Inpatient COVID-19 mortality has reduced over time: Results from an observational cohort.

BACKGROUND: The Covid-19 pandemic in the United Kingdom has seen two waves; the first starting in March 2020 and the second in late October 2020. It is not known whether outcomes for those admitted with severe Covid were different in the first and second waves. METHODS: The study population comprised all patients admitted to a 1,500-bed London Hospital Trust between March 2020 and March 2021, who tested positive for Covid-19 by PCR within 3-days of admissions. Primary outcome was death within 28-days of admission. Socio-demographics (age, sex, ethnicity), hypertension, diabetes, obesity, baseline physiological observations, CRP, neutrophil, chest x-ray abnormality, remdesivir and dexamethasone were incorporated as co-variates. Proportional subhazards models compared mortality risk between wave 1 and wave 2. Cox-proportional hazard model with propensity score adjustment were used to compare mortality in patients prescribed remdesivir and dexamethasone. RESULTS: There were 3,949 COVID-19 admissions, 3,195 hospital discharges and 733 deaths. There were notable differences in age, ethnicity, comorbidities, and admission disease severity between wave 1 and wave 2. Twenty-eight-day mortality was higher during wave 1 (26.1% versus 13.1%). Mortality risk adjusted for co-variates was significantly lower in wave 2 compared to wave 1 [adjSHR 0.49 (0.37, 0.65) p<0.001]. Analysis of treatment impact did not show statistically different effects of remdesivir [HR 0.84 (95%CI 0.65, 1.08), p = 0.17] or dexamethasone [HR 0.97 (95%CI 0.70, 1.35) p = 0.87]. CONCLUSION: There has been substantial improvements in COVID-19 mortality in the second wave, even accounting for demographics, comorbidity, and disease severity. Neither dexamethasone nor remdesivir appeared to be key explanatory factors, although there may be unmeasured confounding present.

The Cardiac Genetics Clinic: a model for multidisciplinary genomic medicine.

OBJECTIVES: To describe patient characteristics, standard operating procedure, and uptake of genetic testing at the multidisciplinary Cardiac Genetics Clinic (CGC) at the Royal Melbourne Hospital during its first 6 years. DESIGN: Database exploration of referral diagnoses, sex, number of clinic visits and incidence of genetic testing in a population of individuals attending the CGC. SETTING: Tertiary referral hospital (Royal Melbourne Hospital) providing cardiac genetics services to the state of Victoria. PARTICIPANTS: All individuals initially attending the clinic between July 2007 and July 2013, either as the proband or as an at-risk family member. MAIN OUTCOME MEASURES: Classification of patients into diagnostic categories, number of probands and at-risk relatives assessed, incidence and outcomes of genetic testing. RESULTS: 1170 individuals were seen for the first time over the 6-year period; 57.5% made only one visit. The median age was 39 years. Most were encompassed within four broad diagnostic categories: cardiomyopathy (315 patients), aortopathy (303 patients), arrhythmia disorders (203 patients) and resuscitated cardiac arrest and/or family history of sudden cardiac death (341 patients); eight patients had "other" diagnoses. Genetic testing (mutation detection or predictive testing) was undertaken in 381 individuals (32.6%), and a pathogenic mutation was identified in 47.6% of tests, representing 15.3% of the total population. CONCLUSION: The CGC fulfils an important role in assisting clinicians and patients by reviewing genetic cardiac diagnoses. Clinical practice during the study period moved from a selected candidate gene approach to broader gene panel-based testing. This move to next-generation sequencing may increase the detection of mutations and variants of unknown significance. A major contribution by the clinic to the care of these individuals and their families is the provision (or negating) of a diagnosis, and of a plan for managing risks of predictable cardiac disease.

Multiple skin hamartomata: a possible novel clinical presentation of SUFU neoplasia syndrome.

Medulloblastoma tumours may arise sporadically or as part of an inherited syndrome. A subset of children with medulloblastoma carry germline and somatic mutations in the SUFU tumour suppressor gene located at 10q24. We report a 55 year old woman referred for investigation on the basis of skin lesions and a family history of two children from different unions with medulloblastoma. Examination of our patient revealed facial papules (classified as benign folliculosebaceous hamartomatous lesions) and dysmorphology (macrocephaly, hypertelorism and prognathism). She reported her father and her son share the same dermatological features; photographs of the son display hypertelorism. Sequencing in our patient revealed a splice-site mutation in intron 6 of SUFU (c. 756+1G>A), predicted to lead to skipping of exon 6. We suggest that the emerging phenotype in SUFU associated with familial medulloblastoma may include hamartomatous skin lesions. Consideration of these features, along with macrocephaly will alert clinicians to the likely genetic basis of the syndrome, affording the opportunity for genetic counselling, prenatal or pre-implantation genetic diagnosis in at-risk families.

Interdisciplinary education for genetic counselors: developing the concept and assessing the need in australasia.

Interdisciplinary teams are increasingly common in healthcare as a means of improving patient care and there is consensus in the literature that a formalized framework of interdisciplinary education for health professionals is an advantageous means of professional development. To our knowledge no such application to genetic counseling has been reported. Prompted by limited direct exposure to the oncology processes discussed during genetic counseling sessions, two genetic counselors completed an interdisciplinary education exercise by observing various oncology settings. As intended we gained a deeper understanding of the: (1) Roles of other health professionals within the oncology interdisciplinary team, (2) Patient experience of cancer screening and treatment, and (3) Clinical processes relevant to cancer genetic counselors' discussions. In addition, further benefits resulted from (4) Insight into how patients and referring providers utilize the FCC within wider oncology care and (5) Strengthening of relationships between the FCC and other oncology-related teams. The observation experience and resulting learnings are described in this paper. To investigate wider application of this novel initiative, a survey of Australasian genetic counselors was conducted, finding that genetic counselors mostly source knowledge about oncology procedures through indirect means and that, overall, anecdotal descriptions from patients were the most common information source (74 %). Over 95 % of respondents expected that interdisciplinary observations would be a beneficial part of their professional development and almost 90 % expected the program to be potentially feasible in their workplace. These findings indicate there is a role for interdisciplinary education to be considered as a formal continual learning tool for genetic counselors.

Familial SDHA mutation associated with pituitary adenoma and pheochromocytoma/paraganglioma.

CONTEXT: Reports of the coexistence of pituitary adenomas and pheochromocytoma/paraganglioma are uncommon. Recently germline mutations in 2 of the genes encoding succinate dehydrogenase, SDHC and SDHD, were associated with pituitary tumors. OBJECTIVE: Our aim was to determine whether the development of a pituitary adenoma was associated with SDHA mutation. PATIENTS: A 46-year-old female presented with carotid body paraganglioma (proband). Subsequently the proband's son was diagnosed with a nonfunctioning pituitary macroadenoma at age 30 years. RESULTS: An immunohistochemical analysis of the resected paraganglioma and pituitary adenoma revealed the loss of succinate dehydrogenase subunit B and succinate dehydrogenase subunit A (SDHA) expression in both tumors, with the preservation of staining in nonneoplastic tissue. Mutation analysis showed a novel SDHA mutation (c.1873C>T, p.His625Tyr) in the germline of the proband as well as in the proband's son. In the paraganglioma of the proband, in addition to the germline mutation, a somatic mutation was observed (c.1865G>A, p.Trp622*). In the pituitary adenoma of the proband's son, loss of SDHA immunoreactivity was paradoxically accompanied by loss of the mutant allele. CONCLUSIONS: This is the first report of a pituitary adenoma arising in the setting of germline SDHA mutation. The loss of SDHA protein expression in both the paraganglioma (proband) and pituitary adenoma (proband's son) argues strongly for a causative role of SDHA mutation. This report further strengthens the link between pituitary neoplasia and germline SDH mutation. Although pituitary adenomas appear rare among patients carrying SDH subunit mutations, they may have been underrecognized due to the low penetrance of disease and lack of systematic surveillance.