Selective permeation up a chemical potential gradient to enable an unusual solvent purification modality.

The need for energy-efficient recovery of organic solutes from aqueous streams is becoming more urgent as chemical manufacturing transitions toward nonconventional and bio-based feedstocks and processes. In addition to this, many aqueous waste streams contain recalcitrant organic contaminants, such as pharmaceuticals, industrial solvents, and personal care products, that must be removed prior to reuse. We observe that rigid carbon membrane materials can remove and concentrate organic contaminants via an unusual liquid-phase membrane permeation modality. Surprisingly, detailed thermodynamic calculations on the chemical potential of the organic contaminant reveal that the organic species has a higher chemical potential on the permeate side of the membrane than on the feed side of the membrane. This unusual observation challenges conventional membrane transport theory that posits that all permeating species move from high chemical potential states to lower chemical potential states. Based on experimental measurements, we hypothesize that the organic is concentrated in the membrane relative to water via favorable binding interactions between the organic and the carbon membrane. The concentrated organic is then swept through the membrane via the bulk flow of water in a modality known as "sorp-vection." We highlight via simplified nonequilibrium thermodynamic models that this "uphill" chemical potential permeation of the organic does not result in second-law violations and can be deduced via measurements of the organic and water sorption and diffusion rates into the carbon membrane. Moreover, this work identifies the need to consider such nonidealities when incorporating unique, rigid materials for the separations of aqueous waste streams.

The SMX DNA Repair Tri-nuclease.

The efficient removal of replication and recombination intermediates is essential for the maintenance of genome stability. Resolution of these potentially toxic structures requires the MUS81-EME1 endonuclease, which is activated at prometaphase by formation of the SMX tri-nuclease containing three DNA repair structure-selective endonucleases: SLX1-SLX4, MUS81-EME1, and XPF-ERCC1. Here we show that SMX tri-nuclease is more active than the three individual nucleases, efficiently cleaving replication forks and recombination intermediates. Within SMX, SLX4 co-ordinates the SLX1 and MUS81-EME1 nucleases for Holliday junction resolution, in a reaction stimulated by XPF-ERCC1. SMX formation activates MUS81-EME1 for replication fork and flap structure cleavage by relaxing substrate specificity. Activation involves MUS81's conserved N-terminal HhH domain, which mediates incision site selection and SLX4 binding. Cell cycle-dependent formation and activation of this tri-nuclease complex provides a unique mechanism by which cells ensure chromosome segregation and preserve genome integrity.

A propensity score matched analysis of liver transplantation outcomes in the setting of preservation solution shortage.

The recent shortage of the University of Wisconsin (UW) solution prompted increased utilization of histidine-tryptophan-ketoglutarate (HTK) solution for liver graft preservation. This contemporary study analyzed deceased donor liver transplant outcomes following preservation with HTK vs UW. Patients receiving deceased donor liver transplantations between January 1, 2019, and June 30, 2022, were retrospectively identified utilizing the Organ Procurement and Transplant Network database, stratified by preservation with HTK vs UW, and a propensity score matching analysis was performed. Outcomes assessed included rates of primary nonfunction, graft survival, and patient survival. There were 4447 patients in each cohort. Primary nonfunction occurred in 60 (1.35%) patients in the HTK group vs 25 (0.54%) in the UW group (P < .001). HTK was associated with lower 90-day graft survival (94.39% vs 96.09%; P < .001) and 90-day patient survival (95.97% vs 97.38%; P = .001). Unmatched donation after cardiac death-specific analysis of HTK vs UW demonstrated respective rates of primary nonfunction of 1.63% vs 0.82% (P = .20), 90-day graft survival of 92.50% vs 95.29% (P = .069), and 90-day patient survival of 93.90% vs 96.35% (P = .077). These results suggest that HTK may not be an equivalent preservation solution for deceased donor liver transplantation.

Reversible Chemical Modification of Antibody Effector Function Mitigates Unwanted Systemic Immune Activation.

Antibody effector functions including antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) are mediated through the interaction of the antibody Fc region with Fcγ receptors present on immune cells. Several approaches have been used to modulate antibody Fc-Fcγ interactions with the goal of driving an effective antitumor immune response, including Fc point mutations and glycan modifications. However, robust antibody-Fcγ engagement and immune cell binding of Fc-enhanced antibodies in the periphery can lead to the unwanted induction of systemic cytokine release and other dose-limiting infusion-related reactions. Creating a balance between effective engagement of Fcγ receptors that can induce antitumor activity without incurring systemic immune activation is an ongoing challenge in the field of antibody and immuno-oncology therapeutics. Herein, we describe a method for the reversible chemical modulation of antibody-Fcγ interactions using simple poly(ethylene glycol) (PEG) linkers conjugated to antibody interchain disulfides with maleimide attachments. This method enables dosing of a therapeutic with muted Fcγ engagement that is restored in vivo in a time-dependent manner. The technology was applied to an effector function enhanced agonist CD40 antibody, SEA-CD40, and experiments demonstrate significant reductions in Fc-induced immune activation in vitro and in mice and nonhuman primates despite showing retained efficacy and improved pharmacokinetics compared to the parent antibody. We foresee that this simple, modular system can be rapidly applied to antibodies that suffer from systemic immune activation due to peripheral FcγR binding immediately upon infusion.

Can 60 days of feeding lead to increased fitness for transport in cull dairy cows?

Welfare of cull cows during transport to slaughter is a current concern in the Canadian dairy industry. Cull cows sold through auction often have a high prevalence of lameness, low body condition score (BCS), hock lesions, and udder engorgement. To evaluate whether drying off and feeding cull dairy cows before transport can mitigate these challenges, 45 cows designated for culling were randomly assigned to either be fed for 60 d after being dried off (Fed; n = 24) or to serve as controls by being sent directly to slaughter (Direct; n = 21). Two Fed cows were removed for health reasons before completing the feeding period. Both Fed and Direct cows were assessed for locomotion (5-point scale), BCS (5-point scale), hock lesions (3-point scale), udder engorgement (3-point scale) and body weight at the time of enrollment. Fed cows, locomotion, BCS, hock, and udder engorgement scores were assessed weekly until slaughter. Weights of the Fed cows were measured again the day before slaughter. Mixed linear regression models were used to assess continuous outcomes BCS and weight. Mixed logistic regression models were used to assess dichotomous outcomes presence of hock lesions and lameness. Fed cows gained an average of 116.9 kg over the feeding period (SE ± 8.20). Fed cows had an average weight at slaughter of 834.2 kg, whereas Direct cows' average weight was 767.3 kg (SE ± 26.8). The Fed cows' average BCS at the start of the trial was 2.4, and at slaughter was 3.6, with an average gain of 1.2 BCS points. At slaughter, proportion of udders involuted in the Fed group was 45.1% (10 out of 22) and in the Direct cows, was 0% (0 out of 21). There were no differences found in locomotion or hock lesions between the Fed and Direct groups. It is important to weigh potential benefits for the Fed cows with the fact that Direct cows did not endure a drying off procedure, nor were they placed at risk of potential adverse health events. However, despite these potential limitations, due to the improved BCS and udder engorgement scores, cows fed for 60 d may be better prepared for transportation to slaughter, as well as sell for a higher price due to increased body weight and body condition.

Attitudes and professional values of veterinarians and veterinary students towards positive welfare states for dairy cattle.

Research that involves agricultural animal welfare has typically aimed to improve welfare by decreasing disease, distress, and pain. Positive welfare does not necessarily occur with the absence of suffering but in combination with opportunities for behaviors or affective states desired by animals. Our objectives were to describe Canadian bovine veterinarians' and veterinary students' attitudes, professional normative values, and perceived ability to promote positive welfare for dairy cows, and to explore participants' provided rationale. With an online cross-sectional survey, Canadian veterinary practitioners (n = 78) and veterinary students (n = 148) were asked, on a 7-point Likert scale, about their attitudes, perceived professional normative values, and perceived ability of veterinarians to promote positive welfare for dairy cows. We used an applied thematic analysis approach within the qualitative description methodology to analyze participants' open-ended text responses. Quantitatively, participants had very favorable attitudes (mean ± SE; 6.3 ± 0.04) and perceived favorable values (5.7 ± 0.06) in the veterinary community toward positive welfare opportunities for dairy cows. Three themes were identified to explain the professional normative values: influences from within the veterinary profession, influences from outside the veterinary profession, and personal views of participants. Participants were confident that veterinarians could suggest positive welfare opportunities for dairy cows (6.1 ± 0.06) but were uncertain that the decision to suggest these opportunities to producers was within a veterinarian's control (4.3 ± 0.11) and were not confident that implementation of positive welfare opportunities was under a veterinarian's control (2.1 ± 0.07). Three themes were identified to explain the barriers to veterinarians promoting positive welfare opportunities for dairy cows: not practical to implement, resistance to change, and concern for the animal. Participants stated that many positive welfare opportunities were impractical or expensive to implement. We conclude that positive attitudes and positive professional values exist in the veterinary community toward positive welfare for dairy cows but that much uncertainty exists regarding a veterinarian's ability to influence change to current practices.

An open trial for adults in a residential program for binge eating spectrum disorders.

The current study assessed treatment outcome for 99 adult admissions to a residential program specifically designed for binge eating spectrum disorders (BESD). Participants completed self-report measures at admission, discharge, and 12-month follow-up and were asked to complete blood draws at admission and follow-up. Primary outcomes were eating behaviors; secondary outcomes included comorbid symptoms and physiological variables. Eating behaviors improved significantly from admission to follow-up, as did most comorbid symptoms and quality of life, despite no change in body mass index. Some variables displayed a curvilinear relationship, with some worsening of symptoms from discharge to follow-up, although scores at follow-up remained well below admission values. Participation in the treatment program was associated with reduced problematic eating and comorbid symptoms and increased quality of life up to one year after discharge. Findings from this study may encourage the development of similar residential treatment programs for BESD for those who have not responded to outpatient care or mixed milieu settings, and may prompt randomized studies testing similar treatments versus usual care.

Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 Using Proximity Labeling and Affinity Purification.

The DNA repair scaffold SLX4 has pivotal roles in cellular processes that maintain genome stability, most notably homologous recombination. Germline mutations in SLX4 are associated with Fanconi anemia, a disease characterized by chromosome instability and cancer susceptibility. The role of mammalian SLX4 in homologous recombination depends critically on binding and activating structure-selective endonucleases, namely SLX1, MUS81-EME1, and XPF-ERCC1. Increasing evidence indicates that cells rely on distinct SLX4-dependent complexes to remove DNA lesions in specific regions of the genome. Despite our understanding of SLX4 as a scaffold for DNA repair proteins, a detailed repertoire of SLX4 interactors has never been reported. Here, we provide a comprehensive map of the human SLX4 interactome using proximity-dependent biotin identification (BioID) and affinity purification coupled to mass spectrometry (AP-MS). We identified 221 unique high-confidence interactors, of which the vast majority represent novel SLX4-binding proteins. Network analysis of these hits revealed pathways with known involvement of SLX4, such as DNA repair, and several emerging pathways of interest, including RNA metabolism and chromatin remodeling. In summary, the comprehensive SLX4 interactome we report here provides a deeper understanding of how SLX4 functions in DNA repair while revealing new cellular processes that may involve SLX4.

Prevalence and Characteristics of Diagnostic Error in Pediatric Critical Care: A Multicenter Study.

OBJECTIVES: Effective interventions to prevent diagnostic error among critically ill children should be informed by diagnostic error prevalence and etiologies. We aimed to determine the prevalence and characteristics of diagnostic errors and identify factors associated with error in patients admitted to the PICU. DESIGN: Multicenter retrospective cohort study using structured medical record review by trained clinicians using the Revised Safer Dx instrument to identify diagnostic error (defined as missed opportunities in diagnosis). Cases with potential errors were further reviewed by four pediatric intensivists who made final consensus determinations of diagnostic error occurrence. Demographic, clinical, clinician, and encounter data were also collected. SETTING: Four academic tertiary-referral PICUs. PATIENTS: Eight hundred eighty-two randomly selected patients 0-18 years old who were nonelectively admitted to participating PICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 882 patient admissions, 13 (1.5%) had a diagnostic error up to 7 days after PICU admission. Infections (46%) and respiratory conditions (23%) were the most common missed diagnoses. One diagnostic error caused harm with a prolonged hospital stay. Common missed diagnostic opportunities included failure to consider the diagnosis despite a suggestive history (69%) and failure to broaden diagnostic testing (69%). Unadjusted analysis identified more diagnostic errors in patients with atypical presentations (23.1% vs 3.6%, p = 0.011), neurologic chief complaints (46.2% vs 18.8%, p = 0.024), admitting intensivists greater than or equal to 45 years old (92.3% vs 65.1%, p = 0.042), admitting intensivists with more service weeks/year (mean 12.8 vs 10.9 wk, p = 0.031), and diagnostic uncertainty on admission (77% vs 25.1%, p < 0.001). Generalized linear mixed models determined that atypical presentation (odds ratio [OR] 4.58; 95% CI, 0.94-17.1) and diagnostic uncertainty on admission (OR 9.67; 95% CI, 2.86-44.0) were significantly associated with diagnostic error. CONCLUSIONS: Among critically ill children, 1.5% had a diagnostic error up to 7 days after PICU admission. Diagnostic errors were associated with atypical presentations and diagnostic uncertainty on admission, suggesting possible targets for intervention.

HPV vaccination uptake among foreign-born Blacks in the US: insights from the National Health Interview Survey 2013-2017.

INTRODUCTION: Human papillomavirus (HPV) vaccination uptake is lower among foreign-born than US-born individuals, but HPV-related (e.g., cervical) cancer risks are disproportionately higher among immigrant populations. Although timely vaccination can help reduce these risks, less is known about differences in the low HPV vaccination uptake among foreign-born groups, especially Black immigrants. The purpose of this study was to examine the differences in HPV vaccination initiation among US- and foreign-born Black men and women. METHOD: Data from the 2013-2017 National Health Interview Survey on Black adults, aged 18-37 years, were analyzed in 2019. HPV vaccination initiation prevalence among US- and foreign-born blacks by region of birth were examined. Multivariate binary logistic regression analysis was used to examine the relationship between foreign-birth status and HPV vaccination initiation separately among men and women, after adjusting for sociodemographic and health-related factors. RESULTS: There were significant differences (p < 0.001) in HPV vaccination initiation among Blacks from the US (22.5%), Africa (14.2%), and Americas/Caribbean Islands (11.4%). Adjusted odds of HPV vaccination initiation were lower among foreign- than US-born Blacks (AOR 0.71, CI 0.52, 0.98) but insignificant after controlling for health-related factors. Being ≤ 17 years versus 18-26 years at age of vaccine eligibility (AOR 3.44, CI 2.90, 4.07) was associated with HPV vaccination, and this relationship remained significant among men and women. Being single was associated with vaccination initiation among men, and some college experience, fair/poor health, obstetric/gynecological visit, and pap test were associated with HPV vaccination. Conclusion Cancer prevention strategies to promote HPV vaccination should consider making age-appropriate, gender-specific, and culturally relevant programs among foreign-born blacks in the US. Health insurance is also a key factor that might help with the lower rates of vaccinated black immigrants.

Development of a yeast whole-cell biocatalyst for MHET conversion into terephthalic acid and ethylene glycol.

BACKGROUND: Over the 70 years since the introduction of plastic into everyday items, plastic waste has become an increasing problem. With over 360 million tonnes of plastics produced every year, solutions for plastic recycling and plastic waste reduction are sorely needed. Recently, multiple enzymes capable of degrading PET (polyethylene terephthalate) plastic have been identified and engineered. In particular, the enzymes PETase and MHETase from Ideonella sakaiensis depolymerize PET into the two building blocks used for its synthesis, ethylene glycol (EG) and terephthalic acid (TPA). Importantly, EG and TPA can be re-used for PET synthesis allowing complete and sustainable PET recycling. RESULTS: In this study we used Saccharomyces cerevisiae, a species utilized widely in bioindustrial fermentation processes, as a platform to develop a whole-cell catalyst expressing the MHETase enzyme, which converts monohydroxyethyl terephthalate (MHET) into TPA and EG. We assessed six expression architectures and identified those resulting in efficient MHETase expression on the yeast cell surface. We show that the MHETase whole-cell catalyst has activity comparable to recombinant MHETase purified from Escherichia coli. Finally, we demonstrate that surface displayed MHETase is active across a range of pHs, temperatures, and for at least 12 days at room temperature. CONCLUSIONS: We demonstrate the feasibility of using S. cerevisiae as a platform for the expression and surface display of PET degrading enzymes and predict that the whole-cell catalyst will be a viable alternative to protein purification-based approaches for plastic degradation.

The Society for Vascular Surgery Objective Performance Goals for Critical Limb Ischemia are attainable in select patients with ischemic wounds managed with wound care alone.

BACKGROUND: To set therapeutic benchmarks, in 2009 the Society for Vascular Surgery defined objective performance goals (OPG) for treatment of patients with chronic limb threatening ischemia (CLTI) with either open surgical bypass or endovascular intervention. The goal of these OPGs are to set standards of care from a revascularization standpoint and to provide performance benchmarks for 1 year patency rates for new endovascular therapies. While OPGs are useful in this regard, a critical decision point in the treatment of patients with CLTI is determining when revascularization is necessary. There is little guidance in the comprehensive treatment of this patient population, especially in the nonoperative cohort. Guidelines are needed for the CLTI patient population as a whole and not just those revascularized, and our aim was to assess whether CLTI OPGs could be attained with nonoperative management alone. METHODS: Our cohort included patients with an incident diagnosis of CLTI (by hemodynamic and symptomatic criteria) at our institution from 2013-2017. The primary outcome measured was mortality. Secondary outcomes were limb loss and failure of amputation-free survival. Descriptive statistics were used to define the 2 groups - patients undergoing primary revascularization and patients undergoing primary wound management. The risk difference in outcomes between the 2 groups was estimated using collaborative-targeted maximum likelihood estimation. RESULTS: Our cohort included 349 incident CLTI patients; 60% male, 51% white, mean age 63 +/- 13 years, 20% Rutherford 4, and 80% Rutherford 5. Most patients (277, 79%) underwent primary revascularization, and 72 (21%) were treated with wound care alone. Demographics and presenting characteristics were similar between groups. Although the revascularized patients were more likely to have femoropopliteal disease (72% vs. 36%), both groups had a high rate of infrapopliteal disease (62% vs. 57%). Not surprisingly, the patients in the revascularization group were less likely to have congestive heart failure (34% vs. 42%), complicated diabetes (52% vs. 79%), obesity (19% vs. 33%), and end stage renal disease (14% vs. 28%). In the wound care group, 2-year outcomes were 65% survival, 51% amputation free survival, 19% major limb amputation, and 17% major adverse cardiac event. The wound care cohort had a 13% greater risk of death at 2 years; however, the risk of limb loss at 2 years was 12% less in the wound care cohort. CONCLUSIONS: A comprehensive set treatment goals and expected amputation free survival outcomes can guide revascularization, but also assure that appropriate outcomes are achieved for patients treated without revascularization. The 2-year outcomes achieved in this cohort provide an estimate of outcomes for nonrevascularized CLTI patients. Although multi-center or prospective studies are needed, we demonstrate that equal, even improved, limb salvage rates are possible.

Predictors of diarrhea, mortality, and weight gain in male dairy calves.

The objective of this prospective cohort study was to determine the effect of an abnormal fecal consistency score on weight gain and mortality in male Holstein calves and to identify risk factors associated with the occurrence of an abnormal fecal consistency score. This study enrolled 2,616 calves entering a calf-raising facility in Ontario, Canada, between January 2018 and December 2020. Fecal consistency scores were assigned twice daily for the first 28 d following arrival, where a score of 2, indicating runny consistency, and 3, indicating watery consistency, were classified as diarrhea. Severe diarrhea was classified by a score of 3. Serum total protein was measured upon arrival and the source of the calf (i.e., whether the calf came from a drover, local farm, or auction) was recorded. Body weight measurements were also collected at arrival and at 14, 56, and 77 d after arrival. Calf mortality and disease treatment during the first 77 d were recorded. On average, calves had diarrhea for 16% (4.51 d) of the first 28 d under observation, and severe diarrhea for 7% (1.87 d) of the 28 d under observation. Using a repeated measures linear regression model, we found the proportion of days with diarrhea significantly decreased weight gain at 14, 56, and 77 d following arrival. An increased proportion of days with diarrhea increased the risk of mortality, which was determined using a Cox proportional hazards model. We also found, using 2 Cox proportional hazards models, that a higher proportion of days with an abnormal fecal score increased the hazard of antibiotic treatment. With respect to factors associated with the occurrence of abnormal fecal consistency, we found that arrival weight and the source of calves were statistically significant predictors. Specifically, for every additional kilogram of body weight at arrival, the proportion of days with diarrhea decreased by 7%. With respect to source, calves from drovers had a higher proportion of days with diarrhea compared with those sourced directly from local dairy farms. Our results highlight the substantial influence the presence of abnormal fecal consistency has on short-term weight gain, mortality risk, and morbidity risk. We also demonstrate that diarrhea occurrence can be predicted using body weight at arrival and calf source. Further research should evaluate longer-term effects of diarrhea and better understand the effect of arrival weight on neonatal calf disease risk.

Coordinated actions of SLX1-SLX4 and MUS81-EME1 for Holliday junction resolution in human cells.

Holliday junctions (HJs) are four-way DNA intermediates that form during homologous recombination, and their efficient resolution is essential for chromosome segregation. Here, we show that three structure-selective endonucleases, namely SLX1-SLX4, MUS81-EME1, and GEN1, define two pathways of HJ resolution in human cells. One pathway is mediated by GEN1, whereas SLX1-SLX4 and MUS81-EME1 provide a second and genetically distinct pathway (SLX-MUS). Cells depleted for SLX-MUS or GEN1 pathway proteins exhibit severe defects in chromosome segregation and reduced survival. In response to CDK-mediated phosphorylation, SLX1-SLX4 and MUS81-EME1 associate at the G2/M transition to form a stable SLX-MUS holoenzyme, which can be reconstituted in vitro. Biochemical studies show that SLX-MUS is a HJ resolvase that coordinates the active sites of two distinct endonucleases during HJ resolution. This cleavage reaction is more efficient and orchestrated than that mediated by SLX1-SLX4 alone, which exhibits a potent nickase activity that acts promiscuously upon DNA secondary structures.

Scurvy and Tinea Corporis Simulating Leukocytoclastic Vasculitis.

ABSTRACT: Leukocytoclastic vasculitis (LCV) is a small vessel inflammatory condition considered to be caused by circulating immune complexes and often occurs after an acute infection or exposure to a new medication, although it may be associated with an underlying systemic disease or be idiopathic in nature. It is important to determine the etiology, identify the extent of the disease for early intervention and appropriate management, and treat and/or eliminate the underlying cause. Here, we report cases of scurvy and tinea corporis that presented with histopathologic features of LCV and had significant clinical improvement with treatment of the underlying etiologies. These cases emphasize that histopathologic features of early evolving LCV may be seen in other settings including scurvy and tinea corporis. Appropriate treatment of the underlying condition is important for optimized patient management.

Beyond Muscle: A Narrative Review of Onabotulinum Toxin A for Skin Quality.

BACKGROUND: Onabotulinum toxin A’s (BoNTA’s) popularity is centered on its quick, predictable, and safe ability to improve clinically apparent rhytides. While this remains the only FDA indication for BoNTA, recent research suggests that BoNTA may have a much wider use for the improvement of overall skin quality. OBJECTIVE: This review will focus on the various evidence and uses of BoNTA for improvement of skin quality. MATERIALS AND METHODS: This review considered published journal articles (clinical trials, case studies, scientific reviews). Studies were identified by searching the PubMed database and reference lists of respective articles. Only articles available in English were considered for this review. RESULTS: Intramuscular and intradermal injections of BoNTA decrease sebum production, pore size, facial erythema and flushing, and resting lines. BoNTA induces neocollagenesis and restores the extracellular matrix. CONCLUSION: The literature provides both in vivo and in vitro evidence that BoNTA enhances skin quality beyond its well-studied neuromuscular effect. J Drugs Dermatol. 2021;20(9):958-962. doi:10.36849/JDD.6038.

Associations between feeding behaviors collected from an automated milk feeder and disease in group-housed dairy calves in Ontario: A cross-sectional study.

The adoption of automated milk feeders and group housing of preweaning dairy calves has become more common in Canada; however, disease detection in group-housed calves remains a challenge. The aim of this cross-sectional study was to assess whether feeding behavior data collected from a single point in time could be used to aid in the detection of neonatal calf diarrhea (NCD), bovine respiratory disease (BRD), and general disease, in preweaning group-housed calves being fed via an automated milk feeder. The data used was collected in an earlier study. A total of 8 dairy farms recruited from an online survey of calf-management practices were enrolled into the study. There was a total of 523 observations with 130 events of NCD, 115 events of BRD, and 210 events of general disease. Each farm was visited once in each of the fall, winter, spring, and summer, when the calves' health was scored, and the data were collected from the automated milk feeders. Mixed linear regression models were used to identify associations between feeding behavior data (milk consumption, time spent at the feeder, drinking speed, and the number of rewarded and unrewarded visits) and the presence of NCD, BRD, or general disease (having one or more of NCD, BRD, or umbilical infection), on the day of health scoring. Generalized linear mixed models were used to analyze the percentage of milk the calf consumed from their daily milk allotment. Calves with BRD consumed 63% less of their daily allotment of milk, had 2 fewer unrewarded visits to the automated milk feeder, and drank milk 152 mL/min slower compared with calves without BRD. Calves with NCD consumed 57% less of their daily milk allotment, consumed 758 mL less per day, and drank 92 mL/min slower than calves compared with calves without NCD. Calves with general disease drank 50% less of their daily milk allowance, consumed 496 mL less per day, drank 80 mL/min slower, and had 2 fewer unrewarded visits to the automated milk feeder, when compared with calves without disease. No significant associations were found between the presence of NCD, BRD, or general disease and time spent at the feeder or number of rewarded visits. Sensitivity and specificity values for disease identification were low when evaluating the feeding behaviors individually, so parallel testing was completed. To do so, if any significant feeding behavior was below the optimal cut point for disease detection as determined using a ROC curve, the calf was considered positive for disease and the sensitivity and specificity were recalculated. Parallel testing resulted in a sensitivity of 0.82, 0.78, and 0.84, and a specificity of 0.26, 0.23, and 0.21, for BRD, NCD, and general disease, respectively. This suggests that automated milk feeders may serve as a useful preliminary tool in the detection of diseased calves. For example, producers could use feeding behavior data to identify calves requiring further inspection; however, they should not use feeding behavior data as a sole disease detection method.

Resolution of single and double Holliday junction recombination intermediates by GEN1.

Genetic recombination provides an important mechanism for the repair of DNA double-strand breaks. Homologous pairing and strand exchange lead to the formation of DNA intermediates, in which sister chromatids or homologous chromosomes are covalently linked by four-way Holliday junctions (HJs). Depending on the type of recombination reaction that takes place, intermediates may have single or double HJs, and their resolution is essential for proper chromosome segregation. In mitotic cells, double HJs are primarily dissolved by the BLM helicase-TopoisomeraseIIIα-RMI1-RMI2 (BTR) complex, whereas single HJs (and double HJs that have escaped the attention of BTR) are resolved by structure-selective endonucleases known as HJ resolvases. These enzymes are ubiquitous in nature, because they are present in bacteriophage, bacteria, archaea, and simple and complex eukaryotes. The human HJ resolvase GEN1 is a member of the XPG/Rad2 family of 5'-flap endonucleases. Biochemical studies of GEN1 revealed that it cleaves synthetic DNA substrates containing a single HJ by a mechanism similar to that shown by the prototypic HJ resolvase, Escherichia coli RuvC protein, but it is unclear whether these substrates fully recapitulate the properties of recombination intermediates that arise within a physiological context. Here, we show that GEN1 efficiently cleaves both single and double HJs contained within large recombination intermediates. Moreover, we find that GEN1 exhibits a weak sequence preference for incision between two G residues that reside in a T-rich region of DNA. These results contrast with those obtained with RuvC, which exhibits a strict requirement for the consensus sequence 5'-A/TTTG/C-3'.

Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. METHODS: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation. RESULTS: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability. DISCUSSION: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Telehealth: Advances in Alternative Payment Models.

Introduction: The hospital sector has shifted its focus to advanced information and communication technologies to facilitate health care delivery through telehealth services to alleviate the industry's most pressing challenges in quality care and access, especially under changing reimbursement payment approaches. The aim of this study was to examine the association between alternative payment models (APMs), market competition, and telehealth provisions in the hospital setting. Materials and Methods: A secondary cross-sectional design to analyze 2018 census data of nonfederal short-term acute care hospitals in the United States was used. Multilevel logistic regressions models were used to analyze data from 4,257 hospitals across 1,874 counties. Counties with less than one hospital were excluded. Results: Regarding APMs, we found that hospital participation in accountable care organizations and participation in a bundled payment risk arrangement are significantly associated with the provision of telehealth services. From the market perspective, competitive advantage was found to be statistically associated with hospitals providing telehealth services. In addition, other hospital characteristics such as ownership, part of a system, part of a network, and major teaching affiliation also have impact on the provision of telehealth. Conclusions: The increase uptake of telehealth-related capabilities and their strong integration into care-delivery systems under APMs present exciting opportunities to enhance the merit of clinical care, and challenges as clinical professionals are not adept to using such technologies. There is a need to provide comprehensive of evidence on telehealth.