Palliative hypnosis approaches in the symptomatic treatment of amyotrophic lateral sclerosis (ALS).

Amyotrophic lateral sclerosis (ALS) is a rare, incurable, and ultimately fatal, devastating, progressive degenerative neurologic disease. It causes upheaval in the lives of patients and family caregivers alike. Palliative care can play an important supportive role in the care of patients and families dealing with the devastation of this illness. Clinical hypnosis has demonstrated benefits in treating the symptoms associated with severe chronic illness. There are, however, few studies looking at the benefits of clinical hypnosis in treating the symptom burden of ALS. This article describes palliative care and how it can provide an additional layer of support to seriously ill patients. A brief review of previous studies of hypnosis in the supportive, symptomatic treatment of ALS is provided, followed by a description of a case series of 30 Veterans who received clinical hypnosis and self-hypnosis training as a complementary treatment for the symptoms of ALS. Details of three case histories are included to highlight and discuss specific strategies and emblematic clinical responses. There is evidence that clinical hypnosis can benefit ALS patients and family caregivers struggling with this devastating illness.

Low expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication.

New therapeutic targets are a valuable resource for treatment of SARS-CoV-2 viral infection. Genome-wide association studies have identified risk loci associated with COVID-19, but many loci are associated with comorbidities and are not specific to host-virus interactions. Here, we identify and experimentally validate a link between reduced expression of EXOSC2 and reduced SARS-CoV-2 replication. EXOSC2 was one of the 332 host proteins examined, all of which interact directly with SARS-CoV-2 proteins. Aggregating COVID-19 genome-wide association studies statistics for gene-specific eQTLs revealed an association between increased expression of EXOSC2 and higher risk of clinical COVID-19. EXOSC2 interacts with Nsp8 which forms part of the viral RNA polymerase. EXOSC2 is a component of the RNA exosome, and here, LC-MS/MS analysis of protein pulldowns demonstrated interaction between the SARS-CoV-2 RNA polymerase and most of the human RNA exosome components. CRISPR/Cas9 introduction of nonsense mutations within EXOSC2 in Calu-3 cells reduced EXOSC2 protein expression and impeded SARS-CoV-2 replication without impacting cellular viability. Targeted depletion of EXOSC2 may be a safe and effective strategy to protect against clinical COVID-19.

The British Athletics Muscle Injury Classification grading system as a predictor of return to play following hamstrings injury in professional football players.

OBJECTIVES: Investigate the British Athletics Muscle Injury Classification (BAMIC) grading system as a predictor of return to play (RTP) following primary hamstring strain injury (HSI) and its agreement with the Peetron's classification system in professional footballers. METHODS: A retrospective cohort study of 39 hamstrings strains in a professional English football club were identified. Two musculoskeletal radiologists reviewed historical MRI's and classified them against the BAMIC and Peetron's grading system. Classification, oedema length and cross-sectional area were compared against RTP. RESULTS: Pearson's correlation coefficient demonstrated a weak but statistically significant correlation between BAMIC and RTP (r = 0.32; 95%CI 0.01 to 0.58; p = 0.05). Maximum length of intramuscular oedema demonstrated weak correlations with RTP (r = 0.3; 95%CI -0.02 to 0.56; p = 0.06). Percentage cross sectional demonstrated a weak correlation with RTP (r = 0.02; 95%CI -0.3 to 0.33; p = 0.91). Multiple regression demonstrated that 16% of the variance in RTP was explained by the model. Kappa for the agreement between BAMIC and Peetron's was 0.21 (95%CI 0 to 0.42). CONCLUSIONS: A significant association between the grade of HSI on the BAMIC system and RTP was found. Findings suggest BAMIC could provide valuable prognostic information on the RTP.

SARS-CoV-2 Incidence in K-12 School Districts with Mask-Required Versus Mask-Optional Policies - Arkansas, August-October 2021.

Masks are effective at limiting transmission of SARS-CoV-2, the virus that causes COVID-19 (1), but the impact of policies requiring masks in school settings has not been widely evaluated (2-4). During fall 2021, some school districts in Arkansas implemented policies requiring masks for students in kindergarten through grade 12 (K-12). To identify any association between mask policies and COVID-19 incidence, weekly school-associated COVID-19 incidence in school districts with full or partial mask requirements was compared with incidence in districts without mask requirements during August 23-October 16, 2021. Three analyses were performed: 1) incidence rate ratios (IRRs) were calculated comparing districts with full mask requirements (universal mask requirement for all students and staff members) or partial mask requirements (e.g., masks required in certain settings, among certain populations, or if specific criteria could not be met) with school districts with no mask requirement; 2) ratios of observed-to-expected numbers of cases, by district were calculated; and 3) incidence in districts that switched from no mask requirement to any mask requirement were compared before and after implementation of the mask policy. Mean weekly district-level attack rates were 92-359 per 100,000 persons in the community* and 137-745 per 100,000 among students and staff members; mean student and staff member vaccination coverage ranged from 13.5% to 18.6%. Multivariable adjusted IRRs, which included adjustment for vaccination coverage, indicated that districts with full mask requirements had 23% lower COVID-19 incidence among students and staff members compared with school districts with no mask requirements. Observed-to-expected ratios for full and partial mask policies were lower than ratios for districts with no mask policy but were slightly higher for districts with partial policies than for those with full mask policies. Among districts that switched from no mask requirement to any mask requirement (full or partial), incidence among students and staff members decreased by 479.7 per 100,000 (p<0.01) upon implementation of the mask policy. In areas with high COVID-19 community levels, masks are an important part of a multicomponent prevention strategy in K-12 settings (5).

Low expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication.

New therapeutic targets are a valuable resource in the struggle to reduce the morbidity and mortality associated with the COVID-19 pandemic, caused by the SARS-CoV-2 virus. Genome-wide association studies (GWAS) have identified risk loci, but some loci are associated with co-morbidities and are not specific to host-virus interactions. Here, we identify and experimentally validate a link between reduced expression of EXOSC2 and reduced SARS-CoV-2 replication. EXOSC2 was one of 332 host proteins examined, all of which interact directly with SARS-CoV-2 proteins; EXOSC2 interacts with Nsp8 which forms part of the viral RNA polymerase. Lung-specific eQTLs were identified from GTEx (v7) for each of the 332 host proteins. Aggregating COVID-19 GWAS statistics for gene-specific eQTLs revealed an association between increased expression of EXOSC2 and higher risk of clinical COVID-19 which survived stringent multiple testing correction. EXOSC2 is a component of the RNA exosome and indeed, LC-MS/MS analysis of protein pulldowns demonstrated an interaction between the SARS-CoV-2 RNA polymerase and the majority of human RNA exosome components. CRISPR/Cas9 introduction of nonsense mutations within EXOSC2 in Calu-3 cells reduced EXOSC2 protein expression, impeded SARS-CoV-2 replication and upregulated oligoadenylate synthase ( OAS) genes, which have been linked to a successful immune response against SARS-CoV-2. Reduced EXOSC2 expression did not reduce cellular viability. OAS gene expression changes occurred independent of infection and in the absence of significant upregulation of other interferon-stimulated genes (ISGs). Targeted depletion or functional inhibition of EXOSC2 may be a safe and effective strategy to protect at-risk individuals against clinical COVID-19.

Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling of motor neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes that represent a 5-fold increase in recovered heritability. Extensive conservation, transcriptome, network, and rare variant analyses demonstrated the functional significance of candidate genes in healthy and diseased motor neurons and brain tissues. Genetic convergence between common and rare variation highlighted KANK1 as a new ALS gene. Reproducing KANK1 patient mutations in human neurons led to neurotoxicity and demonstrated that TDP-43 mislocalization, a hallmark pathology of ALS, is downstream of axonal dysfunction. RefMap can be readily applied to other complex diseases.

Simultaneous ALS and SCA2 associated with an intermediate-length ATXN2 CAG-repeat expansion.

Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) share a common molecular basis: both are associated with CAG-repeat expansion of ATXN2 and TDP-43-positive neuronal cytoplasmic inclusions. To date, the two disorders are viewed as clinically distinct with ALS resulting from 30-33 CAG-repeats and SCA2 from >34 CAG-repeats. We describe a 67-year old with a 32 CAG-repeat expansion of ATXN2 who presented with simultaneous symptoms of ALS and SCA2. Our case demonstrates that the clinical dichotomy between SCA2 and ATXN2-ALS is false. We suggest instead that CAG-repeat expansion length determines the timing of SCA2 clinical symptoms relative to onset of ALS; consistent with this age of onset of SCA2 but not ATXN2-ALS, is dependent upon expansion length. Review of the literature and our local cohort provides evidence for occurrence of ALS in late stage SCA2, which may be under-recognised by clinicians who think of the two diseases as distinct.

Rare Variant Burden Analysis within Enhancers Identifies CAV1 as an ALS Risk Gene.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organize membrane lipid rafts (MLRs) important for cell signaling and neuronal survival, and overexpression of CAV1 ameliorates ALS phenotypes in vivo. Genome-wide association studies localize a large proportion of ALS risk variants within the non-coding genome, but further characterization has been limited by lack of appropriate tools. By designing and applying a pipeline to identify pathogenic genetic variation within enhancer elements responsible for regulating gene expression, we identify disease-associated variation within CAV1/CAV2 enhancers, which replicate in an independent cohort. Discovered enhancer mutations reduce CAV1/CAV2 expression and disrupt MLRs in patient-derived cells, and CRISPR-Cas9 perturbation proximate to a patient mutation is sufficient to reduce CAV1/CAV2 expression in neurons. Additional enrichment of ALS-associated mutations within CAV1 exons positions CAV1 as an ALS risk gene. We propose CAV1/CAV2 overexpression as a personalized medicine target for ALS.

The incidence of post-dural puncture headache in the obese parturient compared to the non-obese parturient after an accidental dural puncture: a systematic review protocol.

OBJECTIVE: The purpose of this systematic review is to determine if there is a difference in the incidence of post-dural puncture headache in the obese parturient compared to the non-obese parturient after an accidental dural puncture. INTRODUCTION: Placement of an epidural catheter is a common technique to ease the pain of childbirth. One potential complication is a headache that occurs if the dura mater is accidentally punctured with the epidural needle during the procedure. Certain factors impact the likelihood of a postdural puncture headache after an accidental dural puncture in parturients. One potential factor is obesity. There is evidence to suggest that obesity lowers the risk of postdural puncture headache, although not all studies agree. There are no current or active systematic reviews that address whether or not obesity in parturients is protective against postdural puncture headache. INCLUSION CRITERIA: Studies with parturients aged 18 to 45 who have had a documented accidental dural puncture with an epidural needle will be included in this review. Studies with parturients with a history of spinal surgery or pre-existing headache pathology will be excluded. Studies involving non-obstetrical patients will be excluded. METHODS: A systematic search of MEDLINE, CINAHL Complete, Scopus, and Wiley Online Library will be conducted to identify studies on the topic of interest. Studies will be selected for review based on the inclusion criteria and will be appraised by two reviewers using the appropriate JBI standardized appraisal tool. SYSTEMATIC REVIEW REGISTRATION NUMBER: 136047 (PROSPERO).

Concurrent sodium channelopathies and amyotrophic lateral sclerosis supports shared pathogenesis.

Amyotrophic lateral sclerosis (ALS) is an invariably fatal adult-onset neurodegenerative disorder; approximately 10% of ALS is monogenic but all ALS exhibits significant heritability. The skeletal muscle sodium channelopathies are a group of inherited, non-dystrophic ion channel disorders caused by heterozygous point mutations in the SCN4A gene, leading to clinical manifestations of congenital myotonia, paramyotonia, and periodic paralysis syndromes. We provide clinical and genetic evidence of concurrence of these two rare disorders which implies a possible shared underlying pathophysiology in two patients. We then identify an enrichment of ALS-associated mutations in another sodium channel, SCN7A, from whole genome sequencing data of 4495 ALS patients and 1925 controls passing multiple testing correction (67 variants, p = 0.0002, Firth logistic regression). These findings suggest dysfunctional sodium channels may play a role upstream in the pathogenesis of ALS in a subset of patients, potentially opening the door to novel personalized medicine approaches.

Phenomenological study exploring ethics in prehospital research from the paramedic's perspective: experiences from the Paramedic-2 trial in a UK ambulance service.

OBJECTIVES: We set out to investigate paramedics' views of ethics and research, drawing on experiences from Paramedic-2, a randomised controlled trial comparing epinephrine and placebo in out-of-hospital cardiac arrest (OHCA). METHODS: An interpretative phenomenological approach was adopted. A purposive sample of paramedics (n=6) from North East Ambulance Service NHS Foundation Trust were invited to a semi-structured, in-depth interview. RESULTS: Three superordinate themes emerged: (1) morality, (2) emotion and (3) equipoise. Some viewed Paramedic-2 as an opportunity to improve OHCA outcomes for the many, viewing participation as a moral obligation; others viewed the study as unethical, equating participation with immoral behaviour. Morality was a motivator to drive individual action. Positive and negative emotions were exhibited by the paramedics involved reflecting the wider view each paramedic held about trial participation. Those morally driven to participate in Paramedic-2 discussed their pride in being associated with the trial, while those who found participation unethical, discussed feelings of guilt and regret. Individual experience and perceptions of epinephrine guided each paramedic's willingness to accept or reject equipoise. Some questioned the role of epinephrine in OHCA; others believed withholding epinephrine was synonymous to denying patient care. CONCLUSION: A paucity of evidence exists to support any beneficial role of epinephrine in OHCA. Despite this, some paramedics were reluctant to participate in Paramedic-2 and relied on their personal perceptions and experiences of epinephrine to guide their decision regarding participation. Failure to acknowledge the importance of individual perspectives may jeopardise the success of future out-of-hospital trials.

Safe injection practices among anesthesia providers: a scoping review protocol.

OBJECTIVE: The objective of this review is to identify and map literature related to safe injection practices among anesthesia providers in developed nations. The mapped literature will be used to determine if there is sufficient literature available to pose specific questions that can be valuably addressed, through a future systematic review, to reduce the prevalence of unsafe injections. INTRODUCTION: A safe injection is one that does not harm the recipient, does not expose the healthcare worker to avoidable risk, and does not result in waste that is a danger to the community. The literature is replete with examples of disease outbreaks connected to unsafe injections via the misuse of syringes, needles and medications. Many such outbreaks involve unsafe injections by anesthesia providers. INCLUSION CRITERIA: This scoping review will consider any research article or policy document, including unpublished reports, that provides information related to safe injection practices by anesthesia providers in developed nations. METHODS: For studies published in English from 2000, the databases to be searched include Ovid MEDLINE, CINAHL and Google Scholar. The search for unpublished literature will include the websites of anesthesia organizations, the Centers for Disease Control and Prevention, and the National Institutes of Health. Results will be screened by two independent reviewers who will use a standardized tool to independently extract data from each included source. The results of the review will be presented as a map of the data extracted in a tabular form and in a narrative descriptive summary.

Central expression of synaptophysin and synaptoporin in nociceptive afferent subtypes in the dorsal horn.

Central sprouting of nociceptive afferents in response to neural injury enhances excitability of nociceptive pathways in the central nervous system, often causing pain. A reliable quantification of central projections of afferent subtypes and their synaptic terminations is essential for understanding neural plasticity in any pathological condition. We previously characterized central projections of cutaneous nociceptive A and C fibers, selectively labeled with cholera toxin subunit B (CTB) and Isolectin B4 (IB4) respectively, and found that they expressed a general synaptic molecule, synaptophysin, largely depending on afferent subtypes (A vs. C fibers) across thoracic dorsal horns. The current studies extended the central termination profiles of nociceptive afferents with synaptoporin, an isoform of synaptophysin, known to be preferentially expressed in C fibers in lumbar dorsal root ganglions. Our findings demonstrated that synaptophysin was predominantly expressed in both peptidergic and IB4-binding C fiber populations in superficial laminae of the thoracic dorsal horn. Cutaneous IB4-labeled C fibers showed comparable expression levels of both isoforms, while cutaneous CTB-labeled A fibers exclusively expressed synaptophysin. These data suggest that central expression of synaptophysin consistently represents synaptic terminations of projecting afferents, at least in part, including nociceptive A-delta and C fibers in the dorsal horn.

Peak Oxygen Uptake in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Meta-Analysis.

To evaluate the magnitude of the difference in VO2peak between patients with Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) and apparently healthy controls, 7 databases (Cochrane, PubMed, PsycINFO, Web of Knowledge, Embase, Scopus, Medline) were searched for articles published up to March 2018. Search terms included "chronic fatigue syndrom*"AND ("peak" OR "maxim*" OR "max") AND ("oxygen uptake" OR "oxygen consumption" OR "VO2peak" or "VO2max". Eligibility criteria were adults>18 y with clinically diagnosed CFS/ME, with VO2peak measured in a maximal test and compared against an apparently healthy control group. The methodological quality of included studies was assessed using a modified Systematic Appraisal of Quality for Observational Research critical appraisal framework. A random effects meta-analysis was conducted on 32 cross-sectional studies (effects). Pooled mean VO2peak was 5.2 (95% CI: 3.8-6.6) ml.kg-1min-1 lower in CFS/ME patients vs. healthy controls. Between-study variability (Tau) was 3.4 (1.5-4.5) ml.kg-1min-1 indicating substantial heterogeneity. The 95% prediction interval was -1.9 to 12.2 ml.kg-1min-1. The probability that the effect in a future study would be>the minimum clinically important difference of 1.1 ml.kg-1min-1 (in favour of controls) was 0.88 - likely to be clinically relevant. Synthesis of the available evidence indicates that CFS/ME patients have a substantially reduced VO2peak compared to controls.

Randomised clinical trial of community-based peer-led and psychologist-led group treatment for hoarding disorder.

BACKGROUND: Treatment for hoarding disorder is typically performed by mental health professionals, potentially limiting access to care in underserved areas. AIMS: We aimed to conduct a non-inferiority trial of group peer-facilitated therapy (G-PFT) and group psychologist-led cognitive-behavioural therapy (G-CBT). METHOD: We randomised 323 adults with hording disorder 15 weeks of G-PFT or 16 weeks of G-CBT and assessed at baseline, post-treatment and longitudinally (≥3 months post-treatment: mean 14.4 months, range 3-25). Predictors of treatment response were examined. RESULTS: G-PFT (effect size 1.20) was as effective as G-CBT (effect size 1.21; between-group difference 1.82 points, t = -1.71, d.f. = 245, P = 0.04). More homework completion and ongoing help from family and friends resulted in lower severity scores at longitudinal follow-up (t = 2.79, d.f. = 175, P = 0.006; t = 2.89, d.f. = 175, P = 0.004). CONCLUSIONS: Peer-led groups were as effective as psychologist-led groups, providing a novel treatment avenue for individuals without access to mental health professionals. DECLARATION OF INTEREST: C.A.M. has received grant funding from the National Institutes of Health (NIH) and travel reimbursement and speakers' honoraria from the Tourette Association of America (TAA), as well as honoraria and travel reimbursement from the NIH for serving as an NIH Study Section reviewer. K.D. receives research support from the NIH and honoraria and travel reimbursement from the NIH for serving as an NIH Study Section reviewer. R.S.M. receives research support from the National Institute of Mental Health, National Institute of Aging, the Hillblom Foundation, Janssen Pharmaceuticals (research grant) and the Alzheimer's Association. R.S.M. has also received travel support from the National Institute of Mental Health for Workshop participation. J.Y.T. receives research support from the NIH, Patient-Centered Outcomes Research Institute and the California Tobacco Related Research Program, and honoraria and travel reimbursement from the NIH for serving as an NIH Study Section reviewer. All other authors report no conflicts of interest.

Contributions of self-criticism and shame to hoarding.

Pathological hoarding-related beliefs, such as need to control possessions, and inflated sense of responsibility over possessions, have been used to explain the development of symptoms of hoarding disorder (HD). While these beliefs have been the focus of the current standard treatment for HD, it is of significant clinical interest to further examine other constructs that may be linked to, or may underliethese beliefs, as well as the pathology of HD. To this end, the current study aimed to build on existing findings regarding the relationship of compromised self-identity with HD. Specifically, we investigated the relationship between self-criticism, shame, hoarding beliefs, and severity of HD symptoms among 104 treatment-seeking individuals with HD. We found that self-criticism and shame are positively associated with HD symptoms and hoarding related beliefs. Moreover, our data shed light on how these factors are connected by elucidating the indirect effects of self-criticism and shame on HD symptoms, mediated through beliefs about inflated sense of responsibility over possessions. The findings have implications for future research to examine interventions targeting compromised self-identity, including self-criticism and shame, among individuals with HD.

Comparison of a peer facilitated support group to cognitive behavior therapy: Study protocol for a randomized controlled trial for hoarding disorder.

Although individual and group cognitive-behavioral therapy (CBT) is the standard treatment approach for hoarding disorder (HD), it requires trained mental health professionals with specialization in HD. There is a need to offer additional options and services due to the limited number of professionals with advanced training, combined with the high prevalence rate of individuals with HD. A structured support group led by trained facilitators or lay professionals using a facilitator's manual and participant workbook (Buried in Treasures or BiT), addresses this need and increases accessibility. Prior studies of BiT groups have shown decreased hoarding symptoms. Only one retrospective study compared BiT and CBT outcomes in a naturalistic setting and showed no difference. Thus, a well-powered randomized controlled trial is needed to directly compare these forms of treatment. This paper presents a non-inferiority controlled trial protocol that compares group CBT to group BiT. Three hundred participants with HD, 18years or older, are being recruited for a 16-week treatment study. Participants are randomly assigned to either the CBT or BiT group. The primary outcome is reduction in hoarding symptom severity. Secondary outcomes include reduction in other indices of hoarding symptomology, including functional impairment, physical clutter, cognition, and changes in neuropsychological functioning.

Skeletal muscle atrogene expression and insulin resistance in a rat model of polytrauma.

Polytrauma is a combination of injuries to more than one body part or organ system. Polytrauma is common in warfare, and in automobile and industrial accidents. The combination of injuries can include burn, fracture, hemorrhage, and trauma to the extremities or specific organ systems. Resistance to anabolic hormones, loss of muscle mass, and metabolic dysfunction can occur following injury. To investigate the effects of combined injuries, we have developed a highly reproducible rodent model of polytrauma. This model combines burn injury, soft tissue trauma, and penetrating injury to the gastrointestinal (GI) tract. Adult, male Sprague-Dawley rats were anesthetized with pentobarbital and subjected to a 15-20% total body surface area scald burn, or laparotomy and a single puncture of the cecum with a G30 needle, or the combination of both injuries (polytrauma). In the current studies, the inflammatory response to polytrauma was examined in skeletal muscle. Changes in skeletal muscle mRNA levels of the proinflammatory cytokines TNF-α, IL-1ß, and IL-6 were observed following single injuries and polytrauma. Increased expression of the E3 ubiquitin ligases Atrogin-1/FBX032 and TRIM63/MuRF-1 were measured following injury, as was skeletal muscle insulin resistance, as evidenced by decreased insulin-inducible insulin receptor (IR) and AKT/PKB (Protein Kinase B) phosphorylation. Changes in the abundance of IR and insulin receptor substrate-1 (IRS-1) were observed at the protein and mRNA levels. Additionally, increased TRIB3 mRNA levels were observed 24 h following polytrauma, the same time when insulin resistance was observed. This may suggest a role for TRIB3 in the development of acute insulin resistance following injury.