Effects of periodic breathing on sleep at high altitude: a randomized, placebo-controlled, crossover study using inspiratory CO2.

Hypoxia at high altitude facilitates changes in ventilatory control that can lead to nocturnal periodic breathing (nPB). Here, we introduce a placebo-controlled approach to prevent nPB by increasing inspiratory CO2 and used it to assess whether nPB contributes to the adverse effects of hypoxia on sleep architecture. In a randomized, single-blinded, crossover design, 12 men underwent two sojourns (three days/nights each, separated by 4 weeks) in hypobaric hypoxia corresponding to 4000 m altitude, with polysomnography during the first and third night of each sojourn. During all nights, subjects' heads were encompassed by a canopy retaining exhaled CO2 , and CO2 concentration in the canopy (i.e. inspiratory CO2 concentration) was controlled by adjustment of fresh air inflow. Throughout the placebo sojourn inspiratory CO2 was ≤0.2%, whereas throughout the other sojourn it was increased to 1.76% (IQR, 1.07%-2.44%). During the placebo sojourn, total sleep time (TST) with nPB was 54.3% (37.4%-80.8%) and 45.0% (24.5%-56.5%) during the first and the third night, respectively (P = 0.042). Increased inspiratory CO2 reduced TST with nPB by an absolute 38.1% (28.1%-48.1%), the apnoea-hypopnoea index by 58.1/h (40.1-76.1/h), and oxygen desaturation index ≥3% by 56.0/h (38.9.1-73.2/h) (all P < 0.001), whereas it increased the mean arterial oxygen saturation in TST by 2.0% (0.4%-3.5%, P = 0.035). Increased inspiratory CO2 slightly increased the percentage of N3 sleep during the third night (P = 0.045), without other effects on sleep architecture. Increasing inspiratory CO2 effectively prevented hypoxia-induced nPB without affecting sleep macro-architecture, indicating that nPB does not explain the sleep deterioration commonly observed at high altitudes. KEY POINTS: Periodic breathing is common during sleep at high altitude, and it is unclear how this affects sleep architecture. We developed a placebo-controlled approach to prevent nocturnal periodic breathing (nPB) with inspiratory CO2 administration and used it to assess the effects of nPB on sleep in hypobaric hypoxia. Nocturnal periodic breathing was effectively mitigated by an increased inspiratory CO2 fraction in a blinded manner. Prevention of nPB did not lead to relevant changes in sleep architecture in hypobaric hypoxia. We conclude that nPB does not explain the deterioration in sleep architecture commonly observed at high altitude.

Cerebral blood flow regulation in hypobaric hypoxia: role of haemoconcentration.

During acute hypoxic exposure, cerebral blood flow (CBF) increases to compensate for the reduced arterial oxygen content (CaO2). Nevertheless, as exposure extends, both CaO2 and CBF progressively normalize. Haemoconcentration is the primary mechanism underlying the CaO2 restoration and may therefore explain, at least in part, the CBF normalization. Accordingly, we tested the hypothesis that reversing the haemoconcentration associated with extended hypoxic exposure returns CBF towards the values observed in acute hypoxia. Twenty-three healthy lowlanders (12 females) completed two identical 4-day sojourns in a hypobaric chamber, one in normoxia (NX) and one in hypobaric hypoxia (HH, 3500 m). CBF was measured by ultrasound after 1, 6, 12, 48 and 96 h and compared between sojourns to assess the time course of changes in CBF. In addition, CBF was measured at the end of the HH sojourn after hypervolaemic haemodilution. Compared with NX, CBF was increased in HH after 1 h (P = 0.001) but similar at all later time points (all P > 0.199). Haemoglobin concentration was higher in HH than NX from 12 h to 96 h (all P < 0.001). While haemodilution reduced haemoglobin concentration from 14.8 ± 1.0 to 13.9 ± 1.2 g·dl-1 (P < 0.001), it did not increase CBF (974 ± 282 to 872 ± 200 ml·min-1; P = 0.135). We thus conclude that, at least at this moderate altitude, haemoconcentration is not the primary mechanism underlying CBF normalization with acclimatization. These data ostensibly reflect the fact that CBF regulation at high altitude is a complex process that integrates physiological variables beyond CaO2. KEY POINTS: Acute hypoxia causes an increase in cerebral blood flow (CBF). However, as exposure extends, CBF progressively normalizes. We investigated whether hypoxia-induced haemoconcentration contributes to the normalization of CBF during extended hypoxia. Following 4 days of hypobaric hypoxic exposure (corresponding to 3500 m altitude), we measured CBF before and after abolishing hypoxia-induced haemoconcentration by hypervolaemic haemodilution. Contrary to our hypothesis, the haemodilution did not increase CBF in hypoxia. Our findings do not support haemoconcentration as a stimulus for the CBF normalization during extended hypoxia.

Prediction of general practice licensure/certification examination performance by a measure of 'questionable' activities in clinical practice: a retrospective cohort study.

PURPOSE: 'Low-value' clinical care and medical services are 'questionable' activities, being more likely to cause harm than good or with disproportionately low benefit relative to cost. This study examined the predictive ability of the QUestionable In Training Clinical Activities Index (QUIT-CAI) for general practice (GP) registrars' (trainees') performance in Australian GP Fellowship examinations (licensure/certification examinations for independent GP). METHODS: The study was nested in ReCEnT, an ongoing cohort study in which Australian GP registrars document their in-consultation clinical practice. Outcome factors in analyses were individual registrars' scores on the three Fellowship examinations ('AKT', 'KFP', and 'OSCE' examinations) and pass/fail rates during 2012-21. Analyses used univariable and multivariable regression (linear or logistic, as appropriate). The study factor in each analysis was 'QUIT-CAI score percentage'-the percentage of times a registrar performed a QUIT-CAI clinical activity when 'at risk' (i.e. when managing a problem where performing a QUIT-CAI activity was a plausible option). RESULTS: A total of 1265, 1145, and 553 registrars sat Applied Knowledge Test, Key Features Problem, and Objective Structured Clinical Exam examinations, respectively. On multivariable analysis, higher QUIT-CAI score percentages (more questionable activities) were significantly associated with poorer Applied Knowledge Test scores (P = .001), poorer Key Features Problem scores (P = .003), and poorer Objective Structured Clinical Exam scores (P = .005). QUIT-CAI score percentages predicted Royal Australian College of General Practitioner exam failure [odds ratio 1.06 (95% CI 1.00, 1.12) per 1% increase in QUIT-CAI, P = .043]. CONCLUSION: Performing questionable clinical activities predicted poorer performance in the summative Fellowship examinations, thereby validating these examinations as measures of actual clinical performance (by our measure of clinical performance, which is relevant for a licensure/certification examination).

'Low-value' clinical care in general practice: a cross-sectional analysis of low-value care in early-career GPs' practice.

Nonevidence-based and 'low-value' clinical care and medical services are 'questionable' clinical activities that are more likely to cause harm than good or whose benefit is disproportionately low compared with their cost. This study sought to establish general practitioner (GP), patient, practice, and in-consultation associations of an index of key nonevidence-based or low-value 'questionable' clinical practices. The study was nested in the Registrar Clinical Encounters in Training study-an ongoing (from 2010) cohort study in which Australian GP registrars (specialist GP trainees) record details of their in-consultation clinical and educational practice 6-monthly. The outcome factor in analyses, performed on Registrar Clinical Encounters in Training data from 2010 to 2020, was the score on the QUestionable In-Training Clinical Activities Index (QUIT-CAI), which incorporates recommendations of the Australian Choosing Wisely campaign. A cross-sectional analysis used negative binomial regression (with the model including an offset for the number of times the registrar was at risk of performing a questionable activity) to establish associations of QUIT-CAI scores. A total of 3206 individual registrars (response rate 89.9%) recorded 406 812 problems/diagnoses where they were at risk of performing a questionable activity. Of these problems/diagnoses, 15 560 (3.8%) involved questionable activities being performed. In multivariable analyses, higher QUIT-CAI scores (more questionable activities) were significantly associated with earlier registrar training terms: incidence rate ratios (IRRs) of 0.91 [95% confidence interval (CI) 0.87, 0.95] and 0.85 (95% CI 0.80, 0.90) for Term 2 and Term 3, respectively, compared to Term 1. Other significant associations of higher scores included the patient being new to the registrar (IRR 1.27; 95% CI 1.12, 1.45), the patient being of non-English-speaking background (IRR 1.24; 95% CI 1.04, 1.47), the practice being in a higher socioeconomic area decile (IRR 1.01; 95% CI 1.00, 1.02), small practice size (IRR 1.05; 95% CI 1.00, 1.10), shorter consultation duration (IRR 0.99 per minute; 95% CI 0.99, 1.00), and fewer problems addressed in the consultation (IRR 0.84; 95% CI 0.79, 0.89) for each additional problem]. Senior registrars' clinical practice entailed less 'questionable' clinical actions than junior registrars' practice. The association of lower QUIT-CAI scores with a measure of greater continuity of care (the patient not being new to the registrar) suggests that continuity should be supported and facilitated during GP training (and in established GPs' practice).

Hypobaric hypoxia and cardiac baroreflex sensitivity in young women.

We sought to determine the effects of prolonged moderate hypobaric hypoxia (HH) on cardiac baroreflex sensitivity (cBRS) in young women and whether these effects are a consequence of the reduced arterial oxygen (O2) tension and/or increased pulmonary ventilation in HH. We hypothesized that HH would reduce cBRS and that this effect would be counteracted by acute restoration of the inspiratory partial pressure of O2 ([Formula: see text]) and/or voluntary attenuation of pulmonary ventilation. Twelve healthy women (24.0 ± 4.2 yr) were studied before (day 0) and twice during a sojourn in a hypobaric chamber (∼8 h, day 1; 4 days, day 4) where barometric pressure corresponded to ∼3,500-m altitude. Minute ventilation (V̇e; pneumotachometer), heart rate (electrocardiogram), and arterial pressure (finger volume clamp method) were recorded. cBRS was calculated using transfer function analysis between systolic pressure and RR interval. Assessments were made during 1) spontaneous breathing and (in HH only), 2) controlled breathing (reducing V̇e by ∼1 to 2 L/min), and 3) breathing a hyperoxic gas mixture that normalized [Formula: see text]. During spontaneous breathing, HH decreased cBRS (12.5 ± 7.1, 8.9 ± 4.4, and 7.4 ± 3.0 ms/mmHg on days 0, 1, and 4, respectively; P = 0.018). The normalization of [Formula: see text] increased cBRS (10.6 ± 3.3 and 10.7 ± 6.1 ms/mmHg on days 1 and 4) in HH compared with values observed during spontaneous breathing (P < 0.001), whereas controlled breathing had no effect on cBRS (P = 0.708). These findings indicate that ongoing arterial chemoreflex activation by the reduced arterial O2 tension, independently of the hypoxic ventilatory response, reduces cBRS in young women exposed to extended HH.NEW & NOTEWORTHY We examined the effects of prolonged hypobaric hypoxia (corresponding to ∼3,500-m altitude) on cardiac baroreflex sensitivity (cBRS) in young women and investigated underlying mechanisms. We found that cBRS was reduced in hypoxia and that this reduction was attenuated by acute restoration of inspiratory oxygen partial pressure but not by volitional restraint of pulmonary ventilation. These findings help to elucidate the role of arterial chemoreflex mechanisms in the control of cBRS during hypobaric hypoxia in young women.

Hypoxia briefly increases diuresis but reduces plasma volume by fluid redistribution in women.

We have recently reported that hypobaric hypoxia (HH) reduces plasma volume (PV) in men by decreasing total circulating plasma protein (TCPP). Here, we investigated whether this applies to women and whether an inflammatory response and/or endothelial glycocalyx shedding could facilitate the TCCP reduction. We further investigated whether acute HH induces a short-lived diuretic response that was overlooked in our recent study, where only 24-h urine volumes were evaluated. In a strictly controlled crossover protocol, 12 women underwent two 4-day sojourns in a hypobaric chamber: one in normoxia (NX) and one in HH equivalent to 3,500-m altitude. PV, urine output, TCPP, and markers for inflammation and glycocalyx shedding were repeatedly measured. Total body water (TBW) was determined pre- and postsojourns by deuterium dilution. PV was reduced after 12 h of HH and thereafter remained 230-330 mL lower than in NX (P < 0.0001). Urine flow was 45% higher in HH than in NX throughout the first 6 h (P = 0.01) but lower during the second half of the first day (P < 0.001). Twenty-four-hour urine volumes (P ≥ 0.37) and TBW (P ≥ 0.14) were not different between the sojourns. TCPP was lower in HH than in NX at the same time points as PV (P < 0.001), but inflammatory or glycocalyx shedding markers were not consistently increased. As in men, and despite initially increased diuresis, HH-induced PV contraction in women is driven by a loss of TCPP and ensuing fluid redistribution, rather than by fluid loss. The mechanism underlying the TCPP reduction remains unclear but does not seem to involve inflammation or glycocalyx shedding.NEW & NOTEWORTHY This study is the first to investigate the mechanisms underlying plasma volume (PV) contraction in response to hypoxia in women while strictly controlling for confounders. PV contraction in women has a similar time course and magnitude as in men and is driven by the same mechanism, namely, oncotically driven redistribution rather than loss of fluid. We further report that hypoxia facilitates an increase in diuresis, that is, however, short-lived and of little relevance for PV regulation.

HE4 and CA125 serum biomarker monitoring in women with epithelial ovarian cancer.

BACKGROUND: CA125 is the gold standard serum biomarker for monitoring patients with epithelial ovarian cancer (EOC). Human epididymal protein 4 (HE4) is a novel serum biomarker for EOC patients. OBJECTIVE: The objective of this trial was to examine the utility of measuring serum HE4 levels for monitoring EOC patients and to compare HE4 performance parameters to serum CA125. METHODS: A retrospective trial using residual longitudinal serum samples drawn during treatment and monitoring from EOC patients. Serum CA125 and HE4 levels were analyzed at each time point, and a velocity of change was calculated and correlated with clinical status. The null hypothesis was that HE4 is inferior to CA125, and this was tested using concordance and two-sided Fisher's exact testing. McNemar's test was used to assess the overall agreement of the two assays with the clinical status. RESULTS: A total of 129 patients with 272 separate clinical periods and 1739 events (serum samples) were evaluated. Using a 25% change in serum biomarker levels to indicate change in disease status, the accuracy and NPV determined for HE4 versus CA125 were 81.8% versus 82.6% (p = 0.846) and 87.4% versus 89.7% (p = 0.082), respectively. Concordance comparison of HE4 accuracy / CA125 accuracy was 0.990, indicating HE4 was not inferior to CA125 (McNemar's test p-value = 0.522). Performing a velocity of change analysis, the accuracy and NPV determined for HE4 versus CA125 were 78.3% versus 78.6% (p = 0.995) and 74.9% versus 76.3% (p = 0.815), respectively. Concordance comparison of HE4 velocity accuracy / CA125 velocity accuracy was 0.996, again indicating HE4 was not inferior to CA125 (McNemar's test p-value = 0.884). The combination of HE4 and CA125 velocity changes showed a similar accuracy of 81.3% (p = 0.797 compared to HE4 and CA125 alone) and NPV of 81.1% (p≥0.172 compared to HE4 and CA125 alone), and an increased sensitivity of 70.5% (p≤0.070 compared to HE4 and CA125 alone). CONCLUSION: HE4 is equivalent to CA125 for monitoring of EOC patients. The combination of CA125 and HE4 velocities is superior to either marker alone.

Expanding narratives of governance constraints to improve coral reef conservation.

To understand and address the failures of reef governance, it is critical to understand the perceptions of diverse policy makers and practitioners about the challenges they face in achieving their goals. Examining the discourse of policy makers and practitioners can reveal the extent to which these perceptions capture the full spectrum of potential governance challenges, including those related to management, institutional structures and processes, the values and principles underpinning governance, and the social and environmental context. We conducted semistructured interviews with 110 policy makers and practitioners across multiple sectors, scales, and contexts in Barbados, St Kitts and Nevis, Belize, and Honduras. We used thematic qualitative analysis informed by theories of interactive governance and governability to examine the challenges perceived by governance actors. Perceived governance challenges were broadly consistent across countries, but differed by sector (V = 0.819, F6,60 = 1.502, p = 0.01) and by level (community compared with national) (V = 0.194, F1,10 = 2.178, = 0.026). Management inputs and outputs, challenges relating to the socioeconomic context, issues of leadership and power, and stakeholder engagement were commonly cited challenges (>75%). Few respondents discussed challenges relating to the ecological context, governance processes, or the values and principles underpinning governance. We argue that examining perceptions can inform efforts to improve governance and assess the appropriateness of particular management tools under context-specific governance constraints. Furthermore, expanding the narratives of governance challenges to encompass the subtle values and images underpinning governance, and the scale of the challenges faced, can help identify a wider set of opportunities for change.

Expansión de las Narrativas de los Límites de la Gobernanza para Mejorar la Conservación de los Arrecifes de Coral Resumen Es muy importante entender las percepciones que tienen los practicantes y los formuladores de políticas sobre los retos que enfrentan para alcanzar sus objetivos para poder entender y abordar los fracasos en la gobernanza de los arrecifes. El análisis del discurso de los formuladores y los practicantes puede revelar la extensión a la que estas percepciones capturan el espectro completo de los retos potenciales para la gobernanza, incluidos aquellos relacionados con el manejo, las estructuras y los procesos institucionales, los valores y principios que apuntalan la gobernanza y el contexto social y ambiental. Realizamos entrevistas semiestructuradas a 110 formuladores y practicantes de múltiples sectores, escalas y contextos en Barbados, San Cristóbal y Nieves, Belice y Honduras. Usamos un análisis cualitativo temático informado por las teorías de la gobernanza interactiva y la gobernabilidad para examinar los retos percibidos por los actores de gobernanza. A grandes rasgos, los retos percibidos en la gobernanza fueron coherentes entre los países, pero difirieron por sector (V = 0.819, F6,60 = 1.502, p = 0.01) y por nivel (comunitario comparado con nacional) (V = 0.194, F1,10 = 2.178, = 0.026). Las aportaciones y producciones del manejo, los retos relacionados con el contexto socioeconómico, los temas de liderazgo y poder y la participación de los actores fueron los retos mencionados comúnmente (>75%). Pocos respondientes discutieron los retos relacionados con el contexto ecológico, los procesos de gobernanza o los valores y principios que apuntalan la gobernanza. Alegamos que el análisis de las percepciones puede guiar a los esfuerzos para mejorar la gobernanza y evaluar cuán apropiadas son las herramientas particulares de manejo bajo los límites de gobernanza específicos al contexto. Además, expandir las narrativas de los retos de gobernanza para englobar los valores e imágenes sutiles que apuntalan la gobernanza, y la escala del reto al que se enfrenta, puede ayudar a identificar un conjunto más amplio de oportunidades de cambio.

Successful use of carbon dioxide laser surgery as an adjunctive treatment for feline herpesvirus-1 dermatitis in two cheetahs (Acinonyx jubatus).

Carbon dioxide (CO2 ) lasers are used for a variety of soft tissue procedures. This report describes their use in dermatitis associated with feline herpesvirus-1 (FHV) in two cheetahs. To the best of the authors' knowledge, this is the first report describing CO2 laser use to adjunctively treat FHV-associated skin lesions.

Les lasers au dioxyde de carbone (CO2) sont utilisés pour une variété de procédures sur les tissus mous. Ce rapport décrit leur utilisation dans la dermatite associée à l'herpèsvirus félin-1 (FHV) chez deux guépards. À la connaissance des auteurs, il s'agit du premier article décrivant l'utilisation du laser CO2 pour traiter de manière complémentaire les lésions cutanées associées au FHV.

Los láseres de dióxido de carbono (CO2 ) se utilizan para una variedad de procedimientos de tejidos blandos. Este informe describe su uso en la dermatitis asociada con el herpesvirus felino-1 (FHV) en dos guepardos. A entender de los autores, este es el primer informe que describe el uso del láser de CO2 para tratar de forma complementaria las lesiones cutáneas asociadas con infección con FHV.

Lasers de dióxido de carbono (CO2 ) são utilizados em uma grande variedade de procedimentos de tecidos moles. Este relato descreve a sua utilização na dermatite associada ao herpesvírus felino (HVF)-1 em duas chitas. De acordo com o conhecimento dos autores, este é o primeiro relato descrevendo a utilização do laser de CO2 no tratamento adjunto de lesões cutâneas associadas o HVF.

Regulation of plasma volume in male lowlanders during 4 days of exposure to hypobaric hypoxia equivalent to 3500 m altitude.

KEY POINTS: Acclimatization to hypoxia leads to a reduction in plasma volume (PV) that restores arterial O2 content. Findings from studies investigating the mechanisms underlying this PV contraction have been controversial, possibly as experimental conditions were inadequately controlled. We examined the mechanisms underlying the PV contraction evoked by 4 days of exposure to hypobaric hypoxia (HH) in 11 healthy lowlanders, while strictly controlling water intake, diet, temperature and physical activity. Exposure to HH-induced an ∼10% PV contraction that was accompanied by a reduction in total circulating protein mass, whereas diuretic fluid loss and total body water remained unchanged. Our data support an oncotically driven fluid redistribution from the intra- to the extravascular space, rather than fluid loss, as the mechanism underlying HH-induced PV contraction. ABSTRACT: Extended hypoxic exposure reduces plasma volume (PV). The mechanisms underlying this effect are controversial, possibly as previous studies have been confounded by inconsistent experimental conditions. Here, we investigated the effect of hypobaric hypoxia (HH) on PV in a cross-over study that strictly controlled for diet, water intake, physical activity and temperature. Eleven males completed two 4-day sojourns in a hypobaric chamber, one in normoxia (NX) and one in HH equivalent to 3500 m altitude. PV, urine output, volume-regulating hormones and plasma protein concentration were determined daily. Total body water (TBW) was determined at the end of both sojourns by deuterium dilution. Although PV was 8.1 ± 5.8% lower in HH than in NX after 24 h and remained ∼10% lower thereafter (all P < 0.002), no differences were detected in TBW (P = 0.17) or in 24 h urine volumes (all P > 0.23). Plasma renin activity and circulating aldosterone were suppressed in HH during the first half of the sojourn (all P < 0.05) but thereafter similar to NX, whereas no differences were detected for copeptin between sojourns (all P > 0.05). Markers for atrial natriuretic peptide were higher in HH than NX after 30 min (P = 0.001) but lower during the last 2 days (P < 0.001). While plasma protein concentration was similar between sojourns, total circulating protein mass (TCP) was reduced in HH at the same time points as PV (all P < 0.03). Despite transient hormonal changes favouring increased diuresis, HH did not enhance urine output. Instead, the maintained TBW and reduced TCP support an oncotically driven fluid redistribution into the extravascular compartment as the mechanism underlying PV contraction.

Plasma volume contraction reduces atrial natriuretic peptide after four days of hypobaric hypoxia exposure.

We investigated whether low arterial oxygen tension ([Formula: see text]) or hypoxia-induced plasma volume (PV) contraction, which reduces central blood volume (BV) and atrial distension, explain reduction in circulating atrial natriuretic peptide (ANP) after prolonged hypoxic exposure. Ten healthy males were exposed for 4 days to hypobaric hypoxia corresponding to an altitude of 3,500 m. PV changes were determined by carbon monoxide rebreathing. Venous plasma concentrations of midregional proANP (MR-proANP) were measured before and at the end of the exposure. At the latter time point, the measurement was repeated after 1) restoration of [Formula: see text] by breathing a hyperoxic gas mixture for 30 min and 2) restoration of BV by fluid infusion. Correspondingly, left ventricular end-diastolic volume (LVEDV), left atrial area (LAA), and right atrial area (RAA) were determined by ultrasound before exposure and both before and after fluid infusion at the end of the exposure. Hypoxic exposure reduced MR-proANP from 37.9 ± 18.5 to 24.5 ± 10.3 pmol/L (P = 0.034), LVEDV from 107.4 ± 33.5 to 91.6 ± 26.3 mL (P = 0.005), LAA from 15.8 ± 4.9 to 13.3 ± 4.2 cm2 (P = 0.007), and RAA from 16.2 ± 3.1 to 14.3 ± 3.5 cm2 (P = 0.001). Hyperoxic breathing did not affect MR-proANP (24.8 ± 12.3 pmol/L, P = 0.890). Conversely, fluid infusion restored LVEDV, LAA, and RAA to near-baseline values (108.0 ± 29.3 mL, 17.2 ± 5.7 cm2, and 17.2 ± 3.1 cm2, respectively, P > 0.05 vs. baseline) and increased MR-proANP to 29.5 ± 13.3 pmol/L (P = 0.010 vs. preinfusion and P = 0.182 vs. baseline). These findings support that ANP reduction in hypoxia is at least partially attributed to plasma volume contraction, whereas reduced [Formula: see text] does not seem to contribute.

Deprescribing in older patients by early-career general practitioners: Prevalence and associations.

RATIONALE AND AIMS: Deprescribing is the health-professional-supervised process of withdrawal of an inappropriate medication to manage polypharmacy and improve patient outcomes. Given the harms of polypharmacy and associated inappropriate medicines, practitioners, especially general practitioners (GPs), are encouraged to take a proactive role in deprescribing in older patients. While trial evidence for benefits of deprescribing is accumulating, there is currently little epidemiologic evidence of clinicians' (including GPs') deprescribing behaviours. We aimed to establish the prevalence and explore associations of deprescribing of inappropriate medicines by early-career GPs. METHODS: A cross-sectional analysis of the ReCEnT study of GP registrars' in-consultation experience, 2016-18. Participants recorded 60 consecutive consultations, three times at 6-month intervals, including medicines ceased (our measure of deprescribing). The outcome was deprescribing of an inappropriate medicine (defined by a synthesis of three accepted classification systems) in patients 65 years or older. Logistic regression determined the associations of deprescribing inappropriate medicines. RESULTS: One thousand one hundred and thirteen registrars reported 19 581 consultations with patients 65 years and older. Inappropriate medicines were deprescribed in 2.6% (95% CIs 2.4%-2.9%) of consultations. Of deprescribed medicines, 43% had been prescribed for three months or longer. Most commonly deprescribed were opioids (19%), proton pump inhibitors (9.2%), anti-inflammatory drugs (9.0%), statins (7.8%), and antidepressants (6.6%). The most common reason for deprescribing was: "no longer indicated" (38%). Significant adjusted associations of deprescribing included patients identifying as Aboriginal or Torres Strait Islander (OR 2.86); continuity-of-care (ORs 0.71 and 0.20 for the patient being new to practice and to the registrar, respectively); inner-regional compared to major-city location (OR 1.33); the problem/diagnosis being chronic (OR 1.90); and longer consultations (OR 1.03 per minute increase in duration). CONCLUSION: These findings will have important implications for the education of GPs in deprescribing as a clinical skill.

Retrospective analysis of ocular disease in a population of captive pteropodid bats, 2003-2020.

OBJECTIVE: To perform retrospective analysis of captive pteropodid bats presented to the University of Florida for ocular or adnexal disease from 2003-2020. ANIMALS STUDIED: Twenty-four individuals from seven species were included. PROCEDURES: Records were analyzed for disease process, methods of treatment, and surgical techniques and complications. RESULTS: The most frequently reported abnormality was corneal disease (79%), followed by cataracts (54%), and uveitis (42%). Corneal disease was primarily attributed to either trauma or exposure keratitis secondary to buphthalmia. The majority of uveitis appeared to be lens-induced. Five cases (21%) of glaucoma were reported, all of which accompanied lens luxation. Of the seven enucleations performed, six had post-operative complications (85.7%), including swelling at the surgical site, seroma formation, and bacterial infection. There was no significant relationship between age and trauma, age and cataract formation, sex and trauma, or species and cataract formation. CONCLUSIONS: The most common underlying cause of ocular pathology in these cases was trauma. While the bats tolerated topical and systemic treatment well, individual temperament must be taken into account when developing treatment plans, and prevention of injury is the most effective management strategy.

Barriers to prescribing of long-acting reversible contraception (LARC) by general practitioner registrars: A cross-sectional questionnaire.

Long-acting reversible contraception (LARC) is highly effective but uptake in Australia is low. We aimed to establish general practitioner (GP) registrars' (vocational trainees') perspectives on barriers to prescribing LARC. We conducted a cross-sectional questionnaire-based study of 191 GP registrars in NSW and ACT. Outcome factors were levels of agreement with eight barriers to prescribing LARC. We found the most-reported barriers to prescribing LARC were limited access to training and limited opportunities to maintain skills. Registrars perceived greater barriers to the use of intrauterine devices, compared to contraceptive implants, regarding indemnity insurance, difficulty accessing training, and insufficient insertion opportunities to maintain skills.

Prescribing of long-acting reversible contraception by general practice registrars across different rural regions of Australia: A cross-sectional analysis of the Registrar Clinical Encounters in Training Study data.

OBJECTIVE: To describe the pattern of prescribing long-acting reversible contraception by Australian general practitioner registrars across different classifications of rurality/urbanicity. METHODS: A study nested within the Registrar Clinical Encounters in Training ongoing cohort study of Australian general practitioner registrars' in-consultation experience. DESIGN: A cross-sectional analysis of Registrar Clinical Encounters in Training data collected 2010-2017. Type of contraception prescribed by general practitioner registrars to women aged 12-55 for contraception-related indications was documented. Chi-square statistical analysis was performed to assess association of specific long-acting reversible contraception methods with rurality/urbanicity. SETTING/PARTICIPANTS: General practitioner registrars enrolled in the Australian General Practice Training program in regional training providers/organisations participating in Registrar Clinical Encounters in Training. MAIN OUTCOME MEASURES: Long-acting reversible contraception was defined as etonogestrel implant, copper intrauterine device, levonorgestrel intrauterine device and medroxyprogesterone injection. RESULTS: In all 1737 registrars recorded 4073 registrar rounds of data from 2010 to 2017 (response rate 96%). Type of long-acting reversible contraception prescribed differed significantly across Australian Statistical Geography Standards classification of rurality (Pearson's χ2  = 17, P = .002). Women living in outer regional/remote/very remote regions are prescribed proportionately more medroxyprogesterone injection and less levonorgestrel intrauterine device compared to major cities/inner regional areas. CONCLUSIONS: Long-acting reversible contraception methods prescribed differ across different classifications of rurality. Women living in more rural/remote regions might have access difficulties for the levonorgestrel intrauterine device.

Endothelial function and shear stress in hypobaric hypoxia: time course and impact of plasma volume expansion in men.

High-altitude exposure typically reduces endothelial function, and this is modulated by hemoconcentration resulting from plasma volume contraction. However, the specific impact of hypobaric hypoxia independent of external factors (e.g., cold, varying altitudes, exercise, diet, and dehydration) on endothelial function is unknown. We examined the temporal changes in blood viscosity, shear stress, and endothelial function and the impact of plasma volume expansion (PVX) during exposure to hypobaric hypoxia while controlling for external factors. Eleven healthy men (25 ± 4 yr, mean ± SD) completed two 4-day chamber visits [normoxia (NX) and hypobaric hypoxia (HH; equivalent altitude, 3,500 m)] in a crossover design. Endothelial function was assessed via flow-mediated dilation in response to transient (reactive hyperemia; RH-FMD) and sustained (progressive handgrip exercise; SS-FMD) increases in shear stress before entering and after 1, 6, 12, 48, and 96 h in the chamber. During HH, endothelial function was also measured on the last day after PVX to preexposure levels (1,140 ± 320 mL balanced crystalloid solution). Blood viscosity and arterial shear stress increased on the first day during HH compared with NX and remained elevated at 48 and 96 h (P < 0.005). RH-FMD did not differ during HH compared with NX and was unaffected by PVX despite reductions in blood viscosity (P < 0.05). The stimulus-response slope of increases in shear stress to vasodilation during SS-FMD was preserved in HH and increased by 44 ± 73% following PVX (P = 0.023). These findings suggest that endothelial function is maintained in HH when other stressors are absent and that PVX improves endothelial function in a shear-stress stimulus-specific manner.NEW & NOTEWORTHY Using a normoxic crossover study design, we examined the impact of hypobaric hypoxia (4 days; altitude equivalent, 3,500 m) and hemoconcentration on blood viscosity, shear stress, and endothelial function. Blood viscosity increased during the hypoxic exposure and was accompanied by elevated resting and exercising arterial shear stress. Flow-mediated dilation stimulated by reactive hyperemia and handgrip exercise was preserved throughout the hypoxic exposure. Plasma volume expansion reversed the hypoxia-associated hemoconcentration and selectively increased handgrip exercise flow-mediated dilation.

KSHV-TK is a tyrosine kinase that disrupts focal adhesions and induces Rho-mediated cell contraction.

Paradoxically, the thymidine kinase (TK) encoded by Kaposi sarcoma-associated herpesvirus (KSHV) is an extremely inefficient nucleoside kinase, when compared to TKs from related herpesviruses. We now show that KSHV-TK, in contrast to HSV1-TK, associates with the actin cytoskeleton and induces extensive cell contraction followed by membrane blebbing. These dramatic changes in cell morphology depend on the auto-phosphorylation of tyrosines 65, 85 and 120 in the N-terminus of KSHV-TK. Phosphorylation of tyrosines 65/85 and 120 results in an interaction with Crk family proteins and the p85 regulatory subunit of PI3-Kinase, respectively. The interaction of Crk with KSHV-TK leads to tyrosine phoshorylation of this cellular adaptor. Auto-phosphorylation of KSHV-TK also induces a loss of FAK and paxillin from focal adhesions, resulting in activation of RhoA-ROCK signalling to myosin II and cell contraction. In the absence of FAK or paxillin, KSHV-TK has no effect on focal adhesion integrity or cell morphology. Our observations demonstrate that by acting as a tyrosine kinase, KSHV-TK modulates signalling and cell morphology.

Early-life Chronic Stressors, Rumination, and the Onset of Vulvodynia.

INTRODUCTION: Vulvodynia is a debilitating, chronic vulvar pain condition. Community-based case-control studies have consistently shown associations between early-life chronic stressors and vulvodynia onset. AIM: We examined rumination as a specific stress response involved in the psychobiological mechanism of vulvodynia. METHODS: A psychosocial survey with questions specific to early-life traumatic events and rumination were administered to 185 matched case-control pairs of women with and without vulvodynia. Conditional logistic regression was used to examine associations between rumination constructs (ie, total rumination, emotion-focused, instrumental, and searching for meaning) and vulvodynia onset. Conditional logistic regression was also used to determine whether these associations depended on early-life stressors (ie, severity of childhood abuse and of self-reported antecedent traumatic events). Age at interview, antecedent pain disorders, any childhood abuse, and antecedent psychiatric morbidity were included as covariates. MAIN OUTCOME MEASURES: We estimated the odds of rumination in relation to the onset of vulvodynia within a community-based and clinically confirmed sample of women with and without vulvodynia. RESULTS: Vulvodynia was associated with the highest tertile of emotion-focused (odds ratio [OR] = 2.1; 95% CI = 1.2, 3.2) and instrumental (OR = 2.1; 95% CI = 1.1, 4.0) rumination. These associations were attenuated after additional adjustment for antecedent psychiatric morbidity. Among women who reported rumination about early-life stressors before vulvar pain in cases or matched reference age in control subjects, those with vulvodynia were >2 times more likely to report the highest tertile of total rumination (OR = 2.3; 95% CI = 1.1, 5.0) compared with those without vulvodynia. CLINICAL IMPLICATIONS: Healthcare providers may be able to identify subsets of women who could benefit from preventive measures before the development of vulvodynia. STRENGTH & LIMITATIONS: This is the first study to use a community-based and clinically confirmed sample of women with and without vulvodynia to examine the associations between rumination about early-life trauma and the onset of vulvodynia. However, as with all retrospective studies, the reporting of information (eg, traumatic events) was subject to recall bias and misclassification. CONCLUSION: Our findings indicate that a prolonged cognitive stress response (ie, rumination) may be 1 important mechanism by which early-life chronic stressors contribute to the onset vulvodynia. Prospective studies are recommended to examine whether and how cognitive, affective, and physiological components of prolonged stress responses interact to influence the development of vulvodynia. Understanding both the psychobiological and behavioral mechanisms may help in addressing and treating individuals to potentially reverse the development of vulvodynia. Khandker M, Brady SS, Rydell SA, et al. Early-life Chronic Stressors, Rumination, and the Onset of Vulvodynia. J Sex Med 2019;16:880-890.

Infraorbital Keratin Cyst in an Umbrella Cockatoo (Cacatua alba).

A 10-year-old, female umbrella cockatoo (Cacatua alba) was presented for evaluation of a mass at the right commissure of the beak, with associated right periorbital swelling. A feather cyst was suspected, based on history and the results of a computed tomography scan and fine-needle aspirate. The cyst was surgically debrided and removed. Histopathologic results confirmed an infraorbital keratin cyst, most likely originating from a feather follicle. To our knowledge, this is the first reported case of a periorbital keratin cyst in a bird.

Isolated psychosis during exposure to very high and extreme altitude - characterisation of a new medical entity.

BACKGROUND: Psychotic episodes during exposure to very high or extreme altitude have been frequently reported in mountain literature, but not systematically analysed and acknowledged as a distinct clinical entity. METHODS: Episodes reported above 3500 m altitude with possible psychosis were collected from the lay literature and provide the basis for this observational study. Dimensional criteria of the Diagnostic and Statistical Manual of Mental Disorders were used for psychosis, and the Lake Louise Scoring criteria for acute mountain sickness and high-altitude cerebral oedema (HACE). Eighty-three of the episodes collected underwent a cluster analysis to identify similar groups. Ratings were done by two independent, trained researchers (κ values 0.6-1).FindingsCluster 1 included 51% (42/83) episodes without psychosis; cluster 2 22% (18/83) cases with psychosis, plus symptoms of HACE or mental status change from other origins; and cluster 3 28% (23/83) episodes with isolated psychosis. Possible risk factors of psychosis and associated somatic symptoms were analysed between the three clusters and revealed differences regarding the factors 'starvation' (χ2 test, p = 0.002), 'frostbite' (p = 0.024) and 'supplemental oxygen' (p = 0.046). Episodes with psychosis were reversible but associated with near accidents and accidents (p = 0.007, odds ratio 4.44). CONCLUSIONS: Episodes of psychosis during exposure to high altitude are frequently reported, but have not been specifically examined or assigned to medical diagnoses. In addition to the risk of suffering from somatic mountain illnesses, climbers and workers at high altitude should be aware of the potential occurrence of psychotic episodes, the associated risks and respective coping strategies.