Multiple sclerosis and COVID-19: Assessing risk perception, patient behaviors and access to disease-modifying therapies.

BACKGROUND: Following the outbreak of COVID-19, global healthcare systems have had to rapidly adapt. People with multiple sclerosis (pwMS) were required to make decisions about their individual risk and consequent work and social behaviors. This study aimed to evaluate risk perception and patterns of shielding behavior amongst pwMS at the onset of the COVID-19 pandemic and the subsequent impact on patients' employment and access to disease modifying therapies (DMTs). METHODS: Postal surveys were sent to 1690 people within a UK population-based MS cohort during the first wave of the COVID-19 pandemic. Patients were surveyed on: (i) perceived vulnerability to COVID-19; (ii) isolation behavior; (iii) interruption to DMT; (iv) employment status; (v) level of satisfaction with their current working arrangement. RESULTS: Responses were received from 1000 pwMS. Two thirds of patients reported isolating at home during the first wave of the pandemic. This behavior was associated with increased age (p<0.0001), higher disability (p<0.0001) and use of high-efficacy DMTs (p = 0.02). The majority of patients reported feeling vulnerable (82%) with perceived vulnerability associated with higher EDSS (p<0.0001) and receiving a high-efficacy DMT (p = 0.04). Clinician-defined risk was associated with shielding behavior, with those at high-risk more likely to self-isolate/shield (p<0.0001). Patients on high-efficacy DMTs were more likely to have an interruption to their treatment (50%) during the first wave of the pandemic. Most pwMS experienced a change to their working environment, and most were satisfied with the adjustments. CONCLUSION: This study highlights the risk perception, social behavioral practices and changes to treatment experienced by pwMS during the first wave of the COVID-19 pandemic in a large, well-described UK cohort. The results may help inform management of pwMS during future pandemic waves.

COVID-19 in Multiple Sclerosis: Clinically reported outcomes from the UK Multiple Sclerosis Register.

BACKGROUND: In March 2020, the United Kingdom Multiple Sclerosis Register (UKMSR) established an electronic case return form, designed collaboratively by MS neurologists, to record data about COVID-19 infections in people with MS (pwMS). OBJECTIVES: Examine how hospital admission and mortality are affected by disability, age and disease modifying treatments (DMTs) in people with Multiple Sclerosis with COVID-19. METHODS: Anonymised data were submitted by clinical teams. Regression models were tested for predictors of hospitalisation and mortality outcomes. Separate analyzes compared the first and second 'waves' of the pandemic. RESULTS: Univariable analysis found hospitalisation and mortality were associated with increasing age, male gender, comorbidities, severe disability, and progressive MS; severe disability showed the highest magnitude of association. Being on a DMT was associated with a small, lower risk. Multivariable analysis found only age and male gender were significant. Post hoc analysis demonstrated that factors were significant for hospitalisation but not mortality. In the second wave, hospitalisation and mortality were lower. Separate models of the first and second wave using age and gender found they had a more important role in the second wave. CONCLUSIONS: Features associated with poor outcome in COVID-19 are similar to other populations and being on a DMT was not found to be associated with adverse outcomes, consistent with smaller studies. Once in hospital, no factors were predictive of mortality. Reassuringly, mortality appears lower in the second wave.

Enteral feeding reduces metabolic activity of the intestinal microbiome in Crohn's disease: an observational study.

BACKGROUND/OBJECTIVES: Enteral feeding will induce remission in as many as 80-90% of compliant patients with active Crohn's disease (CD), but its method of action remains uncertain. This study was designed to examine its effects on the colonic microbiome. METHODS/SUBJECTS: Healthy volunteers and patients with CD followed a regimen confined to enteral feeds alone for 1 or 2 weeks, respectively. Chemicals excreted on breath or in faeces were characterised at the start and at the end of the feeding period by gas chromatography/mass spectrometry. RESULTS: One week of feeding in healthy volunteers caused significant changes in stool colour and deterioration in breath odour, together with increased excretion of phenol and indoles on the breath. Feeding for 2 weeks in patients with CD produced significant improvements in symptoms and a decrease in the concentration of C-reactive protein. The faecal concentrations of microbial products, including short-chain fatty acids (SCFAs), and potentially toxic substances, including 1-propanol, 1-butanol and the methyl and ethyl esters of SCFAs, showed significant falls. CONCLUSIONS: A significant change occurs in the production of microbial metabolites after enteral feeding in both healthy volunteers and patients with CD. Many of those detected in CD are toxic and may feasibly lead to the immunological attack on the gut microbiota, which is characteristic of inflammatory bowel disease. The reduction in the production of such metabolites after enteral feeding may be the reason for its effectiveness in CD.

A novel method for the analysis of clinical biomarkers to investigate the effect of diet on health in a rat model.

Experiments into the relationship between diet and health have been an area of high interest for a long time. In this study, we investigate the application of multivariate data analysis to differentiate between rat populations fed on two different diets: normal rat diet (control) and Western affluent diet (WAD). Two sets of data were acquired and analysed: one from a biochemical clinical analyser, taking measurements of blood-based biochemical markers; the other from the analysis of the volatile organic compounds (VOCs) emitted from faecal samples from the same animals using selected ion flow tube mass spectrometry (SIFT-MS). Five classes were considered: weanlings, 12 month controls, 12 month WADs, 18 month controls, and 18 month WADs. Data from the biochemical analyser, weanlings and 18 month WAD fed rats showed significant differences from the other measurement classes. This was shown in both the exploratory analysis and through multivariate classification. Classification of control diet versus WAD diets suggested there are differences between classes with 92% accuracy for the 12 month classes and 91% for the 18 month classes. Cholesterol markers, especially as low density lipoprotein-cholesterol (LDL), were the main factor in influencing WAD samples. The data from the SIFT-MS analysis also produced very good classification accuracies. Classification of control diet versus WAD diets using the H3O(+) precursor ion data suggested there are differences between classes with 71% accuracy for the 12 month classes and 100% for the 18 month classes. These findings confirm that total cholesterol and LDL-cholesterol are elevated in the 18 month WAD-fed rats. We therefore suggest that the analysis of VOCs from faecal samples in conjunction with multivariate data analysis may be a useful alternative to blood analysis for the detection of parameters of health.

Pyridinium crosslinks excretion in patients with rheumatoid arthritis. Correlation with disease activity and glucocorticoid treatment.

In patients with rheumatoid arthritis, significant positive correlations were found between urinary pyridinium crosslinks and C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and articular index. Also an inverse correlation was observed between pyridinium crosslinks excretion and grip strength. Glucocorticoid therapy, equivalent to daily doses of 7.5 mg of prednisolone or less, did not appear to have deleterious effect on bone metabolism in these patients as measured by urinary pyridinium crosslinks.

Identification of a major determinant of mouse neurovirulence of dengue virus type 2 using stably cloned genomic-length cDNA.

A genomic-length cDNA clone corresponding to the RNA of dengue virus type 2 (DEN-2) New Guinea C strain (NGC) was constructed in a low copy number vector. The cloned cDNA was stably propagated in Escherichia coil and designated pDVWS501. RNA transcripts produced in vitro from the cDNA using T7 RNA polymerase yielded infectious virus (MON501) upon electroporation into BHK-21 cells. When compared with parental NGC virus, MON501 replicated to similar levels in Aedes albopictus C6/36 cells and showed similar neurovirulence in suckling mice. In contrast, a second genomic-length cDNA clone (pDVWS310) used as an intermediate in the construction of pDVWS501 produced virus (MON310) that replicated well in C6/36 cells but was not neurovirulent in mice. MON310 contained the prM and E genes of the non-neurovirulent PUO-218 strain in an NGC background. There were seven amino acid differences between the prM and E proteins of MON310 and MON501. The differences were generally conservative, with the exception of E residue 126, which was Glu in MON310 and Lys in MON501. To examine the role of this residue in mouse neurovirulence, substitutions of Glu --> Lys and Lys --> Glu were made in MON310 and MON501, respectively. The properties of these mutants clearly demonstrated that Lys at E residue 126 is a major determinant of DEN-2 mouse neurovirulence.

Molecular characterization of Camberwell virus and sequence variation in ORF3 of small round-structured (Norwalk-like) viruses.

Five small round-structured viruses (SRSVs) associated with gastroenteritis in Victoria, Australia, from January to November 1994 were examined by sequencing cDNA prepared from faecal samples using RT-PCR. The sequence of the 3' half (3.8 kb) of the genome of one of these viruses, Camberwell, was determined. Camberwell virus was related most closely to Bristol and Lordsdale viruses, and belonged to the genetic group of SRSVs containing Bristol, Lordsdale, Toronto, OTH-25, Mexico, and Hawaii viruses. The amino acid identities between Camberwell and Bristol viruses for proteins encoded by ORF1 (partial), ORF2, and ORF3 were 99%, 98%, and 90%, respectively. A highly variable region in ORF3 corresponding to amino acid residues 123 to 169 (Bristol and Camberwell numbering) were identified. Short segments of ORF1 (polymerase region) and the highly variable ORF3 region was analysed for the other four viruses. The results obtained indicated the potential usefulness of the variable region in distinguishing between closely related viruses.

Screening for ovarian cancer using serum CA125 and vaginal examination: report on 2550 females.

This study was undertaken to assess the effectiveness of using serum CA125 and vaginal examination as a screening test for ovarian cancer in apparently healthy females. Two thousand five hundred and fifty healthy females aged 40 and over were recruited to participate in a screening study involving a questionnaire, serum CA125 measurement and vaginal examination. Females with either an elevated CA125 level or abnormal vaginal examination had a pelvic ultrasound performed as a secondary procedure. The positive predictive values of an elevated serum CA125 level, and a combination of CA125 level measurement and vaginal examination for ovarian cancer, were 1/100 and 1/3, respectively. The specificities of serum CA125 levels, vaginal examination and both in combination were 96.1%, 98.5% and 99.9%, respectively. In postmenopausal females the positive predictive values were improved with CA125 measurement alone, giving a positive predictive value of 1/24. Seventeen females underwent operative procedure as a result of the screening-only one of these was for an ovarian cancer. The combination of serum CA125 measurement and vaginal examination is not an effective screening test in the general population, although in postmenopausal females it does achieve acceptable specificities and positive predictive values.

Predictive factors in recurrent spontaneous aborters--a multicenter study.

PROBLEM: Compare data from several centers relating to success rates in recurrent spontaneous miscarriage and assess the significance of indicators of subsequent pregnancy loss. METHOD: Data from 777 couples with unexplained recurrent spontaneous abortion from independent studies at seven centers were analyzed using logistic regression analysis. The following covariates were considered: age of patient, number of previous spontaneous abortions, length of previous abortions history, sub-fertility index (defined as the product of the number of spontaneous abortions and the abortion history), whether a patient was a primary or secondary aborter, and whether a patient had received leukocyte immunotherapy. RESULTS: There was a highly significant difference between the seven centers in success rates in the subsequent pregnancy and a highly significant association between success rate and each of the following covariates: the number of previous abortions, the length of the previous abortion history and the sub-fertility index. In particular, for each increase of 10 units in the value of the sub-fertility index, up to a value of 30, the odds in favor of a successful pregnancy decreased by a factor of 0.6, i.e., 40%. There was, however, little evidence of an association between the success rate in the subsequent pregnancy and age, parity, or immunization with cells from the husband. CONCLUSIONS: The sub-fertility index may be a useful measure of likelihood of success in a subsequent pregnancy.

Reference ranges for haematology parameters in pregnancy derived from patient populations.

Reference ranges for several haematology parameters in pregnancy were determined by the mathematical detection of Gaussian and Gamma distributions in partitioned but unselected patient data. For each trimester, red cell parameters were shown to be well described by Gaussian distributions. Platelet and white cell parameters were best described by Gamma distributions with the exception of eosinophil and basophil counts for which neither distribution was applicable. The reference ranges derived for each trimester are compared.

DNA methylation patterns of the gamma delta beta-globin genes in human fetal and adult erythroid tissues.

An investigation of the correlation between the gamma----beta-globin switch and DNA methylation was carried out. The restriction patterns obtained with methylation-sensitive and -insensitive enzymes indicated hypomethylation in the promoter region of the gamma-globin genes in fetal liver DNA but high methylation of the same region in all other samples (except in the presence of an elevated erythroblast count or leukemia). All samples appeared to be partially hypomethylated at the 5' end of the delta-globin gene and hypomethylated at the 3' region of the beta-globin gene. Although consistent with a role for DNA methylation in globin gene regulation, the results also suggest that other factors besides methylation may be required for regulation of the level of expression, and switching of the globin genes.

DNA polymorphisms of the human CD46 gene in fetal and adult tissues.

DNA polymorphisms of the CD46 gene were investigated using a full length cDNA probe and five different restriction enzymes in genomic DNA samples from human fetal tissues and adult peripheral blood leukocytes. A HindIII polymorphism was observed and was classed as Types I, II and III at a ratio of approximately 3.5:2:1, depending on the presence or absence of two polymorphic fragments of 4.5 and 2.0 kb. No variation of polymorphic distribution was evident between the fetal and adult samples. Whether variation in CD46 expression between maternal and fetal tissue is relevant to fetal viability in pregnancy remains to be established.

Predictors of pregnancy success in repeated miscarriage.

Factors that may have a bearing on subsequent pregnancy success or failure in patients with recurrent abortion were examined in 165 women with a history of three or more consecutive miscarriages in the first trimester. The overall success rate was 67.9%. Factors that were found to correlate significantly with success rate were length of abortion history, total number of abortions, interval from last miscarriage to present pregnancy, and whether there was any degree of subfertility. Logistic regression analysis showed that the abortion x years index and maternal age accounted for all the variation observed in our data. Where all other known causes of abortions are excluded, recurrent aborters can be subdivided into two populations--namely, those with a relatively good prognosis characterized by a short abortion history and absence of subfertility problems, compared to those with a poor prognosis namely those with a long abortion history or presence of subfertility problems. These data clearly demonstrate major differences in success rates in women depending on the number of abortions and the length of abortion history (abortion x year index), particularly in women over the age of 30 years.

The sensitivity of cell-associated dengue virus proteins to trypsin and the detection of trypsin-resistant fragments of the nonstructural glycoprotein NS1.

Extracts of Vero cells infected with dengue virus type 2 were digested by trypsin in the presence and absence of detergents. The experiments were designed to test the models proposed for flavivirus translation in which the glycoproteins prM, E, and NS1 are inserted into the endoplasmic reticulum of the cell, whereas certain other nonstructural proteins are not. Viral polypeptides were detected by the use of radiolabel, by immunoprecipitation, or by immunoblotting. The results obtained for NS3 and NS5 were as predicted by the models, with membranes providing no protection against digestion by trypsin. Similarly, the results obtained for prM and E were consistent with the models, with membranes protecting against proteolysis. Some molecules of NS1 were protected, while others were sensitive to proteolysis; novel trypsin-resistant fragments of 69,000, 60,000, and 50,000 Mr (all heat-labile), and of 37,000 and 24,000 Mr were detected following treatment of cell extracts with various combinations of trypsin, detergent, and reducing agent. Preliminary experiments suggested that these tryptic fragments are potentially useful in mapping the antigenic epitopes of NS1.

Treatment of recurrent aborters by immunization with paternal cells--controlled trial.

A paired sequential trial was undertaken to establish whether paternal mononuclear cells improved the prognosis in couples with recurrent abortions. For this purpose, 10(7)-10(8) cells obtained from the blood of partners were injected intravenously, subcutaneously, and intra-dermally into women who had had three or more consecutive miscarriages with the same partner. Control women were given normal saline, injected in the same manner. The result of the sequential analysis showed that there was no significant beneficial effect of the cells compared to control. The overall success rate was 70% (32/46 couples). The success rate in patients given cells was 62% (13/21), while in those given saline it was 76% (19/25). While the overall success rate in this study compares with a number of other studies, we find an equally high success rate with non-immunized patients. We conclude that the value of immunization for the prevention of recurrent miscarriage has not been established.

Uterine sarcoma: steroid receptors and response to hormonal therapy.

Seventy-three patients with uterine sarcomas were treated between 1976 and 1987. Steroid receptors were analyzed in 60 cases; 48% were estrogen receptor (ER) positive, and 30% progesterone receptor (PR) positive. Only 1 of 28 patients with residual or recurrent disease showed a response to hormonal therapy. Neither receptor status of the primary tumor nor use of adjuvant hormonal therapy affected survival.