Vasoactive drugs for the treatment of pulmonary hypertension associated with interstitial lung diseases: a systematic review.

OBJECTIVES: Vasoactive drugs have exhibited clinical efficacy in addressing pulmonary arterial hypertension, manifesting a significant reduction in morbidity and mortality. Pulmonary hypertension may complicate advanced interstitial lung disease (PH-ILD) and is associated with high rates of disability, hospitalisation due to cardiac and respiratory illnesses, and mortality. Prior management hinged on treating the underlying lung disease and comorbidities. However, the INCREASE trial of inhaled treprostinil in PH-ILD has demonstrated that PH-ILD can be effectively treated with vasoactive drugs. METHODS: This comprehensive systematic review examines the evidence for vasoactive drugs in the management of PH-ILD. RESULTS: A total of 1442 pubblications were screened, 11 RCTs were considered for quantitative synthesis. Unfortunately, the salient studies are limited by population heterogeneity, short-term follow-up and the selection of outcomes with uncertain clinical significance. CONCLUSIONS: This systematic review underscores the necessity of establishing a precision medicine-oriented strategy, directed at uncovering and addressing the intricate cellular and molecular mechanisms that underlie the pathophysiology of PH-ILD. PROSPERO REGISTRATION NUMBER: CRD42023457482.

Dataset of process-structure-property feature relationships for AlSi10Mg material fabricated using laser powder bed fusion additive manufacturing.

This dataset reports microstructure and mechanical property features of AlSi10Mg manufactured using laser powder bed fusion over a wide range of processing conditions. Samples were fabricated with different combinations of laser power, scan speed, and hatch spacing to probe dense regimes as well as porous samples resulting from keyholing and lack of fusion. Pore and grain/sub-grain features for each processing set were quantified. Sample porosity was measured using Archimedes density measurements and X-ray computed tomography (XCT). XCT was also used to characterize the surface roughness of samples along with pore size and morphology. Electron backscatter diffraction (EBSD) was used to characterize the grain size and morphology while scanning electron microscope (SEM) imaging and was used to measure solidification cell size. Uniaxial tension tests were performed to ascertain yield and ultimate tensile strengths, elongation, and elastic modulus, and microhardness was measured using Vickers indentation.

Improving Sepsis Outcomes in the Era of Pay-for-Performance and Electronic Quality Measures: A Joint IDSA/ACEP/PIDS/SHEA/SHM/SIDP Position Paper.

The Centers for Medicare & Medicaid Services (CMS) introduced the Severe Sepsis/Septic Shock Management Bundle (SEP-1) as a pay-for-reporting measure in 2015 and is now planning to make it a pay-for-performance measure by incorporating it into the Hospital Value-Based Purchasing Program. This joint IDSA/ACEP/PIDS/SHEA/SHM/SIPD position paper highlights concerns with this change. Multiple studies indicate that SEP-1 implementation was associated with increased broad-spectrum antibiotic use, lactate measurements, and aggressive fluid resuscitation for patients with suspected sepsis but not with decreased mortality rates. Increased focus on SEP-1 risks further diverting attention and resources from more effective measures and comprehensive sepsis care. We recommend retiring SEP-1 rather than using it in a payment model and shifting instead to new sepsis metrics that focus on patient outcomes. CMS is developing a community-onset sepsis 30-day mortality electronic clinical quality measure (eCQM) that is an important step in this direction. The eCQM preliminarily identifies sepsis using systemic inflammatory response syndrome (SIRS) criteria, antibiotic administrations or diagnosis codes for infection or sepsis, and clinical indicators of acute organ dysfunction. We support the eCQM but recommend removing SIRS criteria and diagnosis codes to streamline implementation, decrease variability between hospitals, maintain vigilance for patients with sepsis but without SIRS, and avoid promoting antibiotic use in uninfected patients with SIRS. We further advocate for CMS to harmonize the eCQM with the Centers for Disease Control and Prevention's (CDC) Adult Sepsis Event surveillance metric to promote unity in federal measures, decrease reporting burden for hospitals, and facilitate shared prevention initiatives. These steps will result in a more robust measure that will encourage hospitals to pay more attention to the full breadth of sepsis care, stimulate new innovations in diagnosis and treatment, and ultimately bring us closer to our shared goal of improving outcomes for patients.

Digital transformation in schools of two southern regions of Sweden through implementation-informed approach: A mixed-methods study protocol.

BACKGROUND: The enhancement of-or even a shift from-traditional teaching and learning processes to corresponding digital practices has been rapidly occurring during the last two decades. The evidence of this ongoing change is still modest or even weak. However, the adaptation of implementation science in educational settings, a research approach which arose in the healthcare field, offers promising results for systematic and sustained improvements in schools. The aim of this study is to understand how the systematic professional development of teachers and schools principals (the intervention) to use digital learning materials and learning analytics dashboards (the innovations) could allow for innovative and lasting impacts in terms of a sustained implementation strategy, improved teaching practices and student outcomes, as well as evidence-based design of digital learning material and learning analytics dashboards. METHODS: This longitudinal study uses a quasi-experimental cluster design with schools as the unit. The researchers will enroll gradually 145 experimental schools in the study. In the experimental schools the research team will form a School Team, consisting of teachers/learning-technologists, school principals, and researchers, to support teachers' use of the innovations, with student achievement as the dependent variable. For the experimental schools, the intervention is based on the four longitudinal stages comprising the Active Implementation Framework. With an anticipated student sample of about 13,000 students in grades 1-9, student outcomes data are going to be analyzed using hierarchical linear models. DISCUSSION: The project seeks to address a pronounced need for favorable conditions for children's learning supported by a specific implementation framework targeting teachers, and to contribute with knowledge about the promotion of improved teaching practices and student outcomes. The project will build capacity using implementation of educational technology in Swedish educational settings.

Relationship between backpack load location, sex, anthropometric and body composition factors with postural sway in healthy young adults.

Objective: Evaluate the effect of backpack load location on postural sway and correlate sway path length (PL) to anthropometrics and body composition. Methods: Fifteen participants aged 18-25 stood on a force plate with backpack load located high (LH), low (LL) or without backpack (NL). Body composition and anthropometric variables were correlated to PL. Results: Load increased PL, 95% confidence ellipse, and mean velocity while it reduced mediolateral SampEn (p<0.05). Females had increased mean velocity and PL of sway (p<0.05). Larger phase angles correlated with reduced PL under NL. Taller individuals correlated with reduced PL under LL. Greater mass correlated with reduced PL under LH. Conclusions: Load carriage regardless of load location increased postural sway metrics except mediolateral SampEn. Females had greater PL and mean velocity compared to males. Select anthropometric and body composition variables correlated with postural sway under different load conditions.

Objectif: Évaluer l'effet de la position de la charge du sac à dos sur le balancement postural et corréler la longueur du chemin du balancement (PL) aux facteurs anthropométriques et à la composition corporelle. Méthodologie: Quinze participants âgés de 18 à 25 ans se sont tenus debout sur une plateforme biomécanique, la charge du sac à dos étant placée à un niveau élevé (LH), bas (LL) ou sans sac à dos (NL). La composition corporelle et les variables anthropométriques ont été corrélées à la PL. Résultats: La charge a augmenté la PL, l'ellipse de confiance à 95 % et la vitesse moyenne tout en réduisant la SampEn (entropie d'échantillon) médio-latérale (p<0,05). Les femmes avaient une vitesse moyenne et une PL de balancement plus élevées (p<0,05). Les angles de phase plus importants sont en corrélation avec une réduction de la PL sous NL. Les personnes plus grandes étaient en corrélation avec une réduction de la PL sous LL. Une masse plus importante est en corrélation avec une réduction de la PL sous LH. Conclusions: Le port de charge, quelle que soit la position de la charge, a augmenté les paramètres du balancement postural, à l'exception de la SampEn médio-latérale. Les femmes avaient une PL et une vitesse moyenne plus élevées que les hommes. Certaines variables anthropométriques et de composition corporelle sont en corrélation avec le balancement postural dans différentes conditions de charge.

New extralimital breeding records of saltmarsh sparrows (Ammospiza caudacuta) and Nelson's sparrows (Ammospiza nelsoni) and their implications.

Saltmarsh (Ammospiza caudacuta) and Nelson's (A. nelsoni) sparrows are sister taxa that breed in tidal marshes along the coast of the Northeastern United States and Canada. The Saltmarsh Sparrow breeds from mid-coast Maine south to Virginia, while the Acadian Nelson's Sparrow breeds from the Canadian maritime provinces south to northern Massachusetts. Here, we present three extralimital observations of breeding Saltmarsh (n = 2) and Nelson's (n = 1) sparrows. In 2021 and 2022, we observed Saltmarsh Sparrow females attending nests at Mendall Marsh, ME, and Milbridge, ME, respectively, approximately 60 and 110 km beyond the documented northern extent of the Saltmarsh Sparrow breeding range. In 2022, we observed a breeding-condition male Nelson's sparrow singing in the upriver portion of a marsh on Cape Cod, Massachusetts, approximately 115 km beyond the previously documented southern extent of the Nelson's Sparrow breeding range. We confirmed morphological species identification using a panel of microsatellite DNA loci. Due to both the well-documented population declines of these species in the region and the intensity of sampling effort undertaken in recent years, we suggest that these observations likely are not indicative of range expansion. However, they do indicate that these 2 taxa have the capacity to use and successfully reproduce in marshes well beyond their established breeding limits. Our findings provide novel insight into the potential for these taxa to occur and successfully breed outside their documented breeding ranges. Given increased interest in their conservation, these results support the idea that management actions aimed at creating or maintaining nesting habitat across both species ranges could benefit both taxa.

SARS-CoV-2 outbreak among staff and evacuees at Operation Allies Welcome Safe Havens.

We report on five SARS-CoV-2 congregate setting outbreaks at U.S. Operation Allies Welcome Safe Havens/military facilities. Outbreak data were collected, and attack rates were calculated for various populations. Even in vaccinated populations, there was rapid spread, illustrating the importance of institutional prevention and mitigation policies in congregate settings.

Effects of simulated hypo-gravity on lower limb kinematic and electromyographic variables during anti-gravitational treadmill walking.

Introduction: This study investigated kinematic and EMG changes in gait across simulated gravitational unloading levels between 100% and 20% of normal body weight. This study sought to identify if each level of unloading elicited consistent changes-particular to that percentage of normal body weight-or if the changes seen with unloading could be influenced by the previous level(s) of unloading. Methods: 15 healthy adult participants (26.3 ± 2.5 years; 53% female) walked in an Alter-G anti-gravity treadmill unloading system (mean speed: 1.49 ±0.37 mph) for 1 min each at 100%, 80%, 60%, 40% and 20% of normal body weight, before loading back to 100% in reverse order. Lower-body kinematic data were captured by inertial measurement units, and EMG data were collected from the rectus femoris, biceps femoris, medial gastrocnemius, and anterior tibialis. Data were compared across like levels of load using repeated measures ANOVA and statistical parametric mapping. Difference waveforms for adjacent levels were created to examine the rate of change between different unloading levels. Results: This study found hip, knee, and ankle kinematics as well as activity in the rectus femoris, and medial gastrocnemius were significantly different at the same level of unloading, having arrived from a higher, or lower level of unloading. There were no significant changes in the kinematic difference waveforms, however the waveform representing the change in EMG between 100% and 80% load was significantly different from all other levels. Discussion: This study found that body weight unloading from 100% to 20% elicited distinct responses in the medial gastrocnemius, as well as partly in the rectus femoris. Hip, knee, and ankle kinematics were also affected differentially by loading and unloading, especially at 40% of normal body weight. These findings suggest the previous level of gravitational load is an important factor to consider in determining kinematic and EMG responses to the current level during loading and unloading below standard g. Similarly, the rate of change in kinematics from 100% to 20% appears to be linear, while the rate of change in EMG was non-linear. This is of particular interest, as it suggests that kinematic and EMG measures decouple with unloading and may react to unloading uniquely.

Lifetime risk and genetic predisposition to post-traumatic OA of the knee in the UK Biobank.

OBJECTIVE: Acute knee injury is associated with post-traumatic OA (PTOA). Very little is known about the genome-wide associations of PTOA when compared with idiopathic OA (iOA). Our objective was to describe the development of knee OA after a knee injury and its genetic associations in UK Biobank (UKB). DESIGN: Clinically significant structural knee injuries in those ≤50 years were identified from electronic health records and self-reported data in 502,409 UKB participants. Time-to-first knee osteoarthritis (OA) code was compared in injured cases and age-/sex-matched non-injured controls using Cox Proportional Hazards models. A time-to-OA genome-wide association study (GWAS) sought evidence for PTOA risk variants 6 months to 20 years following injury. Evidence for associations of two iOA polygenic risk scores (PRS) was sought. RESULTS: Of 4233 knee injury cases, 1896 (44.8%) were female (mean age at injury 34.1 years [SD 10.4]). Over a median of 30.2 (IQR 19.5-45.4) years, 1096 (25.9%) of injured cases developed knee OA. The overall hazards ratio (HR) for knee OA after injury was 1.81 (1.70,1.93), P = 8.9 × 10-74. Female sex and increasing age at injury were associated with knee OA following injury (HR 1.15 [1.02,1.30];1.07 [1,07,1.07] respectively). OA risk was highest in the first 5 years after injury (HR 3.26 [2.67,3.98]), persisting for 40 years. In 3074 knee injury cases included in the time-to-OA GWAS, no variants reached genome-wide significance. iOA PRS was not associated with time-to-OA (HR 0.43 [0.02,8.41]). CONCLUSIONS: Increasing age at injury and female sex appear to be associated with future development of PTOA in UKB, the risk of which was greatest in the 5 years after injury. Further international efforts towards a better-powered meta-analysis will definitively elucidate genetic similarities and differences of PTOA and iOA.

Normalization of Prevention Principles and Practices to Reduce Substance Use Disorders Through an Integrated Dissemination and Implementation Framework.

Major research breakthroughs over the past 30 years in the field of substance use prevention have served to: (1) enhance understanding of pharmacological effects on the central and peripheral nervous systems and the health and social consequences of use of psychoactive substances, particularly for children and adolescents; (2) delineate the processes that increase vulnerability to or protect from initiation of substance use and progression to substance use disorders (SUDs) and, based on this understanding, (3) develop effective strategies and practices to prevent the initiation and escalation of substance use. The challenge we now face as a field is to "normalize" what we have learned from this research so that it is incorporated into the work of those involved in supporting, planning, and delivering prevention programming to populations around the world, is integrated into health and social service systems, and helps to shape public policies. But we wish to go further, to incorporate these effective prevention practices into everyday life and the mind-sets of the public, particularly parents and educators. This paper reviews the advances that have been made in the field of prevention and presents a framework and recommendations to achieve these objectives generated during several meetings of prevention and implementation science researchers sponsored by the International Consortium of Universities for Drug Demand Reduction (ICUDDR) that guides a roadmap to achieve "normalization."

Increased muscle force does not induce greater stretch-induced damage to calf muscles during work-matched heel drop exercise.

PURPOSE: To investigate the effect of muscle force during active stretch on quantitative and qualitative indicators of exercise-induced muscle damage (EIMD) in the medial gastrocnemius (MG) muscle. METHODS: Twelve recreationally active volunteers performed two trials of an eccentric heel drop exercise. Participants performed a single bout of low-load (body weight) and high-load (body weight + 30% body weight) exercises on separate legs. The total mechanical work output for each condition was matched between legs. Before, two hours and 48 h after each bout of eccentric exercise, electrically stimulated triceps surae twitch torque, muscle soreness, MG active fascicle length at maximum twitch torque and muscle passive stiffness were collected. Triceps surae electromyographic (EMG) activity, MG fascicle stretch and MG muscle-tendon unit (MTU) length were measured during the eccentric tasks. RESULTS: The high-load condition increased triceps surae muscle activity by 6-9%, but reduced MG fascicle stretch (p < 0.001). MTU stretch was similar between conditions. The greater muscle force during stretch did not give rise to additional torque loss (5 vs 6%) or intensify muscle soreness. CONCLUSIONS: Adding 30% body weight during eccentric contractions has a modest impact on exercise-induced muscle damage in the medial gastrocnemius muscle. These results suggest that muscle load may not be an important determinant of stretch-induced muscle damage in the human MG muscle. The muscle investigated does exhibit large pennation angles and high series elastic compliance; architectural features that likely buffer muscle fibres against stretch and damage.

Repeated measures of implementation variables.

It is commonly acknowledged that implementation work is long-term and contextual in nature and often takes years to accomplish. Repeated measures are needed to study the trajectory of implementation variables over time. To be useful in typical practice settings, measures that are relevant, sensitive, consequential, and practical are needed to inform planning and action. If implementation independent variables and implementation dependent variables are to contribute to a science of implementation, then measures that meet these criteria must be established. This exploratory review was undertaken to "see what is being done" to evaluate implementation variables and processes repeatedly in situations where achieving outcomes was the goal (i.e., more likely to be consequential). No judgement was made about the adequacy of the measure (e.g., psychometric properties) in the review. The search process resulted in 32 articles that met the criteria for a repeated measure of an implementation variable. 23 different implementation variables were the subject of repeated measures. The broad spectrum of implementation variables identified in the review included innovation fidelity, sustainability, organization change, and scaling along with training, implementation teams, and implementation fidelity. Given the long-term complexities involved in providing implementation supports to achieve the full and effective use of innovations, repeated measurements of relevant variables are needed to promote a more complete understanding of implementation processes and outcomes. Longitudinal studies employing repeated measures that are relevant, sensitive, consequential, and practical should become common if the complexities involved in implementation are to be understood.

Potassium Channels in Parkinson's Disease: Potential Roles in Its Pathogenesis and Innovative Molecular Targets for Treatment.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the midbrain. The loss of neurons results in a subsequent reduction of dopamine in the striatum, which underlies the core motor symptoms of PD. To date, there are no effective treatments to stop, slow, or reverse the pathologic progression of dopaminergic neurodegeneration. This unfortunate predicament is because of the current early stages in understanding the biologic targets and pathways involved in PD pathogenesis. Ion channels have become emerging targets for new therapeutic development for PD due to their essential roles in neuronal function and neuroinflammation. Potassium channels are the most prominent ion channel family and have been shown to be critically important in PD pathology because of their roles in modulating neuronal excitability, neurotransmitter release, synaptic transmission, and neuroinflammation. In this review, members of the subfamilies of voltage-gated K+ channels, inward rectifying K+ channels, and Ca2+-activated K+ channels are described. Evidence of the role of these channels in PD etiology is discussed together with the latest views on related pathologic mechanisms and their potential as biologic targets for developing neuroprotective drugs for PD. SIGNIFICANCE STATEMENT: Parkinson's disease (PD) is the second most common neurodegenerative disorder, featuring progressive degeneration of dopaminergic neurons in the midbrain. It is a multifactorial disease involving multiple risk factors and complex pathobiological mechanisms. Mounting evidence suggests that ion channels play vital roles in the pathogenesis and progression of PD by regulating neuronal excitability and immune cell function. Therefore, they have become "hot" biological targets for PD, as demonstrated by multiple clinical trials of drug candidates targeting ion channels for PD therapy.

Identification of phosphorylated tau protein interactors in progressive supranuclear palsy (PSP) reveals networks involved in protein degradation, stress response, cytoskeletal dynamics, metabolic processes, and neurotransmission.

Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease defined pathologically by the presence of insoluble phosphorylated-Tau (p-Tau) in neurons and glia. Identifying co-aggregating proteins within p-Tau inclusions may reveal important insights into processes affected by the aggregation of Tau. We used a proteomic approach, which combines antibody-mediated biotinylation and mass spectrometry (MS) to identify proteins proximal to p-Tau in PSP. Using this proof-of-concept workflow for identifying interacting proteins of interest, we characterized proteins proximal to p-Tau in PSP cases, identifying >84% of previously identified interaction partners of Tau and known modifiers of Tau aggregation, while 19 novel proteins not previously found associated with Tau were identified. Furthermore, our data also identified confidently assigned phosphorylation sites that have been previously reported on p-Tau. Additionally, using ingenuity pathway analysis (IPA) and human RNA-seq datasets, we identified proteins previously associated with neurological disorders and pathways involved in protein degradation, stress responses, cytoskeletal dynamics, metabolism, and neurotransmission. Together, our study demonstrates the utility of biotinylation by antibody recognition (BAR) approach to answer a fundamental question to rapidly identify proteins in proximity to p-Tau from post-mortem tissue. The application of this workflow opens up the opportunity to identify novel protein targets to give us insight into the biological process at the onset and progression of tauopathies.

Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma.

We have previously reported that pathogenic variants in a key metabolite repair enzyme NAXD cause a lethal neurodegenerative condition triggered by episodes of fever in young children. However, the clinical and genetic spectrum of NAXD deficiency is broadening as our understanding of the disease expands and as more cases are identified. Here, we report the oldest known individual succumbing to NAXD-related neurometabolic crisis, at 32 years of age. The clinical deterioration and demise of this individual were likely triggered by mild head trauma. This patient had a novel homozygous NAXD variant [NM_001242882.1:c.441+3A>G:p.?] that induces the mis-splicing of the majority of NAXD transcripts, leaving only trace levels of canonically spliced NAXD mRNA, and protein levels below the detection threshold by proteomic analysis. Accumulation of damaged NADH, the substrate of NAXD, could be detected in the fibroblasts of the patient. In agreement with prior anecdotal reports in paediatric patients, niacin-based treatment also partly alleviated some clinical symptoms in this adult patient. The present study extends our understanding of NAXD deficiency by uncovering shared mitochondrial proteomic signatures between the adult and our previously reported paediatric NAXD cases, with reduced levels of respiratory complexes I and IV as well as the mitoribosome, and the upregulation of mitochondrial apoptotic pathways. Importantly, we highlight that head trauma in adults, in addition to paediatric fever or illness, may precipitate neurometabolic crises associated with pathogenic NAXD variants.