Bridging the gap: a resident-led transitional care clinic to improve post hospital care in a safety-net academic community hospital.

The transitional period between hospital discharge and primary care follow-up is a vulnerable time for patients that can result in adverse health outcomes and preventable hospital readmissions. This is especially true for patients of safety-net hospitals (SNHs) who often struggle to secure primary care access when leaving the hospital due to social, economic and cultural barriers. In this study, we describe a resident-led postdischarge clinic that serves patients discharged from NYU Langone Hospital-Brooklyn, an urban safety-net academic hospital. In our multivariable analysis, there was no statistical difference in the readmission rate between those who completed the transitional care management and those who did not (OR 1.32 (0.75-2.36), p=0.336), but there was a statistically significant increase in primary care provider (PCP) engagement (OR 0.53 (0.45-0.62), p<0.001). Overall, this study describes a postdischarge clinic model embedded in a resident clinic in an urban SNH that is associated with increased PCP engagement, but no reduction in 30-day hospital readmissions.

Cell cycle perturbation uncouples mitotic progression and invasive behavior in a post-mitotic cell.

The acquisition of the post-mitotic state is crucial for the execution of many terminally differentiated cell behaviors during organismal development. However, the mechanisms that maintain the post-mitotic state in this context remain poorly understood. To gain insight into these mechanisms, we used the genetically and visually accessible model of C. elegans anchor cell (AC) invasion into the vulval epithelium. The AC is a terminally differentiated uterine cell that normally exits the cell cycle and enters a post-mitotic state before initiating contact between the uterus and vulva through a cell invasion event. Here, we set out to identify the set of negative cell cycle regulators that maintain the AC in this post-mitotic, invasive state. Our findings revealed a critical role for CKI-1 (p21CIP1/p27KIP1) in redundantly maintaining the post-mitotic state of the AC, as loss of CKI-1 in combination with other negative cell cycle regulators-including CKI-2 (p21CIP1/p27KIP1), LIN-35 (pRb/p107/p130), FZR-1 (Cdh1/Hct1), and LIN-23 (ß-TrCP)-resulted in proliferating ACs. Remarkably, time-lapse imaging revealed that these ACs retain their ability to invade. Upon examination of a node in the gene regulatory network controlling AC invasion, we determined that proliferating, invasive ACs do so by maintaining aspects of pro-invasive gene expression. We therefore report that the requirement for a post-mitotic state for invasive cell behavior can be bypassed following direct cell cycle perturbation.

Cell cycle perturbation uncouples mitotic progression and invasive behavior in a post-mitotic cell.

The acquisition of the post-mitotic state is crucial for the execution of many terminally differentiated cell behaviors during organismal development. However, the mechanisms that maintain the post-mitotic state in this context remain poorly understood. To gain insight into these mechanisms, we used the genetically and visually accessible model of C. elegans anchor cell (AC) invasion into the vulval epithelium. The AC is a terminally differentiated uterine cell that normally exits the cell cycle and enters a post-mitotic state, initiating contact between the uterus and vulva through a cell invasion event. Here, we set out to identify the set of negative cell cycle regulators that maintain the AC in this post-mitotic, invasive state. Our findings revealed a critical role for CKI-1 (p21CIP1/p27KIP1) in redundantly maintaining the post-mitotic state of the AC, as loss of CKI-1 in combination with other negative cell cycle regulators-including CKI-2 (p21CIP1/p27KIP1), LIN-35 (pRb/p107/p130), FZR-1 (Cdh1/Hct1), and LIN-23 (ß-TrCP)-resulted in proliferating ACs. Remarkably, time-lapse imaging revealed that these ACs retain their ability to invade. Upon examination of a node in the gene regulatory network controlling AC invasion, we determined that proliferating, invasive ACs do so by maintaining aspects of pro-invasive gene expression. We therefore report that the requirement for a post-mitotic state for invasive cell behavior can be bypassed following direct cell cycle perturbation.

State-of-the-art 2023 on gene therapy for phenylketonuria.

Phenylketonuria (PKU) or hyperphenylalaninemia is considered a paradigm for an inherited (metabolic) liver defect and is, based on murine models that replicate all human pathology, an exemplar model for experimental studies on liver gene therapy. Variants in the PAH gene that lead to hyperphenylalaninemia are never fatal (although devastating if untreated), newborn screening has been available for two generations, and dietary treatment has been considered for a long time as therapeutic and satisfactory. However, significant shortcomings of contemporary dietary treatment of PKU remain. A long list of various gene therapeutic experimental approaches using the classical model for human PKU, the homozygous enu2/2 mouse, witnesses the value of this model to develop treatment for a genetic liver defect. The list of experiments for proof of principle includes recombinant viral (AdV, AAV, and LV) and non-viral (naked DNA or LNP-mRNA) vector delivery methods, combined with gene addition, genome, gene or base editing, and gene insertion or replacement. In addition, a list of current and planned clinical trials for PKU gene therapy is included. This review summarizes, compares, and evaluates the various approaches for the sake of scientific understanding and efficacy testing that may eventually pave the way for safe and efficient human application.

Complete correction of murine phenylketonuria by selection-enhanced hepatocyte transplantation.

BACKGROUND AND AIMS: Hepatocyte transplantation for genetic liver diseases has several potential advantages over gene therapy. However, the low efficiency of cell engraftment has limited its clinical implementation. This problem could be overcome by selectively expanding transplanted donor cells until they replace enough of the liver mass to achieve therapeutic benefit. We previously described a gene therapy method to selectively expand hepatocytes deficient in cytochrome p450 reductase (Cypor) using acetaminophen (APAP). Because Cypor is required for the transformation of APAP to a hepatotoxic metabolite, Cypor-deficient cells are protected from toxicity and are able to expand following APAP-induced liver injury. Here, we apply this selection system to correct a mouse model of phenylketonuria by cell transplantation. APPROACH AND RESULTS: Hepatocytes from a wild-type donor animal were edited in vitro to create Cypor deficiency and then transplanted into phenylketonuric animals. Following selection with APAP, blood phenylalanine concentrations were fully normalized and remained stable following APAP withdrawal. Cypor-deficient hepatocytes expanded from < 1% to ~14% in corrected animals, and they showed no abnormalities in blood chemistries, liver histology, or drug metabolism. CONCLUSIONS: We conclude that APAP-mediated selection of transplanted hepatocytes is a potential therapeutic for phenylketonuria with long-term efficacy and a favorable safety profile.

Dynamic compartmentalization of the pro-invasive transcription factor NHR-67 reveals a role for Groucho in regulating a proliferative-invasive cellular switch in C. elegans.

A growing body of evidence suggests that cell division and basement membrane invasion are mutually exclusive cellular behaviors. How cells switch between proliferative and invasive states is not well understood. Here, we investigated this dichotomy in vivo by examining two cell types in the developing Caenorhabditis elegans somatic gonad that derive from equipotent progenitors, but exhibit distinct cell behaviors: the post-mitotic, invasive anchor cell and the neighboring proliferative, non-invasive ventral uterine (VU) cells. We show that the fates of these cells post-specification are more plastic than previously appreciated and that levels of NHR-67 are important for discriminating between invasive and proliferative behavior. Transcription of NHR-67 is downregulated following post-translational degradation of its direct upstream regulator, HLH-2 (E/Daughterless) in VU cells. In the nuclei of VU cells, residual NHR-67 protein is compartmentalized into discrete punctae that are dynamic over the cell cycle and exhibit liquid-like properties. By screening for proteins that colocalize with NHR-67 punctae, we identified new regulators of uterine cell fate maintenance: homologs of the transcriptional co-repressor Groucho (UNC-37 and LSY-22), as well as the TCF/LEF homolog POP-1. We propose a model in which the association of NHR-67 with the Groucho/TCF complex suppresses the default invasive state in non-invasive cells, which complements transcriptional regulation to add robustness to the proliferative-invasive cellular switch in vivo.

A wavefront adaptive sensing beamformer for ocean acoustic waveguides.

This paper addresses robust adaptive beamforming for passive sonar in uncertain, shallow-water environments. Conventional beamforming is still common in passive sonar because adaptive beamformers suffer from signal mismatch in complex multipath environments. Existing approaches to robust adaptive beamforming try to model and account for the uncertainty in the beamformer's hypothesized signal subspace by using additional linear or quadratic constraints. Doing so, however, reduces the adaptivity of the beamformer and is prone to insufficiently suppressing interference. Instead, this paper uses blind source separation methods to adaptively estimate the complex spatial wavefronts of both targets and interference without requiring detailed physical modeling of the channel. By exploiting the different temporal spectra and/or frequency-selective multipath fading of targets and interference, this approach constructs a "signal-free" covariance matrix without imposing directional gain constraints. In doing so, the wavefront adaptive sensing (WAS) beamformer is able to separate targets from strong interference that is within the conventional beam width of the target. Simulation results in a realistic shallow-water channel are presented as well as results using the SWellEx96 S59 data with an injected target to show that the proposed WAS beamformer outperforms conventional and minimum variance adaptive beamformers in a shallow-water scenario.

Perceptions of Factors Associated With Sustainability of Health Care Innovation Centers.

Importance: Innovation centers in US health care systems are increasingly common but variably successful and sustainable. Few studies have examined how and why some centers achieve sustainable success but others do not. Objective: To explore whether and how innovation centers in US health care systems are able to successfully sustain themselves over multiple years. Design, Setting, and Participants: In this qualitative study, semistructured, qualitative interviews of leaders at 9 innovation centers across the US were conducted from January 1, 2019, to December 31, 2020. Data analysis was conducted from December 2020 to April 2021 using qualitative methods and a deductive framework based on the Consolidated Framework for Implementation Research. Centers were identified through purposeful sampling. The 9 study centers had a mean age of 6 years (range, 2-15 years); most were affiliated with an academic teaching hospital and half with a medical school. Two were wholly separate from the health care system. Two-thirds had fewer than 10 full-time staff members. Exposures: All interviewees were staff of a US-based innovation center. This study did not evaluate particular interventions or innovations. Main Outcomes and Measures: Perceptions of and views on factors associated with the success and sustainability of innovation centers. Results: Staff interviewed at 9 innovation centers across the US described 3 key activities that appeared to be associated with long-term sustainability: facilitating innovation projects that were valued for quality improvement and cost avoidance, not just return on investment; acting as networking nodes for their institutions; and upskilling staff. These activities were associated with improved institutional culture. Two structural characteristics underpinned successful centers: finding an effective balance between being "internal" and being "external" to the organization and providing practical support and skills otherwise lacking within the wider institution. Conclusions and Relevance: This qualitative study of 9 innovation centers explored how centers sustained themselves within US health care institutions and showed that success was often associated with interpersonal relationships and cultural benefits. Independent financial sustainability was not always essential to longevity; systems also valued how centers could create cultures of innovation and upskill staff.

AN OUTBREAK OF FELINE INFECTIOUS PERITONITIS IN THREE RELATED SAND CATS (FELIS MARGARITA) IN HUMAN CARE.

Feline infectious peritonitis (FIP) is a systemic disease in felid species caused by infection with mutated forms of feline coronavirus (FCoV), and outbreaks can devastate exotic felid populations in human care. Feline infectious peritonitis was diagnosed in three of four related juvenile sand cats (Felis margarita) from a single institution over a 6-wk period. Case 1 was a 7-mon-old male found deceased with no premonitory signs. Case 2, an 8-mon-old male (littermate to Case 1), and Case 3, a 6-mon-old male (from a different litter with identical parentage), were evaluated for lethargy and anorexia 1 mon after Case 1. Both exhibited transient anisocoria and progressive lethargy, anorexia, and dehydration despite antibiotic and supportive treatment. Approximately 1 wk after initial presentation, Case 2 was humanely euthanized, and Case 3 was found deceased. Necropsy findings included intrathoracic and/or intra-abdominal lymphadenopathy (3/3 cases), bicavitary effusion (2/3), multifocal tan hepatic and intestinal nodules (1/3), and multifocal yellow renal nodules (1/3). Histologically, all cats had severe pyogranulomatous vasculitis in multiple organs, and the presence of FCoV antigen was confirmed using immunohistochemical staining. Next-generation sequencing of the virus from Case 3's affected kidney demonstrated ∼93% homology to the UG-FH8 virus, a serotype 1 feline alphacoronavirus isolated from Denmark. Future research will focus on comparative viral genomic sequencing with the goals of identifying potential sources of FCoV infection and identifying features that may have contributed to the development of FIP in this species.

Complete correction of murine phenylketonuria by selection-enhanced hepatocyte transplantation.

Hepatocyte transplantation for genetic liver diseases has several potential advantages over gene therapy. However, low efficiency of cell engraftment has limited its clinical implementation. This problem could be overcome by selectively expanding transplanted donor cells until they replace enough of the liver mass to achieve therapeutic benefit. We previously described a gene therapy method to selectively expand hepatocytes deficient in cytochrome p450 reductase (Cypor) using acetaminophen (APAP). Because Cypor is required for the transformation of APAP to a hepatotoxic metabolite, Cypor deficient cells are protected from toxicity and are able to expand following APAP-induced liver injury. Here, we apply this selection system to correct a mouse model of phenylketonuria (PKU) by cell transplantation. Hepatocytes from a wildtype donor animal were edited in vitro to create Cypor deficiency and then transplanted into PKU animals. Following selection with APAP, blood phenylalanine concentrations were fully normalized and remained stable following APAP withdrawal. Cypor-deficient hepatocytes expanded from <1% to ~14% in corrected animals, and they showed no abnormalities in blood chemistries, liver histology, or drug metabolism. We conclude that APAP-mediated selection of transplanted hepatocytes is a potential therapeutic for PKU with long-term efficacy and a favorable safety profile.

Charge, Aspect Ratio, and Plant Species Affect Uptake Efficiency and Translocation of Polymeric Agrochemical Nanocarriers.

An incomplete understanding of how agrochemical nanocarrier properties affect their uptake and translocation in plants limits their application for promoting sustainable agriculture. Herein, we investigated how the nanocarrier aspect ratio and charge affect uptake and translocation in monocot wheat (Triticum aestivum) and dicot tomato (Solanum lycopersicum) after foliar application. Leaf uptake and distribution to plant organs were quantified for polymer nanocarriers with the same diameter (∼10 nm) but different aspect ratios (low (L), medium (M), and high (H), 10-300 nm long) and charges (-50 to +15 mV). In tomato, anionic nanocarrier translocation (20.7 ± 6.7 wt %) was higher than for cationic nanocarriers (13.3 ± 4.1 wt %). In wheat, only anionic nanocarriers were transported (8.7 ± 3.8 wt %). Both low and high aspect ratio polymers translocated in tomato, but the longest nanocarrier did not translocate in wheat, suggesting a phloem transport size cutoff. Differences in translocation correlated with leaf uptake and interactions with mesophyll cells. The positive charge decreases nanocarrier penetration through the leaf epidermis and promotes uptake into mesophyll cells, decreasing apoplastic transport and phloem loading. These results suggest design parameters to provide agrochemical nanocarriers with rapid and complete leaf uptake and an ability to target agrochemicals to specific plant organs, with the potential to lower agrochemical use and the associated environmental impacts.

Self-Reported Long-Term Side Effects of Isotretinoin: A Case Series.

CITATION: Ghadimi TR, Martinez MJ, Rieder EA. Self-reported long-term side effects of isotretinoin: A case series. J Drugs Dermatol. 2023;22(4):423-424. doi:10.36849/JDD.2303.

Temperature-Responsive Bottlebrush Polymers Deliver a Stress-Regulating Agent In Vivo for Prolonged Plant Heat Stress Mitigation.

Anticipated increases in the frequency and intensity of extreme temperatures will damage crops. Methods that efficiently deliver stress-regulating agents to crops can mitigate these effects. Here, we describe high aspect ratio polymer bottlebrushes for temperature-controlled agent delivery in plants. The foliar-applied bottlebrush polymers had near complete uptake into the leaf and resided in both the apoplastic regions of the leaf mesophyll and in cells surrounding the vasculature. Elevated temperature enhanced the in vivo release of spermidine (a stress-regulating agent) from the bottlebrushes, promoting tomato plant (Solanum lycopersicum) photosynthesis under heat and light stress. The bottlebrushes continued to provide protection against heat stress for at least 15 days after foliar application, whereas free spermidine did not. About 30% of the ∼80 nm short and ∼300 nm long bottlebrushes entered the phloem and moved to other plant organs, enabling heat-activated release of plant protection agents in phloem. These results indicate the ability of the polymer bottlebrushes to release encapsulated stress relief agents when triggered by heat to provide long-term protection to plants and the potential to manage plant phloem pathogens. Overall, this temperature-responsive delivery platform provides a new tool for protecting plants against climate-induced damage and yield loss.

A 2-Year Longitudinal Study of Bone Mineral Density in Collegiate Distance Runners.

ABSTRACT: Brimacomb, OE, Martinez, MP, McCormack, WP, and Almstedt, HC. A 2-year longitudinal study of bone mineral density in collegiate distance runners. J Strength Cond Res 37(8): 1654-1659, 2023-The purpose of this investigation was to examine changes in bone mineral density (BMD) of male and female collegiate distance runners over 2 years. Bone mineral density of 29 collegiate distance runners (16 men and 13 women) were measured 5 times over 24 months using dual-energy x-ray absorptiometry (DXA) at the anterior-posterior (AP) and lateral (LAT) spine, femoral neck (FN), total hip (TH), whole body (WB), and ultradistal (UD) forearm. Repeated-measures multivariate analysis of covariance, with bone-free lean mass (BFLM) as covariate, was used to compare mean BMD values. Adjusted for BFLM, there were no significant differences ( p > 0.05) in BMD at any site between sexes. There were no significant differences at the AP or LAT spine, FN, or WB between visit 1 and 5 for either sex. There was a significant increase in BMD ( p = 0.044) at the UD forearm over 2 years in males. However, 56% of the men ( n = 9) had a Z-score < -1.0 at the UD forearm. Seven of 11 women had Z-scores < -1.0 at the LAT spine and 4 of 13 had Z-scores < -1.0 at the AP spine. There were no significant changes in BMD at any site over the 2-year time frame, except a significant increase in BMD at the nondominant forearm in men. The spine appears to be an area of concern for women in this study when examining Z-score results. Coaches and medical staff need to continually educate collegiate endurance athletes about the importance of achieving and maintaining BMD through their college years.

An expandable FLP-ON::TIR1 system for precise spatiotemporal protein degradation in Caenorhabditis elegans.

The auxin-inducible degradation system has been widely adopted in the Caenorhabditis elegans research community for its ability to empirically control the spatiotemporal expression of target proteins. This system can efficiently degrade auxin-inducible degron (AID)-tagged proteins via the expression of a ligand-activatable AtTIR1 protein derived from A. thaliana that adapts target proteins to the endogenous C. elegans proteasome. While broad expression of AtTIR1 using strong, ubiquitous promoters can lead to rapid degradation of AID-tagged proteins, cell type-specific expression of AtTIR1 using spatially restricted promoters often results in less efficient target protein degradation. To circumvent this limitation, we have developed an FLP/FRT3-based system that functions to reanimate a dormant, high-powered promoter that can drive sufficient AtTIR1 expression in a cell type-specific manner. We benchmark the utility of this system by generating a number of tissue-specific FLP-ON::TIR1 drivers to reveal genetically separable cell type-specific phenotypes for several target proteins. We also demonstrate that the FLP-ON::TIR1 system is compatible with enhanced degron epitopes. Finally, we provide an expandable toolkit utilizing the basic FLP-ON::TIR1 system that can be adapted to drive optimized AtTIR1 expression in any tissue or cell type of interest.

Visible-Light-Mediated Controlled Radical Branching Polymerization in Water.

Hyperbranched polymethacrylates were synthesized by green-light-induced atom transfer radical polymerization (ATRP) under biologically relevant conditions in the open air. Sodium 2-bromoacrylate (SBA) was prepared in situ from commercially available 2-bromoacrylic acid and used as a water-soluble inibramer to induce branching during the copolymerization of methacrylate monomers. As a result, well-defined branched polymethacrylates were obtained in less than 30 min with predetermined molecular weights (36 000

A membrane reticulum, the centriculum, affects centrosome size and function in Caenorhabditis elegans.

Centrosomes are cellular structures that nucleate microtubules. At their core is a pair of centrioles that recruit pericentriolar material (PCM). Although centrosomes are considered membraneless organelles, in many cell types, including human cells, centrosomes are surrounded by endoplasmic reticulum (ER)-derived membranes of unknown structure and function. Using volume electron microscopy (vEM), we show that centrosomes in the Caenorhabditis elegans (C. elegans) early embryo are surrounded by a three-dimensional (3D), ER-derived membrane reticulum that we call the centriculum, for centrosome-associated membrane reticulum. The centriculum is adjacent to the nuclear envelope in interphase and early mitosis and fuses with the fenestrated nuclear membrane at metaphase. Centriculum formation is dependent on the presence of an underlying centrosome and on microtubules. Conversely, increasing centriculum size by genetic means led to the expansion of the PCM, increased microtubule nucleation capacity, and altered spindle width. The effect of the centriculum on centrosome function suggests that in the C. elegans early embryo, the centrosome is not membraneless. Rather, it is encased in a membrane meshwork that affects its properties. We provide evidence that the centriculum serves as a microtubule "filter," preventing the elongation of a subset of microtubules past the centriculum. Finally, we propose that the fusion between the centriculum and the nuclear membrane contributes to nuclear envelope breakdown by coupling spindle elongation to nuclear membrane fenestration.

Motivations for Seeking Cosmetic Enhancing Procedures of the Face: A Systematic Review.

BACKGROUND: Cosmetic enhancing procedures continue to grow in demand. Physicians should understand the complex factors that drive patient motivation for seeking such procedures. OBJECTIVE: In contrast to a lens of psychopathology, this review reveals the driving power of everyday intrapersonal, social, and behavioral factors that motivate interest in elective facial cosmetic procedures. MATERIALS AND METHODS: The review was conducted according to PRISMA guidelines and included studies with at least 50 adult patients seeking facial cosmetic enhancements between January 1, 2000, and July 1, 2022. RESULTS: Among 1,239 identified publications, 21 studies with 9,005 participants were selected for inclusion. The review documents everyday factors as patient motivators for pursuing cosmetic enhancements of the face, with the majority of work focusing on intrapersonal factors (17 of 21 studies), such as preventing aging or negative appearance based self-appraisals. For studies reporting social factors (15 of 21 studies), the most common motivators were the patient's social network and a desire to promote social standing. Behavioral factors revealed that social media and media consumption impact patient motivation for cosmetic enhancements (5 of 21 studies). CONCLUSION: In summary, this review demonstrates that patient motivations for facial cosmetic enhancements may be best understood through everyday intrapersonal, social, and behavioral factors.

Postoperative Acute Kidney Injury by Age and Sex: A Retrospective Cohort Association Study.

BACKGROUND: Acute kidney injury (AKI) after noncardiac surgery is common and has substantial health impact. Preclinical and clinical studies examining the influence of sex on AKI have yielded conflicting results, although they typically do not account for age-related changes. The objective of the study was to determine the association of age and sex groups on postoperative AKI. The authors hypothesized that younger females would display lower risk of postoperative AKI than males of similar age, and the protection would be lost in older females. METHODS: This was a multicenter retrospective cohort study across 46 institutions between 2013 and 2019. Participants included adult inpatients without pre-existing end-stage kidney disease undergoing index major noncardiac, nonkidney/urologic surgeries. The authors' primary exposure was age and sex groups defined as females 50 yr or younger, females older than 50 yr, males 50 yr or younger, and males older than 50 yr. The authors' primary outcome was development of AKI by Kidney Disease-Improving Global Outcomes serum creatinine criteria. Exploratory analyses included associations of ascending age groups and hormone replacement therapy home medications with postoperative AKI. RESULTS: Among 390,382 patients, 25,809 (6.6%) developed postoperative AKI (females 50 yr or younger: 2,190 of 58,585 [3.7%]; females older than 50 yr: 9,320 of 14,4047 [6.5%]; males 50 yr or younger: 3,289 of 55,503 [5.9%]; males older than 50 yr: 11,010 of 132,447 [8.3%]). When adjusted for AKI risk factors, compared to females younger than 50 yr (odds ratio, 1), the odds of AKI were higher in females older than 50 yr (odds ratio, 1.51; 95% CI, 1.43 to 1.59), males younger than 50 yr (odds ratio, 1.90; 95% CI, 1.79 to 2.01), and males older than 50 yr (odds ratio, 2.06; 95% CI, 1.96 to 2.17). CONCLUSIONS: Younger females display a lower odds of postoperative AKI that gradually increases with age. These results suggest that age-related changes in women should be further studied as modifiers of postoperative AKI risk after noncardiac surgery.