An investigation into General Practitioners' experience with Long Covid.

BACKGROUND: Long Covid (LC) is the continuation or development of new symptoms after initial COVID-19 infection. Little is known about General Practitioners' (GP) experience of managing patients with LC. AIMS: The aim of this study is to establish GP experiences with LC. METHODS: A survey was designed and piloted in three training practices prior to distribution. The survey was completed by doctors working in GP training scheme practices in Cork, Ireland. RESULTS: Fifty-three of one hundred and sixty invited GPs completed the survey, indicating a 33% response rate. 8% (4/53) of participants agreed and 0% (0/53) strongly agreed with the statement they were "confident in diagnosing Long Covid". 81% (43/53) were not confident in treating patients with LC. 70% (37/53) were unaware of indications for referral to secondary care. 38% (20/53) were aware of the referral pathways to local LC clinics. 93% (49/53) agreed there were educational deficits regarding LC. CONCLUSIONS: There was a lack of confidence in the diagnosis and management of LC, and in the interface with secondary care. There is demand for educational interventions to assist GPs with their care of patients with this emerging condition.

An investigation into exercise prescription post-COVID-19 pandemic amongst Non-Consultant Hospital Doctors in an acute hospital setting.

BACKGROUND: Being sedentary is an independent risk factor for severe COVID-19 infection, suggesting the important role physical activity (PA) has as a modifiable risk factor for COVID-19 outcome. AIMS: The aim of this study was to evaluate NCHD's exercise prescribing practices and establish how these related to their knowledge, attitudes, and demographics and if their practices had changed since the COVID-19 pandemic began. METHODS: An online survey was emailed to NCHDs working in city centre teaching hospitals in southern Ireland. Using a combination of forced choice items and five-point Likert scales, questions examined NCHD's knowledge, attitudes, and practices of exercise prescription. RESULTS: For education, 30% of participants were able to correctly answer both WHO PA guidelines. 10% agreed that they knew where to refer patients for specialist exercise programs. For attitudes, 100% of participants in this study agreed that PA played a role in the prevention of disease. For practices, 36% of participants did not prescribe exercise at all. No participant strongly agreed with being confident in prescribing exercises. 90% did not increase their exercise prescribing practices since the introduction of pandemic restrictions. CONCLUSIONS: Despite an overall positive attitude towards PA in this study, findings suggest exercise prescribing was not carried out regularly amongst the majority of participants. There was a lack of confidence and knowledge regarding exercise prescribing amongst NCHDs. The majority of NCHDs have not changed their exercise prescribing practices since the COVID-19 pandemic began. Findings suggest there is an urgent need for educational tools and supports to assist doctors with exercise prescribing.

Multi-Omic, Histopathologic, and Clinicopathologic Effects of Once-Weekly Oral Rapamycin in a Naturally Occurring Feline Model of Hypertrophic Cardiomyopathy: A Pilot Study.

Hypertrophic cardiomyopathy (HCM) remains the single most common cardiomyopathy in cats, with a staggering prevalence as high as 15%. To date, little to no direct therapeutical intervention for HCM exists for veterinary patients. A previous study aimed to evaluate the effects of delayed-release (DR) rapamycin dosing in a client-owned population of subclinical, non-obstructive, HCM-affected cats and reported that the drug was well tolerated and resulted in beneficial LV remodeling. However, the precise effects of rapamycin in the hypertrophied myocardium remain unknown. Using a feline research colony with naturally occurring hereditary HCM (n = 9), we embarked on the first-ever pilot study to examine the tissue-, urine-, and plasma-level proteomic and tissue-level transcriptomic effects of an intermittent low dose (0.15 mg/kg) and high dose (0.30 mg/kg) of DR oral rapamycin once weekly. Rapamycin remained safe and well tolerated in cats receiving both doses for eight weeks. Following repeated weekly dosing, transcriptomic differences between the low- and high-dose groups support dose-responsive suppressive effects on myocardial hypertrophy and stimulatory effects on autophagy. Differences in the myocardial proteome between treated and control cats suggest potential anti-coagulant/-thrombotic, cellular remodeling, and metabolic effects of the drug. The results of this study closely recapitulate what is observed in the human literature, and the use of rapamycin in the clinical setting as the first therapeutic agent with disease-modifying effects on HCM remains promising. The results of this study establish the need for future validation efforts that investigate the fine-scale relationship between rapamycin treatment and the most compelling gene expression and protein abundance differences reported here.

Pre-Younger Dryas megafaunal extirpation at Rancho La Brea linked to fire-driven state shift.

The cause, or causes, of the Pleistocene megafaunal extinctions have been difficult to establish, in part because poor spatiotemporal resolution in the fossil record hinders alignment of species disappearances with archeological and environmental data. We obtained 172 new radiocarbon dates on megafauna from Rancho La Brea in California spanning 15.6 to 10.0 thousand calendar years before present (ka). Seven species of extinct megafauna disappeared by 12.9 ka, before the onset of the Younger Dryas. Comparison with high-resolution regional datasets revealed that these disappearances coincided with an ecological state shift that followed aridification and vegetation changes during the Bølling-Allerød (14.69 to 12.89 ka). Time-series modeling implicates large-scale fires as the primary cause of the extirpations, and the catalyst of this state shift may have been mounting human impacts in a drying, warming, and increasingly fire-prone ecosystem.

Subchondral defects resembling osteochondrosis dissecans in joint surfaces of the extinct saber-toothed cat Smilodon fatalis and dire wolf Aenocyon dirus.

Skeletal disease may hamper the behavior of large predators both living and extinct. We investigated the prevalence of osteochondrosis dissecans (OCD), a developmental bone disease affecting the joints, in two Ice Age predators: the saber-toothed cat Smilodon fatalis and dire wolf Aenocyon dirus. As published cases in modern Felidae and wild Canidae are rare, we predicted that subchondral defects resembling OCD would be rare in the extinct predators. We examined limb joints in juvenile and adult S. fatalis: 88 proximal humeri (shoulder), 834 distal femora (stifle), and 214 proximal tibiae. We also examined limb joints in juvenile and adult A. dirus: 242 proximal humeri, 266 distal femora, and 170 proximal tibiae. All specimens are from the Late Pleistocene Rancho La Brea fossil locality in Los Angeles, California, USA. While the Smilodon shoulder and tibia showed no subchondral defects, subchondral defects in the Smilodon femur had a prevalence of 6%; most defects were small (<7mm); and nine adult stifles with defects also showed osteoarthritis. Subchondral defects in the A. dirus femur had a prevalence of 2.6%; most defects were large (>12mm); and five stifles further developed mild osteoarthritis. Subchondral defects in the A. dirus shoulder had a prevalence of 4.5%; most defects were small, and three shoulders developed moderate osteoarthritis. No defects were found in the A. dirus tibia. Contrary to our prediction, we found a high prevalence of subchondral defects in the stifle and shoulder of S. fatalis and A. dirus resembling OCD found in humans and other mammals. As modern dogs affected by OCD are highly inbred, this high prevalence in the fossil taxa may suggest that they experienced inbreeding as they approached extinction. The deep-time history of this disease supports the need for monitoring of animal domestication, as well as conservation, to avoid unexpected surges in OCD under conditions like inbreeding.

Delayed-release rapamycin halts progression of left ventricular hypertrophy in subclinical feline hypertrophic cardiomyopathy: results of the RAPACAT trial.

OBJECTIVE: Feline hypertrophic cardiomyopathy (HCM) remains a disease with little therapeutic advancement. Rapamycin modulates the mTOR pathway, preventing and reversing cardiac hypertrophy in rodent disease models. Its use in human renal allograft patients is associated with reduced cardiac wall thickness. We sought to evaluate the effects of once-weekly delayed-release (DR) rapamycin over 6 months on echocardiographic, biochemical, and biomarker responses in cats with subclinical, nonobstructive HCM. ANIMALS: 43 client-owned cats with subclinical HCM. METHODS: Cats enrolled in this double-blinded, multicentered, randomized, and placebo-controlled clinical trial were allocated to low- or high-dose DR rapamycin or placebo. Cats underwent physical examination, quality-of-life assessment, blood pressure, hematology, biochemistry, total T4, urinalysis, N-terminal pro-B-type natriuretic peptide, and cardiac troponin I at baseline and days 60, 120, and 180. Fructosamine was analyzed at screening and day 180. Echocardiograms were performed at all time points excluding day 120. Outcome variables were compared using a repeated measures ANCOVA. RESULTS: No demographic, echocardiographic, or clinicopathologic values were significantly different between study groups at baseline, confirming successful randomization. At day 180, the primary study outcome variable, maximum LV myocardial wall thickness at any location, was significantly lower in the low-dose DR rapamycin group compared to placebo (P = .01). Oral DR rapamycin was well tolerated with no significant differences in adverse events between groups. CLINICAL RELEVANCE: Results demonstrate that DR rapamycin was well tolerated and may prevent or delay progressive LV hypertrophy in cats with subclinical HCM. Additional studies are warranted to confirm and further characterize these results.

Breathlessness and Respiratory Disability After Kidney Transplantation.

BACKGROUND: Dyspnea is a common symptom in patients with end-stage kidney disease being treated with dialysis. This study aimed to ascertain the level of respiratory disability in patients after kidney transplantation through assessing a cohort of kidney allograft recipients for respiratory compromise and thereby identifying a potential target for therapeutic intervention. METHODS: Kidney transplant recipients who were under active observation in a single tertiary referral center were invited to take part in this prevalence study at the time of clinic follow-up. All patients agreed to take part in the study, which involved completing a Medical Research Council (MRC) dyspnea scale, completing the St George's Respiratory Questionnaire, and performing basic spirometry. An MRC score of ≥2 and/or a forced expiratory volume in 1 second <90% predicted prompted formal clinical assessment by a respiratory physician. RESULTS: This study enrolled 103 patients; 35% of all patients reported breathlessness, and 56% of all patients warranted formal respiratory medicine review. After completion of their investigations, 33 patients were found to have an underlying condition accounting for their symptoms. CONCLUSION: Our study highlights the issues of respiratory disability and breathlessness in patients who have undergone kidney transplantation. Although extensive cardiologic evaluation is performed routinely and can rule out many causes of dyspnea, respiratory assessment is not a preoperative prerequisite. This study could suggest that a formal pulmonological evaluation and basic spirometry should be part of the pretransplant evaluation of the kidney transplant recipient.

Reply to Van Valkenburgh et al.

DeSantis et al. respond to the concerns raised by Van Valkenburgh et al. on their original study.

Causes and Consequences of Pleistocene Megafaunal Extinctions as Revealed from Rancho La Brea Mammals.

The fossils preserved in the Rancho La Brea "tar" seeps in southern California span the past ∼50,000 years and provide a rare opportunity to assess the ecology of predators (e.g., the American lion, sabertooth cats, cougars, dire wolves, gray wolves, and coyotes), including clarifying the causes and consequences of the terminal Pleistocene extinction event. Here, a multi-proxy approach elucidates dietary responses of carnivorans to changing climates and megafaunal extinctions. Using sample sizes that are unavailable anywhere else in the world, including hundreds of carnivoran and herbivore specimens, we clarify the paleobiology of the extinct sabertooth cats and dire wolves-overturning the idea that they heavily competed for similar prey. Canids (especially the dire wolf) consumed prey from more open environments than felids, demonstrating minimal competition for prey throughout the latest Pleistocene and largely irrespective of changing climates, including just prior to their extinction. Coyotes experienced a dramatic shift in dietary behavior toward increased carcass utilization and the consumption of forest resources (prey and/or plant resources) after the terminal Pleistocene megafaunal extinction. Extant predators' ability to effectively hunt smaller prey and/or utilize carcasses may have been a key to their survival, especially after a significant reduction in megafaunal prey resources. Collectively, these data suggest that dietary niches of carnivorans are not always static and can instead be substantially affected by the removal of top predators and abundant prey resources.

Food-dependent exercise-induced reactions: lessons from a 15-year retrospective study.

BACKGROUND: Food-dependent exercise-induced anaphylaxis (FDEIA) is a life-threatening disorder in which the signs and symptoms of anaphylaxis occur if physical exertion occurs within a few hours of exposure to a food. AIMS: The aim of this study was to characterise patients diagnosed with FDEIA and related disorders. METHODS: A retrospective review of electronic clinical data from 2001 to 2016 was carried out. Fifty-seven cases were identified and analysed to establish clinical features, triggering factors and sensitisation patterns. RESULTS: The number of patients per annum diagnosed with FDEIA or related reactions increased from 1 in 2001 to 18 patients in 2016. Sixty-nine percent reported systemic symptoms consistent with anaphylaxis, and 31% had skin manifestations only. In 33% of cases, the level of triggering exercise was mild. Forty-four percent of patients were sensitised to the omega-5-gliadin fraction of wheat. CONCLUSIONS: FDEIA is an increasingly recognised serious allergic disease. The clinical diagnosis is supported by targeted sensitisation testing and molecular-based allergy diagnostics. These tools allow implementation of effective dietary and lifestyle modifications that mitigate against future serious reactions. Given the limited access to physicians with specialist allergy training in Ireland, increased awareness of this condition amongst sports medicine specialists and general physicians is required.

Dental caries in the fossil record: a window to the evolution of dietary plasticity in an extinct bear.

During the late Pleistocene of North America (≈36,000 to 10,000 years ago), saber-toothed cats, American lions, dire wolves, and coyotes competed for prey resources at Rancho La Brea (RLB). Despite the fact that the giant short-faced bear (Arctodus simus) was the largest land carnivoran present in the fauna, there is no evidence that it competed with these other carnivores for prey at the site. Here, for the first time, we report carious lesions preserved in specimens of A. simus, recovered from RLB. Our results suggest that the population of A. simus from RLB was more omnivorous than the highly carnivorous populations from the Northwest. This dietary variation may be a consequence of different competitive pressures.

Attempted DNA extraction from a Rancho La Brea Columbian mammoth (Mammuthus columbi): prospects for ancient DNA from asphalt deposits.

Fossil-bearing asphalt deposits are an understudied and potentially significant source of ancient DNA. Previous attempts to extract DNA from skeletons preserved at the Rancho La Brea tar pits in Los Angeles, California, have proven unsuccessful, but it is unclear whether this is due to a lack of endogenous DNA, or if the problem is caused by asphalt-mediated inhibition. In an attempt to test these hypotheses, a recently recovered Columbian mammoth (Mammuthus columbi) skeleton with an unusual pattern of asphalt impregnation was studied. Ultimately, none of the bone samples tested successfully amplified M. columbi DNA. Our work suggests that reagents typically used to remove asphalt from ancient samples also inhibit DNA extraction. Ultimately, we conclude that the probability of recovering ancient DNA from fossils in asphalt deposits is strongly (perhaps fatally) hindered by the organic compounds that permeate the bones and that at the Rancho La Brea tar pits, environmental conditions might not have been ideal for the general preservation of genetic material.

The clavicles of Smilodon fatalis and Panthera atrox (Mammalia: Felidae) from Rancho La Brea, Los Angeles, California.

The Rancho La Brea collections at the George C. Page Museum in Los Angeles, California, contain the largest single inventory of Smilodon fatalis remains representing virtually every bone in the skeleton. Eighteen clavicles of two distinctive shapes have been recovered from historical and recent excavations at Rancho La Brea. In this study, we identify these specimens to species through comparison of their morphology and morphological variability with clavicles found in modern felids. This study includes a reevaluation of clavicles that have been previously assigned to S. fatalis, which are more likely to be those of Panthera atrox, and the description of pantherine cat clavicles. A previously undescribed sample of clavicles not only includes some of the same pantherine morph but also 10 specimens, herein assigned to S. fatalis, which are morphologically distinctive and significantly smaller than the previously described specimens. In addition, we report unexpected variations between clavicles of Panthera leo and P. tigris: the clavicles of P. leo closely resemble those of the large Rancho La Brea clavicle morph-which presumably belongs to P. atrox-thus supporting a P. leo/P. atrox clade. We report distinctive morphology of the clavicles of Acinonyx jubatus. Possible functional and phylogenic significance of felid clavicles is suggested.