Changes in hospital mortality in patients with cancer during the COVID-19 pandemic (ISARIC-CCP-UK): a prospective, multicentre cohort study.

BACKGROUND: Patients with cancer are at greater risk of dying from COVID-19 than many other patient groups. However, how this risk evolved during the pandemic remains unclear. We aimed to determine, on the basis of the UK national pandemic protocol, how factors influencing hospital mortality from COVID-19 could differentially affect patients undergoing cancer treatment. We also examined changes in hospital mortality and escalation of care in patients on cancer treatment during the first 2 years of the COVID-19 pandemic in the UK. METHODS: We conducted a prospective cohort study of patients aged older than 19 years and admitted to 306 health-care facilities in the UK with confirmed SARS-CoV-2 infection, who were enrolled in the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol (CCP) across the UK from April 23, 2020, to Feb 28, 2022; this analysis included all patients in the complete dataset when the study closed. The primary outcome was 30-day in-hospital mortality, comparing patients on cancer treatment and those without cancer. The study was approved by the South Central-Oxford C Research Ethics Committee in England (Ref: 13/SC/0149) and the Scotland A Research Ethics Committee (Ref 20/SS/0028), and is registered on the ISRCTN Registry (ISRCTN66726260). FINDINGS: 177 871 eligible adult patients either with no history of cancer (n=171 303) or on cancer treatment (n=6568) were enrolled; 93 205 (52·4%) were male, 84 418 (47·5%) were female, and in 248 (13·9%) sex or gender details were not specified or data were missing. Patients were followed up for a median of 13 (IQR 6-21) days. Of the 6568 patients receiving cancer treatment, 2080 (31·7%) died at 30 days, compared with 30 901 (18·0%) of 171 303 patients without cancer. Patients aged younger than 50 years on cancer treatment had the highest age-adjusted relative risk (hazard ratio [HR] 5·2 [95% CI 4·0-6·6], p<0·0001; vs 50-69 years 2·4 [2·2-2·6], p<0·0001; 70-79 years 1·8 [1·6-2·0], p<0·0001; and >80 years 1·5 [1·3-1·6], p<0·0001) but a lower absolute risk (51 [6·7%] of 763 patients <50 years died compared with 459 [30·2%] of 1522 patients aged >80 years). In-hospital mortality decreased for all patients during the pandemic but was higher for patients on cancer treatment than for those without cancer throughout the study period. INTERPRETATION: People with cancer have a higher risk of mortality from COVID-19 than those without cancer. Patients younger than 50 years with cancer treatment have the highest relative risk of death. Continued action is needed to mitigate the poor outcomes in patients with cancer, such as through optimising vaccination, long-acting passive immunisation, and early access to therapeutics. These findings underscore the importance of the ISARIC-WHO pandemic preparedness initiative. FUNDING: National Institute for Health Research and the Medical Research Council.

Equity issues rarely addressed in the development of COVID-19 formal recommendations and good practice statements: a cross-sectional study.

BACKGROUND AND OBJECTIVE: To identify COVID-19 actionable statements (e.g., recommendations) focused on specific disadvantaged populations in the living map of COVID-19 recommendations (eCOVIDRecMap) and describe how health equity was assessed in the development of the formal recommendations. METHODS: We employed the place of residence, race or ethnicity or culture, occupation, gender or sex, religion, education, socio-economic status, and social capital-Plus framework to identify statements focused on specific disadvantaged populations. We assessed health equity considerations in the evidence to decision frameworks (EtD) of formal recommendations for certainty of evidence and impact on health equity criteria according to the Grading of Recommendations, Assessment, Development, and Evaluations criteria. RESULTS: We identified 16% (124/758) formal recommendations and 24% (186/819) good practice statements (GPS) that were focused on specific disadvantaged populations. Formal recommendations (40%, 50/124) and GPS (25%, 47/186) most frequently focused on children. Seventy-six percent (94/124) of the recommendations were accompanied with EtDs. Over half (55%, 52/94) of those considered indirectness of the evidence for disadvantaged populations. Considerations in impact on health equity criterion most frequently involved implementation of the recommendation for disadvantaged populations (17%, 16/94). CONCLUSION: Equity issues were rarely explicitly considered in the development COVID-19 formal recommendations focused on specific disadvantaged populations. Guidance is needed to support the consideration of health equity in guideline development during health emergencies.

Energy Metabolism Profile in Individuals with Prader-Willi Syndrome and Implications for Clinical Management: A Systematic Review.

Prader-Willi syndrome (PWS) is a rare genetic disorder associated with excessive weight gain. Hyperphagia associated with PWS may result in higher energy intake, but alterations in energy expenditure may also contribute to energy imbalance. The purpose of this critical literature review is to determine the presence of alterations in energy expenditure in individuals with PWS. Ten studies that measured total energy expenditure (TEE), resting energy expenditure (REE), sleep energy expenditure (SEE), activity energy expenditure (AEE), and diet induced thermogenesis (DIT) were included in this review. The studies provided evidence that absolute TEE, REE, SEE, and AEE are lower in individuals with PWS than in age-, sex-, and body mass index-matched individuals without the syndrome. Alterations in lean body mass and lower physical activity amounts appear to be responsible for the lower energy expenditure in PWS rather than metabolic differences. Regardless of the underlying mechanism for lower TEE, the estimation of energy requirements with the use of equations derived for the general population would result in weight gain in individuals with PWS. The determination of energy requirements for weight management in individuals with PWS requires a more comprehensive understanding of energy metabolism. Future studies should aim to comprehensively profile all specific components of energy expenditure in individuals with PWS with the use of appropriately matched controls and gold standard methods to measure energy metabolism and body composition. One component of energy expenditure that is yet to be explored in detail in PWS is DIT. A reduced DIT (despite differences in fat free mass), secondary to hormonal dysregulation, may be present in PWS individuals, leading to a reduced overall energy expenditure. Further research exploring DIT in PWS needs to be conducted. Dietary energy recommendations for weight management in PWS have not yet been clearly established.

Facilitating Community-Based Exercise for People With Stroke: Cross-Sectional e-Survey of Physical Therapist Practice and Perceived Needs.

BACKGROUND: Educating people with stroke about community-based exercise programs (CBEPs) is a recommended practice that physical therapists are well positioned to implement. OBJECTIVE: The aim of this study was to evaluate the provision of education about CBEPs to people with stroke, barriers to providing education, and preferences for resources to facilitate education among physical therapists in neurological practice. DESIGN: A cross-sectional e-survey of physical therapists treating adults with stroke in Ontario, Canada, was conducted. METHODS: A link to the questionnaire was emailed to physical therapists in a provincial stroke network, a provincial physical therapy association, and on hospital and previous research lists. RESULTS: Responses from 186 physical therapists were analyzed. The percentage of respondents who reported providing CBEP education was 84.4%. Only 36.6% reported typically providing education to ≥7 out of 10 patients with stroke. Physical (90.5%) and preventative (84.6%) health benefits of exercise were most frequently discussed. Therapists reported most commonly delivering education at discharge (73.7%). Most frequently cited barriers to educating patients were a perceived lack of suitable programs (53.2%) and a lack of awareness of local CBEPs (23.8%). Lists of CBEPs (94.1%) or brochures (94.1%) were considered to be facilitators. The percentage of physical therapists providing CBEP education varied across acute, rehabilitation, and public outpatient settings. LIMITATIONS: The percentage of physical therapists providing education may have been overestimated if respondents who deliver CBEP education were more likely to participate and if participants answered in a socially desirable way. CONCLUSIONS: Even though a high proportion of physical therapists provide CBEP education, education is not consistently delivered to the majority of patients poststroke. Although a CBEP list or brochure would facilitate education regarding existing CBEPs, efforts to implement CBEPs are needed to help overcome the lack of suitable programs.

Left ventricular radial colour and longitudinal pulsed-wave tissue Doppler echocardiography in 39 healthy domestic pet rabbits.

This paper reports radial colour and longitudinal mitral annulus pulsed-wave tissue Doppler findings in a large cohort of healthy, adult pet rabbits. Thirty-nine rabbits (22 Dwarf Lops, 14 French Lops and three Alaskans) underwent conscious echocardiography. The median age of the rabbits was 22 months and the median weight was 2.8 kg (Dwarf Lop 2.4 kg/French Lop 6.0 kg). Adequate radial colour and longitudinal pulsed-wave tissue Doppler traces were obtained in 100% and 85% of cases, respectively. Most systolic tissue Doppler parameters were significantly higher in French Lops than in Dwarf Lops. Separation of mitral inflow diastolic waves was present in 40% of cases using conventional spectral Doppler and in >60% of cases using pulsed-wave tissue Doppler which could be beneficial when evaluating diastolic function in rabbits. This study can be used as a reference for normal echocardiographic tissue Doppler values for adult rabbits undergoing conscious echocardiography in clinical practice.

Antinociceptive and selected physiological effects of morphine and xylazine on tiletamine-zolazepam anesthesia in llamas.

OBJECTIVE: Evaluate antinociception, anesthesia, and recovery in llamas given tiletamine-zolazepam (TZ) with either morphine, xylazine, morphine and xylazine, or saline. STUDY DESIGN: Randomized crossover experimental study. ANIMALS: Six healthy, adult intact male llamas. METHODS: Llamas were given each of four treatments intramuscularly with a 1-week washout: TZ (2 mg kg(-1) ) combined with either morphine (0.5 mg kg(-1) ; M), xylazine (0.15 mg kg(-1) ; X), morphine (0.5 mg kg(-1) ) and xylazine (0.15mg kg(-1) ) (MX), or saline (C). Llamas breathed room air during the experiment. Characteristics of anesthesia, recovery, and selected cardiopulmonary variables were recorded. Antinociception was assessed by clamping a claw at 5-minute intervals. Data were analyzed using a mixed-model anova and Tukey-Kramer test, and are expressed as least squares mean ± SEM. Significance was set at p < 0.05. RESULTS: No llama in the control group demonstrated antinociception. Antinociception was longest with treatment MX, followed by treatments X and M, respectively. Heart rates in llamas given treatments X and MX were significantly lower than with other treatments. The respiratory rate in llamas given treatment C was greater (p < 0.05) than for all other treatments, however, the respiratory rate was not significantly different among treatments X, M and MX. The PaO2 for llamas given MX remained <60 mmHg throughout the 20 minute period of blood gas analysis. Mean arterial blood pressure in llamas in treatment MX was less than for treatments M or C. CONCLUSION AND CLINICAL RELEVANCE: The combination of morphine (0.5 mg kg(-1) ) and xylazine (0.15 mg kg(-1) ) increased the duration of antinociception compared with xylazine alone, in TZ-anesthetized llamas. Treatments X, M and MX were associated with hypoxemia (PaO2 < 60 mmHg).

Physiologic and antinociceptive effects following intramuscular administration of xylazine hydrochloride in combination with tiletamine-zolazepam in llamas.

OBJECTIVE: To evaluate antinociceptive and selected effects associated with IM administration of xylazine hydrochloride in combination with tiletamine-zolazepam in llamas. ANIMALS: 8 adult male llamas. Procedures-Each llama received tiletamine-zolazepam (2 mg/kg) combined with either xylazine (0.1, 0.2, or 0.4 mg/kg) or saline (0.9% NaCl) solution IM (treatments designated as TZ-Xy0.1, TZ-Xy0.2, TZ-Xy0.4, and TZ-Sal, respectively) at 1-week intervals. Selected cardiorespiratory variables were assessed during lateral recumbency and anesthesia, and recovery characteristics were recorded. Duration of antinociception was evaluated by clamping a claw every 5 minutes. RESULTS: Interval between treatment administration and lateral recumbency for TZ-Xy0.4 was shorter than that for TZ-Xy0.1 or TZ-Sal. Mean ± SEM duration of antinociception was longer for TZ-Xy0.4 (51.3 ± 7. 0 minutes), compared with findings for TZ-Xy0.2 (31.9 ± 6.0 minutes), TZ-Xy0.1 (8.1 ± 4.0 minutes), and TZ-Sal (0.6 ± 0.6 minutes). Interval between treatment administration and standing was longer for TZ-Xy0.4 (112 ± 9 minutes) than it was for TZ-Xy0.2 (77 ± 9 minutes) or TZ-Sal (68 ± 9 minutes). Mean heart and respiratory rates during the first 30 minutes for TZ-Sal exceeded values for the other treatments. Administration of TZ-Xy0.2 and TZ-Xy0.4 resulted in Pao2 < 60 mm Hg at 5 minutes after llamas attained lateral recumbency, and values differed from TZ-Sal findings at 5, 10, and 15 minutes; Paco2 was greater for TZ-Xy0.2 and TZ-Xy0.4 than for TZ-Sal at 5, 10, 15, and 20 minutes. CONCLUSIONS AND CLINICAL RELEVANCE: Xylazine (0.2 and 0.4 mg/kg) increased the duration of antinociception in llamas anesthetized with tiletamine-zolazepam.

Fetal and postnatal lung defects reveal a novel and required role for Fgf8 in lung development.

The fibroblast growth factor, FGF8, has been shown to be essential for vertebrate cardiovascular, craniofacial, brain and limb development. Here we report that Fgf8 function is required for normal progression through the late fetal stages of lung development that culminate in alveolar formation. Budding, lobation and branching morphogenesis are unaffected in early stage Fgf8 hypomorphic and conditional mutant lungs. Excess proliferation during fetal development disrupts distal airspace formation, mesenchymal and vascular remodeling, and Type I epithelial cell differentiation resulting in postnatal respiratory failure and death. Our findings reveal a previously unknown, critical role for Fgf8 function in fetal lung development and suggest that this factor may also contribute to postnatal alveologenesis. Given the high number of premature infants with alveolar dysgenesis and lung dysplasia, and the accumulating evidence that short-term benefits of available therapies may be outweighed by long-term detrimental effects on postnatal alveologenesis, the therapeutic implications of identifying a factor or pathway that can be targeted to stimulate normal alveolar development are profound.

Effects of domperidone on digital laminar microvascular blood flow in clinically normal adult horses.

OBJECTIVE: To determine effects of domperidone and acepromazine maleate on microvascular blood flow in digital laminae of clinically normal adult horses. ANIMALS: 8 clinically normal adult horses (4 mares and 4 geldings). PROCEDURES: In a 4-period crossover study, domperidone was administered PO at 1.1 mg/ kg and 5.5 mg/kg and IV at 0.2 mg/kg; acepromazine was administered IV at 0.04 mg/kg. The washout period between treatments was 1 week. A 3-minute measurement of laminar microvascular blood flow (LMBF) was obtained with laser Doppler flowmetry. Baseline measurements were obtained at -2, -1, and 0 hours prior to administration of drugs. Post-treatment measurements were obtained at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, and 12 hours. Percentage change from baseline values in LMBF for each treatment was subsequently calculated. RESULTS: Oral administration of domperidone at 1.1 mg/kg and 5.5 mg/kg significantly increased LMBF, compared with baseline values, beginning 4 hours after administration, and this effect persisted for at least 8 hours. Intravenous administration of domperidone at 0.2 mg/kg significantly increased LMBF, compared with baseline values, at 10 and 12 hours after administration. Administration of acepromazine (0.04 mg/kg, IV) significantly increased LMBF, compared with baseline values, at 3, 5, 8, and 10 hours after administration. No adverse effects of drugs were detected in any horse. CONCLUSIONS AND CLINICAL RELEVANCE: Domperidone may be useful for preventing vasoconstriction and reduction in LMBF believed to occur in horses with laminitis, but additional research of the drug's effects in horses with laminitis is required.

Physical and functional interactions between Escherichia coli MutL and the Vsr repair endonuclease.

DNA mismatch repair (MMR) and very-short patch (VSP) repair are two pathways involved in the repair of T:G mismatches. To learn about competition and cooperation between these two repair pathways, we analyzed the physical and functional interaction between MutL and Vsr using biophysical and biochemical methods. Analytical ultracentrifugation reveals a nucleotide-dependent interaction between Vsr and the N-terminal domain of MutL. Using chemical crosslinking, we mapped the interaction site of MutL for Vsr to a region between the N-terminal domains similar to that described before for the interaction between MutL and the strand discrimination endonuclease MutH of the MMR system. Competition between MutH and Vsr for binding to MutL resulted in inhibition of the mismatch-provoked MutS- and MutL-dependent activation of MutH, which explains the mutagenic effect of Vsr overexpression. Cooperation between MMR and VSP repair was demonstrated by the stimulation of the Vsr endonuclease in a MutS-, MutL- and ATP-hydrolysis-dependent manner, in agreement with the enhancement of VSP repair by MutS and MutL in vivo. These data suggest a mobile MutS-MutL complex in MMR signalling, that leaves the DNA mismatch prior to, or at the time of, activation of downstream effector molecules such as Vsr or MutH.