The lower airway microbiome in paediatric health and chronic disease.

The advent of next generation sequencing has rapidly challenged the paediatric respiratory physician's understanding of lung microbiology and the role of the lung microbiome in host health and disease. In particular, the role of "microbial key players" in paediatric respiratory disease is yet to be fully explained. Accurate profiling of the lung microbiome in children is challenging since the ability to obtain lower airway samples coupled with processing "low-biomass specimens" are both technically difficult. Many studies provide conflicting results. Early microbiota-host relationships may be predictive of the development of chronic respiratory disease but attempts to correlate lower airway microbiota in premature infants and risk of developing bronchopulmonary dysplasia (BPD) have produced mixed results. There are differences in lung microbiota in asthma and cystic fibrosis (CF). The increased abundance of oral taxa in the lungs may (or may not) promote disease processes in asthma and CF. In CF, correlation between microbiota diversity and respiratory decline is commonly observed. When one considers other pathogens beyond the bacterial kingdom, the contribution and interplay of fungi and viruses within the lung microbiome further increase complexity. Similarly, the interaction between microbial communities in different body sites, such as the gut-lung axis, and the influence of environmental factors, including diet, make the co-existence of host and microbes ever more complicated. Future, multi-omics approaches may help uncover novel microbiome-based biomarkers and therapeutic targets in respiratory disease and explain how we can live in harmony with our microbial companions.

Pilot study of a community pharmacist led program to treat hepatitis C virus among people who inject drugs.

Background: People who inject drugs (PWID) are a key population for treatment with direct-acting antiviral medications (DAAs) to eliminate hepatitis C virus (HCV). We developed a Pharmacist, Physician, and Patient Navigator Collaborative Care Model (PPP-CCM) for delivery of HCV treatment; this study describes clinical outcomes related to HCV treatment (initial evaluation, treatment initiation, completion, and cure), as well as patient satisfaction. Methods: We conducted a single-arm prospective pilot study of adult PWID living with HCV. Participants completed baseline and six-month follow-up surveys, and treatment and outcomes were abstracted from electronic health records. Primary outcome was linkage to pharmacist for HCV evaluation; secondary outcomes included DAA initiation, completion, and cure, as well as patient-reported satisfaction. Results: Of the 40 PWID enrolled, mean age was 43.6 years, 12 (30 %) were female, 20 (50 %) were non-white, and 15 (38 %) were unhoused. Thirty-eight (95 %) were successfully linked to the pharmacist for initial evaluation. Of those, 21/38 (55 %) initiated DAAs, and 16/21 (76 %) completed treatment. Among those completing treatment who had viral load data to document whether they achieved "sustained virologic response", i.e. cure, 10/11 (91 %) were found to be cured. There was high satisfaction with 100 % responding "agree or strongly agree" that they had a positive experience with the pharmacist. Conclusion: Nearly all participants in this pilot were successfully linked to the pharmacist for evaluation, and more than half were started on DAAs; results provide preliminary evidence of feasibility of pharmacist-led models of HCV treatment for PWID. Clinicaltrialsgov registration number: NCT04698629.

Repeated deep-inspiration breath-hold CT scans at planning underestimate the actual motion between breath-holds at treatment for lung cancer and lymphoma patients.

PURPOSE/OBJECTIVE: Deep-inspiration breath-hold (DIBH) during radiotherapy may reduce dose to the lungs and heart compared to treatment in free breathing. However, intra-fractional target shifts between several breath-holds may decrease target coverage. We compared target shifts between four DIBHs at the planning-CT session with those measured on CBCT-scans obtained pre- and post-DIBH treatments. MATERIAL/METHODS: Twenty-nine lung cancer and nine lymphoma patients were treated in DIBH. An external gating block was used as surrogate for the DIBH-level with a window of 2 mm. Four DIBH CT-scans were acquired: one for planning (CTDIBH3) and three additional (CTDIBH1,2,4) to assess the intra-DIBH target shifts at scanning by registration to CTDIBH3. During treatment, pre-treatment (CBCTpre) and post-treatment (CBCTpost) scans were acquired. For each pair of CBCTpre/post, the target intra-DIBH shift was determined. For lung cancer, tumour (GTV-Tlung) and lymph nodes (GTV-Nlung) were analysed separately. Group mean (GM), systematic and random errors, and GM for the absolute maximum shifts (GMmax) were calculated for the shifts between CTDIBH1,2,3,4 and between CBCTpre/post. RESULTS: For GTV-Tlung, GMmax was larger at CBCT than CT in all directions. GMmax in cranio-caudal direction was 3.3 mm (CT)and 6.1 mm (CBCT). The standard deviations of the shifts in the left-right and cranio-caudal directions were larger at CBCT than CT. For GTV-Nlung and CTVlymphoma, no difference was found in GMmax or SD. CONCLUSION: Intra-DIBH shifts at planning-CT session are generally smaller than intra-DIBH shifts observed at CBCTpre/post and therefore underestimate the intra-fractional DIBH uncertainty during treatment. Lung tumours show larger intra-fractional variations than lymph nodes and lymphoma targets.

Increased prevalence of sleep disturbance in psoriatic arthritis is associated with inflammatory and non-inflammatory measures.

OBJECTIVES: To examine the prevalence of sleep disturbances, quantified by the Pittsburgh Sleep Quality Index (PSQI), in patients with psoriatic arthritis (PsA), psoriasis (PsO) and healthy controls (HCs), explore associations between PSQI and clinical and patient-reported outcomes, and evaluate the effect of treatment on PSQI. METHOD: Patients were included from the Parker Institute's PsA patient cohort to evaluate the prevalence of sleep disturbances. Univariate and multivariate regression analyses were used to explore associations between sleep disturbance and outcome measures. Treatment effect in PsA patients was assessed with a mixed-effect model for repeated measures. RESULTS: In total, 109 PsA patients, 20 PsO patients, and 20 HCs were included. Sleep disturbances were reported by 66.1% of PsA patients, 45.0% of PsO patients, and 15.0% of HCs. Univariate regression analyses revealed statistically significant associations (p < 0.001) between PSQI and Disease Activity Score (DAS28CRP), tender points, visual analogue scale (VAS) patient global and pain, Psoriatic Arthritis Impact of Disease fatigue, Health Assessment Questionnaire (HAQ), and painDETECT score. Multivariate regression analysis demonstrated VAS patient global, VAS pain, and tender points as being independently associated with PSQI. The mixed-effect model revealed no effect of treatment. CONCLUSION: More PsA patients than PsO patients and HCs reported sleep disturbances. Sleep disturbances were associated with inflammatory and non-inflammatory measures possibly explaining the limited effect of treatment. This demonstrates the need for interdisciplinary approaches to improve the management of sleep disturbance in PsA.Trial registration: ClinicalTrials.gov (NCT02572700).

Transatlantic spread of highly pathogenic avian influenza H5N1 by wild birds from Europe to North America in 2021.

Highly pathogenic avian influenza (HPAI) viruses of the A/Goose/Guangdong/1/1996 lineage (GsGd), which threaten the health of poultry, wildlife and humans, are spreading across Asia, Europe, Africa and North America but are currently absent from South America and Oceania. In December 2021, H5N1 HPAI viruses were detected in poultry and a free-living gull in St. John's, Newfoundland and Labrador, Canada. Our phylogenetic analysis showed that these viruses were most closely related to HPAI GsGd viruses circulating in northwestern Europe in spring 2021. Our analysis of wild bird migration suggested that these viruses may have been carried across the Atlantic via Iceland, Greenland/Arctic or pelagic routes. The here documented incursion of HPAI GsGd viruses into North America raises concern for further virus spread across the Americas by wild bird migration.

Immunological effects of dimethyl fumarate treatment in blood and CSF of patients with primary progressive MS.

Dimethyl fumarate is an efficient therapy used widely in patients with relapsing-remitting multiple sclerosis (RRMS). However, lacking effect of treatment has recently been reported in patients with primary progressive MS (PPMS) (Højsgaard Chow et al., 2021). In order to further analyze the immunological treatment response we investigated the systemic and intrathecal immunological effects of dimethyl fumarate (DMF) treatment in 50 patients with PPMS who participated in a 48-week randomized controlled trial with dimethyl fumarate vs placebo. We found substantial systemic immunomodulatory effects of DMF treatment comparable with those observed in patients with RRMS. However, intrathecal effects were limited and restricted to CD4+ T cells presumably resulting in higher concentrations of intrathecal IL-7.

Diagnoses and mortality in a population without acute myocardial infarction, but with elevated high-sensitive troponin I - a retrospective register-based single center study.

AIM: To explore, which differential diagnoses to consider in individuals with elevated troponins without acute myocardial infarction (AMI), and the mortality for those individuals. METHODS: Retrospective, register-based study on a representative sample of the Danish population with the following inclusion criteria: High-sensitive troponin I (hs-TnI) ⋝25 ng/L, age ⋝18 years, and exclusion of AMI. RESULTS: 3067 individuals without AMI but increased hs-TnI were included. Most frequent discharge diagnoses: Pneumonia (12.8%), Aortic valve disorder (11.3%), Medical observation (10.9%) and Heart failure (8.9%). The 30-days and one-year mortality was 15.8% and 32.0%, respectively. CONCLUSIONS: A selected number of alternative diagnoses must be considered in individuals with increased hs-TnI. Due to high mortality it is crucial to carefully evaluate these individuals despite the absence of AMI.

The impact of rising sea temperatures on an Arctic top predator, the narwhal.

Arctic top predators are expected to be impacted by increasing temperatures associated with climate change, but the relationship between increasing sea temperatures and population dynamics of Arctic cetaceans remains largely unexplored. Narwhals (Monodon monoceros) are considered to be among the most sensitive of Arctic endemic marine mammals to climate change due to their limited prey selection, strict migratory patterns and high site fidelity. In the context of climate change, we assume that the population dynamics of narwhals are partly influenced by changes in environmental conditions, with warm areas of increasing sea temperatures having lower abundance of narwhals. Using a unique large dataset of 144 satellite tracked narwhals, sea surface temperature (SST) data spanning 25 years (1993-2018) and narwhal abundance estimates from 17 localities, we (1) assessed the thermal exposure of this species, (2) investigated the SST trends at the summer foraging grounds, and (3) assessed the relationship between SST and abundance of narwhals. We showed a sharp SST increase in Northwest, Mideast and Southeast Greenland, whereas no change could be detected in the Canadian Arctic Archipelago (CAA) and in the Greenland Sea. The rising sea temperatures were correlated with the smallest narwhal abundance observed in the Mideast and Southeast Greenland (< 2000 individuals), where the mean summer sea temperatures were the highest (6.3 °C) compared to the cold waters of the CAA (0.7 °C) that were associated with the largest narwhal populations (> 40,000 individuals). These results support the hypothesis that warming ocean waters will restrict the habitat range of the narwhal, further suggesting that narwhals from Mideast and Southeast Greenland may be under pressure to abandon their traditional habitats due to ocean warming, and consequently either migrate further North or locally go extinct.

Enhancing older adult access to lifelong learning institutes through technology-based instruction: A brief report.

The number of lifelong learning institutes serving older adults in the U.S. has increased in the last few decades. To date, these institutes have functioned primarily in traditional, in-person classroom, and seminar formats; however, technology-enhanced methods may help provide greater access to high-quality lifelong learning experiences. This research note reports the results of a cross-institutional survey of Osher Lifelong Learning Network participants. The survey participants' high levels of computer utilization and experience with modern distance education capabilities opens the possibility that Technology-Based Instruction (TBI) can augment or supplement in-person lifelong learning experiences. Specifically, TBI may be effective in expanding access for older adults who have mobility or other health limitations, as well as those who live far from the location of any such program. Example approaches are suggested for developing blended, hybrid in-person, and online lifelong learning environments, which may offer enriching intellectual engagement and meaningful socialization.

Lymphopenia and neutropenia are associated with subsequent incident proteinuria in Danish patients with systemic lupus erythematosus.

Objective: The aim of this study was to investigate whether incident proteinuria in patients with systemic lupus erythematosus (SLE) was preceded by changes in blood lymphocytes and neutrophil counts and/or neutrophil-lymphocyte ratio (NLR).Method: SLE patients with no proteinuria before or at the time of classification were included. Longitudinal data on SLE manifestations, vital status, and SLE-associated medications were collected during clinical visits and chart review. Laboratory data were collected through a nationwide database. Lymphopenia, severe lymphopenia, and neutropenia were defined as values below 0.8 × 109, 0.5 × 109, and 2.0 × 109 cells/L, respectively. High NLR was defined as values above the median. Proteinuria was defined by at least two measurements of elevated urine protein excretion (> 0.5 g/day). Hazard ratios (HRs) were calculated by Cox modelling using time-dependent continuous and binary covariates based on multiple laboratory measurements adjusted for use of immunosuppressants.Results: In total, 260 SLE patients were available for the analysis, of whom 30 (12%) developed incident proteinuria following the diagnosis of SLE. Median follow-up time was 73.5 months. Lymphocyte and neutrophil counts, but not NLR, were associated with incident proteinuria. HRs for incident proteinuria were 2.71 for lymphopenia [95% confidence interval (CI) 1.20-6.11], 4.73 for severe lymphopenia (95% CI 1.93-11.59), and 2.54 for neutropenia (95% CI 1.14-5.65).Conclusion: Lymphopenia and neutropenia predicted the risk of first-time proteinuria independently of immunosuppressants.

Predicting acoustic dose associated with marine mammal behavioural responses to sound as detected with fixed acoustic recorders and satellite tags.

To understand the consequences of underwater noise exposure for cetaceans, there is a need for assessments of behavioural responses over increased spatial and temporal scales. Bottom-moored acoustic recorders and satellite tags provide such long-term and large spatial coverage of behaviour compared to short-duration acoustic-recording tags. However, these tools result in a decreased resolution of data from which an animal response can be inferred, and no direct recording of the sound received at the animal. This study discusses the consequence of the decreased resolution of data from satellite tags and fixed acoustic recorders on the acoustic dose estimated by propagation modelling and presents a method for estimating the range of sound levels that animals observed with these methods have received. This problem is illustrated using experimental results obtained during controlled exposures of northern bottlenose whales (Hyperoodon ampullatus) exposed to naval sonar, carried out near Jan Mayen, Norway. It is shown that variability and uncertainties in the sound field, resulting from limited sampling of the acoustic environment, as well as decreased resolution in animal locations, can lead to quantifiable uncertainties in the estimated acoustic dose associated with the behavioural response (in this case avoidance and cessation of foraging).

Barriers to Age-Friendly Universities (AFU): Lessons from Osher Lifelong Learning Institute demographics and perceptions.

The age-friendliness of universities and colleges is a growing area of research and practice. This study focuses on lifelong learning institutes at universities and colleges who provide courses and experiences for older adults but do not award academic or work-related credentials. The Osher Lifelong Learning Institute (OLLI) network in the U.S. is used as an exemplary case of institutes that aim to increase the age-friendliness of their supporting institutions, whilst also aiming for greater diversity among their learners. This study draws upon literature regarding OLLIs and Age-Friendly Universities (AFUs) and national demographic surveys of OLLI student members in 2014 and 2016 (n=  5,500). The study highlights the 2016 demographic characteristics of OLLI learners, notes changes since 2014, and makes comparisons to national trends. Furthermore, this study investigates the barriers to participation identified by older learners participating in OLLIs, considered in light of studies that have addressed such obstacles for underrepresented groups.

Muscle endurance, strength, and active range of motion in patients with different subphenotypes in systemic sclerosis: a cross-sectional cohort study.

OBJECTIVE: Proximal muscle weakness is common in patients with systemic sclerosis (SSc). Dynamic muscle endurance, muscle strength in the lower extremities, and active range of motion (AROM) in the upper extremities are less studied. We investigated functional muscle endurance, strength, and AROM, and explored differences depending on skin and/or lung involvement in SSc patients. METHOD: The study divided 205 patients with limited/diffuse cutaneous systemic sclerosis (lcSSc/dcSSc) into no-mild and moderate-end-stage lung involvement, the latter based on the Medsger disease severity score. Dynamic muscle endurance in shoulder and hip flexion was assessed by the Functional Index-2, lower extremity muscle strength by the Timed-Stands Test (TST), and shoulder-arm AROM by the Functional Shoulder Assessment (FSA). RESULTS: Shoulder and hip flexion muscle endurance were reduced in relation to reference values median (IQR) [53% (27-100%) and 40% (23-90%), respectively, p < 0.001]. Patients with moderate-end-stage lung involvement had less endurance in shoulder [39% (21-71%) and hip flexion 35% (20-70%)] than patients with no-mild lung involvement [57% (33-99%) and 48% (28-100%), p < 0.05]. All patients, regardless of subtype/grouping, needed longer to complete the TST [21 s (17-27 s)] compared to reference values [17 s (15-18 s), p < 0.001], and patients with moderate-end-stage lung involvement had worse TST score than patients with no-mild lung involvement,  [25 s (18-30 s) vs 19 s (16-25 s), p < 0.001]. The FSA sum scores were lower compared with reference values (p < 0.01). DcSSc patients had a lower FSA-sum score [53 (48-57)] than lcSSc patients [57 (52-60), p < 0.01]. CONCLUSION: SSc patients have markedly reduced muscle endurance in the upper and lower extremities, reduced muscle strength in the lower extremities, and impaired AROM in the shoulders and arms. Patients with moderate-end-stage lung involvement had more impaired muscle endurance and strength but no differences were found between lcSSc and dcSSc patients. Not only muscle strength, but also dynamic muscle endurance should be measured in SSc patients.

Access to direct-acting antivirals for the treatment of hepatitis C in a country with limited resources. / Evaluación del acceso a antivirales para el tratamiento de la hepatitis C en un país con recursos limitados.

AIMS: To estimate the number of patients that have access to treatment of hepatitis C with direct-acting antivirals in Argentina and evaluate the factors associated with the lack of access. MATERIALS AND METHODS: A cross-sectional cohort study was conducted that included all the consecutive prescriptions of direct-acting antivirals issued at health centers that participated in the ECHOTM telemedicine project directed by the Hospital Italiano de Buenos Aires, within the time frame of January 2016 and February 2017. RESULTS: A total of 143 treatment prescriptions were included and overall access was 70% (95% CI 62-77%). The only independent factor associated with a lack of treatment access was coverage by a public healthcare system (OR 4.98 [95% CI 2.05- 12.09]). CONCLUSION: Patients with hepatitis C that were covered by a public healthcare system had a 4 times higher chance of not having access to treatment with direct-acting antivirals than patients covered by other healthcare systems (private insurance or the social welfare system).

Executive Function Index (EFI) performance in nonclinical individuals with high levels of autistic traits.

This study examined the ability of the Executive Function Index (EFI) to detect differences in executive functioning amongst participants with varying levels of subclinical autistic symptoms as quantified by the Autism Spectrum Quotient (ASQ). Participants were a nonclinical college subject sample classified as displaying either Low (0-15 ASQ score, n = 182) ASQ traits or High (16 or higher ASQ score, n = 91) ASQ traits. Participants were given the ASQ (Baron-Cohen et al., 2001) and the EFI (Spinella, 2005 ). High ASQ subjects were significantly impaired (p's < .04) on the Motivation/Drive (EFI-1) and Organization (EFI-4) subscales of the EFI, as compared to the Low ASQ subjects. However, no High/Low ASQ group differences were observed for EFI-2 (Impulse Control), EFI-3 (Empathy), EFI-5 (Planning) subscales or the EFI-Total Score (p's > .12), although these differences were in the predicted direction (High ASQ < Low ASQ). Use of the EFI as a measure of executive function performance in nonclinical ASQ trait individuals requires further study and may not be sensitive enough of an instrument to assess EF in nonclinical populations with autistic traits.

Comparison of Outcomes Following a Switch From a Brand to an Authorized Versus Independent Generic Drug.

Authorized generics are identical in formulation to brand drugs, manufactured by the brand company but marketed as a generic. Generics, marketed by generic manufacturers, are required to demonstrate pharmaceutical and bioequivalence to the brand drug, but repetition of clinical trials is not required. This retrospective cohort study compared outcomes for generics and authorized generics, which serves as a generic vs. brand proxy that minimizes bias against generics. For the seven drugs studied between 1999 and 2014, 5,234 unique patients were on brand drugs prior to generic entry and 4,900 (93.6%) switched to a generic. During the 12 months following the brand-to-generic switch, patients using generics vs. authorized generics were similar in terms of outpatient visits, urgent care visits, hospitalizations, and medication discontinuation. The likelihood of emergency department (ED) visits was slightly higher for authorized generics compared with generics. These data suggest that generics were clinically no worse than their proxy brand comparators.

Brand vs generic adverse event reporting patterns: An authorized generic-controlled evaluation of cardiovascular medications.

WHAT IS KNOWN AND OBJECTIVE: Some public scepticism exists about generics in terms of whether brand and generic drugs produce identical outcomes. This study explores whether adverse event (AE) reporting patterns are similar between brand and generic drugs, using authorized generics (AGs) as a control for possible generic drug perception biases. METHODS: Events reported to the FDA Adverse Event Reporting System from the years 2004-2015 were analysed. Drugs were classified as brand, AG or generic based on drug and manufacturer names. Reports were included if amlodipine, losartan, metoprolol extended release (ER) or simvastatin were listed as primary or secondary suspect drugs. Disproportionality analyses using the reporting odds ratio (ROR) assessed the relative rate of reporting labelled AEs compared to reporting these AEs with all other drugs. The Breslow-Day test compared RORs across brand, AG and generic. Interrupted time series analysis evaluated the impact of generic entry on reporting trends. RESULTS AND DISCUSSION: Generics accounted for significant percentages of total U.S. reports, but AGs accounted for smaller percentages of reports, including for amlodipine (14.26%), losartan (1.48%), metoprolol ER (0.35%) and simvastatin (0.70%). Whereas the RORs were significantly different for multiple brand vs generic comparisons, the AG vs generic comparisons yielded fewer statistically significant findings. Namely, only the ROR for AG differed from generic for amlodipine with peripheral oedema (P < .01). WHAT IS NEW AND CONCLUSION: Inconsistent reporting patterns were observed more between brand and generic compared with AG and generic. Use of AGs as a control for perception biases against generics is useful, but this approach can be limited by small AG report numbers. Requiring the manufacturer name to be printed on the prescription bottle or packaging could improve the accuracy of assignment for products being reported.

Review article: the gut microbiome in inflammatory bowel disease-avenues for microbial management.

BACKGROUND: The concept of an altered collective gut microbiota rather than identification of a single culprit is possibly the most significant development in inflammatory bowel disease research. We have entered the "omics" era, which now allows us to undertake large-scale/high-throughput microbiota analysis which may well define how we approach diagnosis and treatment of inflammatory bowel disease (IBD) in the future, with a strong steer towards personalised therapeutics. AIM: To assess current epidemiological, experimental and clinical evidence of the current status of knowledge relating to the gut microbiome, and its role in IBD, with emphasis on reviewing the evidence relating to microbial therapeutics and future microbiome modulating therapeutics. METHODS: A Medline search including items 'intestinal microbiota/microbiome', 'inflammatory bowel disease', 'ulcerative colitis', 'Crohn's disease', 'faecal microbial transplantation', 'dietary manipulation' was performed. RESULTS: Disease remission and relapse are associated with microbial changes in both mucosal and luminal samples. In particular, a loss of species richness in Crohn's disease has been widely observed. Existing therapeutic approaches broadly fall into 3 categories, namely: accession, reduction or indirect modulation of the microbiome. In terms of microbial therapeutics, faecal microbial transplantation appears to hold the most promise; however, differences in study design/methodology mean it is currently challenging to elegantly translate results into clinical practice. CONCLUSIONS: Existing approaches to modulate the gut microbiome are relatively unrefined. Looking forward, the future of microbiome-modulating therapeutics looks bright with several novel strategies/technologies on the horizon. Taken collectively, it is clear that ignoring the microbiome in IBD is not an option.