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ABSTRACT Managing fertile eggs and minimizing seasonal impacts is crucial in poultry farming. This study evaluated the effects of the storage time of fertile eggs, broiler breeder strain, and age on hatchability and first-week broiler performance. Twelve treatments were carried out in a factorial arrangement with two broiler breeder strains (Cobb MV and Ross 308AP), two breeder age intervals (between 30-40 weeks and between 50-60 weeks), and three egg storage times (4, 7 and 9 days). The Ross 308AP strain showed the highest hatchability (91.74%) at 30-40 weeks, while Cobb MV had the greatest weight gain (162.75g) from days 1 to 7 at 50-60 weeks. Longer egg storage affected weight gain at 7 days for Cobb MV. Nine-day storage reduced chick weight (45.46g) from breeders aged 50-60 weeks. Lower first-stage embryonic mortality was observed in Ross 308 AP (3.83%) in breeders aged 30-40 weeks (4.13%), and in eggs stored for 4 days (4.01%). The Ross 308AP had the greatest percentage of infertile eggs (10.25%), and breeders aged 50-60 weeks showed greater percentages of infertility (10.14%). The Cobb MV had lower second-stage embryonic mortality but higher percentages of discarded chicks. Hatchability and first-week broiler performance depend on storage time, breeder age and strain.

Abstract Background Structural abnormalities as well as minor variations of the Y chromosome may cause disorders of sex differentiation or, more frequently, azoospermia. This study aimed to determine the prevalence of loss of Y chromosome material within the spectrum ranging from small microdeletions in the azoospermia factor region (AZF) to complete loss of the Y chromosome in azoospermic men. Results Eleven of 865 azoospermic men (1.3%) collected from 1997 to 2022 were found to have a karyotype including a 45,X cell line. Two had a pure 45,X karyotype and nine had a 45,X/46,XY mosaic karyotype. The AZF region, or part of it, was deleted in eight of the nine men with a structural abnormal Y-chromosome. Seven men had a karyotype with a structural abnormal Y chromosome in a non-mosaic form. In addition, Y chromosome microdeletions were found in 34 men with a structural normal Y chromosome. No congenital malformations were detected by echocardiography and ultrasonography of the kidneys of the 11 men with a 45,X mosaic or non-mosaic cell line. Conclusions In men with azoospermia, Y chromosome loss ranging from small microdeletions to complete loss of the Y chromosome was found in 6.1% (53/865). Partial AZFb microdeletions may give a milder testicular phenotype compared to complete AZFb microdeletions.

Enzootic bovine leucosis is caused by bovine leukaemia virus (BLV), a Deltaretrovirus belonging to the family Retroviridae. BLV causes huge economic losses to the dairy industry in the form of decreased milk production, premature culling, and poor reproductive performance of the animals. The aim of the present study was to determine the seroprevalence of BLV infection in buffalo in two districts of Punjab, Pakistan. A total of 384 samples were collected and analysed using a commercial indirect enzyme-linked immunosorbent assay (ELISA) to investigate the seroprevalence of BLV through the detection of the anti-BLV gp51 antibody. A predesigned data questionnaire proforma was employed to find out the association of risk factors with disease. Overall, 18.2% of buffaloes were seropositive for BLV in the study population. The results revealed a significant association (P

Het doel van deze studie is te onderzoeken hoe familieleden van psychogeriatrische verpleeghuispatie¨nten, waarbij het besluit is genomen al dan niet te starten met kunstmatig toedienen van vocht en/of voedsel (ktvv), het besluitvormingsproces beoordelen. Ook de informatieverstrekking van het verpleeghuispersoneel en de geboden zorg aan de patie¨nt worden gee¨valueerd. Het onderzoek was een observationele studie met behulp van vragenlijsten. Familieleden van 99 psychogeriatrische verpleeghuispatie¨nten vulden zowel op het moment van het besluit als zes weken na het nemen van het besluit of zes weken na het overlijden van de patie¨nt een vragenlijst in. Bijna alle familieleden beoordeelden de vier aspecten van het besluitvormingsproces (aantal keren overleg, inhoud van de gesprekken, zorgvuldigheid van de besluitvorming en eigen aandeel in de besluitvorming) op beide tijdstippen als ‘goed’ of ‘voldoende’. Verder bleek men de zorgvuldigheid van de besluitvorming significant vaker als ‘goed’ te beoordelen als men ook de andere drie aspecten ‘goed’ vond. Hierbij speelde met name hun eigen invloed op het besluitvormingsproces een rol. Informatieverstrekking over de mogelijke gevolgen van het al dan niet starten met ktvv als ook over de toestand van de patie¨nt werden bijna altijd als voldoende ervaren. Dit gold ook voor de aan de patie¨nt geboden zorg. Over het geheel genomen zijn bijna alle families tevreden over het verloop van het besluitvormingsproces en het uiteindelijk genomen besluit. Deze tevredenheid veranderde niet noemenswaardig tussen het moment van het besluit en naderhand. Hierbij maakte het feit dat de patie¨nt wel of niet was overleden geen verschil. Toch waren er enkele familieleden die niet tevreden waren over de (besluitvorming en) verpleeghuiszorg. Deze kritiek sluit aan bij de negatieve berichtgeving over de verpleeghuiszorg van de afgelopen jaren

De kans op het krijgen van chronische pijnklachten e´n op het ontstaan van dementie neemt toe naarmate men ouder wordt. Dit betekent dat door de toenemende vergrijzing het aantal demente ouderen met chronische pijn eveneens sterk zal toenemen. De vraag rijst of en op welke wijze demente ouderen pijn ervaren. Het tekortschieten van de pijndiagnostiek, vooral in een gevorderd stadium van dementie, wordt weerspiegeld in een verminderd gebruik van pijnstillers door ouderen met een dementie. Inzicht in mogelijke veranderingen in pijnbeleving zoals die worden waargenomen in de slechts enkele klinische studies, kan vergroot worden door kennis over de neuropathologie die per subtype dementie kan verschillen. Het is opvallend dat er helemaal geen studies zijn verricht naar pijnbeleving bij aandoeningen van het centrale zenuwstelsel met een verhoogd risico op cognitieve achteruitgang zoals de ziekte van Parkinson en multiple sclerose. Bij deze ziekten behoort pijn tot e´e´n van de klinische symptomen en het is tot dusver onbekend of er veranderingen in pijnbeleving optreden in een fase waarin het cognitief functioneren achteruitgaat. Tenslotte worden kort een aantal instrumenten besproken welke het meest geschikt zijn om pijn te diagnostiseren bij communicatieve en non-communicatieve patie¨nten met een dementie.

Few fast-swimming apex fishes are classified as ‘regional endotherms’, having evolved a relatively uncommon suite of traits (e.g. elevated body temperatures, centralised red muscle, and thick-walled hearts) thought to facilitate a fast, predatory lifestyle. Unlike those apex predators, Endangered basking sharks Cetorhinus maximus are massive filter-feeding planktivores assumed to have the anatomy and physiology typical of fully ectothermic fishes. We combined dissections of stranded specimens with biologging of free-swimming individuals and found that basking sharks have red muscle located medially at the trunk, almost 50% compact myocardium of the ventricle, and subcutaneous white muscle temperatures consistently 1.0 to 1.5°C above ambient. Collectively, our findings suggest basking sharks are not full ectotherms, instead sharing several traits used to define a regional endotherm, thus deviating from our current understanding of the species and questioning the link between physiology and ecology of regionally endothermic shark species. With successful forecasting of population dynamics and distribution shifts often improved by accurate physiological data, our results may help explain movement patterns of the species, which could ultimately facilitate conservation efforts.

Introduction/Objective: Human herpesvirus-8 (HHV-8)-associated multicentric Castleman disease (MCD) is a rare lymphoproliferative disorder sometimes associated with acquired human immunodeficiency syndrome. Hemophagocytic lymphohistiocytosis (HLH) and tumor lysis syndrome (TLS) are unusual complications of MCD. Here, we presented a case report of an HIV patient with MCD who evolved for HLH and TLS, atypical presentations in this clinical setting. Methods: Data were obtained reviewing the medical record of a patient diagnosed and treated at the University of São Paulo (USP) in 2023. Case report: A 31 year-old man was admitted at the emergency department of HC-USP in June 2023 presenting multiple adenomegalies, recurrent fever and weight loss during the past 4 months. He had a previous diagnosis of HIV infection in regular treatment, with a T-CD4 lymphocyte count = 514 copies/mL. The patient was previously admitted in another service due to infectious complications, where he underwent an axillary lymph node biopsy, which showed lymphoid hyperplasia rich in interfollicular plasmocytes, compatible with a HHV-8-associated MCD, in addition to a spindle-cell neoplastic proliferation, supporting theconcomitant diagnosis of Kaposi's sarcoma (KS). He was submitted to up-front treatment based on prednisone 1 mg/kg/day. Upon admission at the HC-USP, he presented hepatosplenomegaly, ascites, and multiple lymph node enlargement. Laboratory evaluation revealed anemia, thrombocytopenia, hypoalbuminemia and marked increase in inflammatory tests, fulfilling criteria for MCD activity. After 10 days, he evolved with worsening of hepatosplenomegaly, progressive increase of direct bilirubin, pancytopenia, hyperferritinemia and hypertriglyceridemia. He also had TLS requiring dyalisis. Due to this presentation, a bone marrow evaluation was performed, which showed many figures of hemophagocytosis and high EBV viral load measured by qRT-PCR. The H-Score was applied to this case, with a result of 228 points, inferring 98-99% probability of HLH diagnosis, compatible with the previously formulated hypothesis. Promptly, methylprednisolone pulsotherapy was started at a dose of 1 g/day I.V. and etoposide 50 mg/m2/day I.V. for 3 days. Despite this approach, the patient presented an unfavorable evolution, evolving to death before the institution of up-front treatment for HHV-8-MCD. Discussion: HLH is a potentially lethal condition caused by macrophage hyperactivation following inflammatory, neoplastic or infectious triggers. Among the main causes, the HHV-8 virus highlights, particullarly in the context of immunosuppression. This virus is also involved in the pathogenesis of MCD and KS. There are, however, few reports of association between both disorders. Moreover, the association between MCD and TLS is also rare, since it is a non-neoplastic lymphoproliferative disease with low cellular turn-over. In view of the possible evolution to aggressive non-Hodgkin's lymphoma during the MCD's course, the TLS presence should prompt get to the search for concomitant DLBCL, which was not possible in this case due to the unfavorable premature evolution. Conclusion: This case showed that HLH and TLS, although rarely associated with MCD, can lead to serious organ dysfunctions with a potentially fatal course. Prompt recognition of both conditions is essential to establish early therapeutic measures that are crucial to ensure satisfactory clinical outcomes.

The most common complication in older surgical patients is postoperative delirium (POD). POD is associated with preoperative cognitive impairment and longer durations of intraoperative burst suppression (BSup) – electroencephalography (EEG) with repeated periods of suppression (very low-voltage brain activity). However, BSup has modest sensitivity for predicting POD. We hypothesized that a brain state of lowered EEG power immediately precedes BSup, which we have termed “pre-burst suppression” (preBSup). Further, we hypothesized that even patients without BSup experience these preBSup transient reductions in EEG power, and that preBSup (like BSup) would be associated with preoperative cognitive function and delirium risk. Data included 83 32-channel intraoperative EEG recordings of the first hour of surgery from 2 prospective cohort studies of patients ≥age 60 scheduled for ≥2-h non-cardiac, non-neurologic surgery under general anesthesia (maintained with a potent inhaled anesthetic or a propofol infusion). Among patients with BSup, we defined preBSup as the difference in 3–35 Hz power (dB) during the 1-s preceding BSup relative to the average 3–35 Hz power of their intraoperative EEG recording. We then recorded the percentage of time that each patient spent in preBSup, including those without BSup. Next, we characterized the association between percentage of time in preBSup and (1) percentage of time in BSup, (2) preoperative cognitive function, and (3) POD incidence. The percentage of time in preBSup and BSup were correlated (Spearman’s ρ [95% CI]: 0.52 [0.34, 0.66], p < 0.001). The percentage of time in BSup, preBSup, or their combination were each inversely associated with preoperative cognitive function (β [95% CI]: −0.10 [−0.19, −0.01], p = 0.024; −0.04 [−0.06, −0.01], p = 0.009; −0.04 [−0.06, −0.01], p = 0.003, respectively). Consistent with prior literature, BSup was significantly associated with POD (odds ratio [95% CI]: 1.34 [1.01, 1.78], p = 0.043), though this association did not hold for preBSup (odds ratio [95% CI]: 1.04 [0.95, 1.14], p = 0.421). While all patients had ≥1 preBSup instance, only 20.5% of patients had ≥1 BSup instance. These exploratory findings suggest that future studies are warranted to further study the extent to which preBSup, even in the absence of BSup, can identify patients with impaired preoperative cognition and/or POD risk.

North Atlantic right whales Eubalaena glacialis are most commonly observed along the eastern seaboard of North America; however, their distribution and occupancy patterns have become less predictable in the last decade. This study explored the individual right whales captured photographically from both dedicated and opportunistic sources from 2015 to 2019 in the Gulf of St. Lawrence (GSL), an area previously understudied for right whale presence. A total of 187 individuals, including reproductive females, were identified from all sources over this period. In years when more substantial survey effort occurred (2017-2019), similar numbers of individuals were sighted (mean = 133, SD = 1.5), and dedicated mark-recapture aerial surveys were highly effective at capturing almost all of the whales estimated in the region (2019: N = 137, 95% CI = 135-147). A high rate of inter-annual return was observed between all 5 study years, with 95% of the animals seen in 2019 sighted previously. Capture rates indicated potential residencies as long as 5 mo, and observed behaviors included feeding and socializing. Individuals were observed in the northern and southern GSL, regions divided by a major shipping corridor. Analyses suggest that individuals mostly moved less than 9.1 km d-1, although rates of up to 79.8 km d-1 were also calculated. The GSL is currently an important habitat for 40% of this Critically Endangered species, which underscores how crucial protection measures are in this area.

Animals display fear-like behaviours before escaping from predators. This response triggers both behavioural and physiological changes in multiple body systems, allowing animals to escape danger and ensure survival. Fear-like behaviour is modulated by the serotonergic system in the brain of vertebrates, which shapes social behaviour and cooperative behaviours. Using fluoxetine (FLX), a common pharmaceutical that alters the levels of serotonin in the brain, we aimed to clarify whether the same is true in solitary animals like green turtles Chelonia mydas. Green turtles exhibit individual differences in their response to risk. If fear-related behaviours are regulated by the serotonin system in turtles, the fear-like responses of individuals injected with FLX could change. We therefore assessed the effect of FLX injection on the behavioural responses to a fear stimulus in 9 wild juvenile green turtles in an aquarium setting. We inserted a hand net as a stimulus into the aquarium (within a designated inspection zone) to elicit a fear-like behaviour and measured the time that turtles spent in this zone. All turtles exhibited fear-like behaviour and fled from the stimulus prior to any injection treatment. Turtles with control injection (no FLX) also fled and avoided the inspection zone with the fear stimulus. FLX injection appeared to reduce the turtles’ fear of the stimulus: The total time turtles injected with FLX spent in the inspection zone was significantly longer than for turtles that received a control medium injection. Control turtles fled from the stimulus and were initially vigilant and avoided the area with the stimulus, but then moved throughout the aquarium, including the inspection zone. These data suggest that fear-like behaviour is modulated by the serotonin-mediated nerve system in juvenile green turtles.

Objectives: Disease transmission models are used in impact assessment and economic evaluations of infectious disease prevention and treatment strategies, prominently so in the COVID-19 response. These models rarely consider dimensions of equity relating to the differential health burden between individuals and groups. We describe concepts and approaches which are useful when considering equity in the priority setting process, and outline the technical choices concerning model structure, outputs, and data requirements needed to use transmission models in analyses of health equity. Methods: We reviewed the literature on equity concepts and approaches to their application in economic evaluation and undertook a technical consultation on how equity can be incorporated in priority setting for infectious disease control. The technical consultation brought together health economists with an interest in equity-informative economic evaluation, ethicists specialising in public health, mathematical modellers from various disease backgrounds, and representatives of global health funding and technical assistance organisations, to formulate key areas of consensus and recommendations. Results: We provide a series of recommendations for applying the Reference Case for Economic Evaluation in Global Health to infectious disease interventions, comprising guidance on 1) the specification of equity concepts; 2) choice of evaluation framework; 3) model structure; and 4) data needs. We present available conceptual and analytical choices, for example how correlation between different equity- and disease-relevant strata should be considered dependent on available data, and outline how assumptions and data limitations can be reported transparently by noting key factors for consideration. Conclusions: Current developments in economic evaluations in global health provide a wide range of methodologies to incorporate equity into economic evaluations. Those employing infectious disease models need to use these frameworks more in priority setting to accurately represent health inequities. We provide guidance on the technical approaches to support this goal and ultimately, to achieve more equitable health policies.

Abstract Background Recent advances in the treatment algorithms of early breast cancer have markedly improved overall survival. However, anthracycline- and trastuzumab-associated cardiotoxicity may lead to dose-reduction or halt in potentially life-saving adjuvant cancer therapy. Early initiated neurohormonal blockade may prevent or attenuate the cardiotoxicity-induced reduction in cardiac function, but prior studies have been inconclusive. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan has been shown to be superior to traditional treatment in heart failure with reduced ejection fraction, but its cardioprotective effects in the cardio-oncology setting remains to be tested. Objective To assess if sacubitril/valsartan given concomitantly with early breast cancer treatment regimens including anthracyclines, with or without trastuzumab, may prevent cardiac dysfunction. Methods PRADA II is a randomized, placebo-controlled, double blind, multi-center, investigator-initiated clinical trial. Breast cancer patients from four university hospitals in Norway, scheduled to receive (neo-)adjuvant chemotherapy with epirubicin independently of additional trastuzumab/pertuzumab treatment, will be randomized 1:1 to sacubitril/valsartan or placebo. The target dose is 97/103 mg b.i.d. The patients will be examined with cardiovascular magnetic resonance (CMR), echocardiography, circulating cardiovascular biomarkers and functional testing at baseline, at end of anthracycline treatment and following 18 months after enrolment. The primary outcome measure of the PRADA II trial is the change in left ventricular ejection fraction (LVEF) by CMR from baseline to 18 months. Secondary outcomes include change in LV function by global longitudinal strain by CMR and echocardiography and change in circulating cardiac troponin concentrations. Results The study is ongoing. Results will be published when the study is completed. Conclusion PRADA II is the first randomized, placebo-controlled study of sacubitril/valsartan in a cardioprotective setting during (neo-)adjuvant breast cancer therapy. It may provide new insight in prevention of cardiotoxicity in patients receiving adjuvant or neo-adjuvant therapy containing anthracyclines. Furthermore, it may enable identification of patients at higher risk of developing cardiotoxicity and identification of those most likely to respond to cardioprotective therapy. Trial registration The trial is registered in the ClinicalTrials.gov registry (identifier NCT03760588 ). Registered 30 November 2018.

Lucy R Mgopa,1 B R Simon Rosser,2 Michael W Ross,3 Inari Mohammed,2 Gift Gadiel Lukumay,4 Agnes F Massae,4 Stella E Mushy,4 Dorkasi L Mwakawanga,4 Ever Mkonyi,2 Maria Trent,5 Zobeida E Bonilla,2 James Wadley,6 Sebalda Leshabari4, † 1Department of Psychiatry and Mental Health, School of Medicine, Muhimbili University of Health and Allied Sciences (MUHAS), Dar Es Salaam, Tanzania; 2Department of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA; 3Program in Human Sexuality, Department of Family Medicine, University of Minnesota, Minneapolis, MN, USA; 4Department of Community Health Nursing, School of Nursing, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania; 5Department of Adolescent and Young Adult Medicine, Johns Hopkins University Schools of Medicine and Public Health, Baltimore, MD, USA; 6Department of Counseling and Health Services, Lincoln University, Philadelphia, PA, USA†Dr. Leshabari passed away on October 16th, 2020.Correspondence: B R Simon RosserUniversity of Minnesota, 1300 S. 2 nd St. #300, Minneapolis, 55454, MN Tel +1 612- 624-0358Email rosser@umn.eduIntroduction: Africa has high rates of interpersonal violence and rape, although little is known about how these cases are handled in the clinical setting.Methods: We enrolled 121 health care professionals and students in Tanzania from the fields of midwifery, nursing and medicine, and conducted 18 focus group discussions stratified by both professional and clinical experience. Two clinical scenarios were presented across all groups and participants were asked to give their opinions on how the hospital they worked in would manage the cases. Case 1 focused on how to address a case of an injured woman beaten by her husband (and whether the perpetrator would be reported to the police). Case 2 focused on how to handle a rape victim who is brought to the hospital by the police.Results: Participants considered both cases as emergencies. There was a similarity in the clinical care procedures across both scenarios. This included building rapport with the patient, prioritization of the medical care, history taking, and referring to other specialties for follow-up. Participants differed in how they would handle the legal aspects of both cases, including whether and how to best follow mandated reporting policies. Providers wondered if they should report the husband in case study 1, the criteria for reporting, and where to report. Providers displayed a lack of knowledge about resources needed for sexual violence victim and the availability of resources.Conclusion: These findings indicate that cases of intimate partner violence and rape are likely to be under-reported within hospitals and clinics in Tanzania. Health care providers lack training in their required obligations and procedures that need to be followed to ensure victim’s safety. The findings confirm that there is a need for health care students in Tanzania (and possibly Africa) to receive comprehensive training in how to handle such cases.Keywords: IPV, violence, rape, GBV, health provider, Tanzania

Widespread and unregulated hunting of ungulates in Southeast Asia is resulting in population declines and localised extinctions. Increased access to previously remote tropical forest following logging and changes in land-use facilitates hunting of elusive wild cattle in Borneo, which preferentially select secluded habitat. We collated the first population parameters for the Endangered Bornean banteng Bos javanicus lowi and developed population models to simulate the effect of different hunting offtake rates on survival and the recovery of the population using reintroduced captive-bred individuals. Our findings suggest that the banteng population in Sabah is geographically divided into 4 management units based on connectivity: the Northeast, Sipitang (West), Central and Southeast, which all require active management to prevent further population decline and local extinction. With only 1% offtake, population growth ceased in the Northeast and Sipitang. In the Southeast and Central units, growth ceased at 2 and 4% offtake, respectively. Extinction was estimated at 21-39 yr when offtake was 5%, occurring first in Sipitang and last in the Central unit. Supplementing the population with captive-bred individuals suggested that inbreeding was likely to limit population growth if using ≤20 founder individuals. Translocating 2 individuals for a 10 yr period, starting after 20 yr of captive breeding resulted in a faster population recovery over 100 yr and a lower extinction probability. Our results suggest that shielding the population against further losses from hunting will be key to their survival in the wild, provided that active management in the form of captive breeding is developed in the interim.

Functional connectivity (FC) in the brain has been shown to exhibit subtle but reliable modulations within a session. One way of estimating time-varying FC is by using state-based models that describe fMRI time series as temporal sequences of states, each with an associated, characteristic pattern of FC. However, the estimation of these models from data sometimes fails to capture changes in a meaningful way, such that the model estimation assigns entire sessions (or the largest part of them) to a single state, therefore failing to capture within-session state modulations effectively; we refer to this phenomenon as the model becoming static, or model stasis. Here, we aim to quantify how the nature of the data and the choice of model parameters affect the model's ability to detect temporal changes in FC using both simulated fMRI time courses and resting state fMRI data. We show that large between-subject FC differences can overwhelm subtler within-session modulations, causing the model to become static. Further, the choice of parcellation can also affect the model's ability to detect temporal changes. We finally show that the model often becomes static when the number of free parameters per state that need to be estimated is high and the number of observations available for this estimation is low in comparison. Based on these findings, we derive a set of practical recommendations for time-varying FC studies, in terms of preprocessing, parcellation and complexity of the model.

Cultured Atlantic salmon Salmo salar are of international socioeconomic value, and the process of domestication has resulted in significant behavioural, morphological, and allelic differences from wild populations. Substantial evidence indicates that direct genetic interactions or interbreeding between wild and escaped farmed Atlantic salmon occurs, genetically altering wild salmon and reducing population viability. However, genetic interactions may also occur through ecological mechanisms (e.g. disease, parasites, predation, competition), both in conjunction with and in the absence of interbreeding. Here we examine existing evidence for ecological and non-reproductive genetic interactions between domestic Atlantic salmon and wild populations and the potential use of genetic and genomic tools to resolve these impacts. Our review identified examples of genetic changes resulting from ecological processes, predominately through pathogen or parasite transmission. In addition, many examples were identified where aquaculture activities have either altered the selective landscape experienced by wild populations or resulted in reductions in population abundance, both of which are consistent with the widespread occurrence of indirect genetic changes. We further identify opportunities for genetic or genomic methods to quantify these impacts, though careful experimental design and pre-impact comparisons are often needed to accurately attribute genetic change to aquaculture activities. Our review indicates that ecological and non-reproductive genetic interactions are important, and further study is urgently needed to support an integrated understanding of aquaculture-ecosystem interactions, their implications for ecosystem stability, and the development of potential mitigation and management strategies.

Abstract: Ships brighten low marine clouds from emissions of sulfur and aerosols, resulting in visible “ship tracks”. In 2020, new shipping regulations mandated an ∼80% reduction in the allowed fuel sulfur content. Recent observations indicate that visible ship tracks have decreased. Model simulations indicate that since 2020 shipping regulations have induced a net radiative forcing of +0.12 Wm−2. Analysis of recent temperature anomalies indicates Northern Hemisphere surface temperature anomalies in 2022–2023 are correlated with observed cloud radiative forcing and the cloud radiative forcing is spatially correlated with the simulated radiative forcing from the 2020 shipping emission changes. Shipping emissions changes could be accelerating global warming. To better constrain these estimates, better access to ship position data and understanding of ship aerosol emissions are needed. Understanding the risks and benefits of emissions reductions and the difficultly in robust attribution highlights the large uncertainty in attributing proposed deliberate climate intervention.

Background: Globally, there has been an overall decline in the effectiveness of antibiotics resulting in an upsurge in bacterial resistance, increased cost of healthcare and consequent high morbidity and mortality rates. Objective: To determine antibiotic prescription practices among healthcare workers at the Kenyatta National Hospital, Mbagathi, Pumwani Maternity and Mama Lucy Kibaki Hospitals, Nairobi, Kenya. Methods: The study design was a mixture of quantitative and qualitative methods. Self-administered questionnaires were used to gather information from 230 prescribing healthcare workers. Interviews and Focus Group Discussions (FGDs) were conducted purposively with the prescribing healthcare workers and patients to obtain qualitative data. Results: There was a significant difference in the distribution of study participants with regards to the availability of antibiotics prescribing policy (p = 0.05). Only 53 (23%) prescribers prescribed antibiotics as per the policy guide while 51 (22.2%) did not and 126 (54.8%) were not sure. Oral antibiotics (OR = 0.5, 95%CI 0.3-0.9), always referring to the 2016 Kenya Essential Medicines List (KEML) to prescribe antibiotics (OR = 4.2, 95%CI 1.3-13.1), separating antibiograms for inpatient and outpatient departments (OR = 4.3, 95%CI 1.11-15.5), and confidence of healthcare workers to prescribe antibiotics without laboratory tests (OR = 0.3, 95%CI 0.2-0.8) were associated with the prescription of antibiotics. Conclusion: There is need to improve antibiotic prescription practices among healthcare workers in public tertiary hospitals in Nairobi County to promote rational antibiotic use and control bacterial resistance.

High glucose concentrations have been shown to activate endothelial cells and promote angiogenesis. In the present study, it was investigated whether high glucose concentrations could improve the vascularisation capacity of adipose-tissue-derived microvascular fragments (ad-MVF). Ad-MVF were isolated from the epididymal fat pads of donor mice and cultivated for 24 h in University of Wisconsin (UW) solution supplemented with vehicle or 30 mM glucose. Protein expression, morphology, viability and proliferation of the cultivated ad-MVF were analysed by means of proteome profiler mouse angiogenesis array, scanning electron microscopy and immunohistochemistry. Additional cultivated ad-MVF were seeded on to collagen-glycosaminoglycan scaffolds to study their in vivo vascularisation capacity in the dorsal skinfold chamber model by intravital fluorescence microscopy, histology and immunohistochemistry. In vitro, high glucose exposure changed the protein expression pattern of ad-MVF with endoglin, interleukin (IL)-1β and monocyte chemoattractant protein (MCP)-1 as the most up-regulated pro-angiogenic factors. Moreover, high glucose exposure induced the formation of nanopores in the ad-MVF wall. In addition, ad-MVF contained significantly larger numbers of proliferating endothelial and perivascular cells while exhibiting a comparable number of apoptotic cells when compared to vehicle-treated controls. In vivo, scaffolds seeded with high-glucose-exposed ad-MVF exhibited an improved vascularisation and tissue incorporation. These findings demonstrated that the exposure of cultivated ad-MVF to high glucose concentrations is a promising approach to improve their in vivo performance as vascularisation units for tissue engineering and regenerative medicine.

It is now over 30 years since Demchenko and Ladokhin first posited the potential of the tryptophan red edge excitation shift (REES) effect to capture information on protein molecular dynamics. While there have been many key efforts in the intervening years, a biophysical thermodynamic model to quantify the relationship between the REES effect and protein flexibility has been lacking. Without such a model the full potential of the REES effect cannot be realized. Here, we present a thermodynamic model of the tryptophan REES effect that captures information on protein conformational flexibility, even with proteins containing multiple tryptophan residues. Our study incorporates exemplars at every scale, from tryptophan in solution, single tryptophan peptides, to multitryptophan proteins, with examples including a structurally disordered peptide, de novo designed enzyme, human regulatory protein, therapeutic monoclonal antibodies in active commercial development, and a mesophilic and hyperthermophilic enzyme. Combined, our model and data suggest a route forward for the experimental measurement of the protein REES effect and point to the potential for integrating biomolecular simulation with experimental data to yield novel insights.

Objectives Studies have demonstrated high rates of mortality in people with proximal femoral fracture and SARS-CoV-2, but there is limited published data on the factors that influence mortality for clinicians to make informed treatment decisions. This study aims to report the 30-day mortality associated with perioperative infection of patients undergoing surgery for proximal femoral fractures and to examine the factors that influence mortality in a multivariate analysis.Setting Prospective, international, multicentre, observational cohort study.Participants Patients undergoing any operation for a proximal femoral fracture from 1 February to 30 April 2020 and with perioperative SARS-CoV-2 infection (either 7 days prior or 30-day postoperative).Primary outcome 30-day mortality. Multivariate modelling was performed to identify factors associated with 30-day mortality.Results This study reports included 1063 patients from 174 hospitals in 19 countries. Overall 30-day mortality was 29.4% (313/1063). In an adjusted model, 30-day mortality was associated with male gender (OR 2.29, 95% CI 1.68 to 3.13, p80 years (OR 1.60, 95% CI 1.1 to 2.31, p=0.013), preoperative diagnosis of dementia (OR 1.57, 95% CI 1.15 to 2.16, p=0.005), kidney disease (OR 1.73, 95% CI 1.18 to 2.55, p=0.005) and congestive heart failure (OR 1.62, 95% CI 1.06 to 2.48, p=0.025). Mortality at 30 days was lower in patients with a preoperative diagnosis of SARS-CoV-2 (OR 0.6, 95% CI 0.6 (0.42 to 0.85), p=0.004). There was no difference in mortality in patients with an increase to delay in surgery (p=0.220) or type of anaesthetic given (p=0.787).Conclusions Patients undergoing surgery for a proximal femoral fracture with a perioperative infection of SARS-CoV-2 have a high rate of mortality. This study would support the need for providing these patients with individualised medical and anaesthetic care, including medical optimisation before theatre. Careful preoperative counselling is needed for those with a proximal femoral fracture and SARS-CoV-2, especially those in the highest risk groups.Trial registration number NCT04323644

Background: 5-fluorouracil (5-FU) and mitomycin-C (MMC) with radiotherapy (RT) remain an established treatment for patients with anal cancer (AC). Genetic mutations in two major metabolizing enzymes for 5-FU; dihydropyrimidine dehydrogenase ( DPYD and thymidylate synthetase ( TYMS ), have been associated with clinical response and toxicity. However, their place in the treatment of AC remains undetermined. Methods: We retrospectively reviewed 21 patients with AC, including T2-4, N0-1, M0 or T1-4, N2-3, and M0 treated between 2012 and 2018. All patients were treated with 5-FU 1,000 mg/m 2 /day via continuous intravenous (IV) infusion 1–4 and 29–32, MMC 10 mg/m 2 IV bolus days 1 and 29 plus RT. Patients who developed ⩾3 grade toxicities were tested for the DPYD and TYMS genes. Treatment was either modified with reduced doses or changed to MMC 10 mg/m 2 day 1 and 29 with cisplatin 25 mg/m 2 /week plus RT. Toxicities and responses were collected. Results: Six out of 21 patients who developed ⩾3 grade toxicities including pancytopenia, neutropenia, thrombocytopenia, mucositis, nausea, rash, and nephritis were found to have genetic mutations: TYMS 2RG/3RC ( n = 2), 3RG/3RC ( n = 1), 2R/2R ( n = 2), T YMS 3′UTR del/Ins ( n = 2), and DPYD c.2864A > T heterozygous ( n = 1). Two patients received 5-FU at a 50% reduced dose on days 29–32; one patient refused to receive 5-FU (continued with MMC and RT); one patient received only radiation therapy due to persistent pancytopenia despite the use of growth factors; two patients received an alternative regimen consisting of MMC 10 mg/m 2 on day 29 with cisplatin (CDDP) 25 mg/m 2 /week plus RT; and two patients received cisplatin/MMC with RT from the beginning as they were prospectively detected to have TYMS abnormalities prior to dosing the chemotherapy. These patients tolerated treatment very well with only grade 2 toxicities. All the patients (4/4) on cisplatin/MMC achieved clinical complete response (cCR), while four patients (4/15) on 5-FU/MMC reached cCR at the first assessment. Radiological response showed complete response at the end of 24 weeks assessment. Conclusions: Molecular testing for DPYD and TYMS genes can allow us to identify patients who are most likely to respond or face severe toxicity to 5-FU in a potentially curable cancer. Combining radiation with CDDP with MMC in patients with AC is feasible. A prospective study based on pharmacogenetic testing comparing MMC/cisplatin with MMC/5-FU is indicated in patients with AC.

The seeding of tissue constructs with adipose tissue-derived microvascular fragments (ad-MVF) is an emerging pre-vascularisation strategy. Ad-MVF rapidly reassemble into new microvascular networks after in vivo implantation. Herein it was analysed whether this process was improved by erythropoietin (EPO). Ad-MVF were isolated from green fluorescent protein (GFP)+ as well as wild-type C57BL/6 mice and cultivated for 24 h in medium supplemented with EPO (20 IU/mL) or vehicle. Freshly isolated, non-cultivated ad-MVF served as controls. Protein expression, cell viability and proliferation of ad-MVF were assessed by proteome profiler array and fluorescence microscopy. GFP+ ad-MVF were seeded on collagen-glycosaminoglycan matrices, which were implanted into dorsal skinfold chambers of C57BL/6 mice, to analyse their vascularisation over 14 d by intravital fluorescence microscopy, histology and immunohistochemistry. Cultivation up-regulated the expression of pro- and anti-angiogenic factors within both vehicle- and EPO-treated ad-MVF when compared with non-cultivated controls. Moreover, EPO treatment suppressed cultivation-associated apoptosis and significantly increased the number of proliferating endothelial cells in ad-MVF when compared with vehicle-treated and non-cultivated ad-MVF. Accordingly, implanted matrices seeded with EPO-treated ad-MVF exhibited an improved vascularisation, as indicated by a significantly higher functional microvessel density. The matrices of the three groups contained a comparably large fraction of GFP+ microvessels originating from the ad-MVF, whereas the tissue surrounding the matrices seeded with EPO-treated ad-MVF exhibited a significantly increased microvessel density when compared with the other two groups. These findings indicated that EPO represents a promising cytokine to further boost the excellent vascularisation properties of ad-MVF in tissue-engineering applications.

The seeding of scaffolds with adipose tissue-derived microvascular fragments represents a promising strategy to establish a sufficient blood supply in tissue constructs. Herein, we analysed whether a single application of macrophage-activating lipopeptide-2 (MALP-2) at the implantation site further improves the early vascularisation of such microvessel-seeded constructs. Microvascular fragments were isolated from epididymal fat pads of C57BL/6 mice. The fragments were seeded on polyurethane scaffolds, which were implanted into mouse dorsal skinfold chambers exposed to MALP-2 or vehicle (control). The inflammatory host tissue response and the vascularisation of the scaffolds were analysed using intravital fluorescence microscopy, histology and immunohistochemistry. We found that the numbers of microvascular adherent leukocytes were significantly increased in MALP-2-treated chambers during the first 3 days after scaffold implantation when compared to controls. This temporary inflammation resulted in an improved vascularisation of the host tissue surrounding the implants, as indicated by a higher density of CD31-positive microvessels at day 14. However, the MALP-2-exposed scaffolds themselves presented with a lower functional microvessel density in their centre. In addition, in vitro analyses revealed that MALP-2 promotes apoptotic cell death of endothelial and perivascular cells in isolated microvascular fragments. Hence, despite the beneficial pro-angiogenic properties of MALP-2 at the implantation site, the herein evaluated approach may not be recommended to improve the vascularisation capacity of microvascular fragments in tissue engineering applications.

Abstract Background The interest of health care agencies, private payers and policy makers for patient-reported outcomes (PRO) is continuously increasing. There is a substantial need to improve capacity to collect and interpret relevant PRO data to support implementation of patient-centered research and optimal care in haemophilia. The Patient Reported Outcomes, Burdens and Experiences (PROBE) Project aims to develop a patient-led research network, to develop a standardized questionnaire to gather patient-reported outcomes and to perform a feasibility study of implementing the PROBE questionnaire. Methods A pilot questionnaire was developed using focus group methodology. Content and face validity were assessed by a pool of persons living with haemophilia (PWH) and content experts through interactive workshops. The PROBE questionnaire was translated with the forward-backward approach. PROBE recruited national haemophilia patient non-governmental organizations (NGOs) to administer the questionnaire to people with and without haemophilia. PROBE measured the time to complete the questionnaire and gathered feedback on its content and clarity; staff time and cost required to implement the questionnaire were also collected. Results The PROBE questionnaire is comprised of four major sections (demographic data, general health problems, haemophilia-related health problems and health-related quality of life using EQ-5D-5L and EQ-VAS). Seventeen NGOs participated in the pilot study of the PROBE Project, recruiting 656 participants. Of these, 71% completed the questionnaire within 15 min, and all participants completed within 30 min. The median total staff and volunteer time required for the NGOs to carry out the study within their country was 9 h (range 2 to 40 h). NGO costs ranged from $22.00 to $543.00 USD per country, with printing and postage being the most commonly reported expenditures. Conclusions The PROBE questionnaire assesses patient-important reported outcomes in PWH and control participants, with a demonstrated short completion time. PROBE proved the feasibility to engage diverse patient communities in the structured generation of real-world outcome research at all stages. Trial registration Trial registration: NCT02439710.

Summary: Background: Maternal and neonatal mortality is high in Africa, but few large, prospective studies have been done to investigate the risk factors associated with these poor maternal and neonatal outcomes. Methods: A 7-day, international, prospective, observational cohort study was done in patients having caesarean delivery in 183 hospitals across 22 countries in Africa. The inclusion criteria were all consecutive patients (aged ≥18 years) admitted to participating centres having elective and non-elective caesarean delivery during the 7-day study cohort period. To ensure a representative sample, each hospital had to provide data for 90% of the eligible patients during the recruitment week. The primary outcome was in-hospital maternal mortality and complications, which were assessed by local investigators. The study was registered on the South African National Health Research Database, number KZ_2015RP7_22, and on ClinicalTrials.gov, number NCT03044899. Findings: Between February, 2016, and May, 2016, 3792 patients were recruited from hospitals across Africa. 3685 were included in the postoperative complications analysis (107 missing data) and 3684 were included in the maternal mortality analysis (108 missing data). These hospitals had a combined number of specialist surgeons, obstetricians, and anaesthetists totalling 0·7 per 100 000 population (IQR 0·2–2·0). Maternal mortality was 20 (0·5%) of 3684 patients (95% CI 0·3–0·8). Complications occurred in 633 (17·4%) of 3636 mothers (16·2–18·6), which were predominantly severe intraoperative and postoperative bleeding (136 [3·8%] of 3612 mothers). Maternal mortality was independently associated with a preoperative presentation of placenta praevia, placental abruption, ruptured uterus, antepartum haemorrhage (odds ratio 4·47 [95% CI 1·46–13·65]), and perioperative severe obstetric haemorrhage (5·87 [1·99–17·34]) or anaesthesia complications (11·47 (1·20–109·20]). Neonatal mortality was 153 (4·4%) of 3506 infants (95% CI 3·7–5·0). Interpretation: Maternal mortality after caesarean delivery in Africa is 50 times higher than that of high-income countries and is driven by peripartum haemorrhage and anaesthesia complications. Neonatal mortality is double the global average. Early identification and appropriate management of mothers at risk of peripartum haemorrhage might improve maternal and neonatal outcomes in Africa. Funding: Medical Research Council of South Africa.

Generating realistic time series data is important for many engineering and scientific applications. Existing work tackles this problem using generative adversarial networks (GANs). However, GANs are unstable during training, and they can suffer from mode collapse. While variational autoencoders (VAEs) are known to be more robust to the these issues, they are (surprisingly) less considered for time series generation. In this work, we introduce Koopman VAE (KoVAE), a new generative framework that is based on a novel design for the model prior, and that can be optimized for either regular and irregular training data. Inspired by Koopman theory, we represent the latent conditional prior dynamics using a linear map. Our approach enhances generative modeling with two desired features: (i) incorporating domain knowledge can be achieved by leveraging spectral tools that prescribe constraints on the eigenvalues of the linear map; and (ii) studying the qualitative behavior and stability of the system can be performed using tools from dynamical systems theory. Our results show that KoVAE outperforms state-of-the-art GAN and VAE methods across several challenging synthetic and real-world time series generation benchmarks. Whether trained on regular or irregular data, KoVAE generates time series that improve both discriminative and predictive metrics. We also present visual evidence suggesting that KoVAE learns probability density functions that better approximate the empirical ground truth distribution.

The path of tokamak fusion and International thermonuclear experimental reactor (ITER) is maintaining high-performance plasma to produce sufficient fusion power. This effort is hindered by the transient energy burst arising from the instabilities at the boundary of plasmas. Conventional 3D magnetic perturbations used to suppress these instabilities often degrade fusion performance and increase the risk of other instabilities. This study presents an innovative 3D field optimization approach that leverages machine learning and real-time adaptability to overcome these challenges. Implemented in the DIII-D and KSTAR tokamaks, this method has consistently achieved reactor-relevant core confinement and the highest fusion performance without triggering damaging bursts. This is enabled by advances in the physics understanding of self-organized transport in the plasma edge and machine learning techniques to optimize the 3D field spectrum. The success of automated, real-time adaptive control of such complex systems paves the way for maximizing fusion efficiency in ITER and beyond while minimizing damage to device components.

BackgroundPrior studies of Alzheimer's disease (AD) biomarker disclosure have answered important questions about individuals' safety after learning and comprehending their amyloid PET results; however, these studies have typically employed highly structured disclosure protocols and focused on the psychological impact of disclosure (e.g., anxiety, depression, and suicidality) in homogeneous populations. More work is needed to develop flexible disclosure protocols and study outcomes in ethnoculturally representative samples.MethodsThe Alzheimer's Disease Neuroimaging Initiative (ADNI) is formally incorporating amyloid PET disclosure into the newest protocol (ADNI-4). Participants across the cognitive spectrum who wish to know their amyloid PET results may learn them. The pragmatic disclosure process spans four timepoints: (1) a pre-disclosure visit, (2) the PET scan and its read, (3) a disclosure visit, and (4) a post-disclosure check-in. This process applies to all participants, with slight modifications to account for their cognitive status. In designing this process, special emphasis was placed on utilizing investigator discretion. Participant measures include perceived risk of dementia, purpose in life, and disclosure satisfaction. Investigator assessment of the disclosure visit (e.g., challenges encountered, topics discussed, etc.) is also included.ResultsData collection is ongoing. Results will allow for more robust characterization of the impact of learning amyloid PET results on individuals and describe the perspectives of investigators.ConclusionThe pragmatic design of the disclosure process in ADNI-4 coupled with the novel participant and investigator data will inform future disclosure practices. This is especially important as disclosure of biomarker results expands in research and care.

Adipose tissue-derived microvascular fragments (ad-MVF) represent effective vascularisation units for the seeding of dermal substitutes. However, particularly in case of extensive skin defects, the required amounts of donor fat tissue for the harvesting of ad-MVF may not always be available. Therefore, we herein determined the lowest ad-MVF density needed to induce a sufficient vascularisation and incorporation of seeded implants. Collagen-glycosaminoglycan matrices (Integra®; diameter: 4 mm) were seeded with 15,000 (HD), 10,000 (MD) and 5,000 (LD) ad-MVF and implanted into full-thickness skin defects within mouse dorsal skinfold chambers, to analyse their in vivo vascularisation and incorporation. Intravital fluorescence microscopy showed a comparable vascularisation of HD and MD ad-MVF-seeded Integra®, which was significantly higher when compared to LD ad-MVF-seeded Integra®. As assessed by photoacoustic imaging, this was associated with an increased oxygenation of the implants. Additional histological and immunohistochemical analyses revealed an enhanced cellular infiltration, collagen content, microvessel density and epithelialisation of HD and MD ad-MVF-seeded Integra®, indicating a better incorporation compared to LD ad-MVF-seeded implants. These findings demonstrate that 80,000 ad-MVF/cm² is the least required density to guarantee an effective vascularisation of the dermal substitute.

Adipose tissue-derived microvascular fragments (ad-MVF) represent promising vascularisation units for bioengineered Integra® matrix wound dressing (MWD). However, due to the sheet-like structure with small pore sizes, the seeding of this matrix with ad-MVF is mainly limited to its surface. Integra® flowable wound matrix (FWM) may be suitable to achieve a more homogeneous distribution and, thus, improved vascularisation, because this gel-like matrix allows for the direct admixture of ad-MVF during sample preparation. To test this hypothesis, we seeded MWD and FWM with an identical number of ad-MVF and assessed their distribution and inter-fragment distance within both matrices. Moreover, ad-MVF-seeded MWD and FWM were implanted into full-thickness skin defects within mouse dorsal skinfold chambers to analyse their vascularisation, epithelialisation and tissue incorporation using intravital fluorescence microscopy, histology and immunohistochemistry. Seeded FWM exhibited a more homogeneous ad-MVF distribution, when compared to MWD. This resulted in a significantly increased inter-fragment distance, preventing the reassembly of ad-MVF into new microvascular networks. Accordingly, the vascularisation of FWM was diminished after implantation, as indicated by a reduced functional microvessel density and blood perfusion. This was associated with a decreased tissue incorporation and epithelialisation of the matrix, when compared to ad-MVF-seeded MWD. Hence, the use of FWM as a carrier system may require a tremendous amount of ad-MVF to shorten their inter-fragment distance and, thus, to maintain their vascularisation capacity for tissue engineering applications.

Atrophic non-unions are a major clinical problem. Mineral coated microparticles (MCM) are electrolyte-coated hydroxyapatite particles that have been shown in vitro to bind growth factors electrostatically and enable a tuneable sustained release. Herein, we studied whether MCM can be used in vivo to apply Bone Morphogenetic Protein-2 (BMP-2) to improve bone repair of atrophic non-unions. For this purpose, atrophic non-unions were induced in femurs of CD-1 mice (n = 48). Animals either received BMP-2-coated MCM (MCM + BMP; n = 16), uncoated MCM (MCM; n = 16) or no MCM (NONE; n = 16). Bone healing was evaluated 2 and 10 weeks postoperatively by micro-computed tomographic (µCT), biomechanical, histomorphometric and immunohistochemical analyses. µCT revealed more bone volume with more highly mineralised bone in MCM + BMP femurs. Femurs of MCM + BMP animals showed a significantly higher bending stiffness compared to other groups. Histomorphometry further demonstrated that the callus of MCM + BMP femurs was larger and contained more bone and less fibrous tissue. After 10 weeks, 7 of 8 MCM + BMP femurs presented with complete osseous bridging, whereas NONE femurs exhibited a non-union rate of 100 %. Of interest, immunohistochemistry could not detect macrophages within the callus, indicating a good biocompatibility of MCM. In conclusion, the local application of BMP-2-coated MCM improved bone healing in a challenging murine non-union model and, thus, should be of clinical interest in the treatment of non-unions.

This study explores U.S. wine consumers’ perception of wine and health by gender, age, and ethnic background. An extensive body of epidemiological studies suggests that there are health benefits from moderate wine drinking. In light of an increased consumer preference over healthier foods and beverages, it is important to understand the health orientation of wine consumers and the effect of gender, age, or ethnicity on their perceptions of wine and health. An online survey was used to collect data from more than 1000 U.S. wine consumers. The results show that there is a statistically significant difference across demographic segments in terms of the level of health consciousness. Millennials and Asians are the most concerned, whereas Whites are the least, about health in their respective segments. Red wine is considered the healthiest wine type compared to other colors and styles. Moreover, more than 80% of the sample believes drinking red wine is healthier than drinking beer or spirits. However, nearly 50% of the sample thinks sulfites in wine can cause headaches. Managerial implications are discussed.

This study examines the experience of temptation through the accounts of consumers who have entered a debt management plan (DMP). During 12 weeks, participants reported weekly temptations. The results are consistent with socio-cognitive theory; participants with higher self-efficacy are better able to manage their emotions, resist justifications connected with entitlement, and perceive their difficult circumstances as providing them the opportunity to develop new financial skills and an improved financial identity. The results show that DMP consumers engage in three patterns of responses to temptation that vary in degree of self-efficacy: mindlessness, acceptance, and mindfulness. The highest level of self-efficacy and success in the DMP is associated with mindfulness, as these participants feel pride when they “work the program” and resist temptation.

Fracture injection/shut-in tests are commonly used to measure the state of stress in the subsurface. Injection creates a hydraulic fracture (or in some cases, opens a preexisting fracture), and then the pressure after shut-in is monitored to identify fracture closure. Different interpretation procedures have been proposed for estimating closure, and the procedures sometimes yield significantly different results. In this study, direct, in-situ strain measurements are used to observe fracture reopening and closure. The tests were performed as part of the EGS Collab project, a mesoscale project performed at 1.25 and 1.5 km depth at the Sanford Underground Research Facility. The tests were instrumented with the SIMFIP tool, a double-packer probe with a high-resolution three-dimensional borehole displacement sensor. The measurements provide a direct observation of the fracture closure signature, enabling a high-fidelity estimate of the fracture closure stress (ie, the normal stress on the fracture). In two of the four tests, injection created an opening mode fracture, and so the closure stress can be interpreted as the minimum principal stress. In the other two tests, injection probably opened preexisting natural fractures, and so the closure stress can be interpreted as the normal stress on the fractures. The strain measurements are compared against different proposed methods for estimating closure stress from pressure transients. The shut-in transients are analyzed with two techniques that are widely used in the field of petroleum engineering – the ‘tangent’ method and the ‘compliance’ method. In three of the four tests, the tangent method significantly underestimates the closure stress. The compliance method is reasonably accurate in all four tests. Closure stress is also interpreted using two other commonly-used methods – ‘first deviation from linearity’ and the method of (Hayashi and Haimson, 1991). In comparison with the SIMFIP data, these methods tend to overestimate the closure stress, evidently because they identify closure from early-time transient effects, such as near-wellbore tortuosity. In two of the tests, microseismic imaging provides an independent estimate of the size of the fracture created by injection. When combined with a simple mass balance calculation, the SIMFIP stress measurements yield predictions of fracture size that are reasonably consistent with the estimates from microseismic. The calculations imply an apparent fracture toughness 2-3x higher than typical laboratory-derived values.

The dorsal skinfold chamber is a rodent model for non-invasive microcirculatory analyses of striated muscle and skin tissue throughout an observation period of 2-3 weeks. In combination with intravital fluorescence microscopy, this model allows the quantitative assessment of dynamic processes such as inflammation, angiogenesis, vascular remodelling and microcirculation. Accordingly, the dorsal skinfold chamber is increasingly used for preclinical research in tissue engineering and regenerative medicine. This includes studies on biocompatibility, vascularisation and incorporation of medical implants and artificial tissue constructs. Moreover, the chamber implantation procedure has been modified to analyse primary and secondary wound healing as well as revascularisation and blood perfusion of dermal substitutes, skin grafts and myocutaneous flaps. Hence, the dorsal skinfold chamber model does not only provide deep insights into fundamental regenerative mechanisms but also represents a versatile tool for the development of novel therapeutic strategies.

Despite the high innate regenerative capacity of bone, large osseous defects fail to heal and remain a clinical challenge. Healing such defects requires the formation of large amounts of bone in an environment often rendered hostile to osteogenesis by damage to the surrounding soft tissues and vasculature. In recent years, there have been intensive research efforts directed towards tissue engineering and regenerative approaches designed to overcome this multifaceted challenge. In this paper, we describe and critically evaluate the state-of-the-art approaches to address the various components of this intricate problem. The discussion includes (i) the properties of synthetic and natural scaffolds, their use in conjunction with cell and growth factor delivery, (ii) their vascularisation, (iii) the potential of gene therapies and (iv) the role of the mechanical environment. In particular, we present a critical analysis of where the field stands, and how it can move forward in a coordinated fashion.

Hege Ihle-Hansen,1 Bente Thommessen,2 Morten W Fagerland,3 Anne R Øksengård,4 Torgeir B Wyller,5 Knut Engedal,6 Brynjar Fure7 1Department of Internal Medicine, Vestre Viken Hospital Trust, Bærum Hospital, Bærum, Norway; 2Department of Neurology, Akershus University Hospital, Lørenskog, Norway; 3Oslo Centre for Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Norway; 4Department of Internal medicine, Vestre Viken Hospital Trust, Bærum Hospital, Bærum, Norway; 5Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway; 6Norwegian Centre for Dementia Research, Oslo University Hospital, Oslo, Norway; 7Norwegian Knowledge Centre for the Health Services, Oslo, Norway Background: Treatment of hypertension post-stroke preserves cognition through prevention of recurrent stroke, but it is not clear whether it prevents cognitive decline through other mechanisms. We aimed to describe changes in blood pressure from baseline to 1 year post-stroke and to evaluate the association between achieved blood pressure targets and cognitive function, mild cognitive impairment (MCI), and dementia.Methods: We included patients with first-ever stroke, and defined achieved blood pressure goals as systolic blood pressure (SBP) in the categories ≤125 mmHg, ≤140 mmHg, and ≤160 mmHg, SBP reduction of ≥10 mmHg, and diastolic blood pressure (DBP) reduction of ≥5 mmHg. The main outcome variables were cognitive assessments 1 year post stroke. Secondary outcomes were diagnoses of MCI or dementia.Results: Forty-one of 166 patients (25%) reached SBP ≤125 mmHg after 1 year, 92/166 (55%) reached SBP ≤140 mmHg, and 150/166 (90%) reached SBP ≤160 mmHg. SBP was reduced by ≥10 mmHg in 44/150 (29%) and DBP by ≥5 mmHg in 57/150 (38%). We did not find any statistically significant associations between cognitive test performances and different blood pressure goals (P=0.070–1.0). Nor was there any significant association between achieved goal blood pressure or blood pressure reduction after 1 year and the diagnoses of MCI or dementia (P=0.32–0.56).Conclusion: Treatment of hypertension is important for primary and secondary prevention of stroke. Showing a potential beneficial effect of blood pressure control on cognitive function, however, probably needs longer follow-up. Keywords: cognitive impairment, hypertension, cerebrovascular disease, risk factor management, secondary prevention

Adipose tissue-derived microvascular fragments represent promising vascularisation units for implanted tissue constructs. However, their reassembly into functional microvascular networks takes several days, during which the cells inside the implants are exposed to hypoxia. In the present study, we analysed whether this critical phase may be overcome by pre-cultivation of fragment-seeded scaffolds prior to their implantation. Green fluorescent protein (GFP)-positive microvascular fragments were isolated from epididymal fat pads of male C57BL/6-TgN (ACTB-EGFP) 1Osb/J mice. Nano-size hydroxyapatite particles/poly (ester-urethane) scaffolds were seeded with these fragments and cultivated for 28 days. Subsequently, these scaffolds or control scaffolds, which were freshly seeded with GFP-positive microvascular fragments, were implanted into the dorsal skinfold chamber of C57BL/6 wild-type mice to study their vascularisation and incorporation by means of intravital fluorescence microscopy, histology and immunohistochemistry over 2 weeks. Pre-cultivation of microvascular fragments resulted in the loss of their native vessel morphology. Accordingly, pre-cultivated scaffolds contained a network of individual CD31/GFP-positive endothelial cells with filigrane cell protuberances. After implantation into the dorsal skinfold chamber, these scaffolds exhibited an impaired vascularisation, as indicated by a significantly reduced functional microvessel density and lower fraction of GFP-positive microvessels in their centre when compared to freshly seeded control implants. This was associated with a deteriorated incorporation into the surrounding host tissue. These findings indicate that freshly isolated, non-cultivated microvascular fragments should be preferred as vascularisation units. This would also facilitate their use in clinical practice during intra-operative one-step procedures.

Adipose tissue-derived microvascular fragments are promising vascularisation units for applications in the field of tissue engineering. Elderly patients are the major future target population of such applications due to an increasing human life expectancy. Therefore, we herein investigated the effect of aging on the fragments’ vascularisation capacity. Microvascular fragments were isolated from epididymal fat pads of adult (8 months) and aged (16 months) C57BL/6 donor mice. These fragments were seeded onto porous polyurethane scaffolds, which were implanted into dorsal skinfold chambers to study their vascularisation using intravital fluorescence microscopy, histology and immunohistochemistry. Scaffolds seeded with fragments from aged donors exhibited a significantly lower functional microvessel density and intravascular blood flow velocity. This was associated with an impaired vessel maturation, as indicated by vessel wall irregularities, constantly elevated diameters and a lower fraction of CD31/α-smooth muscle actin double positive microvessels in the implants’ border and centre zones. Additional in vitro analyses revealed that microvascular fragments from adult and aged donors do not differ in their stem cell content as well as in their release of angiogenic growth factors, survival and proliferative activity under hypoxic conditions. However, fragments from aged donors exhibit a significantly lower number of matrix metalloproteinase -9-positive perivascular cells. Taken together, these findings demonstrate that aging is a crucial determinant for the vascularisation capacity of isolated microvascular fragments.

This position paper summarises a vision of how cell-based therapies can be applied clinically to regenerate bone, as well as the steps needed to narrow the gap between that vision and clinical reality. It is a result of the presentations and discussion of the “Cell Therapy for Bone Repair” breakout session at the AO Foundation Symposium “Where Science Meets Clinics” in Davos, Switzerland from September 5-7, 2013. Participants included leaders from science, medicine, and industry from around the world. The session included clinical and scientific presentations, as well as an extended discussion among participants. Bone tissue has an innate regenerative capacity that in most cases allows functional healing at damage sites. However, there are a number of serious conditions in which bone does not fully heal and the result is significant morbidity. The clinical need for new therapies is clear, and the breakout session participants were enthusiastic about the potential impact on cell-based therapies for bone repair in the clinic. However, they also recognised the significant challenges that face the development of commercially viable cell therapy products. This paper outlines a vision in which patient selection is based on expected therapeutic outcome to create a consistently successful, cost-effective, cell-based therapy for bone repair. The need for a more complete understanding of bone repair, a better infrastructure for preclinical studies, and the need for collaboration among stakeholders is discussed.

Since the 2006 listing of the staghorn coral Acropora cervicornis as threatened under the US Endangered Species Act, interest has increased in its culture for laboratory studies, restoration and ex situ conservation efforts. A pervasive problem in coral culture is substrate overgrowth by algae and other spatial competitors. We conducted a laboratory study to examine the utility of introducing herbivores, juvenile variegated sea urchins Lytechinus variegatus, to tanks containing small (

Cell spheroids represent attractive building units for bone tissue engineering, because they provide a three-dimensional environment with intensive direct cell-cell contacts. Moreover, they allow for co-culture of both osteoblasts and vessel-forming cells, which may markedly increase their survival and vascularisation after transplantation. To test this hypothesis, we generated co-culture spheroids by aggregating different combinations of primary human osteoblasts (HOB), human dermal microvascular endothelial cells (HDMEC) and normal human dermal fibroblasts (NHDF) using the liquid overlay technique. Mono-culture spheroids consisting either of HOB or HDMEC served as controls. After in vitro characterisation, the different spheroids were transplanted into dorsal skinfold chambers of CD1 nu/nu mice to study in vivo their viability and vascularisation over a 2-week observation period by means of repetitive intravital fluorescence microscopy and immunohistochemistry. In vitro, co-culture spheroids containing HDMEC rapidly formed dense tubular vessel-like networks within 72 h and exhibited a significantly decreased rate of apoptotic cell death when compared to mono-culture HDMEC spheroids. After transplantation, these networks interconnected to the host microvasculature by external inosculation. Of interest, this process was most pronounced in HOB-HDMEC spheroids and could not further be improved by the addition of NHDF. Accordingly, HOB-HDMEC spheroids were larger when compared to the other spheroid types. These findings indicate that HOB-HDMEC spheroids exhibit excellent properties to preserve viability and to promote proliferation and vascularisation. Therefore, they may be used as functional vascularisation units in bone tissue engineering for the seeding of scaffolds or for the vitalisation of non-healing large bone defects.

Orbital angular momentum (OAM) and torque transfer play central roles in a wide range of magnetic textures and devices including skyrmions and spin-torque electronics. Analogous topological structures are now also being explored in ferroelectrics, including polarization vortex arrays in ferroelectric/dielectric superlattices. Unlike magnetic toroidal order, electric toroidal order does not couple directly to linear external fields. Instead, we find that the presence of an electric toroidal moment in a ferrorotational phase transfers measurable torque and OAM to a localized electron beam in the ballistic limit. We record these torque transfers from a high-energy electron beam using a momentum-resolved detector. This approach provides a high-sensitivity method to detect polarization fields and their more complex order parameters and topologies. In addition to toroidal order, we also demonstrate high-precision measurements of vorticity and chirality for polar vortexlike phases.