Patient-reported experience with Fabry disease and its management in the real-world setting: results from a double-blind, cross-sectional survey of 280 respondents.

BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disorder with a heterogeneous clinical presentation. Patients with FD may exhibit early signs/symptoms including neuropathic pain, gastrointestinal complaints, and dermatologic manifestations. FD may ultimately progress to renal, neurologic, and cardiac dysfunction. Current treatments for FD have significantly improved the management and outcomes for patients with FD, but important clinical and convenience limitations still exist. METHODS: To illuminate the impact of FD on daily life from the patient's perspective, we asked adult patients (≥ 18 years old) with FD in the United States and Canada to complete a 33-question online survey to assess patient-reported disease severity, management, and treatment outcomes. RESULTS: A total of 280 respondents with FD completed the survey; they had a mean age of 47 years, and 68% (191/280) were women. Most were currently receiving FD treatment (84%, 234/280) with enzyme replacement therapy (ERT) (89%, 208/234) or chaperone therapy (11%, 26/234). Common symptoms included low energy/fatigue (72%, 201/280), tingling (62%, 174/280) or pain in the hands/feet (60%, 168/280), ringing in ears/hearing loss (54%, 151/280), general body pains/pain crises (51%, 143/280), and abdominal/stomach pain (50%, 140/280). More than half (51%, 144/280) of respondents reported their symptoms as bothersome (38%, 106/280) or difficult to control (14%, 38/280). Temporary symptom worsening between infusions was reported by about half of respondents: 51% (108/211) currently receiving ERT and 48% (14/29) previously receiving ERT. Only 48% (59/122) of respondents reported their symptom worsening to their physician. Of those who reported it, 41% (24/59) said that their physician prescribed medication to manage their symptoms or changed their treatment regimen. CONCLUSIONS: Our analysis highlights the gap between current standard-of-care in disease monitoring and patient perception of disease progression among patients with FD. This information may be helpful for healthcare providers and drug developers seeking to improve the care of patients with FD by addressing unmet needs of high relevance.

Breath Analysis of COVID-19 Patients in a Tertiary UK Hospital by Optical Spectrometry: The E-Nose CoVal Study.

Throughout the SARS-CoV-2 pandemic, diagnostic technology played a crucial role in managing outbreaks on a national and global level. One diagnostic modality that has shown promise is breath analysis, due to its non-invasive nature and ability to give a rapid result. In this study, a portable FTIR (Fourier Transform Infra-Red) spectrometer was used to detect chemical components in the breath from Covid positive symptomatic and asymptomatic patients versus a control cohort of Covid negative patients. Eighty-five patients who had a nasopharyngeal polymerase chain reaction (PCR) test for the detection of SARS-CoV-2 within the last 5 days were recruited to the study (36 symptomatic PCR positive, 23 asymptomatic PCR positive and 26 asymptomatic PCR negative). Data analysis indicated significant difference between the groups, with SARS-CoV-2 present on PCR versus the negative PCR control group producing an area under the curve (AUC) of 0.87. Similar results were obtained comparing symptomatic versus control and asymptomatic versus control. The asymptomatic results were higher than the symptomatic (0.88 vs. 0.80 AUC). When analysing individual chemicals, we found ethanol, methanol and acetaldehyde were the most important, with higher concentrations in the COVID-19 group, with symptomatic patients being higher than asymptomatic patients. This study has shown that breath analysis can provide significant results that distinguish patients with or without COVID-19 disease/carriage.

Prospective, randomised, parallel-group, open-label study to evaluate the effectiveness and safety of IMU-838, in combination with oseltamivir, in adults with COVID-19: the IONIC trial protocol.

BACKGROUND: Globally, there is a scarcity of effective treatments for SARS-CoV-2 infections (causing COVID-19). Repurposing existing medications may offer the best hope for treating patients with COVID-19 to curb the pandemic. IMU-838 is a dihydroorotate dehydrogenase inhibitor, which is an effective mechanism for antiviral effects against respiratory viruses. When used synergistically with oseltamivir, therapeutic effects have been observed against influenza and SARS-CoV-2 in rodents. The IMU-838 and Oseltamivir in the Treatment of COVID-19 (IONIC) trial is a randomised controlled trial that will investigate whether time to clinical improvement in patients with COVID-19 is improved following a 14-day course of IMU-838+oseltamivir versus oseltamivir alone. METHODS: IONIC trial is an open-label study in which participants will be randomised 1:1 in two parallel arms: the intervention arm (IMU-838+oseltamivir) and the control arm (oseltamivir only). The primary outcome is time to clinical improvement; defined as the time from randomisation to a two-point improvement on WHO ordinal scale; discharge from hospital, or death (whichever occurs first). The study is sponsored by the University Hospitals Coventry and Warwickshire NHS Trust and funded by LifeArc. DISCUSSION: The IONIC protocol describes an overarching trial design to provide reliable evidence on the effectiveness of IMU-838 (vidofludimus calcium) when delivered in combination with an antiviral therapy (oseltamivir) (IONIC intervention) for confirmed or suspected COVID-19 infection in adult patients receiving usual standard of care. ETHICS AND DISSEMINATION: This study has been independently reviewed and approved by Wales Research Ethics Committee. In addition, required regulatory approvals were received from Medicines and Healthcare products Regulatory Agency. TRIAL REGISTRATION NUMBER: EudraCT 2020-001805-21, ISRCTN53038326, NCT04516915.

A Qualitative Study: Mothers' Experiences of Their Child's Late-Onset Pompe Disease Diagnosis Following Newborn Screening.

Pompe disease was added to the United States recommended uniform screening panel in 2015 to avoid diagnostic delay and implement prompt treatment, specifically for those with infantile-onset Pompe disease (IOPD). However, most newborns with abnormal newborn screening (NBS) for Pompe disease have late-onset Pompe disease (LOPD). An early diagnosis of LOPD raises the question of when symptoms will arise which is challenging for parents, patients, and providers managing an LOPD diagnosis. This study aimed to characterize mothers' experiences of their child's LOPD diagnosis and medical monitoring. A qualitative descriptive approach was chosen to gain an in-depth understanding of parental experiences. Eight mothers were interviewed about their experiences with positive NBS and diagnosis, experiences with living with the diagnosis, and experiences with medical monitoring. Interview transcripts were analyzed through conventional content analysis. Negative emotions like fear were more frequent with communication of NBS results. Participants expressed uncertainty surrounding age of symptom onset and the future. The medical monitoring experience increased worry but participants expressed that being vigilant with management reassured them. Parental emotions shifted to thankfulness and reassurance with time and education. These findings can provide guidance to providers about the psychosocial implications of receiving positive NBS results and an LOPD diagnosis.

Healthcare Staff Perceptions Following Inoculation with the BNT162b2 mRNA COVID-19 Vaccine at University Hospitals Coventry & Warwickshire NHS Trust.

Background: COVID-19 vaccination programmes offer hope for a potential end to the acute phase of the COVID-19 pandemic. We present perceptions following from a cohort of healthcare staff at the UK NHS hospital, which first initiated the BNT162b2 mRNA COVID-19 ("Pfizer") vaccination program. Methods: A paper-based survey regarding perceptions on the BNT162b2 mRNA COVID-19 vaccine was distributed to all healthcare workers at the University Hospitals Coventry & Warwickshire NHS Trust following receipt of the first vaccine dose. Results: 535 healthcare workers completed the survey, with a 40.9% response rate. Staff felt privileged to receive a COVID-19 vaccine. Staff reported that they had minimised contact with patients with confirmed or suspected COVID-19. Reported changes to activity following vaccination both at work and outside work were guarded. Statistically significant differences were noted between information sources used by staff groups and between groups of different ethnic backgrounds to inform decisions to receive vaccination. Conclusions: NHS staff felt privileged to receive the COVID-19 vaccine, and felt that their actions would promote uptake in the wider population. Concerns regarding risks and side effects existed, but were minimal. This research can be used to help inform strategies driving wider vaccine uptake amongst healthcare staff and the public.

Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial.

BACKGROUND: Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19 (AZD1222), in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older. METHODS: In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18-55 years, 56-69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 1010 virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18-55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56-69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5-6·5 × 1010 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18-55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. FINDINGS: Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18-55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56-69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18-55 years group, 22 (73%) of 30 in the 56-69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18-55 years group, 23 (77%) in the 56-69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18-55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898-33 550], n=39; 56-69 years, 16 170 AU/mL [10 233-40 353], n=26; and ≥70 years 17 561 AU/mL [9705-37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18-55 years, 193 [IQR 113-238], n=39; 56-69 years, 144 [119-347], n=20; and ≥70 years, 161 [73-323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18-55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841-2428], n=24; 56-69 years: 797 SFCs [383-1817], n=29; and ≥70 years: 977 SFCs [458-1914], n=48). INTERPRETATION: ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.

Asymmetric Transcription Factor Partitioning During Yeast Cell Division Requires the FACT Chromatin Remodeler and Cell Cycle Progression.

The polarized partitioning of proteins in cells underlies asymmetric cell division, which is an important driver of development and cellular diversity. The budding yeast Saccharomyces cerevisiae divides asymmetrically, like many other cells, to generate two distinct progeny cells. A well-known example of an asymmetric protein is the transcription factor Ace2, which localizes specifically to the daughter nucleus, where it drives a daughter-specific transcriptional network. We screened a collection of essential genes to analyze the effects of core cellular processes in asymmetric cell division based on Ace2 localization. This screen identified mutations that affect progression through the cell cycle, suggesting that cell cycle delay is sufficient to disrupt Ace2 asymmetry. To test this model, we blocked cells from progressing through mitosis and found that prolonged metaphase delay is sufficient to disrupt Ace2 asymmetry after release, and that Ace2 asymmetry is restored after cytokinesis. We also demonstrate that members of the evolutionarily conserved facilitates chromatin transcription (FACT) chromatin-reorganizing complex are required for both asymmetric and cell cycle-regulated localization of Ace2, and for localization of the RAM network components.

CATS: Cas9-assisted tag switching. A high-throughput method for exchanging genomic peptide tags in yeast.

BACKGROUND: The creation of arrays of yeast strains each encoding a different protein with constant tags is a powerful method for understanding how genes and their proteins control cell function. As genetic tools become more sophisticated there is a need to create custom libraries encoding proteins fused with specialised tags to query gene function. These include protein tags that enable a multitude of added functionality, such as conditional degradation, fluorescent labelling, relocalization or activation and also DNA and RNA tags that enable barcoding of genes or their mRNA products. Tools for making new libraries or modifying existing ones are becoming available, but are often limited by the number of strains they can be realistically applied to or by the need for a particular starting library. RESULTS: We present a new recombination-based method, CATS - Cas9-Assisted Tag Switching, that switches tags in any existing library of yeast strains. This method employs the reprogrammable RNA guided nuclease, Cas9, to both introduce endogenous double strand breaks into the genome as well as liberating a linear DNA template molecule from a plasmid. It exploits the relatively high efficiency of homologous recombination in budding yeast compared with non-homologous end joining. CONCLUSIONS: The method takes less than 2 weeks, is cost effective and can simultaneously introduce multiple genetic changes, thus providing a rapid, genome-wide approach to genetic modification.

Tertiary Pediatric Academic Institution's Experience With Intraoperative Neuromonitoring for Nonspinal Surgery in Children With Mucopolysaccharidosis, Based on a Novel Evidence-Based Care Algorithm.

BACKGROUND: Musculoskeletal deformities in mucopolysaccharidoses (MPSs) patients pose unique challenges when patients present for surgery, especially nonspinal surgery. MPS patients have developed postsurgical neurological deficits after nonspinal surgery. While the incidence of neurological deficits after nonspinal surgery under anesthesia is unknown, accumulating evidence provides impetus to change current practice and increased neurological monitoring in these patients. Intraoperative neurophysiologic monitoring (IONM) with somatosensory evoked potentials (SSEPs) and transcranial motor evoked potentials (TcMEPs) has been implemented at select institutions with varying degree of success. This report describes our experience with IONM in the context of a multidisciplinary evidence-based care algorithm we developed at Cincinnati Children's Hospital Medical Center. METHODS: We conducted a retrospective chart review of the electronic medical record (EPIC), for data from all MPS patients at our institution undergoing nonspinal surgery between September 2016 and March 2018. Patients were identified from IONM logs, which include procedure and patient comorbidities. Data concerning demographics, morbidities, degree of kyphoscoliosis, intraoperative administered medications and vital signs, surgical procedure, the IONM data, duration of surgery, and blood loss were extracted. Descriptive analyses were generated for all variables in the data collected. In addition, any IONM changes noted during the surgeries were identified and factors contributing to the changes described. RESULTS: Thirty-eight patients with a diagnosis of MPS underwent nonspinal surgery, and of those 38, 21 received IONM based on preoperative decision-making according to our care algorithm. Of the 21 patients who received IONM, we were able to get reliable baseline potentials on all patients. Of the 21 patients, 3 had significant neurophysiologic changes necessitating surgical/anesthetic intervention. All of these changes lasted several minutes, and the real-time IONM monitoring was able to capture them as they arose. None of the patients sustained residual neurological deficits. Thus, children who did not fit the criteria for IONM (n = 13) based on our algorithm had 0% incidence of any untoward neurological deficits after surgery (97.5% confidence interval [CI], 00%-25.5%), while 14% (95% CI, 11.5%-30.1%) of children who did fit criteria for IONM and had IONM had significant IONM changes. CONCLUSIONS: Through this case series, we describe our experience with the use of IONM and a novel care algorithm for guiding the anesthetic management of MPS patients undergoing nonspinal surgery. We conclude that they can be useful tools for provision of safe anesthetic care in this high-risk cohort.

Cervical cancer.

Essential facts In the UK in 2013 there were about 3,200 new cases of cervical cancer. It is the 12th most common cancer in UK women, resulting in 890 deaths in 2014. Deaths in England are more common in women living in the most deprived areas.

Comparison of self-collected meatal swabs with urine specimens for the diagnosis of Chlamydia trachomatis and Neisseria gonorrhoeae in men.

PURPOSE: Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) are common bacterial causes of sexually transmitted infections. Self-taken meatal swabs are a possible alternative to urine samples in testing for infection; however, the data surrounding their use are limited. METHODOLOGY: We carried out a prospective service review in a large sexual health clinic comparing urine samples and self-taken meatal swabs in men presenting for sexual transmissible infection screening for CT and GC with the BD Viper XTR system. RESULTS: We found an overall prevalence of 10.5 % for CT infections and 4.2 % for GC infections in our patient population. Meatal swab testing had a sensitivity and specificity of 91 and 99 % with an negative predictive value (NPV) of 99 % and a positive predictive value (PPV) of 96 % for CT testing compared to a sensitivity and specificity of 100 and 99 % with an NPV of 100 % and a PPV of 98 % for urine samples. The sensitivity and specificity of meatal swabs was 100 and 99 %, respectively, for GC detection with an NPV of 100 % and PPV of 89 % compared to urine which had 93 % sensitivity and 99 % specificity with an NPV and PPV of 99 and 93 %, respectively. CONCLUSIONS: Meatal samples were not inferior to urine samples for the detection of CT and GC. Male urethral meatal self-sampling offers an alternative sample type when compared to male urine specimens.

Skin cancer.

Essential facts Skin cancer can be split into 2 groups: malignant melanoma, which can be fatal; and non-melanoma, such as squamous cell carcinoma and basal cell carcinomas, which are rarely lethal. In 2013 there were 14,509 new cases of malignant melanoma in the UK and, in 2014, 2,459 people died from the disease. Non-melanoma skin cancers are more common; 72,100 new cases were diagnosed in the UK in 2013.

Our Commitment to You for End of Life Care.

Essential facts In July the government announced a new commitment to improve end of life care in England in response to What's Important to Me: A Review of Choice in End of Life Care (the Choice Review).

End of life care.

Essential facts In July, the government announced a new commitment to improve end of life care in England in response to What's Important to Me: A Review of Choice in End of Life Care.

Oral health for adults in care homes.

Essential facts It is estimated that more than 400,000 adults live in UK care homes, 80% of whom have dementia. More than half of older people in care homes have tooth decay compared with 40% of over 75s and 33% of over 85s who do not live in care homes. Care home residents are more likely to have fewer natural teeth, and those with teeth are less likely to have enough teeth to eat comfortably and socialise without embarrassment.