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Pulmonary nocardiosis is a granulomatous disease with high mortality that affects both immunosuppressed and immunocompetent patients. The mechanisms leading to the establishment and progression of the infection are currently unknown. An animal model to study these mechanisms is sorely needed. We report the first in vivo model of granulomatous pulmonary nocardiosis that closely resembles human pathology. BALB/c mice infected intranasally with two different doses of GFP-expressingNocardia brasiliensisATCC700358 (NbGFP), develop weight loss and pulmonary granulomas. Mice infected with 109CFUs progressed towards death within a week while mice infected with 108CFUs died after five to six months. Histological examination of the lungs revealed that both the higher and lower doses of NbGFP induced granulomas with NbGFP clearly identifiable at the center of the lesions. Mice exposed to 108CFUs and subsequently to 109CFUs were not protected against disease severity but had less granulomas suggesting some degree of protection. Attempts to identify a cellular target for the infection were unsuccessful but we found that bacterial microcolonies in the suspension used to infect mice were responsible for the establishment of the disease. Small microcolonies of NbGFP, incompatible with nocardial doubling times starting from unicellular organisms, were identified in the lung as early as six hours after infection. Mice infected with highly purified unicellular preparations of NbGFP did not develop granulomas despite showing weight loss. Finally, intranasal delivery of nocardial microcolonies was enough for mice to develop granulomas with minimal weight loss. Taken together these results show that Nocardia brasiliensis microcolonies are both necessary and sufficient for the development of granulomatous pulmonary nocardiosis in mice.

Abstract Many protocols have been used in clinical and research settings for collecting systolic blood pressure (SBP) measurements to calculate the ankle–brachial index (ABI); however, it is not known how useful it is to replicate measurements and which measures best reflect cardiovascular risk. Standardized measurements of ankle and arm SBP from 5140 overweight or obese individuals with type 2 diabetes were used to estimate sources of variation. Measurement characteristics of leg-specific ABI, as calculated using a standard algorithm based on the highest SBP of the dorsalis pedis or posterior tibial arteries, were projected using simulations. Coefficients of variability ranged from 2% to 3% when single SBP measurements were used and ABI was overestimated by 2–3%. Taking two SBP measurements at each site reduced standard errors and bias each by 30–40%. The sensitivity of detecting low ABI ranges exceeded 90% for ABI within 0.05 of the 0.90 clinical cut-point. The average and the minimum of the two (i.e. right and left) leg-specific ABI values had similar U-shaped relationships with Framingham risk scores; however, the average leg ABI had slightly greater precision. Replicating SBP measurements reduces the error and bias of ABI. Averaging leg-specific values may increase power for characterizing cardiovascular disease risk.

Loss of cerebral hemodynamic autoregulation plays an important pathophysiological role in brain injury such as stroke.1 It has been shown that the magnitude of vasodilation in the anterior circulation serves as an indirect measure of cerebral autoregulation and that degree of vasoreactivity loss correlates with subsequent risk of stroke in symptomatic and asymptomatic carotid occlusive disease. 2–6 Similar data for the posterior circulation have not been consistent. Some evidence suggests that vertebrobasilar circulation may harbor significantly different autoregulative characteristics which could explain its susceptibility to the posterior reversible leukoencephalopathies, hypertensive encephalopathy, immunosuppressive vasculopathy, and pre-/eclampsia. 7 Our goal was to better characterize the autoregulatory profile of the vertebrobasilar circulation in healthy controls. By simultaneously assessing vasodilatory capacity (CVC) in anterior and posterior circulation, we aimed to establish normative data for the vertebrobasilar system, to compare the two circulations, and to assess for differential contributions of age, gender or blood pressure.

Background Increasingly, genetic specimens are collected to expand the value of clinical trials through study of genetic effects on disease incidence, progression or response to interventions. Purpose and methods We describe the experience obtaining IRB-approved DNA consent forms across the 19 institutions in the Action for Health in Diabetes (Look AHEAD), a clinical trial examining the effect of a lifestyle intervention for weight loss on the risk of serious cardiovascular events among individuals with type 2 diabetes. We document the rates participants provided consent for DNA research, identify participant characteristics associated with consent, and discuss implications for genetics research. Results IRB approval to participate was obtained from 17 of 19 institutions. The overall rate of consent was 89.6% among the 15 institutions that had completed consenting at the time of our analysis, which was higher than reported for other types of cohort studies. Consent rates were associated with factors expected to be associated with weight loss and cardiovascular disease and to affect the distribution of candidate genes. Non-consent occurred more frequently among participants grouped as African-American, Hispanic, female, more highly educated or not dyslipidemic. Limitations The generalizabilty of results is limited by the inclusion/exclusion criteria of the trial. Conclusions Barriers to obtaining consent to participate in genetic studies may differ from other recruitment settings. Because of the potentially complex associations between personal characteristics related to adherence, outcomes and gene distributions, differential rates of consent may introduce biases in estimates of genetic relationships.

Sir .—Friedman et al 1 suggest three different mechanisms to explain the elevated serum iron concentrations found in adolescent alcohol users, the most likely being an enhanced absorption of dietary iron. Alcohol abuse can affect the nutrient status of an individual, eg, by reducing total food intake because of the high energy content of ethanol and by interfering with the absorption and metabolism of specific nutrients. 2,3 The existence of an alcohol-trace metal interaction is known. Alcohol consumption in humans and animals reduces tissue zinc levels because of the diminished intake and intestinal absorption, for example, as well as the increased urinary excretion, of the trace element. 3-8 Severe zinc deficiency in rats is accompanied by a striking elevation of iron concentrations in serum, liver, and other body tissues. 9 Rogers et al 9 have suggested that this effect could explain increased iron absorption and/or increased binding of iron to

The prolonged lockdown of health services providing high-complexity fertility treatments –as currently recommended by many reproductive medicine entities– is detrimental for society as a whole, and infertility patients in particular. Globally, approximately 0.3% of all infants born every year are conceived using assisted reproductive technology (ART) treatments. By contrast, the total number of COVID-19 deaths reported so far represents approximately 1.0% of the total deaths expected to occur worldwide over the first three months of the current year. It seems, therefore, that the number of infants expected to be conceived and born –but who will not be so due to the lockdown of infertility services– might be as significant as the total number of deaths attributed to the COVID-19 pandemic. We herein propose remedies that include a prognostic-stratification of more vulnerable infertility cases in order to plan a progressive restart of worldwide fertility treatments. At a time when preventing complications and limiting burdens for national health systems represent relevant issues, our viewpoint might help competent authorities and health care providers to identify patients who should be prioritized for the continuation of fertility care in a safe environment.

Women with impaired ovarian reserve or poor ovarian response (POR) to exogenous gonadotropin stimulation present a challenge for reproductive specialists. The primary reasons relate to the still limited knowledge about the POR pathophysiology and the lack of practical solutions for the management of these conditions. Indeed, clinical trials using the current standards to define POR failed to show evidence in favor of a particular treatment modality. Furthermore, critical factors for reproductive success, such as the age-dependent embryo aneuploidy rates and the intrinsic ovarian resistance to gonadotropin stimulation, are not taken into consideration by the current POR criteria. As a result, the accepted definitions for POR have been criticized for their inadequacy concerning the proper patient characterization and for not providing clinicians a guide for therapeutic management. A novel system to classify infertility patients with "expected" or "unexpected" inappropriate ovarian response to exogenous gonadotropins-the POSEIDON criteria-was developed to provide a more nuanced picture of POR and to guide physicians in the management of such patients. The new standards are provoking as they challenge the current terminology of POR in favor of the newly defined concept of "low prognosis." This article provides readers a critical appraisal of the existing criteria that standardize the definition of POR and explains the primary reasons for the development of the POSEIDON criteria.

Background: Frailty-related characteristics, such as sarcopenia, malnutrition and cognitive impairment, are often overlooked, both in clinical practice and research, as potential contributors to functional recovery during geriatric rehabilitation. Objective: The aim of the study was to identify frailty-related characteristics associated with functional recovery in a cohort of post-orthopedic surgery and post-stroke older adults. Design: Multi-centric cohort study. Participanst and Settings: Patients over 65 years, admitted to three geriatric rehabilitation units, in Spain and Italy, after an orthopedic event or a stroke, from December 2014 to May 2016. Measurements: The Absolute Functional Gain (AFG) defined as the difference between Barthel Index score at discharge and at admission, and the Relative Functional Gain (RFG) that represents the percentage of recovery of the function lost due to the event, were selected as outcomes. Both outcomes were analyzed as continuous and dichotomous variables. Analyses were also stratified as diagnostic at admission. Results: We enrolled 459 patients (mean age±SD=80.75±8.21 years), 66.2% women, 69.5% with orthopedic conditions and with a length of stay of 28.8±9.1 days. Admission after a stroke (Odds Ratio=0.36, 95% Confidence Interval=0.22-0.59]) and a better functional status at admission (OR=0.96, 95% CI=0.94-0.97), were associated with a lower likelihood of AFG, while a better pre-event Barthel index (OR=1.03 for each point in score, 95% CI=1.01-1.04), being able to walk (OR=2.07, 95% CI=1.16-3.70), and a better cognitive status at admission (OR=1.05, 95% CI=1.01-1.09), were associated with a higher chance of AFG. Post-stroke patients with delirium at admission had a re-duced chance of AFG (OR=0.25, 95% CI=0.07-0.91]). Patients admitted after an orthopedic event with better pre-event functional status (OR=1.04, 95% CI=1.02-1.06) and able to walk at admission (OR=2.79, 95% CI=1.29-6.03]) had an increased chance of AFG. Additionally, in both diagnostics groups, a better handgrip strength increased the chance of RFG. Conclusions: Among frailty-related variables, physical, cognitive and muscular function at admission could be relevant for functional improvement during geriatric reha-bilitation. If confirmed, this data might orient targeted interventions.