevalence of preoperative cognitive impairment in older surgical patients. DESIGN: Systematic review and meta-analysis. SETTING: MEDLINE (Ovid), PubMed (non-MEDLINE records only), Embase, Cochrane Central, Cochrane Database of Systematic Reviews, PsycINFO, and EMCare Nursing for relevant articles from 1946 to April 2021. PATIENTS: Patients aged ≥60 years old undergoing surgery, and preoperative cognitive impairment assessed by validated cognitive assessment tools. INTERVENTIONS: Preoperative assessment. MEASUREMENTS: Primary outcomes were the pooled prevalence of preoperative cognitive impairment in older patients undergoing either elective (cardiac or non-cardiac) or emergency surgery. MAIN RESULTS: Forty-eight studies (n = 42,498) were included. In elective non-cardiac surgeries, the pooled prevalence of unrecognized cognitive impairment was 37.0% (95% confidence interval [CI]: 30.0%, 45.0%) among 27,845 patients and diagnosed cognitive impairment was 18.0% (95% CI: 9.0%, 33.0%) among 11,676 patients. Within the elective non-cardiac surgery category, elective orthopedic surgery was analyzed. In this subcategory, the pooled prevalence of unrecognized cognitive impairment was 37.0% (95% CI: 26.0%, 49.0%) among 1117 patients, and diagnosed cognitive impairment was 17.0% (95% CI: 3.0%, 60.0%) among 6871 patients. In cardiac surgeries, the unrecognized cognitive impairment prevalence across 588 patients was 26.0% (95% CI: 15.0%, 42.0%). In emergency surgeries, the unrecognized cognitive impairment prevalence was 50.0% (95% CI: 35.0%, 65.0%) among 2389 patients. CONCLUSIONS: A substantial number of surgical patients had unrecognized cognitive impairment. In elective non-cardiac and emergency surgeries, the pooled prevalence of unrecognized cognitive impairment was 37.0% and 50.0%. Preoperative cognitive screening warrants more attention for risk assessment and stratification.

Frequency and Duration of Early Non-serious Adverse Events in Patients with Rheumatoid Arthritis and Psoriatic Arthritis Treated with Tofacitinib.

INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA). This post hoc analysis assessed frequency or duration of early select non-serious adverse events (AEs; excluding infections), and their impact on treatment discontinuation, in patients with RA or PsA treated with tofacitinib 5 or 10 mg twice daily, or placebo. METHODS: Data were pooled from five phase 3 and one phase 3b/4 studies in patients with moderate-to-severe RA, and two phase 3 studies in patients with active PsA. Select all-causality, non-serious AEs, reported to month 3 (placebo-controlled period), were headache, diarrhea, nausea, vomiting, and gastric discomfort (including dyspepsia, gastritis, epigastric discomfort, and abdominal discomfort or pain); incidence rates (unique patients with events per 100 patient-years of follow-up), duration of, and discontinuations due to these non-serious AEs were reported. RESULTS: We analyzed 3871 and 710 patients with RA and PsA, respectively. Incidence of non-serious AEs to month 3 was generally similar with tofacitinib and placebo. The most frequent non-serious AEs were headache and diarrhea with tofacitinib, and dyspepsia, nausea, and headache with placebo. Most events were mild or moderate in severity, lasting ≤ 4 weeks. Permanent discontinuations due to non-serious AEs were not observed in patients with PsA, and were < 1.0% in patients with RA across treatment groups. The most frequent cause of temporary discontinuation across all groups was gastric discomfort (0.3-0.8%). CONCLUSIONS: Non-serious AE incidence was generally similar in patients with RA or PsA receiving tofacitinib or placebo. Most events were mild or moderate and generally resolved within 4 weeks. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01877668; NCT01882439; NCT02187055.

Tofacitinib is a medicine that can be taken by patients to treat rheumatoid arthritis (RA) or psoriatic arthritis (PsA). Serious side effects that might occur in patients taking tofacitinib are more frequently discussed than the mild, non-serious side effects that patients might consider to be more of a 'nuisance', which often occur shortly (< 3 months) after starting treatment. Here we looked at patients with RA or PsA who were taking tofacitinib or placebo (no medicine) during clinical trials, to find out how often they had certain non-serious side effects, how long they lasted, and whether they caused the patients to stop taking their medication. A similar number of patients with RA or PsA taking tofacitinib or placebo had non-serious side effects. The most common non-serious side effects in patients taking tofacitinib were a headache and diarrhea. The most common non-serious side effects in patients taking placebo (no medicine) were indigestion, a feeling of sickness, and/or headache. Most non-serious side effects were mild or moderate and stopped within about 4 weeks. Fewer than one in every 100 patients with RA, and no patients with PsA, stopped taking their medication because of non-serious side effects. Most patients who stopped taking their medication did so due to a feeling of gastrointestinal (stomach) discomfort.

A conserved strategy for inducing appendage regeneration in moon jellyfish, Drosophila, and mice.

Can limb regeneration be induced? Few have pursued this question, and an evolutionarily conserved strategy has yet to emerge. This study reports a strategy for inducing regenerative response in appendages, which works across three species that span the animal phylogeny. In Cnidaria, the frequency of appendage regeneration in the moon jellyfish Aurelia was increased by feeding with the amino acid L-leucine and the growth hormone insulin. In insects, the same strategy induced tibia regeneration in adult Drosophila. Finally, in mammals, L-leucine and sucrose administration induced digit regeneration in adult mice, including dramatically from mid-phalangeal amputation. The conserved effect of L-leucine and insulin/sugar suggests a key role for energetic parameters in regeneration induction. The simplicity by which nutrient supplementation can induce appendage regeneration provides a testable hypothesis across animals.

The ability of animals to replace damaged or lost tissue (or 'regenerate') is a sliding scale, with some animals able to regenerate whole limbs, while others can only scar. But why some animals can regenerate while others have more limited capabilities has puzzled the scientific community for many years. The likes of Charles Darwin and August Weismann suggested regeneration only evolves in a particular organ. In contrast, Thomas Morgan suggested that all animals are equipped with the tools to regenerate but differ in whether they are able to activate these processes. If the latter were true, it could be possible to 'switch on' regeneration. Animals that keep growing throughout their life and do not regulate their body temperatures are more likely to be able to regenerate. But what do growth and temperature regulation have in common? Both are highly energy-intensive, with temperature regulation potentially diverting energy from other processes. A question therefore presents itself: could limb regeneration be switched on by supplying animals with more energy, either in the form of nutrients like sugars or amino acids, or by giving them growth hormones such as insulin? Abrams, Tan, Li et al. tested this hypothesis by amputating the limbs of jellyfish, flies and mice, and then supplementing their diet with sucrose (a sugar), leucine (an amino acid) and/or insulin for eight weeks while they healed. Typically, jellyfish rearrange their remaining arms when one is lost, while fruit flies are not known to regenerate limbs. House mice are usually only able to regenerate the very tip of an amputated digit. But in Abrams, Tan, Li et al.'s experiments, leucine and insulin supplements stimulated limb regeneration in jellyfish and adult fruit flies, and leucine and sucrose supplements allowed mice to regenerate digits from below the second knuckle. Although regeneration was not observed in all animals, these results demonstrate that regeneration can be induced, and that it can be done relatively easily, by feeding animals extra sugar and amino acids. These findings highlight increasing the energy supplies of different animals by manipulating their diets while they are healing from an amputated limb can aid in regeneration. This could in the future pave the way for new therapeutic approaches to tissue and organ regeneration.

Screening for subjective cognitive decline in the elderly via subjective cognitive complaints and informant-reported questionnaires: a systematic review.

BACKGROUND: Subjective cognitive decline may represent at-risk persons progressing to mild cognitive impairment (MCI), which can be exacerbated by effects of anesthesia and surgery. The objective of this systematic review is to identify the most common questions in subjective cognitive complaint and informant-reported questionnaires used in assessing cognitive impairment of elderly patients that are correlated with standardized tests for cognitive impairment screening. METHODS: We searched Medline, PubMed, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database, Emcare Nursing, Web of Science, Scopus, CINAHL, ClinicalTrials.Gov, and ICTRP between September 20, 2005 to August 31, 2020. We included studies that evaluated subjective cognitive complaints and informant-reported questions in elderly patients. RESULTS AND CONCLUSION: A total of 28,407 patients were included from 22 studies that assessed 21 subjective complaint questionnaires and nine informant-reported questionnaires. The most common subjective cognitive complaints were those assessing anterograde memory, closely followed by perceptual-motor function and executive function. The most common informant-reported questions were those assessing executive function, temporal orientation, and anterograde memory. Questions assessing learning and memory were most associated with results from standardized tests assessing cognitive impairment. Assessing learning and memory plays a key role in evaluating subjective cognitive decline in elderly patients. Delivering subjective cognitive complaints questions to elderly patient preoperatively may aid in screening for those exhibiting cognitive signs, and in turn are at risk of postoperative complications. Thus, the results from this review contribute to knowledge for healthcare professionals regarding the use of subjective cognitive complaints and informant-reported complaints in preoperative settings.