Brain (EEG) and muscle (EMG) activity related to 3D sit-to-stand kinematics in healthy adults and in central neurological pathology - A systematic review.

BACKGROUND: The sit-to-stand transfer is a fundamental functional movement during normal activities of daily living. Central nervous system disorders can negatively impact the execution of sit-to-stand transfers, often impeding successful completion. Despite its importance, the neurophysiological basis at muscle (electromyography (EMG)) and brain (electroencephalography (EEG)) level as related to the kinematic movement is not well understood. OBJECTIVES: This review synthesises the published literature addressing central and peripheral neural activity during 3D kinematic capture of sit-to-stand transfers. METHODS: A pre-registered systematic review was conducted. Electronic databases (PubMed, CINAHL Plus, Web of Science, Scopus and EMBASE) were searched from inception using search operators that included sit-to-stand, kinematics and EMG and/or EEG. The search was not limited by study type but was limited to populations comprising of healthy individuals or individuals with a central neurological pathology. RESULTS: From a total of 28,770 identified papers, 59 were eligible for inclusion. Ten of these 59 studies received a moderate quality rating; with the remainder rated as weak using the Effective Public Health Practice Project tool. Fifty-eight studies captured kinematic data of sit-to-stand with associated EMG activity only and one study captured kinematics with co-registered EMG and EEG data. Fifty-six studies examined sit-to-stand transfer in healthy individuals, reporting four dynamic movement phases and three muscle synergies commonly used by most individuals to stand-up. Pre-movement EEG activity was reported in one study with an absence of data during execution. Eight studies examined participants following stroke and two examined participants with Parkinson's disease, both reporting no statistically significant differences between their kinematics and muscle activity and those of healthy controls. SIGNIFICANCE: Little is known about the neural basis of the sit-to-stand transfer at brain level with limited focus in central neurological pathology. This poses a barrier to targeted mechanistic-based rehabilitation of the sit-to-stand movement in neurological populations.

Bladder tumour focused adaptive radiotherapy: Clinical outcomes of a phase I dose escalation study.

PURPOSE/OBJECTIVES: We determine the maximum tolerated tumour focused dose (MTD) for the radical treatment of muscle invasive bladder cancer (MIBC) enabled by image guided adaptive radiotherapy (IGART) and long-term clinical outcomes. MATERIALS/METHODS: Fifty-nine patients with T2-T4aN0M0 unifocal urothelial MIBC suitable for daily radical radiotherapy were recruited prospectively to an ethics approved protocol (XX). The uninvolved bladder (PTVbladder) was planned to 52Gy in 32 fractions (f). The bladder tumour (PTVtumour) was planned to an assigned dose level of 68, 70, 72, or 74Gy. If organ at risk (OAR) dose constraints were violated, then PTVtumour was planned to 64Gy. Dose level allocation was determined by concurrent toxicity assessment of all previous patients recruited. Acute toxicity was evaluated using CTCAE v3.0; late toxicity was evaluated using RTOG criteria. The MTD was predefined as the highest dose level with estimated probability of ≤ 15% ≥G3 late toxicity and observed rate <50% acute G3 and <10% acute G4 toxicity. RESULTS: Twenty-six patients were assigned to 68Gy, of whom 6 were planned to 64Gy; 29 patients were assigned to 70Gy of whom 1 was planned to 68Gy, 2 patients were assigned and planned to 72Gy; no patients were assigned to 74Gy. Three patients did not complete treatment as planned, of whom only 1 patient stopped treatment because dose limiting toxicity occurred. The MTD was 70Gy. Acute genitourinary (GU) and gastrointestinal (GI) G3 acute toxicity was seen in 19% and 7% patients respectively. No grade 4 GU or GI toxicity was seen. Late toxicity (any) G3 and G4 was seen in 14% and 2% patients respectively. The 5-year overall survival was 58% (95% CI 44-71%). The bladder preservation rate was 89% (95% CI, 88 to 96%) with 6 patients not retaining native bladder function. CONCLUSION: Bladder tumour focused dose escalation to 70Gy using IGART is feasible with acceptable toxicity. This dose level has been evaluated in a phase II randomised control trial (XXXXX).

Human CYP2D6 varies across the estrous cycle in brains of transgenic mice altering drug response.

Cytochrome P450 (CYP) 2Ds are drug metabolizing enzymes found in brain and liver which metabolize numerous centrally acting drugs. Inhibition and induction of CYP2D-mediated metabolism in rodent brain alters brain drug and metabolite concentrations and resulting drug response. In female rats, brain CYP2D metabolism varies across the estrous cycle and with exogenous estrogen, changing brain drug concentrations and response. In this study harmine-induced hypothermia was lower in humanized CYP2D6 transgenic female mice during estrus compared to diestrus. Pretreatment into the cerebral ventricles with propranolol, a selective irreversible inhibitor of human CYP2D6 in brain, increased hypothermia in estrus but not in diestrus. In vivo enzyme activity was higher in brains of transgenic mice in estrus compared to diestrus and was lower after pretreatment with inhibitor in estrus, but not in diestrus. Hepatic activity and plasma harmine concentrations were unaffected by either estrous phase or inhibition of brain CYP2D6. In wild-type female mice, harmine-induced hypothermia was unaffected by either estrous phase or inhibitor pretreatment. Male mice were used as positive controls, where pretreatment with inhibitor increased harmine-induced hypothermia in transgenic but not wild-type, mice. This study provides evidence for female hormone cycle-based regulation of drug metabolism by human CYP2D6 in brain and resulting drug response. This suggests that brain CYP2D6 metabolism may vary, for example, during the menstrual cycle, pregnancy, or menopause, or while taking oral contraceptives or hormone therapy. This variation could contribute to individual differences in response to centrally acting CYP2D6-substrate drugs by altering local brain drug and/or metabolite concentrations.

Female sex hormones exacerbate retinal neurodegeneration.

Neurodegenerative disorders such as Alzheimer's disease and macular degeneration represent major sources of human suffering, yet the factors influencing disease severity remain poorly understood. Sex has been implicated as one potential modifying factor. Here, we show that female sex is a risk factor for worsened outcomes in a model of retinal degeneration. Further, we show that this susceptibility is caused by the presence of female-specific circulating sex hormones. The adverse effect of female sex hormones was specific to diseased retinal neurons, and depletion of these hormones ameliorated this phenotypic effect. These findings provide novel insights into the pathogenesis of neurogenerative diseases and how sex hormones can impact the severity of disease. These findings have far-reaching implications for clinical trial design and the use of hormonal therapy in females with certain neurogenerative disorders.

Development of tools for the genetic manipulation of Campylobacter and their application to the N-glycosylation system of Campylobacter hepaticus, an emerging pathogen of poultry.

Various species of campylobacters cause significant disease problems in both humans and animals. The continuing development of tools and methods for genetic and molecular manipulation of campylobacters enables the detailed study of bacterial virulence and disease pathogenesis. Campylobacter hepaticus is an emerging pathogen that causes spotty liver disease (SLD) in poultry. SLD has a significant economic and animal welfare impact as the disease results in elevated mortalities and significant decreases in egg production. Although potential virulence genes of C. hepaticus have been identified, they have not been further studied and characterized, as appropriate genetic tools and methods to transform and perform mutagenesis studies in C. hepaticus have not been available. In this study, the genetic manipulation of C. hepaticus is reported, with the development of novel plasmid vectors, methods for transformation, site-specific mutagenesis, and mutant complementation. These tools were used to delete the pglB gene, an oligosaccharyltransferase, a central enzyme of the N-glycosylation pathway, by allelic exchange. In the mutant strain, N-glycosylation was completely abolished. The tools and methods developed in this study represent innovative approaches that can be applied to further explore important virulence factors of C. hepaticus and other closely related Campylobacter species. IMPORTANCE: Spotty liver disease (SLD) of layer chickens, caused by infection with Campylobacter hepaticus, is a significant economic and animal welfare burden on an important food production industry. Currently, SLD is controlled using antibiotics; however, alternative intervention methods are needed due to increased concerns associated with environmental contamination with antibiotics, and the development of antimicrobial resistance in many bacterial pathogens of humans and animals. This study has developed methods that have enabled the genetic manipulation of C. hepaticus. To validate the methods, the pglB gene was inactivated by allelic exchange to produce a C. hepaticus strain that could no longer N-glycosylate proteins. Subsequently, the mutation was complemented by reintroduction of the gene in trans, on a plasmid vector, to demonstrate that the phenotypic changes noted were caused by the mutation of the targeted gene. The tools developed enable ongoing studies to understand other virulence mechanisms of this important emerging pathogen.

Humanized Mouse Models of Bacterial Infections.

Bacterial infections continue to represent a significant healthcare burden worldwide, causing considerable mortality and morbidity every year. The emergence of multidrug-resistant bacterial strains continues to rise, posing serious risks to controlling global disease outbreaks. To develop novel and more effective treatment and vaccination programs, there is a need for clinically relevant small animal models. Since multiple bacterial species have human-specific tropism for numerous virulence factors and toxins, conventional mouse models do not fully represent human disease. Several human disease characteristic phenotypes, such as lung granulomas in the case of Mycobacterium tuberculosis infections, are absent in standard mouse models. Alternatively, certain pathogens, such as Salmonella enterica serovar typhi and Staphylococcus aureus, can be well tolerated in mice and cleared quickly. To address this, multiple groups have developed humanized mouse models and observed enhanced susceptibility to infection and a more faithful recapitulation of human disease. In the last two decades, multiple humanized mouse models have been developed to attempt to recapitulate the human immune system in a small animal model. In this review, we first discuss the history of immunodeficient mice that has enabled the engraftment of human tissue and the engraftment methods currently used in the field. We then highlight how humanized mouse models successfully uncovered critical human immune responses to various bacterial infections, including Salmonella enterica serovar Typhi, Mycobacterium tuberculosis, and Staphylococcus aureus.

Visualization of Cerebrospinal Fluid Outflow and Egress along the Nerve Roots of the Lumbar Spine.

Intrinsic cerebrospinal fluid (CSF) dynamics in the brain have been extensively studied, particularly the egress sites of tagged intrinsic CSF in the meninges. Although spinal CSF recirculates within the central nervous system (CNS), we hypothesized that CSF outflows from the lumbar spinal canal. We aimed to visualize and semi-quantify the outflow using non-contrast MRI techniques. We utilized a 3 Tesla clinical MRI with a 16-channel spine coil, employing time-spatial labeling inversion (Time-SLIP) with tag-on and tag-off acquisitions, T2-weighted coronal 2D fluid-attenuated inversion recovery (FLAIR) and T2-weighted coronal 3D centric ky-kz single-shot FSE (cSSFSE). Images were acquired using time-spatial labeling inversion pulse (Time-SLIP) with tag-on and tag-off acquisitions with varying TI periods. Ten healthy volunteers with no known spinal diseases participated. Variations in tagged CSF outflow were observed across different thoracolumbar nerve root segments in all participants. We quantified CSF outflow at all lumbar levels and the psoas region. There was no significant difference among the ROIs for signal intensity. The tagged CSF outflow from the spinal canal is small but demonstrates egress to surrounding tissues. This finding may pave the way for exploring intrathecal drug delivery, understanding of CSF-related pathologies and its potential as a biomarker for peripheral neuropathy and radiculopathy.

A bacteriocin expression platform for targeting pathogenic bacterial species.

Bacteriocins are antimicrobial peptides that are naturally produced by many bacteria. They hold great potential in the fight against antibiotic resistant bacteria, including ESKAPE pathogens. Engineered live biotherapeutic products (eLBPs) that secrete bacteriocins can be created to deliver targeted bacteriocin production. Here we develop a modular bacteriocin secretion platform that can be used to express and secrete multiple bacteriocins from non-pathogenic Escherichia coli host strains. As a proof of concept we create Enterocin A (EntA) and Enterocin B (EntB) secreting strains that show strong antimicrobial activity against Enterococcus faecalis and Enterococcus faecium in vitro, and characterise this activity in both solid culture and liquid co-culture. We then develop a Lotka-Volterra model that can be used to capture the interactions of these competitor strains. We show that simultaneous exposure to EntA and EntB can delay Enterococcus growth. Our system has the potential to be used as an eLBP to secrete additional bacteriocins for the targeted killing of pathogenic bacteria.

The role of dupilumab in the treatment of eosinophilic esophagitis.

Dupilumab has been approved to treat a variety of atopic disorders and was the first US FDA-approved medication for the treatment of eosinophilic esophagitis (EoE), initially approved in May 2022, with expansion in use to patients as young as 1 year of age weighing at least 15 kg in January 2024. It is a fully human monoclonal antibody that inhibits both IL-4 and IL-13 signaling, suppressing TH2-mediated proinflammatory cytokines, chemokines and IgE implicated in EoE pathogenesis. Phase II and III trials in EoE have demonstrated histologic, endoscopic and symptomatic improvement in disease activity with an overall favorable safety profile. This article will review the available clinical trial data and real-world efficacy of dupilumab in EoE.

Dupilumab is a biologic medication used for the treatment of eosinophilic esophagitis. Clinical trials have shown that this medication is effective in treating both inflammation in the esophagus and symptoms associated with eosinophilic esophagitis in a high proportion of patients. Dupilumab was well tolerated by the majority of clinical trial patients, though side effects such as injection site redness and swelling have been reported. More serious side effects are overall rare.

A call to action: How pharmacy leadership can manage burnout and resilience.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

Investigation of the Genetic Determinants of Telangiectasia and Solid Organ Arteriovenous Malformation Formation in Hereditary Hemorrhagic Telangiectasia (HHT).

Telangiectases and arteriovenous malformations (AVMs) are the characteristic lesions of Hereditary Hemorrhagic Telangiectasia (HHT). Somatic second-hit loss-of-function variations in the HHT causative genes, ENG and ACVRL1, have been described in dermal telangiectasias. It is unclear if somatic second-hit mutations also cause the formation of AVMs and nasal telangiectasias in HHT. To investigate the genetic mechanism of AVM formation in HHT, we evaluated multiple affected tissues from fourteen individuals. DNA was extracted from fresh/frozen tissue of 15 nasal telangiectasia, 4 dermal telangiectasia, and 9 normal control tissue biopsies, from nine unrelated individuals with HHT. DNA from six formalin-fixed paraffin-embedded (FFPE) AVM tissues (brain, lung, liver, and gallbladder) from five individuals was evaluated. A 736 vascular malformation and cancer gene next-generation sequencing (NGS) panel was used to evaluate these tissues down to 1% somatic mosaicism. Somatic second-hit mutations were identified in three in four AVM biopsies (75%) or half of the FFPE (50%) samples, including the loss of heterozygosity in ENG in one brain AVM sample, in which the germline mutation occurred in a different allele than a nearby somatic mutation (both are loss-of-function mutations). Eight of nine (88.9%) patients in whom telangiectasia tissues were evaluated had a somatic mutation ranging from 0.68 to 1.96% in the same gene with the germline mutation. Six of fifteen (40%) nasal and two of four (50%) dermal telangiectasia had a detectable somatic second hit. Additional low-level somatic mutations in other genes were identified in several telangiectasias. This is the first report that nasal telangiectasias and solid organ AVMs in HHT are caused by very-low-level somatic biallelic second-hit mutations.

Hair Dye and Relaxer Use among Cisgender Women in Embu and Nakuru Counties, Kenya: Associations with Perceived Risk of Breast Cancer and Other Health Effects.

Despite widespread use of hair products globally, little is known about the prevalence and patterns of use in populations outside the United States. As some hair products contain endocrine-disrupting chemicals (EDCs) and EDCs have been linked to breast cancer, which is increasing globally, in this study, we addressed key knowledge gaps about hair product use and practices, and perceptions of use among women in two counties in Kenya. Using community-engaged approaches in Embu and Nakuru, Kenya, we recruited women aged 15-50 years to complete a questionnaire that ascertained hair product use in the last 7-14 days, ever using hair dyes and chemical relaxers, and participants' perceptions or harm around hair product use. In multivariable-adjusted regression models, we evaluated associations between participants' sociodemographic characteristics and perceptions of hair product use in relation to if they have ever used hair dyes and relaxers. In our sample of 746 women (mean age, 30.4 ± 8.1 years), approximately one-third of participants reported ever using permanent and/or semi-permanent hair dyes, with approximately one-fifth reporting current use. Almost 60% reported ever using chemical relaxers, with a little over one-third reporting current use. Increasing age and having an occupation in the sales and service industry were statistically significant predictors of hair dye use (OR 1.04, 95% CI: 1.02-1.06 and OR 2.05, 95% CI: 1.38-3.03, respectively) and relaxer use (OR 1.03, 95% CI: 1.01-1.06 and OR 1.93, 95% CI: 1.30-2.87). On average, participants reported moderate-to-high levels of concern about exposures and general health effects from using hair products, and relatively high levels of perceived risk of breast cancer related to hair product use. However, in contrast to our hypotheses, we observed mixed evidence regarding whether higher levels of perceived risk were associated with lower odds of ever using hair dyes and relaxers. These findings add new knowledge to the extant literature on hair product use among women in Kenya, where breast cancer incidence rates are increasing. Improving the understanding of patterns of use of specific products and their chemical ingredients-which may be hormone disruptors or carcinogens-and exploring the role of environmental health literacy are critical for developing interventions to reduce potentially harmful exposures found in these products.

Does Topical Capsaicin Affect the Central Nervous System in Neuropathic Pain? A Narrative Review.

Research has been conducted investigating the neuronal pathways responsible for the generation of chronic neuropathic pain, including the components of it in conditions such as chronic post-surgical pain, phantom limb pain, and cluster headaches. Forming part of the management of such conditions, capsaicin as a molecule has proven effective. This review has investigated the central nervous system modifications exhibited in such conditions and the pharmacological mechanisms of capsaicin relevant to this. The current paradigm for explaining topical capsaicin-induced analgesia is that TRPV1-mediated calcium ion influx induces calpain, in turn causing axonal ablation and functional defunctionalisation in the PNS (Peripheral Nervous System). Demonstrated through the analysis of existing data, this review demonstrates the changes seen in the CNS (Central Nervous System) in chronic neuropathic pain, as well as some of the evidence for capsaicin modulation on the CNS. Further supporting this, the specific molecular mechanisms of capsaicin-induced analgesia will also be explored, including the action of TRPV1, as well as discussing the further need for clinical research into this area of uncertainty due to the limited specific data with suitable parameters. Further research this review identified as potentially useful in this field included fMRI (functional Magnetic Resonance Imaging) studies, though more specific observational studies of patients who have already been administered capsaicin as a current treatment may prove helpful in studying the modification of the CNS in the long term.

Navigation-Based Telehealth Informed Decision-Making for Prostate Cancer Screening in Black Men.

The rapid increase in telehealth has the potential to bring informed decision-making for prostate cancer screening (PCS) at the population level to high-risk individuals. We utilized a global technology platform of electronic health records data repositories (TriNetX) to determine its utility for Navigator-guided decision-making aid for PCS in Black men ages 45-79 years with no history of prostate cancer and PSA testing. Patients from Pennsylvania were invited to participate in a telehealth-delivered informed decision-making session for PCS. Focus groups, social learning theory, visual diagrams, and quantitative data on PCS risks and benefits were used to develop the content of the sessions, which included numerical discussions of risks vs. benefits in Black men. Participants completed several surveys, including baseline demographic and numeracy questionnaires, a one-on-one telehealth session with a trained Navigator, post-Navigation surveys, and an optional follow-up session with a urologist. Eighty-seven participants were consented and recruited. Although the mean numeracy score was only 1.9 out of 6, more than 90% rated as good or excellent that the sessions aided their PCS decision-making skills. This study indicates that Navigation by telehealth offers the ability to assist in informed decision-making for PCS at the population level.

An Effective Fluorescent Marker for Tracking the Dispersal of Small Insects with Field Evidence of Mark-Release-Recapture of Trissolcus japonicus.

Understanding insect dispersal helps us predict the spread of insect pests and their natural enemies. Dispersal can be studied by marking, releasing, and recapturing insects, known as mark-release-recapture (MRR). MRR techniques should be convenient, economical, and persistent. Currently, there are limited options for marking small parasitoids that do not impact their fitness and dispersal ability. We evaluated commercially available fluorescent markers used in forensics. These fluorophores can easily be detected by ultraviolet (UV) light, requiring minimal costs and labor to process the marked specimens. This fluorophore marking technique was evaluated with the pest Drosophila suzukii and three parasitoids: Trissolcus japonicus, Pachycrepoideus vindemiae, Ganaspis brasiliensis (=G. kimorum). We evaluated the persistence of the marks on all the insects over time and examined the parasitoids for impacts on longevity, parasitism, locomotor activity, and flight take-off. The green fluorophore marker persisted for over 20 days on all four species. Marking generally did not consistently reduce the survival, parasitism rate, locomotor activity, or take-off of the parasitoids tested. Marked T. japonicus were recaptured in the field up to 100 m away from the release point and three weeks after release, indicating that this technique is a viable method for studying parasitoid dispersal.

Association of PHACTR1 with Coronary Artery Calcium Differs by Sex and Cigarette Smoking.

Background: Coronary artery calcium (CAC) is a marker of subclinical atherosclerosis and is a complex heritable trait with both genetic and environmental risk factors, including sex and smoking. Methods: We performed genome-wide association (GWA) analyses for CAC among all participants and stratified by sex in the COPDGene study (n = 6144 participants of European ancestry and n = 2589 participants of African ancestry) with replication in the Diabetes Heart Study (DHS). We adjusted for age, sex, current smoking status, BMI, diabetes, self-reported high blood pressure, self-reported high cholesterol, and genetic ancestry (as summarized by principal components computed within each racial group). For the significant signals from the GWA analyses, we examined the single nucleotide polymorphism (SNP) by sex interactions, stratified by smoking status (current vs. former), and tested for a SNP by smoking status interaction on CAC. Results: We identified genome-wide significant associations for CAC in the chromosome 9p21 region [CDKN2B-AS1] among all COPDGene participants (p = 7.1 × 10-14) and among males (p = 1.0 × 10-9), but the signal was not genome-wide significant among females (p = 6.4 × 10-6). For the sex stratified GWA analyses among females, the chromosome 6p24 region [PHACTR1] had a genome-wide significant association (p = 4.4 × 10-8) with CAC, but this signal was not genome-wide significant among all COPDGene participants (p = 1.7 × 10-7) or males (p = 0.03). There was a significant interaction for the SNP rs9349379 in PHACTR1 with sex (p = 0.02), but the interaction was not significant for the SNP rs10757272 in CDKN2B-AS1 with sex (p = 0.21). In addition, PHACTR1 had a stronger association with CAC among current smokers (p = 6.2 × 10-7) than former smokers (p = 7.5 × 10-3) and the SNP by smoking status interaction was marginally significant (p = 0.03). CDKN2B-AS1 had a strong association with CAC among both former (p = 7.7 × 10-8) and current smokers (p = 1.7 × 10-7) and the SNP by smoking status interaction was not significant (p = 0.40). Conclusions: Among current and former smokers of European ancestry in the COPDGene study, we identified a genome-wide significant association in the chromosome 6p24 region [PHACTR1] with CAC among females, but not among males. This region had a significant SNP by sex and SNP by smoking interaction on CAC.

Familial Recurrence of Autism: Updates From the Baby Siblings Research Consortium.

OBJECTIVES: Autism spectrum disorder (ASD) is estimated to be ∼10 times higher in children with versus without an autistic sibling in population-based studies. Prospective studies of infant siblings have revealed even higher familial recurrence rates. In the current prospective longitudinal study, we provide updated estimates of familial ASD recurrence using a multinational database of infants with older autistic siblings. METHODS: Data were collated across 18 sites of the Baby Siblings Research Consortium, an international network studying the earliest manifestations of ASD. A total of 1605 infants with an older autistic sibling were followed from early in life to 3 years, when they were classified as ASD or non-ASD. Hierarchical generalized linear modeling, with site as a random effect, was used to examine predictors of recurrence in families and calculate likelihood ratios. RESULTS: A total of 20.2% of siblings developed ASD, which is not significantly higher than the previously reported rate of 18.7%. Male infant sex and >1 older affected sibling were significant predictors of familial recurrence. Proband sex also influenced recurrence rates, with siblings of female probands significantly more likely to develop ASD than siblings of male probands. Race and maternal education were also associated with recurrence in families. CONCLUSIONS: The familial recurrence rate of ASD, as measured in infant sibling studies, has not changed appreciably since previous estimates were made in 2011. Younger siblings of autistic children, particularly those who are male, have an affected female sibling, multiple affected siblings, or are impacted by social inequities, should be closely monitored and promptly referred for diagnostic evaluation.

Title evaluation of FluSight influenza forecasting in the 2021-22 and 2022-23 seasons with a new target laboratory-confirmed influenza hospitalizations.

Accurate forecasts can enable more effective public health responses during seasonal influenza epidemics. For the 2021-22 and 2022-23 influenza seasons, 26 forecasting teams provided national and jurisdiction-specific probabilistic predictions of weekly confirmed influenza hospital admissions for one-to-four weeks ahead. Forecast skill is evaluated using the Weighted Interval Score (WIS), relative WIS, and coverage. Six out of 23 models outperform the baseline model across forecast weeks and locations in 2021-22 and 12 out of 18 models in 2022-23. Averaging across all forecast targets, the FluSight ensemble is the 2nd most accurate model measured by WIS in 2021-22 and the 5th most accurate in the 2022-23 season. Forecast skill and 95% coverage for the FluSight ensemble and most component models degrade over longer forecast horizons. In this work we demonstrate that while the FluSight ensemble was a robust predictor, even ensembles face challenges during periods of rapid change.

Typology of solutions addressing diagnostic disparities: gaps and opportunities.

OBJECTIVES: Diagnostic disparities are preventable differences in diagnostic errors or opportunities to achieve diagnostic excellence. There is a need to summarize solutions with explicit considerations for addressing diagnostic disparities. We aimed to describe potential solutions to diagnostic disparities, organize them into an action-oriented typology with illustrative examples, and characterize these solutions to identify gaps for their further development. METHODS: During four human-centered design workshops composed of diverse expertise, participants ideated and clarified potential solutions to diagnostic disparities and were supported by environmental literature scan inputs. Nineteen individual semi-structured interviews with workshop participants validated identified solution examples and solution type characterizations, refining the typology. RESULTS: Our typology organizes 21 various types of potential diagnostic disparities solutions into four primary expertise categories needed for implementation: healthcare systems' internal expertise, educator-, multidisciplinary patient safety researcher-, and health IT-expertise. We provide descriptions of potential solution types ideated as focused on disparities and compare those to existing examples. Six types were characterized as having diagnostic-disparity-focused examples, five as having diagnostic-focused examples, and 10 as only having general healthcare examples. Only three solution types had widespread implementation. Twelve had implementation on limited scope, and six were mostly hypothetical. We describe gaps that inform the progress needed for each of the suggested solution types to specifically address diagnostic disparities and be suitable for the implementation in routine practice. CONCLUSIONS: Numerous opportunities exist to tailor existing solutions and promote their implementation. Likely enablers include new perspectives, more evidence, multidisciplinary collaborations, system redesign, meaningful patient engagement, and action-oriented coalitions.

Examining the Case for Palliative Care in Patients with Systemic Sclerosis.

Systemic sclerosis is a complex, multi-organ disease which causes substantial and progressive symptoms and impairs quality of life. International guidelines recommend early, integrated palliative care for patients with advanced cardiopulmonary disease such as heart failure, and interstitial lung disease, as this care can improve patient, caregiver and health care outcomes. In this article, we examine the potential need and role for palliative care in systemic sclerosis. We propose early, integrated palliative care could improve symptom control and quality of life, and recommend a research agenda for palliative care in systemic sclerosis, to address the lack of evidence in this area.