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.

Transmission of viable Haemophilus ducreyi by Musca domestica.

Haemophilus ducreyi was historically known as the causative agent of chancroid, a sexually-transmitted disease causing painful genital ulcers endemic in many low/middle-income nations. In recent years the species has been implicated as the causative agent of nongenital cutaneous ulcers affecting children of the South Pacific Islands and West African countries. Much is still unknown about the mechanism of H. ducreyi transmission in these areas, and recent studies have identified local insect species, namely flies, as potential transmission vectors. H. ducreyi DNA has been detected on the surface and in homogenates of fly species sampled from Lihir Island, Papua New Guinea. The current study develops a model system using Musca domestica, the common house fly, as a model organism to demonstrate proof of concept that flies are a potential vector for the transmission of viable H. ducreyi. Utilizing a green fluorescent protein (GFP)-tagged strain of H. ducreyi and three separate exposure methods, we detected the transmission of viable H. ducreyi by 86.11% ± 22.53% of flies sampled. Additionally, the duration of H. ducreyi viability was found to be directly related to the bacterial concentration, and transmission of H. ducreyi was largely undetectable within one hour of initial exposure. Push testing, Gram staining, and PCR were used to confirm the identity and presence of GFP colonies as H. ducreyi. This study confirms that flies are capable of mechanically transmitting viable H. ducreyi, illuminating the importance of investigating insects as vectors of cutaneous ulcerative diseases.

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.

The vedotin antibody-drug conjugate payload drives platform-based nonclinical safety and pharmacokinetic profiles.

Nonclinical safety and pharmacokinetic data for MMAE and 14 vedotin ADCs were evaluated to determine patterns of toxicity, consistency of pharmacokinetic results, and species differences between rats and monkeys. Most nonclinical toxicities were antigen-independent, common across ADCs, and included hematologic, lymphoid, and reproductive toxicity related to MMAE pharmacology. Hematologic toxicity was the dose-limiting or predominant toxicity for the majority of vedotin ADCs in both species. Tissue expression of the targeted antigen of an ADC rarely correlated with dose-limiting toxicity (DLT); only two ADCs had antigen-dependent skin DLTs. For two additional ADCs, antigen-dependent delivery of MMAE in the bone marrow may have exacerbated the antigen-independent hematologic DLT. The highest tolerated doses and pharmacokinetics were similar within a given species, with rats tolerating higher doses than monkeys. Studies longer than one month in duration detected the same or fewer toxicities than one-month studies and had no additional findings that affected the human risk assessment. These data support opportunities to streamline ADC toxicity assessments without compromising human starting dose selection or target organ identification.

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.

Efficacy and Durability of Intravenous Ertapenem Therapy for Recalcitrant Hidradenitis Suppurativa.

Importance: Hidradenitis suppurativa (HS) is a debilitating follicular skin disorder in which bacterial colonization is typical. Oral antibiotic efficacy can be unreliable; however, selective intravenous antibiotics, specifically ertapenem, may provide favorable clinical outcomes. Objective: To explore optimal course duration, efficacy, and patient satisfaction associated with intravenous ertapenem for HS. Design, Setting, and Participants: This retrospective review of the medical records of 98 patients with HS between 2018 and 2022 measured and evaluated patient outcomes before and after treatment with intravenous ertapenem. Participants were followed up in a telephone survey assessing patient perspectives and satisfaction. All of those included in this study received medical care from the Albert Einstein College of Medicine's Montefiore HS Center. Exposures: Patients were treated with 1 g of ertapenem that was self-administered at home through a peripheral intravenous central catheter using an elastomeric pump for 12 to 16 weeks. Antiandrogens and immunomodulatory biologic therapies initiated prior to ertapenem were maintained throughout the treatment course. Main Outcomes and Measures: The primary outcomes, encompassing clinical severity (evaluated through the HS Physician Global Assessment score [a 6-point scale ranging from clear to very severe] and a numerical rating scale for pain [an 11-point scale in which a score of 0 indicates no pain and a score of 10 indicates the worst possible pain]) and markers of inflammation (such as leukocytes, erythrocyte sedimentation rate, C-reactive protein, and interleukin-6), were measured at baseline, the midcourse of intravenous ertapenem treatment, at the end of the course, and posttherapy. Bacterial abundance was also examined at these 4 points, and patient satisfaction was assessed during follow-up. Results: A total of 98 patients (mean [SD] age, 35.8 [13.0] years; 61 [62.2%] female) with HS were treated with intravenous ertapenem. The self-reported racial distribution included 3 individuals identifying as Asian (3.1%), 59 as Black/African American (60.2%), 13 as White (13.3%), and 23 as either other or unknown (23.5%). Additionally, 24 participants (24.5%) reported Spanish/Hispanic/Latino ethnicity. The mean (SD) treatment duration spanned 13.1 (4.0) weeks, with posttherapy follow-up occurring after 7.8 (3.6) weeks. From baseline to posttherapy follow-up, significant reductions were found in the mean (SD) HS Physician Global Assessment scores (3.9 [1.0] vs 2.7 [1.2]; P < .001) and the numerical rating scale for pain (4.2 [3.3] vs 1.8 [2.7]; P < .001), C-reactive protein (5.4 [11.4] vs 2.4 [2.0] mg/dL; P < .001), interleukin-6 (25.2 [21.1] vs 13.7 [13.9]; P < .001), and leukocytes (11.34 [3.9] vs 10.0 [3.4]; P < .001). At follow-up, 76 patients (78.0%) participated in the telephone survey, where 63 (80.3%) reported medium to high satisfaction; further, 69 (90.8%) would recommend ertapenem to other patients. Conclusions and Relevance: In this retrospective review of medical records and telephone survey, treating HS with intravenous ertapenem, administered for a mean of 13 weeks, was associated with improvement in clinical and inflammatory markers, as well as heightened patient satisfaction. Nonetheless, this approach should be monitored for the emergence of antimicrobial resistance given a longer than standard treatment course.

A foundational description of Antilocapra americana pronghorn core osteohistology.

Cranial bony projections ("headgear") have diverse forms and functions, such as defense, species recognition, mate selection, and thermoregulation. Most commonly, they are associated with the artiodactyl infraorder, Pecora. All pecoran headgear-antlers, horns, ossicones, and pronghorns-are osseous protrusions of the frontal or parietal bone with an integumentary covering, although there is taxonomic, developmental, and compositional variation. However, compared with other pecorans, there is a dearth of literature addressing extant antilocaprids-Antilocapra americana. This study provides a foundational osteohistological description of A. americana pronghorn cores in order to start building a framework to better understand the complex interplay among microanatomy, development, behavior, environment, and phylogenetic history of pronghorn headgear. Osteohistological analysis of adult A. americana pronghorn cores reveal the inner medullary region is composed of trabecular bone. Based on similar studies in bovids, we propose that these trabeculae may function to reduce the effects of repeated loading incurred by intraspecific combat. The deep aspect of the outer region was found to be composed of compacted coarse cancellous bone and primary bone remodeled to dense Haversian bone, in both male and female specimens, respectively, and superficially composed of highly vascularized fibrolamellar bone. The presence of fibrolamellar bone may indicate that the bone is fast-growing, and its presence at the periosteal surface suggests protracted growth of the pronghorn core beyond sexual maturity.

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.

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.

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.

Hospital COVID-19 preparedness: Are (were) we ready?

BACKGROUND: Terrorist attacks and natural disasters such as Hurricanes Katrina and Harvey have increased focus on disaster preparedness planning. Despite the attention on planning, many studies have found that hospitals in the United States are underprepared to manage extended disasters appropriately and the surge in patient volume it might bring. AIM: This study aims to profile and examine the availability of hospital capacity specifically related to COVID-19 patients, such as emergency department (ED) beds, intensive care unit (ICU) beds, temporary space setup, and ventilators. METHOD: A cross-sectional retrospective study design was used to examine secondary data from the 2020 American Hospital Association (AHA) Annual Survey. A series of multivariate logistic analyses were conducted to investigate the strength of association between changes in ED beds, ICU beds, staffed beds, and temporary spaces setup, and the 3,655 hospitals' characteristics. RESULTS: Our results highlight that the odds of a change in ED beds are 44 percent lower for government hospitals and 54 percent for for-profit hospitals than not-for-profit hospitals. The odds of ED bed change for nonteaching hospitals were 34 percent lower compared to teaching hospitals. Small and medium hospitals have significantly lower odds (75 and 51 percent, respectively) than large hospitals. For ICU bed change, staffed bed change, and temporary spaces setup, the conclusions were consistently significant regarding the impact of hospital ownership, teaching status, and hospital size. However, temporary spaces setup differs by hospital location. The odds of change is significantly lower (OR = 0.71) in urban hospitals compared with rural hospitals, while for ED beds, the odds of change is considerably higher (OR = 1.57) in urban hospitals compared to rural hospitals. CONCLUSION: There is a need for policymakers to consider not only resource limitations that were created from supply line disruptions during the COVID-19 pandemic but also a more global assessment of the adequacy of funding and support for insurance coverage, hospital finance, and how hospitals meet the needs of the populations they serve.

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.

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.

Split Brachioradialis Tendon Causing Wartenberg Syndrome in a Professional Baseball Pitcher.

Wartenberg syndrome can occur when external factors compress the superficial radial nerve. It can also be due to anatomic variations, such as a split brachioradialis tendon entrapping the nerve. This case report describes a unique example of a professional baseball player diagnosed with Wartenberg syndrome who was later found to have a split brachioradialis tendon during surgical management. It is an important addition to the field of hand surgery since, to our knowledge, we have not identified such a rare case concerning a professional athlete previously described in the literature.

Protocol for in vitro phosphorylation of the MUS81-binding region of SLX4 using CDK1-cyclin B.

Phosphorylation is a post-translational modification that can alter protein structure and regulate protein-protein interactions. Here, we present a procedure for in vitro phosphorylation of the MUS81-binding region of SLX4 (SLX4MBR) using cyclin-dependent kinase 1-cyclin B. We describe steps for the dialysis and phosphorylation of target proteins followed by purification using size-exclusion chromatography. Finally, we detail a system to monitor phosphorylation effectiveness and identify phosphorylated residues. We anticipate this protocol to be readily adapted for other protein targets or kinases. For complete details on the use and execution of this protocol, please refer to Payliss et al. (2022).1.

Protective Relational Factors of Lesbian Couples Navigating the Fertility Process.

Little research about lesbian couples' experiences with fertility treatment exists in the counseling literature. While there is an increase in lesbian couples exploring fertility options to expand their families, it is important to understand their experiences during this stressful process. This research seeks to understand these experiences using Moustakas' Imaginative Variation method with seven lesbian couples. Results include feelings of isolation, psychological and physical stress. Despite myriad difficulties associated with assisted reproductive technology, participants' experiences show the presence of strong relationship factors, divided into three categories: connectedness, mutuality, and resilience. The use of Relational Cultural Theory may be helpful to lesbian couples looking to expand their families through reproductive methods.

Adalimumab efficacy is inversely correlated with body mass index (BMI) in hidradenitis suppurativa.

BACKGROUND: Adalimumab is the only FDA-approved biologic for hidradenitis suppurativa (HS). In the setting of increasing obesity rates worldwide, the relationship between adalimumab efficacy for HS and BMI is essential to understand. We assessed this relationship through markers of disease severity and inflammation. METHODS: Institutional review board-approved retrospective chart review of Montefiore/Einstein HS Center (HSC) patients (n = 57) treated with adalimumab. The relationship between BMI and adalimumab efficacy was assessed through disease severity (HS-Physician Global Assessment [HS-PGA] 0 and Numerical Rating Scale Pain [NRS-Pain]) and inflammatory markers (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], and interleukin-6 [IL-6]). A BMI ≥ 30 is defined as obese; BMI < 30 is defined as non-obese. RESULTS: The mean age was 35.8 ± 13.0 years. After adalimumab therapy, those with BMI < 30 experienced significant reductions in HS-PGA (-1.5 ± 0.9; P < 0.0001) and NRS-Pain (-1.6 ± 2.1; P < 0.0001), as well as mean decreases in inflammatory markers ESR, CRP, and IL-6 (-17.90 ± 23.6, -0.71 ± 1.4, -5.88 ± 7.9, respectively; P > 0.05). Obese patients (BMI ≥ 30) experienced mean increases in HS-PGA (+0.22 ± 0.8; P > 0.05) and NRS-Pain scores (+1.41 ± 3.5; P > 0.05) as well as mean increases in ESR, CRP, and IL-6 (+2.62 ± 28.3, +0.44 ± 3.0, +2.35 ± 6.9, respectively; P > 0.05). Comparing the cohorts, differences in changes in HS-PGA, NRS-Pain, ESR, and IL-6 after therapy are significantly different (P < 0.05). CONCLUSIONS: We identified significantly lower efficacy of adalimumab in HS patients with BMI ≥ 30 compared to those with BMI < 30. Those with BMI ≥ 30 demonstrated signs of both clinical and physiological deterioration while on adalimumab. Future studies are needed to examine adalimumab dosing for HS patients with high BMI, as well as a critical reconsideration of weight-based therapies.

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.

Highest resolution microCT scan of the human brainstem reveals putative anatomical basis for infrequency of medial medullary syndrome.

Ischemic strokes affecting the medial medulla are exceedingly rare. The anatomical basis for the relative infrequency of this stroke syndrome has been largely uninvestigated due to historically coarse MRI and CT scan resolution. We capture and digitally dissect the highest-ever-resolution diffusible iodine-based contrast-enhanced CT (diceCT) scanned images of a cadaveric brainstem to map arterial territories implicated in medial medullary infarctions. 3D reconstructions show that within the anterior spinal artery territory previously implicated in medial medullary syndrome (MMS), there are numerous, small sulcal artery branches perforating the medulla within the anterior median fissure. These branches proceed in parallel through the anteroposterior depth of the medulla as expected; however, we also identify a network of intraparenchymal, rostrocaudal anastomoses between these sulcal perforating branches. This network of intraparenchymal sulcal artery anastomoses has never been described and may provide a significant collateral supply of oxygenated blood flow throughout the medial medulla. By ramifying deeper tissues, these anastomoses can help explain the infrequency of MMS.

COVID-19 Deaths and the Impact of Health Disparities, Hospital Characteristics, Community, Social Distancing, and Health System Competition.

The United States has one of the highest cumulative mortalities of coronavirus disease 2019 (COVID-19) and has reached 1 million deaths as of May 19th, 2022. Understanding which community and hospital factors contributed to disparities in COVID-19 mortality is important to inform public health strategies. This study aimed to explore the potential relationship between hospital service area (1) community (ie, health professional shortage areas, market competition, and uninsured percentage) and (2) hospital (ie, teaching, system, and ownership status) characteristics (2013-2018) on publicly available COVD-19 (February to October 2020) mortality data. The study included 2514 health service areas and used multilevel mixed-effects linear model to account for the multilevel data structure. The outcome measure was the number of COVID-19 deaths. This study found that public health, as opposed to acute care provision, was associated with community health and, ultimately, COVID-19 mortality. The study found that population characteristics including more uninsured greater proportion of those over 65 years, more diverse populations, and larger populations were all associated with a higher rate of death. In addition, communities with fewer hospitals were associated with a lower rate of death. When considering region in the United States, the west region showed a higher rate of death than all other regions. The association between some community characteristics and higher COVID-19 deaths demonstrated that access to health care, either for COVID-19 infection or worse health from higher disease burden, is strongly associated with COVID-19 deaths. Thus, to be better prepared for potential future pandemics, a greater emphasis on public health infrastructure is needed.