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Human activities and climate change threaten coldwater organisms in freshwater ecosystems by causing rivers and streams to warm, increasing the intensity and frequency of warm temperature events, and reducing thermal heterogeneity. Cold-water refuges are discrete patches of relatively cool water that are used by coldwater organisms for thermal relief and short-term survival. Globally, cohesive management approaches are needed that consider interlinked physical, biological, and social factors of cold-water refuges. We review current understanding of cold-water refuges, identify gaps between science and management, and evaluate policies aimed at protecting thermally sensitive species. Existing policies include designating cold-water habitats, restricting fishing during warm periods, and implementing threshold temperature standards or guidelines. However, these policies are rare and uncoordinated across spatial scales and often do not consider input from Indigenous peoples. We propose that cold-water refuges be managed as distinct operational landscape units, which provide a social and ecological context that is relevant at the watershed scale. These operational landscape units provide the foundation for an integrated framework that links science and management by (1) mapping and characterizing cold-water refuges to prioritize management and conservation actions, (2) leveraging existing and new policies, (3) improving coordination across jurisdictions, and (4) implementing adaptive management practices across scales. Our findings show that while there are many opportunities for scientific advancement, the current state of the sciences is sufficient to inform policy and management. Our proposed framework provides a path forward for managing and protecting cold-water refuges using existing and new policies to protect coldwater organisms in the face of global change.

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Alpha-cyclodextrin (αCD) is a bacterial product that is widely used as a food ingredient. In the European Union (EU), αCD is regulated as a dietary fiber with an authorized health claim "for contributing to the reduction of postprandial glycemic responses." In the US, αCD is generally recognized as save (GRAS), but on April 25, 2022, the U.S. Food and Drug Administration (FDA) rejected the inclusion of αCD in the list of dietary fibers because "the strength of the scientific evidence does not support a finding of a beneficial effect of αCD on postprandial blood glucose …" To evaluate the strength of this scientific evidence, this meta-analysis reviews clinical trials conducted to test the effect of αCD on the rise of blood glucose and insulin levels during three hours after consumption of a meal comprising carbohydrates, fats, and proteins. Several issues related to the standardization of the outcomes, the choice of the statistical methods in the cross-over studies conducted, and the choice of methods for the aggregation of P-values are discussed. It is concluded that the administration of αCD not only reduces the postprandial glycemic responses, but the absence of an increase in insulin levels suggests that αCD acts independently of increasing insulin production and, thus, the beneficial effect of αCD is not affected by insulin resistance.

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About a month after the COVID-19 epidemic peaked in Mainland China and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) migrated to Europe and then the USA, the epidemiological data began to provide important insights into the risks associated with the disease and the effectiveness of intervention strategies such as travel restrictions and lockdowns ("social distancing"). Respiratory diseases, including the 2003 severe acute respiratory syndrome (SARS) epidemic, remain only about two months in any given population, although peak incidence and lethality can vary. The epidemiological data suggested that at least two strains of SARS-CoV-2 had evolved during the first months of the epidemic while the virus migrated from Mainland China to Europe. South Korea (SK), Iran, Italy (IT), and Italy's neighbors were then hit by the more dangerous "SKII" variant. While the first epidemic in continental Asia was about to end and in Europe about to level off, the more recent epidemic in the younger US population was still increasing, albeit not exponentially anymore. The same models that help us to understand the epidemic also help us to choose prevention strategies. The containment of high-risk people, such as the elderly with comorbidities, and reducing disease severity, by either vaccination, reduction of comorbidities (seen as risk factors already in Italy), or early treatment of complications, are the best strategies against a respiratory virus disease (RVD). Lockdowns can be effective during the month following the peak incidence of infections when the exponential increase of cases ends (the window of opportunity). From the standard susceptible-infectious-resistant (SIR) model used, containing low-risk people too early, instead, merely prolongs the time the virus needs to circulate until the incidence is high enough to reach "herd immunity." Containing low-risk people too late is also not helpful, unless to prevent a rebound if containment started too early.

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Severely injured trauma patients are often coagulopathic and early hemostatic resuscitation is essential. Previous studies have revealed linear relationships between thrombelastography (TEG®) five- and ten-min amplitudes (A5 and A10), and maximum amplitude (MA), using TEG® 5000 technology. We aimed to investigate the performance of A5 and A10 in predicting low MA in severely injured trauma patients and identify optimal cut-off values for hemostatic intervention based on early amplitudes, using the cartridge-based TEG® 6s technology. Adult trauma patients with hemorrhagic shock were included in the iTACTIC randomized controlled trial at six European Level I trauma centers between 2016 and 2018. After admission, patients were randomized to hemostatic therapy guided by conventional coagulation tests (CCT) or viscoelastic hemostatic assays (VHA). Patients with available admission-TEG® 6s data were included in the analysis, regardless of treatment allocation. Low MA was defined as <55 mm for Kaolin TEG® and RapidTEG®, and <17 mm for TEG® functional fibrinogen (FF). One hundred eighty-seven patients were included. Median time to MA was 20 (Kaolin TEG®), 21 (RapidTEG®) and 12 (TEG® FF) min. For Kaolin TEG®, the optimal Youden index (YI) was at A5 < 36 mm (100/93% sensitivity/specificity) and A10 < 47 mm (100/96% sensitivity/specificity). RapidTEG® optimal YI was at A5 < 34 mm (98/92% sensitivity/specificity) and A10 < 45 mm (96/95% sensitivity/specificity). TEG® FF optimal YI was at A5 < 12 mm (97/93% sensitivity/specificity) and A10 < 15 mm (97/99% sensitivity/specificity). In summary, we found that TEG® 6s early amplitudes were sensitive and specific predictors of MA in severely injured trauma patients. Intervening on early amplitudes can save valuable time in hemostatic resuscitation.

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Perioperative care of patients undergoing liver transplantation (LT) is very complex. Metabolic derangements, hypothermia, coagulopathy and thromboses, severe infections, and graft dysfunction can affect outcomes. In this manuscript, we discuss several perioperative problems that can be encountered in LT recipients. The authors present the most up-to-date information regarding predicting and treating hemodynamic instability, coagulation monitoring and management, postoperative ventilation strategies and early extubation, management of infections, and ESLD-related pulmonary complications. In addition, early post-transplant allograft dysfunction will be discussed.

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Acquired hemophilia A (AHA) is a rare disease with a prevalence in Europe of 1.5 per million. This diagnosis is significantly delayed in about one-third of all cases, leading to deferred treatment. The main signs of AHA are spontaneous bleeding seen in about two-thirds of all patients. AHA can be lethal in 20% of all symptomatic cases. This patient population's main standard laboratory finding is a prolonged aPTT (activated prothrombin Time) with otherwise normal coagulation results. In addition, antibodies against FVIII (in Bethesda Units) and a quantitative reduction of FVIII activity are necessary to confirm AHA. The therapy of acute bleeding related to AHA is based on the following main principles: Pharmacologic control of the bleeding is of absolute importance. It can be achieved by administering either recombinant activated FVIIa "bypass therapy"; activated prothrombin complex; or Emicizumab, a bispecific monoclonal antibody. Eradication of the FVIII antibodies should be initiated simultaneously. The combination of steroids with cyclophosphamide leads to the highest eradication rates. Causes of AHA may be related to neoplasms, autoimmune diseases, and pregnancy. We report on a patient who underwent four surgical procedures before the diagnosis of AHA was established.

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In the framework of homogeneous susceptible-infected-recovered (SIR) models, we use a control theory approach to identify optimal pandemic mitigation strategies. We derive rather general conditions for reaching herd immunity while minimizing the costs incurred by the introduction of societal control measures (such as closing schools, social distancing, lockdowns, etc.), under the constraint that the infected fraction of the population does never exceed a certain maximum corresponding to public health system capacity. Optimality is derived and verified by variational and numerical methods for a number of model cost functions. The effects of immune response decay after recovery are taken into account and discussed in terms of the feasibility of strategies based on herd immunity.

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About one month after the COVID-19 epidemic peaked in Mainland China and SARS-CoV-2 migrated to Europe and then the U.S., the epidemiological data begin to provide important insights into the risks associated with the disease and the effectiveness of intervention strategies such as travel restrictions and lockdowns ("social distancing"). Respiratory diseases, including the 2003 SARS epidemic, remain only about two months in any given population, although peak incidence and lethality can vary. The epidemiological data suggest that at least two strains of the 2020 SARS-CoV-2 virus have evolved during its migration from Mainland China to Europe. South Korea, Iran, Italy, and Italys neighbors were hit by the more dangerous "SKII" variant. While the epidemic in continental Asia is about to end, and in Europe about to level off, the more recent epidemic in the younger US population is still increasing, albeit not exponentially anymore. The peak level will likely depend on which of the strains has entered the U.S. first. The same models that help us to understand the epidemic also help us to choose prevention strategies. Containment of high-risk people, like the elderly, and reducing disease severity, either by vaccination or by early treatment of complications, is the best strategy against a respiratory virus disease. Lockdowns can be effective during the month following the peak incidence in infections, when the exponential increase of cases ends. Earlier containment of low-risk people merely prolongs the time the virus needs to circulate until the incidence is high enough to initiate "herd immunity". Later containment is not helpful, unless to prevent a rebound if containment started too early. About the AuthorDr. Wittkowski received his PhD in computer science from the University of Stuttgart and his ScD (Habilitation) in Medical Biometry from the Eberhard-Karls-University Tubingen, both Germany. He worked for 15 years with Klaus Dietz, a leading epidemiologist who coined the term "reproduction number", on the Epidemiology of HIV before heading for 20 years the Department of Biostatistics, Epidemiology, and Research Design at The Rockefeller University, New York. Dr. Wittkowski is currently the CEO of ASDERA LLC, a company discovering novel interventions against complex (incl. coronavirus) diseases from data of genome-wide association studies.

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[This corrects the article DOI: 10.1371/journal.pone.0199012.].

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BACKGROUND: Vasoplegia is a clinical condition typically manifested by cardiovascular instability unresponsive to the usual doses of inotropes or vasopressors. It can occur in a variety of clinical settings including liver transplantation (LT). Immunoglobulins have been used to treat sepsis-related vasoplegia. We performed a retrospective study to evaluate the efficacy of IgM-enriched immunoglobulin (IgMIg) on 30-day mortality and its ability to reverse vasoplegia in patients undergoing LT. METHODS: Between May 2013 and November 2017, 473 LT were performed at our institution. We identified 21 patients who received IgMIg for 3 days to treat vasoplegia. Patients included in the study met the criteria for having vasoplegia and required noradrenaline administration greater than 1 µg·kg·min for more than 24 hours to maintain a mean arterial pressure of 70 mm Hg or greater. Procalcitonin and interleukin-6 (IL-6) levels were used as surrogate markers for inflammation and were measured at the beginning and end of IgM treatment. RESULTS: After IgMIg administration, median noradrenaline infusion rates could be significantly reduced from 1.6 µg·kg·min (1.3-2 µg·kg·min) to 0.16 µg·kg·min (0.08-0.34 µg·kg·min) (P < 0.001). In addition, after treatment, procalcitonin levels decreased significantly from 44 ng/mL (24-158) to 26.1 ng/mL (10.9-48.7) (P < 0.001) and IL-6 levels decreased significantly from 63 pg/mL (29-102) to 20 pg/mL (11-20) (P < 0.001). Thirty-day morality was 14.3%. CONCLUSIONS: The administration of IgMIg in patients with vasoplegia after LT is associated with a return of hemodynamic stability. Despite a predicted mortality of over 90% by Sepsis-Related Organ Failure Assessment score, the mortality rate of patients receiving IgMIg in our study was less than 20%.

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Most breast cancer deaths are caused by metastasis and treatment options beyond radiation and cytotoxic drugs, which have severe side effects, and hormonal treatments, which are or become ineffective for many patients, are urgently needed. This study reanalyzed existing data from three genome-wide association studies (GWAS) using a novel computational biostatistics approach (muGWAS), which had been validated in studies of 600-2000 subjects in epilepsy and autism. MuGWAS jointly analyzes several neighboring single nucleotide polymorphisms while incorporating knowledge about genetics of heritable diseases into the statistical method and about GWAS into the rules for determining adaptive genome-wide significance. Results from three independent GWAS of 1000-2000 subjects each, which were made available under the National Institute of Health's "Up For A Challenge" (U4C) project, not only confirmed cell-cycle control and receptor/AKT signaling, but, for the first time in breast cancer GWAS, also consistently identified many genes involved in endo-/exocytosis (EEC), most of which had already been observed in functional and expression studies of breast cancer. In particular, the findings include genes that translocate (ATP8A1, ATP8B1, ANO4, ABCA1) and metabolize (AGPAT3, AGPAT4, DGKQ, LPPR1) phospholipids entering the phosphatidylinositol cycle, which controls EEC. These novel findings suggest scavenging phospholipids as a novel intervention to control local spread of cancer, packaging of exosomes (which prepare distant microenvironment for organ-specific metastases), and endocytosis of ß1 integrins (which are required for spread of metastatic phenotype and mesenchymal migration of tumor cells). Beta-cyclodextrins (ßCD) have already been shown to be effective in in vitro and animal studies of breast cancer, but exhibits cholesterol-related ototoxicity. The smaller alpha-cyclodextrins (αCD) also scavenges phospholipids, but cannot fit cholesterol. An in-vitro study presented here confirms hydroxypropyl (HP)-αCD to be twice as effective as HPßCD against migration of human cells of both receptor negative and estrogen-receptor positive breast cancer. If the previous successful animal studies with ßCDs are replicated with the safer and more effective αCDs, clinical trials of adjuvant treatment with αCDs are warranted. Ultimately, all breast cancer are expected to benefit from treatment with HPαCD, but women with triple-negative breast cancer (TNBC) will benefit most, because they have fewer treatment options and their cancer advances more aggressively.

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Networks of elastic fibers are ubiquitous in biological systems and often provide mechanical stability to cells and tissues. Fiber-reinforced materials are also common in technology. An important characteristic of such materials is their resistance to failure under load. Rupture occurs when fibers break under excessive force and when that failure propagates. Therefore, it is crucial to understand force distributions. Force distributions within such networks are typically highly inhomogeneous and are not well understood. Here we construct a simple one-dimensional model system with periodic boundary conditions by randomly placing linear springs on a circle. We consider ensembles of such networks that consist of N nodes and have an average degree of connectivity z but vary in topology. Using a graph-theoretical approach that accounts for the full topology of each network in the ensemble, we show that, surprisingly, the force distributions can be fully characterized in terms of the parameters (N,z). Despite the universal properties of such (N,z) ensembles, our analysis further reveals that a classical mean-field approach fails to capture force distributions correctly. We demonstrate that network topology is a crucial determinant of force distributions in elastic spring networks.

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BACKGROUND: The impact of rectal cancer tumor height on local recurrence and metastatic spread is unknown. The objective was to evaluate the impact of rectal cancer tumor height from the anal verge on metastatic spread and local recurrence patterns. METHODS: The Norwegian nationwide surgical quality registry was reviewed for curative rectal cancer resections from 1/1/1996-12/15/2006. Cancers were stratified into five height groups: 0-3 cm, >3-5 cm, >5-9 cm, >9-12 cm, 12 cm-HI. Competing risk and proportional hazards models assessed the relationship between tumor height and patterns of metastasis and survival. RESULTS: 6859 patients were analyzed. After median follow-up of 52 months (IQR 20-96), 26.7% (n = 1835) experienced recurrence. With tumors >12 cm, the risk of liver metastases increased (crude HR 1.49, p = 0.03), while lung metastases decreased (crude HR 0.66, p = 0.03), and risk of death decreased (crude HR 0.81, p = 0.001) The cumulative incidence of pelvic recurrence were highest for the low tumors (p = 0.01). Median time to liver metastases was 14months (IQR 7-24), lung metastases 25months (IQR 13-39), pelvic recurrence 19months (IQR10-32), (p < 0.0001). Time to metastases in liver and lungs were significantly associated with tumor height (p < 0.001) CONCLUSION: There are distinct differences in metastatic recurrence patterns and time to recurrence from different anatomic areas of the rectum. In crude analyses, tumor height impacted metastatic spread to the liver and lungs. However, when adjusting for treatment variables, the hazard of metastatic spread to the liver and lungs are limited. Nevertheless, time to metastases in liver and lungs is significantly impacted by tumor height. Venous drainage of the rectal cancer may be a significant contributor of rectal cancer metastatic spread, but further research is warranted.

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BACKGROUND: The middle colic artery (MCA) is of crucial importance in abdominal surgery, for laparoscopic or open right and transverse colectomies. Against this background, a high number of reports concerning anatomical variations of the MCA have been published intended to contribute to the improvement of operative techniques for the treatment of colon cancer. Despite this extensive literature, briefly reviewed in the present paper, a course of the MCA posterior to the superior mesenteric vein, called a retromesenteric trajectory, has been related to only once, to the best of our knowledge. METHODS: A total series of 507 patients included in two prospective trials concerning laparoscopic or open right colectomy for cancer between 2011 and 2017 are reported. The investigation included preoperative or postoperative multidetector-computed tomography angiography. RESULTS: We found four (0.79%) cases of retromesenteric MCA. They all underwent meticulous image analysis with mesenteric vessels' road mapping, detailed morphometry, and surgical validation which revealed that, apart from their course, those cases did not differ significantly from the rest of the series. CONCLUSION: This paper therefore documents the worth-knowing behavior causing considerable confusion for the operating surgeon unaware of the abnormality and shows its concrete impact on patient-tailored surgical practice, in particular for laparoscopic D3 colectomy (including the "uncinated process first" approach).

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Filamentous polymer networks govern the mechanical properties of many biological materials. Force distributions within these networks are typically highly inhomogeneous, and, although the importance of force distributions for structural properties is well recognized, they are far from being understood quantitatively. Using a combination of probabilistic and graph-theoretical techniques, we derive force distributions in a model system consisting of ensembles of random linear spring networks on a circle. We show that characteristic quantities, such as the mean and variance of the force supported by individual springs, can be derived explicitly in terms of only two parameters: (i) average connectivity and (ii) number of nodes. Our analysis shows that a classical mean-field approach fails to capture these characteristic quantities correctly. In contrast, we demonstrate that network topology is a crucial determinant of force distributions in an elastic spring network. Our results for 1D linear spring networks readily generalize to arbitrary dimensions.

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BACKGROUND: Quality is the major driver for both clinical and financial assessment. There remains a need for simple, affordable, quality metric tools to evaluate patient outcomes, which led us to develop the HospitAl length of stay, Readmission and Mortality (HARM) score. We hypothesized that the HARM score would be a reliable tool to assess patient outcomes across various surgical specialties. METHODS: From 2011 to 2015, we identified colorectal, hepatobiliary, upper gastrointestinal, and hernia surgery admissions using the Vizient Clinical Database. Individual and hospital HARM scores were calculated from length of stay, 30-day readmission, and mortality rates. We evaluated the correlation of HARM scores with complication rates using the Clavien-Dindo classification. RESULTS: We identified 525,083 surgical patients: 206,981 colorectal, 164,691 hepatobiliary, 97,157 hernia, and 56,254 upper gastrointestinal. Overall, 53.8% of patients were admitted electively with a mean HARM score of 2.24; 46.2% were admitted emergently with a mean HARM score of 1.45 (p < 0.0001). All HARM components correlated with patient complications on logistic regression (p < 0.0001). The mean length of stay increased from 3.2 ± 1.8 days for a HARM score < 2 to 15.1 ± 12.2 days for a HARM score > 4 (p < 0.001). In elective admissions, for HARM categories of < 2, 2-< 3, 3-4, and > 4, complication rates were 9.3, 23.2, 38.8, and 71.6%, respectively. There was a similar trend for increasing HARM score in emergent admissions as well. For all surgical procedure categories, increasing HARM score, with and without risk adjustment, correlated with increasing severity of complications by Clavien-Dindo classification. CONCLUSIONS: The HARM score is an easy-to-use quality metric that correlates with increasing complication rates and complication severity across multiple surgical disciplines when evaluated on a large administrative database. This inexpensive tool could be adopted across multiple institutions to compare the quality of surgical care.

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BACKGROUND: The HospitAl length of stay, Readmissions and Mortality (HARM) score is a simple, inexpensive quality tool, linked directly to patient outcomes. We assess the HARM score for measuring surgical quality across multiple surgical populations. METHODS: Upper gastrointestinal, hepatobiliary, and colorectal surgery cases between 2005 and 2009 were identified from the Healthcare Cost and Utilization Project California State Inpatient Database. Composite and individual HARM scores were calculated from length of stay, 30-day readmission and mortality, correlated to complication rates for each hospital and stratified by operative type. RESULTS: 71,419 admissions were analyzed. Higher HARM scores correlated with higher complication rates for all cases after risk adjustment and stratification by operation type, elective or emergent status. CONCLUSIONS: The HARM score is a simple and valid quality measurement for upper gastrointestinal, hepatobiliary and colorectal surgery. The HARM score could facilitate benchmarking to improve patient outcomes and resource utilization, and may facilitate outcome improvement.

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OBJECTIVE: The aim of this study was to examine changes over time in the female: male HIV prevalence ratio in 18 countries in Sub-Saharan Africa, overall and when stratified by area of residence, educational attainment and marital status. METHODOLOGY: We used data from the Demographic and Health Surveys, which are nationally representative household surveys. By using data from 18 countries with at least two survey rounds with HIV testing, and dividing the countries into three regions (Western/Central, Eastern and Southern) we were able to examine cross-country and regional changes in the female: male HIV prevalence ratio over time. Logistic regression was used to estimate female: male HIV prevalence ratios in urban versus rural areas and for different categories of education and marital status. To assess changes over time, we compared the confidence intervals of the prevalence ratios. RESULTS: The female: male HIV prevalence ratio was above one in all countries in at least one survey round for both ages 15-24 years and 25-49 years. In 13 out of 18 countries the prevalence ratio was higher for the younger age group compared to the age group 25-49 years (3 significant) and this difference in prevalence ratios between the age groups did not change over time. Overall, there was a higher frequency of increasing than decreasing prevalence ratios. The gender disparity was greater among those who were married/living together than among the never-married, and over time, the ratio was more stable among the married/living together. The study found no clear differential changes by education. CONCLUSION: Women continue to carry the greater burden of HIV in Sub-Saharan Africa and there is no clear pattern of change in the gap between men and women as the direction and magnitude of change in the prevalence ratios varied greatly.

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IMPORTANCE: Laparoscopic colectomy is safe and effective in the treatment of many colorectal diseases. However, the effect of increasing use of laparoscopy on overall health care utilization and costs, especially in the long term, has not been thoroughly investigated. OBJECTIVE: To evaluate the effect of laparoscopic vs open colectomy on short- and long-term health care utilization and costs. DESIGN, SETTING, AND PARTICIPANTS: Retrospective multivariate regression analysis of national health insurance claims data was used to evaluate health care utilization and costs up to 1 year following elective colectomy. Data were obtained from the Truven Health Analytics MarketScan Commercial Claims and Encounters database. Patients aged 18 to 64 years who underwent elective laparoscopic or open colectomy from January 1, 2010, through December 31, 2010, were included. Patients with complex diagnoses that require increased non-surgery-related health care utilization, including malignant neoplasm, inflammatory bowel disease, human immunodeficiency virus, transplantation, and pregnancy, were excluded. Of 25 481 patients who underwent colectomy, 4160 were included in the study. MAIN OUTCOMES AND MEASURES: Healthcare utilization, including office, hospital outpatient, and emergency department visits and inpatient services 90 and 365 days after the index procedure; total health care costs; and estimated days off from work owing to health care utilization. RESULTS: Of 25 481 patients who underwent colectomy, 4160 were included in the study (laparoscopic, 45.6%; open, 54.4%). The mean (SD) net and total payments were lower for laparoscopy ($23 064 [$14 558] and $24 196 [$14 507] vs $29 753 [$21 421] and $31 606 [$23 586]). In the first 90 days after surgery, an open approach was significantly associated with a 1.26-fold increase in health care costs (estimated, $1715; 95% CI, $338-$2853), increased use of heath care services, and more estimated days off from work (2.78 days; 95% CI, 1.93-3.59). Similar trends were found in the full postoperative year, with an estimated 1.18-fold increase (95% CI, 1.04-1.35) in health care expenditures and an increase of 1.15 times (95% CI, 1.08-1.23) the number of health care utilization days compared with laparoscopy. CONCLUSIONS AND RELEVANCE: Laparoscopic colectomy results in a significant reduction in health care costs and utilization in the short- and long-term postoperative periods.

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