Biomechanical Gain in Joint Excursion from the Curvature of the Achilles Tendon: Role of the Geometrical Arrangement of Inflection Point, Center of Rotation, and Calcaneus

The dorsal movement of the Achilles tendon during ankle rotation is restricted by anatomical obstructions. Previously, we demonstrated that the anatomical obstruction provides a gain (gainAT) in the proximal displacement of the calcaneus compared to the change in the Achilles tendon length. Here, we empirically validate and extend our previous modeling study by investigating the effects of a broad range of obstruction locations on gainAT. The largest gainAT could be achieved when the obstruction was located on the most ventral and distal sides within the physiological range of the Achilles tendon, irrespective of the ankle position.

Determining a target SpO2 to maintain PaO2 within a physiological range

Objective In the context of an ongoing debate on the potential risks of hypoxemia and hyperoxemia, it seems prudent to maintain the partial arterial oxygen pressure (PaO2) in a physiological range during administration of supplemental oxygen. The PaO2 and peripheral oxygen saturation (SpO2) are closely related and both are used to monitor oxygenation status. However, SpO2 values cannot be used as an exact substitute for PaO2. The aim of this study in acutely ill and stable patients was to determine at which SpO2 level PaO2 is more or less certain to be in the physiological range. Methods This is an observational study prospectively collecting data pairs of PaO2 and SpO2 values in patients admitted to the emergency room or intensive care unit (Prospective Inpatient Acutely ill cohort; PIA cohort). A second cohort of retrospective data of patients who underwent pulmonary function testing was also included (Retrospective Outpatient Pulmonary cohort; ROP cohort). Arterial hypoxemia was defined as PaO2 < 60 mmHg and hyperoxemia as PaO2 > 125 mmHg. The SpO2 cut-off values with the lowest risk of hypoxemia and hyperoxemia were determined as the 95th percentile of the observed SpO2 values corresponding with the observed hypoxemic and hyperoxemic PaO2 values. Results 220 data pairs were collected in the PIA cohort. 95% of hypoxemic PaO2 measurements occurred in patients with an SpO2 below 94%, and 95% of hyperoxemic PaO2 measurements occurred in patients with an SpO2 above 96%. Additionally in the 1379 data pairs of the ROP cohort, 95% of hypoxemic PaO2 measurements occurred in patients with an SpO2 below 93%. Conclusion The SpO2 level marking an increased risk of arterial hypoxemia is not substantially different in acutely ill versus stable patients. In acutely ill patients receiving supplemental oxygen an SpO2 target of 95% maximizes the likelihood of maintaining PaO2 in the physiological range.

Swine Small Intestine Sealing Performed by Different Vessel Sealing Devices: Ex-Vivo Test

This study aimed to evaluate the sealing quality of swine small intestine using different laparoscopic radiofrequency vessel sealing devices (two 5 mm: RFVS-1 and -2; one 10 mm: RFVS-3) and a harmonic scalpel (HS) compared to golden standard closure technique. The study was divided into two arms. In study arm 1: n = 50 swine intestinal loops (10 per group) were transected with each instrument and the loops in which the devices provided complete sealing, at the gross inspection, were tested for maximum burst pressure (BP) and histological evaluation and compared to an automatic linear stapler. After the BP tests, the devices that achieved significantly lower BP values were excluded from the second arm. The RFVS-1 and -3 provided statistically significant results and were used in study arm 2, to obtain full-thickness biopsies along the antimesenteric border of the loop and were compared with hand-sewn intestinal closure (n = 30; 10 per group). The biopsies were histologically evaluated for thermal injury and diagnostic features, and intestinal loops tested for BP. RFVS-3 achieved comparable results (69.78 ± 4.23 mmHg, interquartile range (IQR) 5.8) to stapler closing technique (71.09 ± 4.22 mmHg, IQR 4.38; p > 0.05), while the RFVS-1 resulted in significantly (p < 0.05) lower BP (45.28 ± 15.23 mmHg, IQR 24.95) but over the physiological range, conversely to RFVS-2 (20.16 ± 7.19 mmHg, IQR 12.02) and HS (not measurable). RFVS-3 resulted not significantly different (p > 0.05) (45.09 ± 8.75 mmHg, IQR 10.48) than Suture (35.71 ± 17.51 mmHg, IQR 23.77); RFVS-1 resulted significantly lower values (23.96 ± 10.63 mmHg, IQR 9.62; p < 0.05). All biopsies were judged diagnostic. Data confirmed that RFVS-1 and -3 devices provided suitable intestinal sealing, with BP pressures over the physiological range. Conversely, the HS and RFVS-2 should not be considered for intestinal sealing. RFVS devices could be employed to obtain small intestine stump closure or full-thickness biopsies. However, further studies should be performed in live animals to assess the role of the healing process.

Plasma androgens and the presence and course of depression in a large cohort of women

Major depressive disorder (MDD) has a higher prevalence in women with supraphysiologic androgen levels. Whether there is also an association between depression and androgen levels in the physiological range, is unknown. This study examined if women with current MDD have higher androgen levels compared to women who have never had MDD, and if androgen levels are associated with onset and remission of MDD. In 1659 women (513 current MDD, 754 remitted MDD, and 392 never MDD), baseline plasma levels of total testosterone, 5α-dihydrotestosterone, and androstenedione were determined with liquid chromatography-tandem mass spectrometry, and dehydroepiandrosterone-sulfate and sex hormone binding globulin (SHBG) with radioimmunoassays. Free testosterone was calculated. MDD status was assessed at baseline, and at 2 and 4 years follow-up. Women were aged between 18 and 65 years (mean age 41) with total testosterone levels in the physiological range (geometric mean 0.72 nmol/L [95% CI 0.27–1.93]). After adjusting for covariates and multiple testing, women with current MDD had a higher mean free testosterone than women who never had MDD (adjusted geometric mean 8.50 vs. 7.55 pmol/L, p = 0.0005), but this difference was not large enough to be considered clinically meaningful as it was consistent with statistical equivalence. Levels of other androgens and SHBG did not differ and were also statistically equivalent between the groups. None of the androgens or SHBG levels predicted onset or remission of MDD. Our findings support the idea that plasma androgens within the physiological range have no or only limited effects on depressive disorders in women.

TOXPANEL: A Gene-Set Analysis Tool to Assess Liver and Kidney Injuries

Gene-set analysis is commonly used to identify trends in gene expression when cells, tissues, organs, or organisms are subjected to conditions that differ from those within the normal physiological range. However, tools for gene-set analysis to assess liver and kidney injury responses are less common. Furthermore, most websites for gene-set analysis lack the option for users to customize their gene-set database. Here, we present the ToxPanel website, which allows users to perform gene-set analysis to assess liver and kidney injuries using activation scores based on gene-expression fold-change values. The results are graphically presented to assess constituent injury phenotypes (histopathology), with interactive result tables that identify the main contributing genes to a given signal. In addition, ToxPanel offers the flexibility to analyze any set of custom genes based on gene fold-change values. ToxPanel is publically available online at https://toxpanel.bhsai.org. ToxPanel allows users to access our previously developed liver and kidney injury gene sets, which we have shown in previous work to yield robust results that correlate with the degree of injury. Users can also test and validate their customized gene sets using the ToxPanel website.

Variation of vital signs with potential to influence the performance of qSOFA scoring in the Ethiopian general population at different altitudes of residency: A multisite cross-sectional study

Introduction The physiological range of different vital signs is dependent on various environmental and individual factors. There is a strong interdependent relationship between vital signs and health conditions. Deviations of the physiological range are commonly used for risk assessment in clinical scores, e.g. respiratory rate (RR) and systolic blood pressure (BPsys) in patients with infections within the quick sequential organ failure assessment (qSOFA) score. A limited number of studies have evaluated the performance of such scores in resource-limited health care settings, showing inconsistent results with mostly poor discriminative power. Divergent standard values of vital parameters in different populations, e.g. could influence the accuracy of various clinical scores. Methods This multisite cross-sectional observational study was performed among Ethiopians residing at various altitudes in the cities of Asella (2400m above sea level (a.s.l.)), Adama (1600m a.s.l.), and Semara (400m a.s.l.). Volunteers from the local general population were asked to complete a brief questionnaire and have vital signs measured. Individuals reporting acute or chronic illness were excluded. Results A positive qSOFA score (i.e. ≥2), indicating severe illness in patients with infection, was common among the studied population (n = 612). The proportion of participants with a positive qSOFA score was significantly higher in Asella (28.1%; 55/196), compared with Adama, (8.3%; 19/230; p<0.001) and Semara (15.1%; 28/186; p = 0.005). Concerning the parameters comprised in qSOFA, the thresholds for RR (≥22/min) were reached in 60.7%, 34.8%, and 38.2%, and for BPsys (≤100 mmHg) in 48.5%, 27.8%, and 36.0% in participants from Asella, Adama, and Semara, respectively. Discussion The high positivity rate of qSOFA score in the studied population without signs of acute infection may be explained by variations of the physiological range of different vital signs, possibly related to the altitude of residence. Adaptation of existing scores using local standard values could be helpful for reliable risk assessment.

Anti-Müllerian hormone (AMH) autocrine signaling promotes survival and proliferation of ovarian cancer cells

In ovarian carcinoma, anti-Müllerian hormone (AMH) type II receptor (AMHRII) and the AMH/AMHRII signaling pathway are potential therapeutic targets. Here, AMH dose-dependent effect on signaling and proliferation was analyzed in four ovarian cancer cell lines, including sex cord stromal/granulosa cell tumors and high grade serous adenocarcinomas (COV434-AMHRII, SKOV3-AMHRII, OVCAR8 and KGN). As previously shown, incubation with exogenous AMH at concentrations above the physiological range (12.5–25 nM) decreased cell viability. Conversely, physiological concentrations of endogenous AMH improved cancer cell viability. Partial AMH depletion by siRNAs was sufficient to reduce cell viability in all four cell lines, by 20% (OVCAR8 cells) to 40% (COV434-AMHRII cells). In the presence of AMH concentrations within the physiological range (5 to 15 pM), the newly developed anti-AMH B10 antibody decreased by 25% (OVCAR8) to 50% (KGN) cell viability at concentrations ranging between 3 and 333 nM. At 70 nM, B10 reduced clonogenic survival by 57.5%, 57.1%, 64.7% and 37.5% in COV434-AMHRII, SKOV3-AMHRII, OVCAR8 and KGN cells, respectively. In the four cell lines, B10 reduced AKT phosphorylation, and increased PARP and caspase 3 cleavage. These results were confirmed in ovarian cancer cells isolated from patients’ ascites, demonstrating the translational potential of these results. Furthermore, B10 reduced COV434-MISRII tumor growth in vivo and significantly enhanced the median survival time compared with vehicle (69 vs 60 days; p = 0.0173). Our data provide evidence for a novel pro-survival autocrine role of AMH in the context of ovarian cancer, which was targeted therapeutically using an anti-AMH antibody to successfully repress tumor growth.

Serum Total Bilirubin and Progression of Chronic Kidney Disease and Mortality: A Systematic Review and Meta-Analysis

Background: Previous studies have suggested that serum total bilirubin (STB) levels are associated with heightened chronic kidney disease (CKD) and mortality in both the general population and nephropathy patients. However, these results remain inconsistent. The aim of our study was to investigate whether STB was a predictor for progression of CKD and mortality by meta-analysis.Methods: We performed a systematic literature search in PubMed, Web of Science, MEDLINE, EMBASE, Google Scholar, and Cochrane Library's database up to June 30, 2019. Pooled risk ratios (RR) and corresponding 95% confidence intervals (CI) were extracted for the highest vs. lowest category STB levels within the physiological range, and a random-effects model was applied to calculate the dose–response relationships. A pooled hazard ratio (HR) was used to investigate the association between STB levels and mortality in dialysis patients.Results: A total of 16 studies, wherein participants were followed from 21 months to 7 years, were eligible for inclusion in the study. For the categorized STB, 11 studies with 41,188 participants were identified and analyzed. Patients with the highest STB levels were associated with a lower risk of CKD (RR = 0.64; 95% CI 0.55–0.73) compared to those with the lowest STB levels. Furthermore, based on seven studies, a pooled RR of 0.89, 95% CI (0.80–0.99) was observed for the continuous STB levels (per 0.2 mg/dL increase). Four studies that included 51,764 participants illustrated that there was no association between STB levels and all-cause mortality (HR = 0.77; 95% CI 0.42–1.41). A prominent negative linear relationship (X2 = 14.70; P = 0.0001) was found between STB levels and risk of CKD. Subgroup analyses showed that there were no significant differences in the subgroup adjustment factor except for sample size.Conclusions: Elevated STB levels within a physiological range are associated with lower risk of CKD regardless of the study characteristics and coincide with a liner dose–response relationship. However, whether high STB levels are a protective factor against mortality remains inconclusive. Large-scale randomized controlled trails are needed to target STB levels for predicting renal outcomes.

Bringing the Ca 2+ sensitivity of myristoylated recoverin into the physiological range

The prototypical Ca 2+ -sensor protein recoverin (Rec) is thought to regulate the activity of rhodopsin kinase (GRK1) in photoreceptors by switching from a relaxed (R) disc membrane-bound conformation in the dark to a more compact, cytosol-diffusing tense (T) conformation upon cell illumination. However, the apparent affinity for Ca 2+ of its physiologically relevant form (myristoylated recoverin) is almost two orders of magnitude too low to support this mechanism in vivo . In this work, we compared the individual and synergistic roles of the myristic moiety, the GRK1 target and the disc membrane in modulating the calcium sensitivity of Rec. We show that the sole presence of the target or the disc membrane alone are not sufficient to achieve a physiological response to changes in intracellular [Ca 2+ ]. Instead, the simultaneous presence of GRK1 and membrane allows the T to R transition to occur in a physiological range of [Ca 2+ ] with high cooperativity via a conformational selection mechanism that drives the structural transitions of Rec in the presence of multiple ligands. Our conclusions may apply to other sensory transduction systems involving protein complexes and biological membranes.