Multisystem Involvement in Post-Acute Sequelae of Coronavirus Disease 19.

OBJECTIVE: The purpose of this study was to describe cerebrovascular, neuropathic, and autonomic features of post-acute sequelae of coronavirus disease 2019 ((COVID-19) PASC). METHODS: This retrospective study evaluated consecutive patients with chronic fatigue, brain fog, and orthostatic intolerance consistent with PASC. Controls included patients with postural tachycardia syndrome (POTS) and healthy participants. Analyzed data included surveys and autonomic (Valsalva maneuver, deep breathing, sudomotor, and tilt tests), cerebrovascular (cerebral blood flow velocity [CBFv] monitoring in middle cerebral artery), respiratory (capnography monitoring), and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/autoimmune markers. RESULTS: Nine patients with PASC were evaluated 0.8 ± 0.3 years after a mild COVID-19 infection, and were treated as home observations. Autonomic, pain, brain fog, fatigue, and dyspnea surveys were abnormal in PASC and POTS (n = 10), compared with controls (n = 15). Tilt table test reproduced the majority of PASC symptoms. Orthostatic CBFv declined in PASC (-20.0 ± 13.4%) and POTS (-20.3 ± 15.1%), compared with controls (-3.0 ± 7.5%, p = 0.001) and was independent of end-tidal carbon dioxide in PASC, but caused by hyperventilation in POTS. Reduced orthostatic CBFv in PASC included both subjects without (n = 6) and with (n = 3) orthostatic tachycardia. Dysautonomia was frequent (100% in both PASC and POTS) but was milder in PASC (p = 0.002). PASC and POTS cohorts diverged in frequency of small fiber neuropathy (89% vs 60%) but not in inflammatory markers (67% vs 70%). Supine and orthostatic hypocapnia was observed in PASC. INTERPRETATION: PASC following mild COVID-19 infection is associated with multisystem involvement including: (1) cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction; (2) small fiber neuropathy and related dysautonomia; (3) respiratory dysregulation; and (4) chronic inflammation. ANN NEUROL 2022;91:367-379.

British mental healthcare responses to adult homosexuality and gender non-conforming children at the turn of the twenty-first century.

The roots of the recent controversy about how mental health professionals should respond to gender non-conforming children are traced. To make historical sense, this paper distinguishes between epistemological (discursive) and ontological (non-discursive) aspects and describes their features, since 1970. This helps to clarify some of the confusions at the centre of the still heated debate about sexuality and gender identity today. In the concluding discussion, the philosophical resource of critical realism is used to interpret the historical narrative provided. It cautions against the anachronistic tendency to amalgamate the short-lived, and now defunct, experiment of aversion therapy for homosexuality with more recent defences of exploratory psychotherapy. The latter have challenged a different form of experimentation: the bio-medicalisation of gender non-conforming children.

Network autonomic analysis of post-acute sequelae of COVID-19 and postural tachycardia syndrome.

BACKGROUND: The autonomic nervous system (ANS) is a complex network where sympathetic and parasympathetic domains interact inside and outside of the network. Correlation-based network analysis (NA) is a novel approach enabling the quantification of these interactions. The aim of this study is to assess the applicability of NA to assess relationships between autonomic, sensory, respiratory, cerebrovascular, and inflammatory markers on post-acute sequela of COVID-19 (PASC) and postural tachycardia syndrome (POTS). METHODS: In this retrospective study, datasets from PASC (n = 15), POTS (n = 15), and matched controls (n = 11) were analyzed. Networks were constructed from surveys (autonomic and sensory), autonomic tests (deep breathing, Valsalva maneuver, tilt, and sudomotor test) results using heart rate, blood pressure, cerebral blood flow velocity (CBFv), capnography, skin biopsies for assessment of small fiber neuropathy (SFN), and various inflammatory markers. Networks were characterized by clusters and centrality metrics. RESULTS: Standard analysis showed widespread abnormalities including reduced orthostatic CBFv in 100%/88% (PASC/POTS), SFN 77%/88%, mild-to-moderate dysautonomia 100%/100%, hypocapnia 87%/100%, and elevated inflammatory markers. NA showed different signatures for both disorders with centrality metrics of vascular and inflammatory variables playing prominent roles in differentiating PASC from POTS. CONCLUSIONS: NA is suitable for a relationship analysis between autonomic and nonautonomic components. Our preliminary analyses indicate that NA can expand the value of autonomic testing and provide new insight into the functioning of the ANS and related systems in complex disease processes such as PASC and POTS.

The Policy Alignment of the British False Memory Society and the British Psychological Society.

This paper describes the alignment between the goals of the British False Memory Society (BFMS) and a group of sympathetic academics within the British Psychological Society (BPS). Since the 1990s, the policy formation process of the BPS has excluded critical colleagues concerned with child protection and the demonstration of the link between childhood adversity and adult mental health problems. Those involved in the nexus between the BPS and BFMS have focused singularly on the experimental evidence for false-positive outcomes and have systematically excluded a consideration of false negatives. We describe how this biased policy development emerged and was maintained. We discuss this skewed policy formation with reference to social network formation in professional life, as well as the wider context of child abuse in society.

Health and Social Care Diversity Among Individuals with Longstanding Physical and Psychological Health Problems: Pooled Repeated Cross Sectional Analyses.

This paper examines differences in health-and-social care utilisation for individuals with physical and/or mental health problems. Logistic regression models are used to determine disparity in the percentage of General Household/Lifestyle Survey participants with physical compared to mental health problems receiving disability benefits or health care services between 2000 and 2011. Our findings of a relative underutilisation of secondary health care combined with a relative overutilization of out-of-work benefits by individuals with mental health problems is novel to the field of rehabilitative health care. These results provide evidence for the previously suspected disparity in health care utilisation of individuals with mental health problems and indicate problems in labour force integration. The findings support the political call for a 'parity of esteem', which, in Britain, was enshrined in the Health and Social Care Act of 2012.

Antagonistic Behaviors of NMY-1 and NMY-2 Maintain Ring Channels in the C. elegans Gonad.

Contractile rings play critical roles in a number of biological processes, including oogenesis, wound healing, and cytokinesis. In many cases, the activity of motor proteins such as nonmuscle myosins is required for appropriate constriction of these contractile rings. In the gonad of the nematode worm Caenorhabditis elegans, ring channels are a specialized form of contractile ring that are maintained at a constant diameter before oogenesis. We propose a model of ring channel maintenance that explicitly incorporates force generation by motor proteins that can act normally or tangentially to the ring channel opening. We find that both modes of force generation are needed to maintain the ring channels. We demonstrate experimentally that the type II myosins NMY-1 and NMY-2 antagonize each other in the ring channels by producing force in perpendicular directions: the experimental depletion of NMY-1/theoretical decrease in orthogonal force allows premature ring constriction and cellularization, whereas the experimental depletion of NMY-2/theoretical decrease in tangential force opens the ring channels and prevents cellularization. Together, our experimental and theoretical results show that both forces, mediated by NMY-1 and NMY-2, are crucial for maintaining the appropriate ring channel diameter and dynamics throughout the gonad.

The titin A-band rod domain is dispensable for initial thick filament assembly in zebrafish.

The sarcomeres of skeletal and cardiac muscle are highly structured protein arrays, consisting of thick and thin filaments aligned precisely to one another and to their surrounding matrix. The contractile mechanisms of sarcomeres are generally well understood, but how the patterning of sarcomeres is initiated during early skeletal muscle and cardiac development remains uncertain. Two of the most widely accepted hypotheses for this process include the "molecular ruler" model, in which the massive protein titin defines the length of the sarcomere and provides a scaffold along which the myosin thick filament is assembled, and the "premyofibril" model, which proposes that thick filament formation does not require titin, but that a "premyofibril" consisting of non-muscle myosin, α-actinin and cytoskeletal actin is used as a template. Each model posits a different order of necessity of the various components, but these have been difficult to test in vivo. Zebrafish motility mutants with developmental defects in sarcomere patterning are useful for the elucidation of such mechanisms, and here we report the analysis of the herzschlag mutant, which shows deficits in both cardiac and skeletal muscle. The herzschlag mutant produces a truncated titin protein, lacking the C-terminal rod domain that is proposed to act as a thick filament scaffold, yet muscle patterning is still initiated, with grossly normal thick and thin filament assembly. Only after embryonic muscle contraction begins is breakdown of sarcomeric myosin patterning observed, consistent with the previously noted role of titin in maintaining the contractile integrity of mature sarcomeres. This conflicts with the "molecular ruler" model of early sarcomere patterning and supports a titin-independent model of thick filament organization during sarcomerogenesis. These findings are also consistent with the symptoms of human titin myopathies that exhibit a late onset, such as tibial muscular dystrophy.

Research priorities for public mental health in Europe: recommendations of the ROAMER project.

BACKGROUND: The ROAdmap for MEntal health Research in Europe project aimed to create an integrated European roadmap for mental health research. Leading mental health research experts across Europe have formulated consensus-based recommendations for future research within the public mental health field. METHODS: Experts were invited to compile and discuss research priorities in a series of topic-based scientific workshops. In addition, a Delphi process was carried out to reach consensus on the list of research priorities and their rank order. Three web-based surveys were conducted. Nearly 60 experts were involved in the priority setting process. RESULTS: Twenty priorities for public mental health research were identified through the consensus process. The research priorities were divided into summary principles-encompassing overall recommendations for future public mental health research in Europe-and thematic research priorities, including area-specific top priorities on research topics and methods. The priorities represent three overarching goals mirroring societal challenges, that is, to identify causes, risk and protective factors for mental health across the lifespan; to advance the implementation of effective public mental health interventions and to reduce disparities in mental health. CONCLUSIONS: The importance of strengthening research on the implementation and dissemination of promotion, prevention and service delivery interventions in the mental health field needs to be emphasized. The complexity of mental health and its broader conceptualisation requires complementary research approaches and interdisciplinary collaboration to better serve the needs of the European population.

Mismatch between subjective and objective dysautonomia.

Autonomic symptom questionnaires are frequently used to assess dysautonomia. It is unknown whether subjective dysautonomia obtained from autonomic questionnaires correlates with objective dysautonomia measured by quantitative autonomic testing. The objective of our study was to determine correlations between subjective and objective measures of dysautonomia. This was a retrospective cross-sectional study conducted at Brigham and Women's Faulkner Hospital Autonomic Laboratory between 2017 and 2023 evaluating the patients who completed autonomic testing. Analyses included validated autonomic questionnaires [Survey of Autonomic Symptoms (SAS), Composite Autonomic Symptom Score 31 (Compass-31)] and standardized autonomic tests (Valsalva maneuver, deep breathing, sudomotor, and tilt test). The autonomic testing results were graded by a Quantitative scale for grading of cardiovascular reflexes, sudomotor tests and skin biopsies (QASAT), and Composite Autonomic Severity Score (CASS). Autonomic testing, QASAT, CASS, and SAS were obtained in 2627 patients, and Compass-31 in 564 patients. The correlation was strong between subjective instruments (SAS vs. Compass-31, r = 0.74, p < 0.001) and between objective instruments (QASAT vs. CASS, r = 0.81, p < 0.001). There were no correlations between SAS and QASAT nor between Compass-31 and CASS. There continued to be no correlations between subjective and objective instruments for selected diagnoses (post-acute sequelae of COVID-19, n = 61; postural tachycardia syndrome, 211; peripheral autonomic neuropathy, 463; myalgic encephalomyelitis/chronic fatigue syndrome, 95; preload failure, 120; post-treatment Lyme disease syndrome, 163; hypermobile Ehlers-Danlos syndrome, 213; neurogenic orthostatic hypotension, 86; diabetes type II, 71, mast cell activation syndrome, 172; hereditary alpha tryptasemia, 45). The lack of correlation between subjective and objective instruments highlights the limitations of the commonly used questionnaires with some patients overestimating and some underestimating true autonomic deficit. The diagnosis-independent subjective-objective mismatch further signifies the unmet need for reliable screening surveys. Patients who overestimate the symptom burden may represent a population with idiosyncratic autonomic-like symptomatology, which needs further study. At this time, the use of autonomic questionnaires as a replacement of autonomic testing cannot be recommended.

A dominant dpy-10 co-transformation marker using CRISPR/Cas9 and a linear repair template in Caenorhabditis tropicalis.

Caenorhabditis elegans is an excellent genetic model system with a large arsenal of forward and reverse genetic techniques. However, not all approaches are easily ported to related Caenorhabditis species (which are useful for gene conservation and gene pathway evolution studies). For CRISPR/Cas9 genetic editing, an easily screenable and dominant co-transformation marker is required - a secondary mutation that won't impact the phenotype of a desired mutation but is capable of being screened for in heterozygous mutants. We describe here the adaptation of a dominant dumpy/roller CRISPR/Cas9-induced mutation in the C. tropicalis dpy-10 orthologue.

The British welfare state and mental health problems: the continuing relevance of the work of Claus Offe.

It is now over thirty years since Claus Offe theorised the crisis tendencies of the welfare state in late capitalism. As part of that work he explored ongoing and irresolvable forms of crisis management in parliamentary democracies: capitalism cannot live with the welfare state but also cannot live without it. This article examines the continued relevance of this analysis by Offe, by applying its basic assumptions to the response of the British welfare state to mental health problems, at the turn of the twenty first century. His general theoretical abstractions are tested against the empirical picture of mental health service priorities, evident since the 1980s, in sections dealing with: re-commodification tendencies; the ambiguity of wage labour in the mental health workforce; the emergence of new social movements; and the limits of legalism.

Improving the quality of primary care.

BACKGROUND: This paper considers the role of teaching primary care trusts (tPCTs) at the turn of the century. A retrospective evaluation of a complex intervention is used. The evaluation has three perspectives. These are (1) a commentary on tPCTs in health policy in England, (2) the authors' reflections as senior members of a tPCT in Northern England and (3) a look-back exercise with tPCT members. RESULTS: It outlines the achievements and reflects on the experience of the tPCT and its relationship with its stakeholders. The resultant themes and challenges experienced by the tPCT members working at their organisational boundaries with their stakeholder both provide organisational developmental insight for the emergent primary care commissioning groups (Health and Social Care Bill 2011) and highlight the continuing need for organisational cultural change within general practice. CONCLUSION: Quality criteria for acceptability, accessibility, appropriateness, equity, clinical effectiveness and cost-effectiveness can only be truly addressed by a learning organisation approach. This was one of the original remits for tPCTs.

Transgender debates and healthcare: A critical realist account.

The meta-theoretical resource of critical realism (CR) is deployed in order to examine transgender and healthcare. CR treads a middle way between positivism and postmodernism, within post-Popperian discussions of the philosophy of natural and social science. It focuses on the conditions of possibility for the emergence of a phenomenon under investigation. In this case, the focus is on the emergence of debates about transgenderism in healthcare. These have been technological (about the prospect of biomedical solutions to personal problems) and ideological, with the enlarged salience of identity politics and our currently unresolved "culture wars." Identity politics have brought a focus on epistemological privilege or "lived experience" and on rights to healthcare being driven by consumer choice. The current contestation and its history are discussed in relation to our four planar social being (nature, relationality, socio-economic structures, and our particular personalities) and future scenarios are rehearsed.

Integrating Advanced Practice Providers in an Academic Department of Neurology.

BACKGROUND AND OBJECTIVES: Integrating advanced practice providers (APPs) into neurologic practice can improve access, promote patient education, and reduce health care costs. APPs receive limited formal education in neurology, so on-the-job training is essential. We set out to identify common challenges and best practices for onboarding, training, and integrating APPs into neurologic practice. METHODS: We conducted a survey and focus group with 8 APPs currently practicing within an academic neurology department as part of a clinical quality improvement initiative. We explored their roles in multidisciplinary teams, challenges faced during onboarding and training, and strategies for success. Qualitative thematic analysis was performed. RESULTS: Neurology APPs serve diverse roles including caring for hospitalized and ambulatory patients, performing procedures, assisting trainees, and performing research. Participants reported limited formal neurologic education before their job and a need for educational sessions and resources tailored to APPs. Neuroanatomy, neuroimaging, and generating a neurologic differential diagnosis were key knowledge gaps identified. We identified 7 informal strategies for on-the-job training, 7 challenges to on-the-job training, and factors promoting or threatening job satisfaction. Graded responsibility and clinical mentorship were essential for successful onboarding. APPs desired peer-to-peer mentorship and structured educational opportunities. DISCUSSION: Common challenges and success strategies identified can inform the design of a formal curriculum for onboarding neurology APPs. Our findings suggest that an optimal APP training process involves graded responsibility and support for self-directed learning, employs peer mentors, and targets education of the multidisciplinary team including physicians and patients. Our results may inform other institutions recruiting, hiring, and training APPs.

The Axenfeld-Rieger Syndrome Gene FOXC1 Contributes to Left-Right Patterning.

Precise spatiotemporal expression of the Nodal-Lefty-Pitx2 cascade in the lateral plate mesoderm establishes the left-right axis, which provides vital cues for correct organ formation and function. Mutations of one cascade constituent PITX2 and, separately, the Forkhead transcription factor FOXC1 independently cause a multi-system disorder known as Axenfeld-Rieger syndrome (ARS). Since cardiac involvement is an established ARS phenotype and because disrupted left-right patterning can cause congenital heart defects, we investigated in zebrafish whether foxc1 contributes to organ laterality or situs. We demonstrate that CRISPR/Cas9-generated foxc1a and foxc1b mutants exhibit abnormal cardiac looping and that the prevalence of cardiac situs defects is increased in foxc1a-/-; foxc1b-/- homozygotes. Similarly, double homozygotes exhibit isomerism of the liver and pancreas, which are key features of abnormal gut situs. Placement of the asymmetric visceral organs relative to the midline was also perturbed by mRNA overexpression of foxc1a and foxc1b. In addition, an analysis of the left-right patterning components, identified in the lateral plate mesoderm of foxc1 mutants, reduced or abolished the expression of the NODAL antagonist lefty2. Together, these data reveal a novel contribution from foxc1 to left-right patterning, demonstrating that this role is sensitive to foxc1 gene dosage, and provide a plausible mechanism for the incidence of congenital heart defects in Axenfeld-Rieger syndrome patients.

Gdf6a is required for the initiation of dorsal-ventral retinal patterning and lens development.

Dorsal-ventral patterning of the vertebrate retina is essential for accurate topographic mapping of retinal ganglion cell (RGC) axons to visual processing centers. Bone morphogenetic protein (Bmp) growth factors regulate dorsal retinal identity in vertebrate models, but the developmental timing of this signaling and the relative roles of individual Bmps remain unclear. In this study, we investigate the functions of two zebrafish Bmps, Gdf6a and Bmp4, during initiation of dorsal retinal identity, and subsequently during lens differentiation. Knockdown of zebrafish Gdf6a blocks initiation of retinal Smad phosphorylation and dorsal marker expression, while knockdown of Bmp4 produces no discernable retinal phenotype. These data, combined with analyses of embryos ectopically expressing Bmps, demonstrate that Gdf6a is necessary and sufficient for initiation of dorsal retinal identity. We note a profound expansion of ventral retinal identity in gdf6a morphants, demonstrating that dorsal BMP signaling antagonizes ventral marker expression. Finally, we demonstrate a role for Gdf6a in non-neural ocular tissues. Knockdown of Gdf6a leads to defects in lens-specific gene expression, and when combined with Bmp signaling inhibitors, disrupts lens fiber cell differentiation. Taken together, these data indicate that Gdf6a initiates dorsal retinal patterning independent of Bmp4, and regulates lens differentiation.

Diagnosis and formulation: what should we tell the students?

Appropriately assessing and coherently conceptualising psychological problems are important precursors to delivering effective interventions. In this regard, trainee psychologists and, in particular, clinical psychology trainees, are faced with a dilemma. Training programme documentation is unequivocal in its emphasis on formulation in preference to diagnosis. In practice, however, diagnosis is often seen as an important skill for a clinician to develop. A lack of clarity concerning the relationship between diagnosis and formulation is reflected in the literature. In this paper we highlight training programme documentation from both Australia and the United Kingdom to illustrate the clarity that exists. We also summarise the literature with regard to the confusion surrounding the relationship between formulation and diagnosis and we explore the concept of psychiatric diagnosis from a definitional perspective. It appears that even the creators of psychiatric classificatory systems are not clear about exactly what a psychiatric diagnosis is. We conclude by offering some suggestions to improve the situation and to assist psychologists to make a greater contribution to the understanding and amelioration of psychological distress.