Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease.

RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1-7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1-/- mice died postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.

The impact of sex and gender on burden for caregivers of stroke patients: A narrative review.

BACKGROUND: When a patient is disabled after stroke, they require both emotional support and medical management and may require the assistance of a caregiver. Given the often-sudden onset of disability and the complex challenges related to caring for someone after stroke, caregivers can experience a heavy burden. Caregiver burden negatively affects quality of care, quality of life, and physical and psychological health. The impact of gender on caregiver burden has been in many other conditions; however, the association has not yet been thoroughly assessed in stroke. OBJECTIVE: The aim of this paper is to define caregiver burden, discuss how it is assessed, discuss unique aspects of burden for stroke caregivers, and determine the impact of sex and gender on stroke caregiver role and burden. METHODS: A narrative review was performed to synthesize the available literature and explore how the role of sex and gender impact caregiving for patients who have suffered stroke and whether sex and gender of the caregiver contribute to caregiver burden r. RESULTS: Review of the available literature suggests that sex and gender significantly impact caregiving burden following stroke dipropionately affecting women. CONCLUSIONS: Caregiving for patients who have suffered stroke is often provided by women both inside the home and when patients are within institutions. Women who serve as caregivers to stroke patients may be at higher risk of experiencing burden and its negative effects, including emotional strain, anxiety, and/or depression. More research is needed to determine the best ways to provide support for women who act as caregivers for stroke patients to mitigate caregiver burden.

Physiotherapy private practitioners' opinions regarding interprofessional collaborative practice: A qualitative study.

Physiotherapy private practitioners comprise a growing proportion of Australia's primary care workforce, yet their views and experiences of interprofessional collaborative practice (IPCP) are poorly documented. The aim of this study was to explore Australian physiotherapy private practitioners' opinions regarding IPCP. Twenty-eight semi-structured interviews were conducted with physiotherapists in 10 private practice sites in Queensland, Australia. Interviews were analyzed using reflexive thematic analysis. Data analysis produced five themes that characterized physiotherapists' perceptions of IPCP: (a) quality of care considerations; (b) not a one-size-fits-all approach; (c) the need for effective interprofessional communication; (d) fostering a positive work culture; and (e) fear of losing clientele. The findings from this study suggest that physiotherapy private practitioners value IPCP because it can deliver superior client outcomes, can strengthen interprofessional relationships, and has the potential to enhance the professional reputation of the organizations within which they work. Physiotherapists also claimed that IPCP can contribute to poor client outcomes when performed inappropriately, while some reported approaching interprofessional referrals with caution following instances of lost clientele. The mixed views toward IPCP in this study highlight the need to explore the facilitators and barriers to IPCP in the Australian physiotherapy private practice setting.

Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease.

BACKGROUND: Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders. METHODS: We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function. RESULTS: We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation. CONCLUSIONS: Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).

Integrating Behavioral Health and Primary Care: Turning a Duet Into a Trio.

Family physicians are at the front lines of mental health concerns and distress, yet often feel stymied in their attempts to fully support patients' biopsychosocial needs within the barriers of a fragmented health care system. This article describes a practice transformation designed to facilitate more empowered care experiences. We reflect on our interdisciplinary work as a family physician and a behavioral health consultant working closely together in a Primary Care Behavioral Health model within a university setting. We describe our collaborative approach to a composite character from clinical practice: a college student with symptoms of psychomotor depression who screened negative for mood and anxiety concerns. Akin to a musical ensemble, wherein the inclusion of each voice turns a solo into a symphony, we describe key details of interdisciplinary collaboration which promotes holistic care for patients and fulfilling biopsychosocial practice for us as colleagues.

Caterpillar Salivary Glucose Oxidase Decreases Green Leaf Volatile Emission and Increases Terpene Emission from Maize.

Caterpillar salivary glucose oxidase (GOX) can function as both an elicitor or as an effector of plant defense responses depending upon the system. Treatment with GOX reduces the stomatal aperture of tomato and soybean leaves, thereby reducing the emission of volatile organic compounds (VOCs), that are important indirect defense responses of plants by attracting natural enemies of the caterpillars. Here we examined the effect of fungal GOX (fungal glucose oxidases have been used to determine specificity in defense response elicitation) on stomatal closure of maize leaves and on the volatile emission pattern whole maize plants. We also used salivary gland homogenate from wild-type and CRISPR-Cas9 Helicoverpa zea mutants deficient in GOX activity to determine the effect caterpillar saliva with and without GOX had on maize volatile emission. Collecting volatiles at 2-hour intervals allowed us to examine the changes in emission over time. Fungal GOX reduced the stomatal aperture in maize leaves, which may have influenced the observed significant reduction in total green leaf volatile (GLV) emission. Furthermore, fungal GOX significantly increased the emission of several key terpenes: linalool, DMNT, and Z-ß-farnesene from maize, while salivary gland homogenate from wild type (WT; GOX+) H. zea increased the emission of α-pinene, ß-pinene, and ocimene compared to H. zea unable to synthesize GOX. This study addressed a significant knowledge gap about the effect of GOX on maize volatiles and provides a baseline for further research on the effect of GOX on the regulation of terpene synthase genes and their relation to terpene volatile emission.

Bacterial extracellular electron transfer components are spin selective.

Metal-reducing bacteria have adapted the ability to respire extracellular solid surfaces instead of soluble oxidants. This process requires an electron transport pathway that spans from the inner membrane, across the periplasm, through the outer membrane, and to an external surface. Multiheme cytochromes are the primary machinery for moving electrons through this pathway. Recent studies show that the chiral-induced spin selectivity (CISS) effect is observable in some of these proteins extracted from the model metal-reducing bacteria, Shewanella oneidensis MR-1. It was hypothesized that the CISS effect facilitates efficient electron transport in these proteins by coupling electron velocity to spin, thus reducing the probability of backscattering. However, these studies focused exclusively on the cell surface electron conduits, and thus, CISS has not been investigated in upstream electron transfer components such as the membrane-associated MtrA, or periplasmic proteins such as small tetraheme cytochrome (STC). By using conductive probe atomic force microscopy measurements of protein monolayers adsorbed onto ferromagnetic substrates, we show that electron transport is spin selective in both MtrA and STC. Moreover, we have determined the spin polarization of MtrA to be ∼77% and STC to be ∼35%. This disparity in spin polarizations could indicate that spin selectivity is length dependent in heme proteins, given that MtrA is approximately two times longer than STC. Most significantly, our study indicates that spin-dependent interactions affect the entire extracellular electron transport pathway.

Women's knowledge of and attitudes towards group B streptococcus (GBS) testing in pregnancy: a qualitative study.

BACKGROUND: 20-25% pregnant women in the UK carry group B streptococcus (GBS) which, if left undetected, is transmitted from pregnant mothers to their babies during birth in 36% of cases. This transmission leads to early onset GBS infection (EOGBS) in 1% of babies which is a significant cause of mortality and morbidity in newborns. The literature available suggests women's knowledge of GBS is low, with many women unaware of the GBS bacterium. In addition, attitudes towards GBS testing have not been widely examined, with research mostly focusing on attitudes towards potential GBS vaccination. AIM: To examine women's knowledge of GBS in pregnancy and their attitudes towards GBS testing. METHODS: Semi-structured interviews with 19 women (5 pregnant and 14 postpartum). Interviews were transcribed and analysed using systematic thematic analysis. RESULTS: Four main theme categories were identified. Participants had varying levels of awareness of GBS, with the information provided by health professionals not being clearly explained or the importance of GBS being downplayed. Participants wanted more information and to feel informed. Overall, the majority had positive attitudes towards being offered and taking up GBS testing, and this study identified some of the key factors influencing their decision. These included: seeing GBS testing as just another routine procedure during pregnancy; that it would lower the risk of their baby becoming unwell; provide reassurance; and allow them to prepare; and provide informed choices. Participants also expressed a few common concerns about GBS testing: questioning the invasiveness of the procedure; risks to themselves and the baby; and the risk of receiving antibiotics. CONCLUSIONS: Women need clear, detailed information about GBS and GBS testing, and women's concerns are important to address if routine GBS testing is implemented. The efficacy of implementing routine universal testing in the UK is currently being investigated in a large multi-centre clinical trial; the GBS3trial, further qualitative research is needed to look at the acceptability of different methods of GBS testing, as well as the acceptability of GBS testing to women in specific groups, such as those planning a home birth or those from different ethnic backgrounds.

Common genetic susceptibility loci link PFAPA syndrome, Behçet's disease, and recurrent aphthous stomatitis.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the pathogenesis is unknown. We queried two European-American cohorts and one Turkish cohort (total n = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behçet's disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of IL12A (rs17753641) is strongly associated with PFAPA (OR 2.13, P = 6 × 10-9). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ and LPS stimulation than those from individuals without the risk allele. We also found that variants near STAT4, IL10, and CCR1-CCR3 were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behçet's disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet's disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet's spectrum disorders to highlight their relationship. HLA alleles may be factors that influence phenotypes along this spectrum as we found new class I and II HLA associations for PFAPA distinct from Behçet's disease and recurrent aphthous stomatitis.

Pandemic Response Officers: Integration Between Medical, Public Health, and Higher Education Systems to Expedite Prevention and Response.

CONTEXT: Research and policy studies alike have enumerated population and community health benefits of system integration between medical, public health, and social entities. The emergence of the COVID-19 pandemic revealed the necessity of a well-trained and adequately staffed public health and medical workforce in order to process SARS-CoV-2 cases and prevent subsequent transmission. Higher education systems, in particular, represented defined populations of exposure and transmission. Opportunities existed for collaboration and task sharing between institutions of higher education and local public health departments to limit spread and impacts. PROGRAM: This article describes the Pandemic Response Officer (PRO) program at Cornell University, a team of staff and students created during the intensity of the pandemic to benefit the Tompkins County and Cornell University communities. IMPLEMENTATION: The PRO program was formed in January 2021, with an original team of 8 individuals, working iteratively to investigate and support employee cases and exposures. Implementation was motivated by Cornell University's dual responsibility as a large employer that also possessed SARS-CoV-2 test results of employees. PROs loaded case information into a shared HIPPA-compliant electronic record that collected information for case notification, case investigation, isolation support, contact tracing, contact notification, and quarantine support. Over time, the PROs grew to a team of 25, gaining responsibilities as university and public health systems shared roles to maximize resources. EVALUATION: From January 1 to December 31, 2021, PROs managed 773 employee and 2943 student cases. During the Omicron surge (November 28-December 31, 2021), PROs saved the public health department an estimated 2797 hours of effort, equating to more than 10 professionals working full-time, evenings and weekends, to process cases and contacts during this interval. DISCUSSION: By integrating efforts between a university and public health agency, this intervention minimized SARS-CoV-2 transmission via expedient case support and alleviated strain on public health systems by expanding the public health workforce.

The dual function of elicitors and effectors from insects: reviewing the 'arms race' against plant defenses.

KEY MESSAGE: This review provides an overview, analysis, and reflection on insect elicitors and effectors (particularly from oral secretions) in the context of the 'arms race' with host plants. Following injury by an insect herbivore, plants rapidly activate induced defenses that may directly or indirectly affect the insect. Such defense pathways are influenced by a multitude of factors; however, cues from the insect's oral secretions are perhaps the most well studied mediators of such plant responses. The relationship between plants and their insect herbivores is often termed an 'evolutionary arms race' of strategies for each organism to either overcome defenses or to avoid attack. However, these compounds that can elicit a plant defense response that is detrimental to the insect may also benefit the physiology or metabolism of an insect species. Indeed, several insect elicitors of plant defenses (such as the fatty acid-amino acid conjugate, volicitin) are known to enhance an insect's ability to obtain nutritionally important compounds from plant tissue. Here we re-examine the well-known elicitors and effectors from chewing insects to demonstrate not only our incomplete understanding of the specific biochemical and molecular cascades involved in these interactions but also to consider the role of these compounds for the insect species itself. Finally, this overview discusses opportunities for research in the field of plant-insect interactions by utilizing tools such as genomics and proteomics to integrate the future study of these interactions through ecological, physiological, and evolutionary disciplines.

Integrated Surveillance System for Controlling COVID-19 on a University Campus, 2020‒2021.

To minimize the impacts of COVID-19 and to keep campus open, Cornell University's Ithaca, NY, campus implemented a comprehensive process to monitor COVID-19 spread, support prevention practices, and assess early warning indicators linked to knowledge, behaviors, and attitudes of campus community members. The integrated surveillance approach informed leadership and allowed for prompt adjustments to university policies and practices through evidence-based decisions. This approach enhanced healthy behaviors and promoted the well-being and safety of all community members. (Am J Public Health. 2022;112(7):980-984. https://doi.org/10.2105/AJPH.2022.306838).

Herbivorous Caterpillars and the Green Leaf Volatile (GLV) Quandary.

Several herbivorous caterpillars contain effectors in their oral secretions that alter the emission of green leaf volatiles (GLVs) produced by the plants upon which the caterpillars are feeding. These effectors include an isomerase, a fatty acid dehydratase (FHD), and a heat-stable hexenal trapping (HALT) molecule. GLVs serve as signaling compounds in plant-insect interactions and inter-and intra-plant communication. However, it is not known whether these GLV-altering effectors are common among herbivorous caterpillars, or the evolutionary context of these effectors in relation to GLV emission by host plants in response to feeding damage. Here, we examined the distribution and activity of the isomerase, FHD, and HALT effectors across 10 species spanning 7 lepidopteran families. Six of the 10 species possessed all three effectors in their oral secretions. Activity from the HALT and FHD effectors was observed in all examined caterpillar species, while activity from the isomerase effector varied in some species and was absent in others. There was no discernable pattern in effector activity based on evolutionary divergence, since individual species within a family did not possess similar mechanisms to alter GLV emission. These data, demonstrating the GLV-altering effectors acting at different steps in the GLV biosynthetic pathway and present in the examined caterpillar species at different combinations with different activities, highlight the importance of these effectors in changing the emission of these compounds during caterpillar herbivory. Understanding the prevalence and roles of GLV-altering effectors and GLV emission itself will open new research areas in the dynamics of plant-insect interactions.

Marine Natural Products as Leads against SARS-CoV-2 Infection.

Since early 2020, disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic, causing millions of infections and deaths worldwide. Despite rapid deployment of effective vaccines, it is apparent that the global community lacks multipronged interventions to combat viral infection and disease. A major limitation is the paucity of antiviral drug options representing diverse molecular scaffolds and mechanisms of action. Here we report the antiviral activities of three distinct marine natural products─homofascaplysin A (1), (+)-aureol (2), and bromophycolide A (3)─evidenced by their ability to inhibit SARS-CoV-2 replication at concentrations that are nontoxic toward human airway epithelial cells. These compounds stand as promising candidates for further exploration toward the discovery of novel drug leads against SARS-CoV-2.

The Arc Toward Hope in Postapocalyptic American Films: From On the Beach to The Midnight Sky.

An arc toward hope in postapocalyptic American films can be seen between Stanley Kramer's 1959 film On the Beach, based on Nevil Shute's 1957 novel of the same name, and George Clooney's 2020 film The Midnight Sky, adapted from Lily Brooks-Dalton's 2016 novel Good Morning, Midnight. Clooney's film makes direct and indirect references to On the Beach, which brought international attention to the threat that radiation fallout from nuclear weapons could end all human life on Earth. In On the Beach, no one survives. Already underway before the COVID-19 pandemic developed, Clooney's ambitious project for The Midnight Sky underwent a script revision after filming had begun to accommodate the unexpected pregnancy of its lead actress. In the revised ending, there is hope, albeit slight, that the expectant astronaut couple aboard spaceship Aether might avoid the environmental disaster from the unspecified "event" that has occurred on Earth by returning to the moon of Jupiter their mission had explored and found capable of sustaining human life. Released on Netflix in December 2020, The Midnight Sky was viewed by millions even as the first vaccines for COVID-19 were becoming available. The arc toward hope, Clooney believes, is the right ending.

What are the perspectives of speech pathologists, occupational therapists and physiotherapists on using telehealth videoconferencing for service delivery to children with developmental delays? A systematic review of the literature.

OBJECTIVE: To identify the attitudes and perspectives of speech pathologists, occupational therapists and physiotherapists on using telehealth videoconferencing for service delivery to children with developmental delays. DESIGN: Systematic Literature Review. METHOD: An electronic search of databases Scopus, CINAHL, MEDLINE, PEDro, Speechbite, OTseeker and ScienceDirect was undertaken in October 2020. Articles were compared with eligibility criteria by 2 authors. All articles were appraised for quality and level of evidence. FINDINGS: Fourteen studies were deemed to be eligible. Results were synthesised using a narrative analysis. The themes identified were technology, self-efficacy, replacement of face-to-face services, time management, relationships, access and family-centred care. Each of these themes was seen as both a potential barrier and a facilitator when trying to provide services via telehealth. CONCLUSIONS: The results in this review cannot be generalised due to small sampling size, low response rates, lack of maximum variation sampling and under-representation of occupational therapists and physiotherapists. Study design was either mixed-methods survey or interview or only survey or interview. Risk of bias in studies was high. Further research is required including comparison studies and cost-benefit analysis.

Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features.

BACKGROUND: Monogenic autoinflammatory diseases (AID) are caused by mutations in innate immune genes. The effects of these mutations on allergic inflammation are unknown. OBJECTIVES: We investigated allergic, immunological and clinical phenotypes in FMF (familial Mediterranean fever), CAPS (cryopyrin-associated periodic syndrome), TRAPS (tumour necrosis factor receptor-associated periodic syndrome), HIDS (hyper-IgD syndrome), PAPA (pyogenic arthritis, pyoderma gangrenosum and acne), DADA2 (deficiency of adenosine deaminase 2), HA20 (haploinsufficiency of A20), CANDLE (chronic atypical neutrophilic dermatosis, lipodystrophy, elevated temperature) and SAVI (STING-associated vasculopathy of infancy). METHODS: In this cross-sectional study, clinical data were assessed in 425 patients with AID using questionnaires and chart reviews. Comparator data were obtained from public databases. Peripheral blood mononuclear cells obtained from 55 patients were stimulated and CD4+ cytokine production assessed. RESULTS: Clinical laboratory features of Type 2 immunity were elevated in CAPS but reduced in most AID, particularly DADA2. Physician-diagnosed allergic diseases were prevalent in multiple AID, including CAPS and DADA2. T helper 2 (Th2) cells were expanded in CAPS, TRAPS and HIDS; Th9 cells were expanded in HA20. CONCLUSIONS: CAPS is characterised by an enhanced Type 2 signature, whereas FMF and CANDLE are associated with reduced Type 2 responses. DADA2 is associated with reduced Type 2 responses but a high rate of physician-diagnosed allergy. Therefore, NLRP3-driven autoinflammation may promote Type 2 immunity, whereas AID like DADA2 may manifest clinical phenotypes that masquerade as allergic disorders. Further investigations are needed to determine the contribution of autoinflammation to allergic clinical and immunological phenotypes, to improve the treatment of patients with AID.

Mild cognitive impairment: the Manchester consensus.

Given considerable variation in diagnostic and therapeutic practice, there is a need for national guidance on the use of neuroimaging, fluid biomarkers, cognitive testing, follow-up and diagnostic terminology in mild cognitive impairment (MCI). MCI is a heterogenous clinical syndrome reflecting a change in cognitive function and deficits on neuropsychological testing but relatively intact activities of daily living. MCI is a risk state for further cognitive and functional decline with 5-15% of people developing dementia per year. However, ~50% remain stable at 5 years and in a minority, symptoms resolve over time. There is considerable debate about whether MCI is a useful clinical diagnosis, or whether the use of the term prevents proper inquiry (by history, examination and investigations) into underlying causes of cognitive symptoms, which can include prodromal neurodegenerative disease, other physical or psychiatric illness, or combinations thereof. Cognitive testing, neuroimaging and fluid biomarkers can improve the sensitivity and specificity of aetiological diagnosis, with growing evidence that these may also help guide prognosis. Diagnostic criteria allow for a diagnosis of Alzheimer's disease to be made where MCI is accompanied by appropriate biomarker changes, but in practice, such biomarkers are not available in routine clinical practice in the UK. This would change if disease-modifying therapies became available and required a definitive diagnosis but would present major challenges to the National Health Service and similar health systems. Significantly increased investment would be required in training, infrastructure and provision of fluid biomarkers and neuroimaging. Statistical techniques combining markers may provide greater sensitivity and specificity than any single disease marker but their practical usefulness will depend on large-scale studies to ensure ecological validity and that multiple measures, e.g. both cognitive tests and biomarkers, are widely available for clinical use. To perform such large studies, we must increase research participation amongst those with MCI.

Allied health professionals' perceptions of interprofessional collaboration in primary health care: an integrative review.

This integrative review synthesizes research studies in order to explore the perceptions of allied health professionals regarding interprofessional collaboration in primary health care. A comprehensive literature search was conducted using three electronic databases and a manual search of the Journal of Interprofessional Care. The Crowe Critical Appraisal Tool was used to assess the quality of included papers. Study findings were extracted, critically examined and grouped into themes. Twelve studies conducted in six different countries met the inclusion criteria. Thematic analysis revealed five themes: (1) shared philosophy; (2) communication and clinical interaction; (3) physical environment; (4) power and hierarchy; and (5) financial considerations. This review has identified diverse key elements related to interprofessional collaboration in primary health care, as perceived by allied health professionals. Opportunity for frequent, informal communication appeared essential for interprofessional collaboration to occur. Allied health professionals working in close proximity to health practitioners from other professions had more regular interprofessional interactions than those who were geographically separated. Co-location of multiple primary health care services within the same physical space may offer increased opportunities for interprofessional collaboration. Future research should avoid reporting on allied health professionals in primary health care collectively, and isolate data to the individual professions. Direct observational methods are warranted to investigate whether allied health professionals' perceptions of interprofessional collaboration align with their actual clinical interactions in primary health care settings.

Tuning Catalytic Bias of Hydrogen Gas Producing Hydrogenases.

Hydrogenases display a wide range of catalytic rates and biases in reversible hydrogen gas oxidation catalysis. The interactions of the iron-sulfur-containing catalytic site with the local protein environment are thought to contribute to differences in catalytic reactivity, but this has not been demonstrated. The microbe Clostridium pasteurianum produces three [FeFe]-hydrogenases that differ in "catalytic bias" by exerting a disproportionate rate acceleration in one direction or the other that spans a remarkable 6 orders of magnitude. The combination of high-resolution structural work, biochemical analyses, and computational modeling indicates that protein secondary interactions directly influence the relative stabilization/destabilization of different oxidation states of the active site metal cluster. This selective stabilization or destabilization of oxidation states can preferentially promote hydrogen oxidation or proton reduction and represents a simple yet elegant model by which a protein catalytic site can confer catalytic bias.