Distinct clinical symptom patterns in patients hospitalised with COVID-19 in an analysis of 59,011 patients in the ISARIC-4C study

COVID-19 is clinically characterised by fever, cough, and dyspnoea. Symptoms affecting other organ systems have been reported. However, it is the clinical associations of different patterns of symptoms which influence diagnostic and therapeutic decision-making. In this study, we applied clustering techniques to a large prospective cohort of hospitalised patients with COVID-19 to identify clinically meaningful sub-phenotypes. We obtained structured clinical data on 59,011 patients in the UK (the ISARIC Coronavirus Clinical Characterisation Consortium, 4C) and used a principled, unsupervised clustering approach to partition the first 25,477 cases according to symptoms reported at recruitment. We validated our findings in a second group of 33,534 cases recruited to ISARIC-4C, and in 4,445 cases recruited to a separate study of community cases. Unsupervised clustering identified distinct sub-phenotypes. First, a core symptom set of fever, cough, and dyspnoea, which co-occurred with additional symptoms in three further patterns: fatigue and confusion, diarrhoea and vomiting, or productive cough. Presentations with a single reported symptom of dyspnoea or confusion were also identified, alongside a sub-phenotype of patients reporting few or no symptoms. Patients presenting with gastrointestinal symptoms were more commonly female, had a longer duration of symptoms before presentation, and had lower 30-day mortality. Patients presenting with confusion, with or without core symptoms, were older and had a higher unadjusted mortality. Symptom sub-phenotypes were highly consistent in replication analysis within the ISARIC-4C study. Similar patterns were externally verified in patients from a study of self-reported symptoms of mild disease. The large scale of the ISARIC-4C study enabled robust, granular discovery and replication. Clinical interpretation is necessary to determine which of these observations have practical utility. We propose that four sub-phenotypes are usefully distinct from the core symptom group: gastro-intestinal disease, productive cough, confusion, and pauci-symptomatic presentations. Importantly, each is associated with an in-hospital mortality which differs from that of patients with core symptoms

Age at maturity in cavies and guinea-pigs (Cavia aperea and Cavia aperea f. porcellus): influence of social factors

Trillmich F, Laurien-Kehnen C, Adrian A, Linke S. Age at maturity in cavies and guinea-pigs (Cavia aperea and Cavia aperea f. porcellus): influence of social factors. JOURNAL OF ZOOLOGY. 2006;268(3):285-294.Age at maturity, a particularly important parameter in the life history of small mammals, contributes greatly to fitness. Social influences on age at maturity have been demonstrated for altricial rodents, in particular, mice. Nothing is known about such effects in precocial small mammals. Wild cavies Cavia aperea are born in a highly precocial state and mature early in life, briefly after weaning. We investigated whether the wild cavy C. aperea and the domestic guinea-pig Cavia aperea f. porcellus reach maturity earlier in the presence of adults of the opposite sex. Juvenile females kept in pairs without males showed first vaginal opening (=oestrus) when 59 days old in cavies and at about 40 days in the guinea-pig. However, in the company of adult males, cavy females kept in pairs reached maturity when about 30 days old, and guinea-pig females when 26 days old. Most cavy females experienced successful pregnancy following first vaginal opening. In cavies, female mass at birth and at first oestrus was not correlated with age at first oestrus. In guinea-pigs, birth mass predicted age at maturity only when a male was present. The growth rate from birth to first oestrus related to age at first oestrus. In the wild cavy, the presence of a male appeared to influence maturation more between days 25 and 30 than earlier in life. Male C. aperea matured and had fully descended testes when about 65-70 days old. All male cavies produced abundant motile sperm from day 75. First successful copulations occurred at about the same age. Surprisingly, the priming effect of the presence of an adult male on female maturation proved stronger in these highly precocial caviomorphs than in altricial rodents investigated so far