Early Physical Therapist Interventions for Patients With COVID-19 in the Acute Care Hospital: A Case Report Series.

OBJECTIVE: The aim of this case series was to describe the experience of Swiss physical therapists in the treatment of patients with COVID-19 during their acute care hospital stay and to discuss challenges and potential strategies in the clinical management of these patients. METHODS: We report 11 cases of patients with COVID-19 from 5 Swiss hospitals that illustrate the various indications for physical therapy, clinical challenges, potential treatment methods, and short-term response to treatment. RESULTS: Physical therapists actively treated patients with COVID-19 on wards and in the intensive care unit. Interventions ranged from patient education, to prone positioning, to early mobilization and respiratory therapy. Patients were often unstable with quick exacerbation of symptoms and a slow and fluctuant recovery. Additionally, many patients who were critically ill developed severe weakness, postextubation dysphagia, weaning failure, or presented with anxiety or delirium. In this setting, physical therapy was challenging and required specialized and individualized therapeutic strategies. Most patients adopted the proposed treatment strategies, and lung function and physical strength improved over time. CONCLUSION: Physical therapists clearly have a role in the COVID-19 pandemic. Based on our experience in Switzerland, we recommend that physical therapists routinely screen and assess patients for respiratory symptoms and exercise tolerance on acute wards. Treatment of patients who are critically ill should start as soon as possible to limit further sequelae. More research is needed for awake prone positioning and early breathing exercises as well as post-COVID rehabilitation. IMPACT: To date, there are few data on the physical therapist management of patients with COVID-19. This article is among the first to describe the role of physical therapists in the complex pandemic environment and to describe the potential treatment strategies for countering the various challenges in the treatment of these patients.

Length of FMR1 repeat alleles within the normal range does not substantially affect the risk of early menopause.

STUDY QUESTION: Is the length of FMR1 repeat alleles within the normal range associated with the risk of early menopause? SUMMARY ANSWER: The length of repeat alleles within the normal range does not substantially affect risk of early menopause. WHAT IS KNOWN ALREADY: There is a strong, well-established relationship between length of premutation FMR1 alleles and age at menopause, suggesting that this relationship could continue into the normal range. Within the normal range, there is conflicting evidence; differences in ovarian reserve have been identified with FMR1 repeat allele length, but a recent population-based study did not find any association with age at menopause as a quantitative trait. STUDY DESIGN, SIZE, DURATION: We analysed cross-sectional baseline survey data collected at recruitment from 2004 to 2010 from a population-based, prospective epidemiological cohort study of >110 000 women to investigate whether repeat allele length was associated with early menopause. PARTICIPANTS/MATERIALS, SETTING, METHOD: We included 4333 women from the Breakthrough Generations Study (BGS), of whom 2118 were early menopause cases (menopause under 46 years) and 2215 were controls. We analysed the relationship between length of FMR1 alleles and early menopause using logistic regression with allele length as continuous and categorical variables. We also conducted analyses with the outcome age at menopause as a quantitative trait as well as appropriate sensitivity and exploratory analyses. MAIN RESULTS AND THE ROLE OF CHANCE: There was no association of the shorter or longer FMR1 allele or their combined genotype with the clinically relevant end point of early menopause in our main analysis. Likewise, there were no associations with age at menopause as a quantitative trait in our secondary analysis. LIMITATIONS, REASONS FOR CAUTION: Women with homozygous alleles in the normal range may have undetected FMR1 premutation alleles, although there was no evidence to suggest this. We estimate minor dilution of risk of early menopause from the likely inclusion of some women with menopause at over 45 years in the early menopause cases due to age-rounding bias in self-reports. WIDER IMPLICATIONS OF THE FINDINGS: There is no robust evidence in this large study that variation within the normal range of FMR1 repeat alleles influences timing of menopause in the general population, which contradicts findings from some earlier, mainly smaller studies. The FMR1 CGG repeat polymorphism in the normal range is unlikely to contribute to genetic susceptibility to early menopause. STUDY FUNDING/COMPETING INTERESTS: We thank Breast Cancer Now and The Institute of Cancer Research for funding the BGS. The Institute of Cancer Research acknowledges NHS funding to the NIHR Biomedical Research Centre. The study was funded by the Wellcome Trust (grant number 085943). There are no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Blue-Light Inhibition of Listeria monocytogenes Growth Is Mediated by Reactive Oxygen Species and Is Influenced by σB and the Blue-Light Sensor Lmo0799.

UNLABELLED: Listeria monocytogenes senses blue light via the flavin mononucleotide-containing sensory protein Lmo0799, leading to activation of the general stress response sigma factor SigB (σ(B)). In this study, we investigated the physiological response of this foodborne pathogen to blue light. We show that blue light (460 to 470 nm) doses of 1.5 to 2 mW cm(-2) cause inhibition of growth on agar-based and liquid culture media. The inhibitory effects are dependent on cell density, with reduced effects evident when high cell numbers are present. The addition of 20 mM dimethylthiourea, a scavenger of reactive oxygen species, or catalase to the medium reverses the inhibitory effects of blue light, suggesting that growth inhibition is mediated by the formation of reactive oxygen species. A mutant strain lacking σ(B) (ΔsigB) was found to be less inhibited by blue light than the wild type, likely indicating the energetic cost of deploying the general stress response. When a lethal dose of light (8 mW cm(-2)) was applied to cells, the ΔsigB mutant displayed a marked increase in sensitivity to light compared to the wild type. To investigate the role of the blue-light sensor Lmo0799, mutants were constructed that either had a deletion of the gene (Δlmo0799) or alteration in a conserved cysteine residue at position 56, which is predicted to play a pivotal role in the photocycle of the protein (lmo0799 C56A). Both mutants displayed phenotypes similar to the ΔsigB mutant in the presence of blue light, providing genetic evidence that residue 56 is critical for light sensing in L. monocytogenes Taken together, these results demonstrate that L. monocytogenes is inhibited by blue light in a manner that depends on reactive oxygen species, and they demonstrate clear light-dependent phenotypes associated with σ(B) and the blue-light sensor Lmo0799. IMPORTANCE: Listeria monocytogenes is a bacterial foodborne pathogen that can cause life-threatening infections in humans. It is known to be able to sense and respond to visible light. In this study, we examine the effects of blue light on the growth and survival of this pathogen. We show that growth can be inhibited at comparatively low doses of blue light, and that at higher doses, L. monocytogenes cells are killed. We present evidence suggesting that blue light inhibits this organism by causing the production of reactive oxygen species, such as hydrogen peroxide. We help clarify the mechanism of light sensing by constructing a "blind" version of the blue-light sensor protein. Finally, we show that activation of the general stress response by light has a negative effect on growth, probably because cellular resources are diverted into protective mechanisms rather than growth.

Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency.

PURPOSE: Primary ovarian insufficiency before the age of 40 years affects 1% of the female population and is characterized by permanent cessation of menstruation. Genetic causes include FMR1 expansion mutations. Previous studies have estimated mutation prevalence in clinical referrals for primary ovarian insufficiency, but these are likely to be biased as compared with cases in the general population. The prevalence of FMR1 expansion mutations in early menopause (between the ages of 40 and 45 years) has not been published. METHODS: We studied FMR1 CGG repeat number in more than 2,000 women from the Breakthrough Generations Study who underwent menopause before the age of 46 years. We determined the prevalence of premutation (55-200 CGG repeats) and intermediate (45-54 CGG repeats) alleles in women with primary ovarian insufficiency (n = 254) and early menopause (n = 1,881). RESULTS: The prevalence of the premutation was 2.0% in primary ovarian insufficiency, 0.7% in early menopause, and 0.4% in controls, corresponding to odds ratios of 5.4 (95% confidence interval = 1.7-17.4; P = 0.004) for primary ovarian insufficiency and 2.0 (95% confidence interval = 0.8-5.1; P = 0.12) for early menopause. Combining primary ovarian insufficiency and early menopause gave an odds ratio of 2.4 (95% confidence interval = 1.02-5.8; P = 0.04). Intermediate alleles were not significant risk factors for either early menopause or primary ovarian insufficiency. CONCLUSION: FMR1 premutations are not as prevalent in women with ovarian insufficiency as previous estimates have suggested, but they still represent a substantial cause of primary ovarian insufficiency and early menopause.

Common genetic variants are significant risk factors for early menopause: results from the Breakthrough Generations Study.

Women become infertile approximately 10 years before menopause, and as more women delay childbirth into their 30s, the number of women who experience infertility is likely to increase. Tests that predict the timing of menopause would allow women to make informed reproductive decisions. Current predictors are only effective just prior to menopause, and there are no long-range indicators. Age at menopause and early menopause (EM) are highly heritable, suggesting a genetic aetiology. Recent genome-wide scans have identified four loci associated with variation in the age of normal menopause (40-60 years). We aimed to determine whether theses loci are also risk factors for EM. We tested the four menopause-associated genetic variants in a cohort of approximately 2000 women with menopause≤45 years from the Breakthrough Generations Study (BGS). All four variants significantly increased the odds of having EM. Comparing the 4.5% of individuals with the lowest number of risk alleles (two or three) with the 3.0% with the highest number (eight risk alleles), the odds ratio was 4.1 (95% CI 2.4-7.1, P=4.0×10(-7)). In combination, the four variants discriminated EM cases with a receiver operator characteristic area under the curve of 0.6. Four common genetic variants identified by genome-wide association studies, had a significant impact on the odds of having EM in an independent cohort from the BGS. The discriminative power is still limited, but as more variants are discovered they may be useful for predicting reproductive lifespan.

CCAAT/enhancer binding protein alpha, beta and delta gene variants: associations with obesity related phenotypes in the Leeds Family Study.

OBJECTIVE: To identify novel polymorphisms in the genes encoding the transcription factors CCAAT/enhancer binding protein alpha, beta and delta ( CEBPA, CEBPB, CEBPD) and investigate associations between polymorphisms and obesity-related phenotypes. METHODS: Denaturing high-performance liquid chromatography (HPLC) was used to screen for novel gene variants and polymorphisms were genotyped in stored DNA from participants of the Leeds Family Study (537 subjects from 89 families). Genotype and haplotype analyses were carried out in STATA and PBAT, respectively. RESULTS: Twenty-five polymorphisms were identified; 11 in CEBPA, 12 in CEBPB and 2 in CEBPD. Several allelic variants were associated at a nominal 5% level with waist-to-hip ratio (-919G>A in CEBPA, -412G>T and 646C>T in CEBPB), leptin (1558G>A in CEBPA, -1051A>G and 1383T>- in CEBPB) and adiponectin (1382G>T and 1903G>T in CEBPB). Effects of CEBPA and CEBPB allelic variants were independent, but variants within each gene were in linkage disequilibrium. Several associations were observed between other obesity-related traits and allelic variants in CEBPA and CEBPB, but not CEBPD. CONCLUSION: These findings suggest that common allelic variants in CEBPA and CEBPB could influence abdominal obesity and related metabolic abnormalities associated with type 2 diabetes and cardiovascular disease in healthy White Northern European families, although results require independent confirmation.

Intermediate sized CGG repeats are not a common cause of idiopathic premature ovarian failure.

BACKGROUND: It is recognized that FMR1 premutation expansions are associated with premature ovarian failure (POF), but the role of smaller repeats at the boundary of premutation and normal is less clear. METHODS: We have therefore investigated the incidence of these intermediate sized FMR1 CGG repeats (35-58 repeats) in a series of 366 women ascertained because of menopause before the age of 40. RESULTS: We found no significant difference in the incidence of intermediates in cases compared with controls. Thus, we were unable to replicate previous studies showing a positive association, despite a significantly larger sample size. CONCLUSIONS: We therefore conclude that intermediate sized FMR1 CGG repeat alleles should not be considered a high-risk factor for POF based on current evidence.

Benefits of an insulin dosage calculation device for adolescents with type 1 diabetes mellitus.

OBJECTIVE: Multiple daily injection insulin regimens (MDI) and continuous subcutaneous insulin infusion (CSII) allow adolescents with type 1 diabetes mellitus (DM) meal flexibility, and may improve metabolic control. The insulin dosage calculations, however, involve ratios of insulin to carbohydrate and corrections for high blood glucose values, and are labor-intensive and prone to error. We evaluated the impact of an insulin dosage calculation device (IDC) on metabolic control, treatment satisfaction, regimen adherence and quality of life in adolescents using MDI or CSII. RESEARCH DESIGN AND METHODS: We conducted a randomized control trial using the IDC in 83 adolescents on MDI or CSII. At enrollment, patients received training on dosage calculation using either the IDC or conventional methods, and performed sample calculations. At enrollment, 6 months and 12 months, we recorded HbA1c and frequency of hypoglycemia, and patients completed questionnaires assessing treatment satisfaction, regimen adherence and quality of life. After 6 months, patients in the control group were also given the IDC. RESULTS: We observed a higher frequency of errors with conventional calculations (53-67% incorrect calculations) than with the IDC (25-32% incorrect). At 6 months, there was a trend toward improved HbA1c in the IDC group overall (9.3 vs 8.9, p = 0.07) and a significant improvement in the subset (42%) who used the IDC consistently (9.7 vs 8.8, p = 0.03). There was no change in HbA1c in the control group during this interval (9.0 vs 8.9, p = 0.90). During months 6-12, when both groups were combined, there was a significant increase in HbA1c in patients using the IDC inconsistently or not at all (8.9 vs 9.4, p = 0.005), but no change in HbA1c in those using the IDC consistently (9.1 vs 8.9, p = 0.57). Treatment satisfaction, adherence and quality of life improved throughout the study in both groups. CONCLUSIONS: Errors in calculation of insulin dosage by adolescents occur frequently. Consistent use of an insulin dosage calculation device may help to improve metabolic control in adolescents using MDI or CSII.

Genetic variation at the interleukin-1 locus is a determinant of changes in soluble endothelial factors in patients with acute coronary syndromes.

Acute coronary syndromes (ACSs) are associated with both systemic inflammatory activation and endothelial cell activation, and both of these are linked to patient outcome. Genetic variation at the interleukin-1 (IL-1) locus influences the clinical patterns of inflammatory disease. We therefore examined the association between IL-1 gene polymorphisms and levels of systemic inflammatory activation markers [C-reactive protein (CRP) and IL-1 receptor antagonist (IL-1ra)] and of soluble endothelial activation markers [von Willebrand factor (vWF) and E-selectin], in a cohort of 63 patients presenting with non-ST-elevation ACS. The IL-1 locus did not significantly influence any of the markers studied at 24 h after presentation. Associations of IL-1 polymorphisms with the changes (Delta) in CRP, IL-1ra, E-selectin and vWF levels between 24 and 48 h were examined in later studies. Delta CRP and Delta IL-1ra showed no significant association with any of the polymorphisms studied. There was a strong association between carriage of the rare allele (allele 2) of the intron 2 variable number of tandem repeats polymorphism of IL-1RN (designated IL-1RN*2) and Delta E-selectin levels: [carriage of *2, 3.03 ng/ml [95% confidence interval (CI) 6.26 to 1.51 ng/ml]; non-carriage of *2, 0.12 ng/ml (95% CI 1.07 to -1.76 ng/ml); P=0.0016], and also between carriage of IL-1RN*2 and Delta vWF levels [carriage of *2, 0.78 i.u./ml (95% CI 0.96 to 0.44 i.u./ml); non-carriage of *2, 0.1 i.u./ml (95% CI 0.19 to -0.1 i.u./ml); P=0.0003]. A composite analysis consisting of carriage of IL-1RN*2 and the genotype at position -511 in the IL-1B gene suggests the existence of haplotypes that influence Delta vWF and Delta E-selectin in patients with ACS. Carriage of IL-1RN*2 was also associated with a 2-fold increased likelihood of a troponin-positive status compared with non-carriage (P=0.0385). These data indicate that, in the setting of non-ST-elevation ACS, genetic variation at the IL-1 gene locus contributes to the changes in soluble markers of endothelial inflammation.