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We examined the effect of intermittent hypoxia (IH, a hallmark feature of sleep apnea) on adipose tissue lipolysis and the role of endothelin-1 (ET-1) in this response. We hypothesized that IH can increase ET-1 secretion and plasma free fatty acid (FFA) concentrations. We further hypothesized that inhibition of ET-1 receptor activation with bosentan could prevent any IH-mediated increase in FFA. To test this hypothesis, 16 healthy male participants (32 ± 5 yr, 26 ± 2 kg/m2) were exposed to 30 min of IH in the absence (control) and presence of bosentan (62.5 mg oral twice daily for 3 days prior). Arterial blood samples for ET-1, epinephrine, and FFA concentrations, as well as abdominal subcutaneous adipose tissue biopsies (to assess transcription of cellular receptors/proteins involved in lipolysis), were collected. Additional proof-of-concept studies were conducted in vitro using primary differentiated human white preadipocytes (HWPs). We show that IH increased circulating ET-1, epinephrine, and FFA ( P < 0.05). Bosentan treatment reduced plasma epinephrine concentrations and blunted IH-mediated increases in FFA ( P < 0.01). In adipose tissue, bosentan had no effect on cellular receptors and proteins involved in lipolysis ( P > 0.05). ET-1 treatment did not directly induce lipolysis in differentiated HWP. In conclusion, IH increases plasma ET-1 and FFA concentrations. Inhibition of ET-1 receptors with bosentan attenuates the FFA increase in response to IH. Based on a lack of a direct effect of ET-1 in HWP, we speculate the effect of bosentan on circulating FFA in vivo may be secondary to its ability to reduce sympathoadrenal tone.

To investigate the influence of the Single Nucleotide Polymorphisms (SNPs) TP53 rs1625895, TP73 rs3765730, MMP9 rs17576, and MTHFR rs868014 on ovarian reserve (OR) in infertile patients.A prospective cross-sectional study was carried out in 145 infertile women. The patients were divided into two groups according to ovarian reserve, characterized by association between AMH levels and AFC:After patient distribution, both groups were compared (LOR X NOR) regarding the genotypes of the SNPs TP53 T/C rs1625895, TP73 G/A rs3765730, MMP9 Gln/Arg rs17576, and MTHFR A/G rs868014.The frequency of the TP53-T/T genotype was greater in the LOR and the TP53-C/C genotype was more frequent in patients with NOR. This association was confirmed by the frequency of alleles, where the presence of the T allele was significantly higher in patients who exhibited LOR (P = 0.0003). The frequency of the TP73-G/G genotype and of the G allele was higher in the LOR group (P = 0.01). Considering the MMP9 gene, the frequency of the Gln/Gln genotype was higher in the LOR group. However, the Gln/Arg genotype and the Arg allele prevailed in the NOR group (P = 0.006). The frequency of the MTHFR-A/A genotype was higher in the LOR group, whereas that of the MTHFR-GG genotype was higher in the NOR group. The presence of allele A was significantly higher in the LOR group (P = 0.002). The regression analysis shows that patients who present the TP53-T/T, TP73-G/G, MMP9-Gln/Gln, and MTHFR-A/A genotypes are 3.6X, 3.1X, 3.2X, and 3.7X more likely of having LOR, respectively. In addition, the association of the TP53/TT + TP73/GG genotypes increased the chance of women being included in the LOR group in 5.7-fold.The genotypes TP53-T/T, TP73-G/G, MMP9-Gln/Gln, and MTHFR-A/A increase the chance of women to exhibit LOR. These polymorphisms could be useful as genetic markers of low ovarian reserve in infertile patients.

Changes in the gravitational vector by postural changes or weightlessness induce fluid shifts impacting ocular hemodynamics and regional pressures. This investigation explores the impact of changes in direction of the gravitational vector on intraocular pressure (IOP), mean arterial pressure at eyelevel (MAPeye), and ocular perfusion pressure (OPP), which is critical for ocular health. Thirteen subjects underwent 360° of tilt (including both prone and supine positions) at 15o increments. At each angle, steady-state IOP and MAPeye were measured and OPP calculated as MAPeye-IOP. Experimental data were compared to a 6-compartment lumped parameter model of the eye. Mean IOP, MAPeye, and OPP significantly increased from 0o supine to 90o head down tilt (HDT) by 20.7±1.7 mmHg (ᵅD; < 0.001), 38.5±4.1 mmHg (ᵅD; < 0.001), and 17.4±3.2 mmHg (ᵅD

INTRODUCTION: We identified risk factors and outcomes associated with SARS-CoV-2 infection in pregnancy in a universally tested population according to disease severity and validated information on SARS-CoV-2 during pregnancy in national health registers in Denmark.MATERIAL AND METHODS: Cohort study using data from national registers and medical records including all pregnancies between March 1, 2020 and February 28, 2021. We compared women with a validated positive SARS-CoV-2 test during pregnancy with non-infected pregnant women. Risk factors and pregnancy outcomes were assessed by Poisson and Cox regression models and stratified according to disease severity defined by hospital admission status and admission reason (COVID-19 symptoms or other). Using medical record data on actual period of pregnancy, we calculated predictive values of the SARS-CoV-2 diagnosis in pregnancy in the registers.RESULTS: SARS-CoV-2 infection was detected in 1819 (1.6%) of 111 185 pregnancies. Asthma was associated with infection (relative risk [RR] 1.63, 95% confidence interval [CI] 1.28-2.07). Risk factors for severe COVID-19 disease requiring hospital admission were high body mass index (median ratio 1.06, 95% CI 1.04-1.09), asthma (RR 7.47, 95% CI 3.51-15.90) and gestational age at the time of infection (gestational age 28-36 vs CONCLUSIONS: Women infected with SARS-CoV-2 during pregnancy were at increased risk of hypertensive disorders in pregnancy, early pregnancy loss, preterm delivery and having children small for gestational age. The validity of Danish national registers was acceptable for identification of SARS-CoV-2 infection during pregnancy.

The disruption of the COVID-19 pandemic crisis has triggered worldwide multiple environmental, social, political, and economic consequences. In the entrepreneurship domain, now it is the time for reimagining the relationship between people (employees, customers) and technology. This is very important in the Australasian area (Oceania countries, OC), which aspire to digital transformation and scalable green entrepreneurship (enjoying a broad range of social, cultural, and corporate programs and initiatives) whilst facing serious environmental, social, political, economic and governance problems. The disruptions brought by the COVID-19 pandemic crisis have made OC countries and a number of international and domestic companies think about increasing the resilience of their production through sustainable, green, and scalable investments and management (e.g. supply diversification, geographically closer to customers activities and delivery centers, shorter supply chains, smarter solutions, thoughtful initiatives, increased home production, smart scalable inventories, open governance, new technology transformation, adaptable management, trusted relations, etc.). In this article, we examine several green entrepreneurship perceptions and green investment initiatives should formed in the Australasian area just after the COVID-19 pandemic crisis, the factors that influenced these perceptions/initiatives, and the consequences should they had on the political, social, and economic dynamics in OC. This article is an empirical one as the data collection process was performed by specific designed questionaries and several person reviews to CEOs of about twenty (20) enterprises operating at the wider Oceanian area (greater Oceania). The main article’s objectives are the following: (i) to analyze how the OC economies could benefit from these initiatives after the COVID-19 pandemic crisis; and (ii) to form the suitable environmental, social, economic, and governance commitments. Findings and proposed entrepreneurship analysis is complemented, in Section 4, by a review of the environmental, social, and governance commitments (operating as nine “financing constraints” with great corporate finance functionalities), which should operate (in the post COVID-19 era) as economic reform by national authorities in Oceania countries, through specific financial support programmes/initiatives and various policy measures, mostly for small and medium-sized enterprises. For instance, four key findings were recorded in the commitment “Environmental issues”. The results of the presented research, as recommendations, were referred to the adoption of good and innovative practices for sustainable green entrepreneurship in OC. In particular, the relationship between people (employees, customers) and the new technology was discussed and documented, as well as the issue of “digital transformation in the OC entrepreneurship” by identified nine (9) commitments that fully or partially support green entrepreneurship; the concept of “team-work collaboration” (collaborative entrepreneurship and solutions); and the “geospatial optimization” initiative (e.g. geospatial optimization for delivery centers) were introduced, analyzed and documented. The major findings of the presented applied research are these nine (9) perceptions/commitments as they presented and documented in this article. Also, the impact and significant influence of these findings to international and local (Oceanian) companies is obvious -because of the scalable nature of these nine (9) restrictions- particularly in the green entrepreneurship domain and for those companies involved in a digital transformation process. Also, in order to support a scalable green entrepreneurship, in the post COVID-19 times, we propose new financial initiatives like the Australasia External Investment Plan (A-EIP) with its three pillars: The Australasia Fund for Sustainable Development (A-EFSD); The Australasia Fund for Sustainable Development Plus (EFSD+); and The Australasia Multiannual Financial Framework (A-MFF). Finally, the concept “team-work” and the terms “team Australasia” and “working better together” as they are related to a scalable green entrepreneurship in the post COVID-19 era are introduced and documented.

Altered gravity environments introduce cardiovascular changes that may require continuous hemodynamic monitoring in both spaceflight and terrestrial analogs. Conditions in such environments are often prohibitive to direct/invasive methods and therefore, indirect measurement techniques must be used. This study compares two common cardiac measurement techniques used in the human spaceflight domain, pulse contour analysis (PCA—Nexfin) and inert gas rebreathing (IGR—Innocor), in subjects completing ergometer exercise under altered gravity conditions simulated using a tilt paradigm. Seven subjects were tilted to three different angles representing Martian, Lunar, and microgravity conditions in the rostrocaudal direction. They completed a 36-min submaximal cardiovascular exercise protocol in each condition. Hemodynamics were continuously monitored using Nexfin and Innocor. Linear mixed-effects models revealed a significant bias of $$25.7\pm 1.7$$ ml ( $$p

The bondage-discipline, dominance-submission, and sadism-masochism (BDSM) community has achieved diversity with respect to gender identity and sexual orientation yet does so to a lesser extent with respect to race and ethnicity. A total of 398 BDSM practitioners recruited in 2018 and 2019 from BDSM conferences located within the Southern, Midwestern, and Western regions of the U.S., as well as online, completed surveys asking about racial and ethnic discrimination, fetishization, and inclusivity. People of color were 16 times more likely than non-people of color to feel discriminated against at BDSM events and 17 times more likely to feel fetishized. Qualitative results included troubling stories of overt racism and offensive racial slurs, and examples of microaggressions, feelings of isolation, and feelings of being dismissed. The results suggest that organizations can increase inclusivity by understanding the unique costs faced by people of color with an awareness that these costs might be invisible to non-people of color, diversifying positions of authority and leadership, and teaching well-meaning members what types of behaviors could create a hostile environment.

Lower body negative pressure (LBNP) has been implemented as a tool to simulate systemic effects of hypovolemia, understand orthostatic challenges and study G load stress in humans. However, the exact hemodynamic mechanisms of graded LBNP followed by its abrupt release have not been characterized in detail, limiting its potential applications in humans. Here, we set out to investigate the immediate hemodynamic alterations occurring during LBNP in healthy Landrace pigs. Invasive cardiac monitoring via extensive pressure volume loop analysis was carried out during application of incremental LBNP up to life threatening levels from −15 to −45 mmHg as well as during its abrupt release. Three different sealing positions were evaluated. Incremental LBNP consistently induced a preload dependent depression of systemic hemodynamics according to the Frank-Starling mechanism. Overall, the pressure–volume loop progressively shifted leftwards and downwards with increasing LBNP intensity. The abrupt release of LBNP reverted the above-described hemodynamic changes to baseline values within only three respiratory cycles. These data provide quantitative translational insights into hemodynamic mechanisms of incremental and very high levels of LBNP, levels of seal and effect of abrupt release for future human applications, such as countermeasure development for long spaceflight.

Introduction: Assessing the risk factors for and consequences of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy is essential to guide clinical care. Previous studies on SARS-CoV-2 infection in pregnancy have been among hospitalized patients, which may have exaggerated risk estimates of severe outcomes because all cases of SARS-CoV-2 infection in the pregnant population were not included. The objectives of this study were to identify risk factors for and outcomes after SARS-CoV-2 infection in pregnancy independent of severity of infection in a universally tested population, and to identify risk factors for and outcomes after severe infection requiring hospital admission. Material and methods: This was a prospective population-based cohort study in Denmark using data from the Danish National Patient Register and Danish Microbiology Database and prospectively registered data from medical records. We included all pregnancies between March 1 and October 31, 2020 and compared women with a positive SARS-CoV-2 test during pregnancy to non-infected pregnant women. Cases of SARS-CoV-2 infection in pregnancy were both identified prospectively and through register linkage to ensure that all cases were identified and that cases were pregnant during infection. Main outcome measures were pregnancy, delivery, maternal, and neonatal outcomes. Severe infection was defined as hospital admission due to coronavirus disease 2019 (COVID-19) symptoms. Results: Among 82 682 pregnancies, 418 women had SARS-CoV-2 infection during pregnancy, corresponding to an incidence of 5.1 per 1000 pregnancies, 23 (5.5%) of which required hospital admission due to COVID-19. Risk factors for infection were asthma (odds ratio [OR] 2.19, 95% CI 1.41–3.41) and being foreign born (OR 2.12, 95% CI 1.70–2.64). Risk factors for hospital admission due to COVID-19 included obesity (OR 2.74, 95% CI 1.00–7.51), smoking (OR 4.69, 95% CI 1.58–13.90), infection after gestational age (GA) 22 weeks (GA 22–27 weeks: OR 3.77, 95% CI 1.16–12.29; GA 28–36 weeks: OR 4.76, 95% CI 1.60–14.12), and having asthma (OR 4.53, 95% CI 1.39–14.79). We found no difference in any obstetrical or neonatal outcomes. Conclusions: Only 1 in 20 women with SARS-CoV-2 infection during pregnancy required admission to hospital due to COVID-19. Risk factors for admission comprised obesity, smoking, asthma, and infection after GA 22 weeks. Severe adverse outcomes of SARS-CoV-2 infection in pregnancy were rare.

Lower body negative pressure (LBNP) is a tool to study compensatory mechanisms to central hypovolemia for decades. However, the underlying hemodynamic mechanisms were mostly assessed noninvasively and remain unclear. We hypothesized that incremental LBNP reduces diastolic filling and thereby affects left ventricular (LV) diastolic suction (DS). Here, we investigated the impact of graded LBNP at three different levels of seal as well as during b-adrenergic stimulation by invasive pressure-volume (PV) analysis. Eight Landrace pigs were instrumented closed-chest for PV assessment. LBNP was applied at three consecutive locations: I) cranial, 10 cm below xiphoid process; II) medial, half-way between cranial and caudal; III) caudal, at the iliac spine. Level III was repeated under dobutamine infusion. At each level, baseline measurements were followed by application of incremental LBNP of -15, -30, and -45 mmHg. LBNP induced varying degrees of preload-dependent hemodynamic changes, with cranial LBNP inducing more pronounced effects than caudal. According to the Frank???Starling mechanism, graded LBNP progressively reduced LV stroke volume (LV SV) following a decrease in LV end-diastolic volume. Negative intraventricular minimal pressures were observed during dobutamine-infusion as well as higher levels of LBNP. Of note, incremental LV negative pressures were accompanied by increasing DS volumes, derived by extrapolating the volume at zero transmural pressure, the so-called equilibrium volume (V0), related to LV SV. In conclusion, graded preload reduction via LBNP shifts the PV loop to smaller volumes and end-systolic volume below V0, which induces negative LV pressures and increases LV suction. Accordingly, NEW & NOTEWORTHY This study examined the effects of incremental lower body negative pressure (LBNP) from -15 to -45 mmHg on hemodynamic regulation using invasive pressure-volume assessment in closed-chest pigs. Graded preload reduction via LBNP induces negative left ventricular (LV) pressures while increasing LV suction and thus allowing the ventricle to eject below the equilibrium volume at the end of systole. Accordingly, LBNP-induced central hypovolemia is associated with increased diastolic suction.

Objective: To determine whether administration of progesterone on the day of oocyte retrieval may reverse accumulation of fluid in the endometrial cavity. Methods: A total of 50 patients who underwent assisted reproductive technology (ART) cycles with endometrial cavity fluid (ECF) observed by ultrasound at the time of oocyte retrieval were included. Upon the identification of ECF, vaginal administration of natural progesterone was started. Two days later, the endometrial cavity was re-evaluated, and embryo transfer was performed in the absence of ECF. Results: ECF was absent two days after administration of vaginal progesterone in 47 of the 50 patients (94%). ECF persisted in 3 of the 50 patients (6%). The clinical pregnancy rate per transfer was 34.0%, and the implantation rate was 21.6%. Conclusion: Our data suggest that, in the presence of ECF, administration of intravaginal progesterone in ART cycles must be initiated on the day of follicle aspiration to reverse ECF and to avoid the deleterious effects of fluid on the blastocyst-endometrial interaction.

The deadly global COVID-19 pandemic has disrupted global supply chains and the working environment in most organizations. This paper looks at the safety and physical distancing implications on order picking operations using routing, storage and picking strategies. Research has shown that the use of traversal and in some cases midpoint routing can yield near optimal results and enable physical distancing. The use of ABC storage does result in less travel for order picking workers but can potentially result in more congestion. Picking strategies that utilize picking zones naturally promote physical distancing but may not be feasible given the picking volume and the layout of the distribution center. Overall, this paper shows that order picking managers can still provide safe workspaces for their employees while achieving cost effective results.

Mitigation of spaceflight-related pathologies such as spaceflight-associated neuro-ocular syndrome (SANS) and the recently discovered risk of venous thrombosis must happen before deep space exploration can occur. Lower body negative pressure (LBNP) can simulate gravitational stress during spaceflight that is likely to counteract SANS and venous thrombosis, but the ideal dose and method of delivery have yet to be determined. We undertook a review of current LBNP literature and conducted a gap analysis to determine the steps needed to adapt LBNP for in-flight use. We found that to use LBNP in flight, it must be adapted to long time duration/low pressure use that should be compatible with crew activities. A lack of understanding of the etiology of the pathologies that LBNP can counteract hinders the application of LBNP as a countermeasure during spaceflight. Future research should aim at filling the knowledge gaps outlined in this review.

OBJECTIVEDecompressive craniectomy (DC) is an emergency neurosurgical procedure used in cases of severe intracranial hypertension or impending intracranial herniation. The procedure is often lifesaving, but it exposes the brain to atmospheric pressure in the subsequent rehabilitation period, which changes intracranial physiology and probably leads to complications such as hydrocephalus, hygromas, and “syndrome of the trephined.” The objective of the study was to study the effect of cranioplasty on intracranial pressure (ICP), postural ICP changes, and intracranial pulse wave amplitude (PWA).METHODSThe authors performed a prospective observational study including patients who underwent DC during a 12-month period. Telemetric ICP sensors were implanted in all patients at the time of DC. ICP was evaluated before and after cranioplasty during weekly measurement sessions including a standardized postural change program.RESULTSTwelve of the 17 patients enrolled in the study had cranioplasty performed and were included in the present investigation. Their mean ICP in the supine position increased from –0.5 ± 4.8 mm Hg the week before cranioplasty to 6.3 ± 2.5 mm Hg the week after cranioplasty (p < 0.0001), whereas the mean ICP in the sitting position was unchanged (–1.2 ± 4.8 vs –1.1 ± 3.6 mm Hg, p = 0.90). The difference in ICP between the supine and sitting positions was minimal before cranioplasty (1.1 ± 1.8 mm Hg) and increased to 7.4 ± 3.6 mm Hg in the week following cranioplasty (p < 0.0001). During the succeeding 2 weeks of the follow-up period, the mean ICP in the supine and sitting positions decreased in parallel to, respectively, 4.6 ± 3.0 mm Hg (p = 0.0003) and –3.9 ± 2.7 mm Hg (p = 0.040), meaning that the postural ICP difference remained constant at around 8 mm Hg. The mean intracranial PWA increased from 0.7 ± 0.7 mm Hg to 2.9 ± 0.8 mm Hg after cranioplasty (p < 0.0001) and remained around 3 mm Hg throughout the following weeks.CONCLUSIONSCranioplasty restores normal intracranial physiology regarding postural ICP changes and intracranial PWA. These findings complement those of previous investigations on cerebral blood flow and cerebral metabolism in patients after decompressive craniectomy.

Astronauts have presented with a constellation of visual changes referred to as spaceflight-associated neuro-ocular syndrome (SANS). However, neither have early markers of microgravity-induced optic remodeling been fully identified nor have countermeasures been developed. To identify early markers of SANS, we studied 10 subjects with optical coherence tomography and ultrasonography when upright and supine and again after 24 h of 6° head-down tilt (HDT) bed rest. Upon acute transition from the upright to the supine position, choroid area (2.24 ± 0.53 to 2.28 ± 0.52 mm

Sirtuin 5 (SIRT5) is a protein lysine deacylase enzyme that regulates diverse biology by hydrolyzing ϵ-N-carboxyacyllysine posttranslational modifications in the cell. Inhibition of SIRT5 has been linked to potential treatment of several cancers but potent compounds with activity in cells have been lacking. Here we developed mechanism-based inhibitors that incorporate isosteres of a carboxylic acid residue that is important for high-affinity binding to the enzyme active site. By masking of the tetrazole moiety of the most potent candidate from our initial SAR study, we achieved potent and cytoselective growth inhibition for the treatment of SIRT5-dependent leukemic cancer cell lines in culture. Thus, we provide an efficient, cellularly active small molecule that targets SIRT5, which can help elucidate its function and potential as a future drug target. This work shows that masked isosteres of carboxylic acids are viable chemical motifs for the development of inhibitors that target mitochondrial enzymes, which may have applications beyond the sirtuin field.