The type 3 secretion effector IpgD promotes S. flexneri dissemination.

The bacterial pathogen Shigella flexneri causes 270 million cases of bacillary dysentery worldwide every year, resulting in more than 200,000 deaths. S. flexneri pathogenic properties rely on its ability to invade epithelial cells and spread from cell to cell within the colonic epithelium. This dissemination process relies on actin-based motility in the cytosol of infected cells and formation of membrane protrusions that project into adjacent cells and resolve into double-membrane vacuoles (DMVs) from which the pathogen escapes, thereby achieving cell-to-cell spread. S. flexneri dissemination is facilitated by the type 3 secretion system (T3SS) through poorly understood mechanisms. Here, we show that the T3SS effector IpgD facilitates the resolution of membrane protrusions into DMVs during S. flexneri dissemination. The phosphatidylinositol 4-phosphatase activity of IpgD decreases PtdIns(4,5)P2 levels in membrane protrusions, thereby counteracting de novo cortical actin formation in protrusions, a process that restricts the resolution of protrusions into DMVs. Finally, using an infant rabbit model of shigellosis, we show that IpgD is required for efficient cell-to-cell spread in vivo and contributes to the severity of dysentery.

Pilot Study of a Novel Online Comprehensive Pelvic Floor Program for Urinary Incontinence in Women.

INTRODUCTION AND HYPOTHESIS: Urinary incontinence (UI) is common in women and has a vast impact on quality of life (QOL), financial health, and work disability. Robust evidence demonstrates the efficacy of comprehensive conservative therapy (pelvic floor muscle training [PFMT], and behavioral and dietary modification) in the treatment of UI. However, numerous barriers impede access to this care, including limited specialized therapists, financial barriers, and scheduling obstacles. To address these barriers, we developed a novel comprehensive online pelvic floor program (oPFP). METHODS: We performed a prospective study assessing continence and QOL outcomes in women with stress urinary incontinence (SUI), urge urinary incontinence (UUI), or mixed urinary incontinence (MUI) treated with oPFP between May 2019 and November 2022. Outcomes were assessed at baseline and following completion of the 2-month program using the validated International Consultation on Incontinence Questionnaire-Female Lower Urinary Tract Symptoms, Urgency Perception Scale (UPS), Incontinence Impact Questionnaire (IIQ-7) questionnaires, and 24-h bladder diary. Data were analyzed using linear, Poisson mixed models, or generalized estimating equations. RESULTS: Twenty-eight women (2 SUI, 3 UUI, 23 MUI) were enrolled and 19 (2 SUI, 2 UUI, 15 MUI) completed the study. Following oPFP, participants showed significantly improved SUI domain scores (3.04 ± 0.19 vs 1.81 ± 0.23, p < 0.001), UPS reason score (2.52 ± 0.18 vs 2.05 ± 0.14, p = 0.003), IIQ-7 sum scores (5.16 ± 0.88 vs 3.07 ± 0.70, p = 0.038), and daily incontinence episodes (2.96 ± 0.60 vs 1.06 ± 0.29, p < 0.001). Mean patient-reported improvement was 5.4 ± 2.5 (ten-point Likert scale). Of respondents, 89% reported program satisfaction, ease of use, and would recommend the program to others. CONCLUSION: The oPFP results in significant improvements to a variety of UI and QOL measures. This program provides an important UI treatment option and gives women greater access to effective conservative therapy.

Physiological impacts of housing maned wolves (Chrysocyon brachyurus) with female relatives or unrelated males.

The maned wolf is a threatened canid species native to South America. Previous studies have suggested the species exhibits induced ovulation. In captive breeding facilities, reproductive success is low while rates of neonatal mortality are high. Females that are not recommended for breeding are frequently housed together. However there has never been a systematic study of the reproductive consequences of co-housing females. This study was conducted for three purposes, to: (1) corroborate the presence of induced ovulation, (2) determine whether elevated cortisol is implicated in neonatal pup mortality, and (3) evaluate the endocrine correlates of group housed females. Using fecal hormone monitoring for estrogen, progesterone, and cortisol, 43 cycles from 33 female maned wolves were studied from 2002 to 2015. Females were categorized by their reproductive status: pregnant and successfully raised pups (PR; n = 11), pregnant with neonatal pup demise within 3 days (PL; n = 7), housed with a male but no signs of breeding or pregnancy (PP; n = 10), housed singly (S; n = 8), or housed with related females (F; n = 7). Estrogen and progestagen remained at baseline for all females not housed with a male (S, F), while elevations consistent with ovulation were seen in females housed with a male (PP, PL, PR). Compared to PR females, PL individuals showed similar cortisol levels throughout the cycle and slightly lower progesterone levels during gestation. As for the effect of co-housing related females, F females showed estrogen and progesterone levels lower even than S females while cortisol levels were elevated compared to all other groups. These findings support the previous evidence of induced ovulation in the maned wolf. Although elevated cortisol does not seem to be implicated in pup loss, a non-significant trend towards lower progesterone during gestation could be implicated. Future studies should assess depressed progesterone levels as a correlate to neonatal pup mortality. Female maned wolves housed with related females experience suppressed reproductive hormones and elevated adrenal hormones. Therefore, a more systematic study of hormonal and behavioral correlates to co-housing with related females is warranted.

HEMATOLOGY AND SERUM BIOCHEMISTRY VALUES OF THE RED PANDA SUBSPECIES ( AILURUS FULGENS STYANI).

Health evaluations were conducted on individuals ( n = 62, age < 1 to 11 yr) from a captive red panda ( Ailurus fulgens styani) population at the Chengdu Research Base for Giant Panda Breeding in Sichuan Province, People's Republic of China. Individuals were anesthetized using combinations of ketamine, dexmedetomidine, diazepam, isoflurane, and tiletamine/zolazepam. Whereas physical exams revealed no abnormalities for 40% of red pandas, 24% had dental abnormalities and 18% had orthopedic abnormalities. As the red panda is the only member of the family Ailuridae, complete blood count and serum biochemistry samples were collected and used to develop reference intervals for this species. When hematologic and serum chemistry values of male and female red pandas were compared within this A. f. styani population, males had higher mean cell hemoglobin, mean cell hemoglobin concentration, and blood urea nitrogen concentrations, whereas females had higher alkaline phosphatase, cholesterol, and iron. Adult red pandas (≥2 yr) had higher lymphocyte percentage, total protein, globulin, and chloride levels, whereas juveniles (<2 yr) had higher white blood cell concentrations, neutrophil percentage and absolute neutrophil values, alkaline phosphatase, creatine kinase, cholesterol, potassium, total and ionized calcium, and phosphorus levels. Reference values and expected age and sex differences will assist with health management of the captive A. f. styani population.

Comparison of In-person Versus Online Comprehensive Pelvic Floor Rehabilitation Program Following Prostatectomy.

OBJECTIVE: To compare continence outcomes in post-prostatectomy patients undergoing supervised in-person versus online pelvic floor muscle training and pelvic floor education (iPMFT vs oPFMT/PFE). Despite the proven benefit of in-person PFMT for urinary incontinence (UI) following prostatectomy, numerous barriers impede access. We developed a comprehensive online program to deliver oPFMT/PFE. METHODS: We performed a retrospective review of patients receiving iPFMT versus oPFMT/PFE with minimum 12-month follow-up. Outcomes were assessed at 3 weeks, 3-, 6-, and 12 months following robotic-assisted laparoscopic prostatectomy using validated ICIQ-MLUTS and IIQ-7 questionnaires and additional items (daily pad use [PPD] and satisfaction). The primary study outcome was ICIQ-MLUTS SUI domain score (SDS). Secondary outcomes were PPD, PPD cure (0 PPD at 12 months), SUI cure (12-month SDS=baseline score), and QOL score (IIQ-7 Sum). RESULTS: Analysis included 41 men. Though men enrolled in oPFMT/PFE demonstrated lower SUI domain scores than iPFMT at most time points (3wk P <.01, 3 mo P = .04, 6 mo P = .15, 12 mo P = .04), the rate of improvement from 3 weeks to other time points was similar between groups (P = NS at all time points). SDS Cure was no different for oPFMT/PFE (75%, 15/20) compared to iPFMT (60%, 12/20, P = .3). PPD and IIQ-7 were also similar at all time points and demonstrated a similar rate of decrease over time through 12 months. CONCLUSION: Significant and similar improvements in UI and QOL are seen both in men completing iPFMT or oPFMT/PFE programs. Our novel online program provides another option to improve PFMT/PFE access in men undergoing RALP.

Hypoglossal Nerve Transfer for Facial Nerve Paralysis: A Systematic Review and Meta-Analysis.

Background: Hypoglossal-facial nerve (12-7) anastomosis can restore symmetry and voluntary movement on the face in patients with facial nerve paralysis. Traditional 12-7 transfer includes direct end-to-end nerve anastomosis, sacrificing the entire hypoglossal nerve. Contemporary, end-to-side anastomosis, or split anastomosis techniques limit tongue morbidity by preserving some hypoglossal nerve. Direct outcome comparisons between these techniques are limited. Objective: To compare reported outcomes of facial movement, tongue, speech, and swallow outcomes among the different types of hypoglossal-facial nerve anastomosis schemes. Evidence Review: For this systematic review and meta-analysis, a comprehensive strategy was designed to search PubMed, Scopus, and the Cochrane Database from inception to January 2021, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis, reporting guideline yielding 383 results. Any participant who underwent 12-7 transfer using any of the three techniques, with or without an interposition graft, and had documented preoperative and postoperative evaluation of facial nerve function with a validated instrument such as House-Brackmann (HB), was considered for inclusion. Secondary outcomes of synkinesis, tongue atrophy, and speech or swallowing dysfunction were also compared. Forty-nine studies met inclusion criteria, representing data from 961 total patients who underwent 12-7 transfer. Results: The proportion of good HB outcomes (HB I-III) did not differ by anastomosis type: End-to-side and end-to-end anastomosis (73% vs. 59%, p = 0.07), split and end-to-end anastomosis (62% vs. 59%, p = 0.88), and end-to-side anastomosis and split anastomosis (73% vs. 62%, p = 0.46). There was no difference in reported synkinesis rates between the anastomosis types. However, end-to-side anastomosis (z = 6.55, p < 0.01) and split anastomosis (z = 3.58, p < 0.01) developed less tongue atrophy than end-to-end anastomosis. End-to-side anastomosis had less speech/swallowing dysfunction than end-to-end anastomosis (z = 3.21, p < 0.01). Conclusion: End-to-side and split anastomoses result in similar HB facial nerve outcomes as the traditional end-to-end 12-7 anastomosis. End-to-side anastomosis has decreased complications of tongue atrophy and speech/swallow dysfunction compared to end-to-end anastomosis. In addition, split anastomosis has decreased rates of tongue atrophy compared to end-to-end anastomosis.

Pelvic floor therapy program for the treatment of female urinary incontinence in Belize: a pilot study.

Introduction: Urinary incontinence (UI) is highly prevalent in low- and middle-income countries (LMIC). Concurrently, the availability of surgical or conservative UI treatments in LMIC is limited. Methods: We conducted a prospective feasibility study of Belize women with UI treated with pelvic floor physical therapy (PFPT) and education (PFE). Patients received individual PFPT/PFE over 2 days, consisting of biofeedback-enhanced PFMT in addition to behavioral, dietary, and general pelvic education. Patient completed a daily 6-month home regimen including 7 PFMT exercises (total 70 repetitions) comprising both endurance and quick flick exercises. Patients also performed comprehensive dietary and behavioral modification activities. Outcomes were assessed at baseline and 6-months, including validated symptom (ICIQ-FLUTS) and QOL (IIQ-7) questionnaires, and strength testing (PERFECT score, perineometry). Results: Twenty-eight patients underwent baseline assessment. Four patients were lost to in-person 6-month follow-up, with two of these patients completing subjective assessment only by telephone. The mean (±SD) patient age, BMI, and parity were 50.0 (±10.0) years, 33.2 (±5.8), and 2.8 (±1.5). Provider assessment demonstrated patient comprehension of basic, endurance, and quick flick pelvic floor contractions in 28 (100%), 24 (86%), and 24 (86%) patients, respectively. At 6-month follow-up, significant improvements were seen across multiple validated questionnaire and strength measurement assessments. Median patient-reported improvement level was 7.0 on a 10-point Likert scale. Discussion: Study patients demonstrated good understanding of PFMT/PFE and program completion was associated with significant improvements across a variety of subjective incontinence and quality of life outcomes, as well as objective strength testing.

Prospective validation of clinical deterioration predictive models prior to intensive care unit transfer among patients admitted to acute care cardiology wards.

Objective. Very few predictive models have been externally validated in a prospective cohort following the implementation of an artificial intelligence analytic system. This type of real-world validation is critically important due to the risk of data drift, or changes in data definitions or clinical practices over time, that could impact model performance in contemporaneous real-world cohorts. In this work, we report the model performance of a predictive analytics tool developed before COVID-19 and demonstrate model performance during the COVID-19 pandemic.Approach. The analytic system (CoMETⓇ, Nihon Kohden Digital Health Solutions LLC, Irvine, CA) was implemented in a randomized controlled trial that enrolled 10 422 patient visits in a 1:1 display-on display-off design. The CoMET scores were calculated for all patients but only displayed in the display-on arm. Only the control/display-off group is reported here because the scores could not alter care patterns.Main results.Of the 5184 visits in the display-off arm, 311 experienced clinical deterioration and care escalation, resulting in transfer to the intensive care unit, primarily due to respiratory distress. The model performance of CoMET was assessed based on areas under the receiver operating characteristic curve, which ranged from 0.725 to 0.737.Significance.The models were well-calibrated, and there were dynamic increases in the model scores in the hours preceding the clinical deterioration events. A hypothetical alerting strategy based on a rise in score and duration of the rise would have had good performance, with a positive predictive value more than 10-fold the event rate. We conclude that predictive statistical models developed five years before study initiation had good model performance despite the passage of time and the impact of the COVID-19 pandemic.

Toxoplasma gondii infection supports the infiltration of T cells into brain tumors.

Few T cells infiltrate into primary brain tumors, fundamentally hampering the effectiveness of immunotherapy. We hypothesized that Toxoplasma gondii, a microorganism that naturally elicits a Th1 response in the brain, can promote T cell infiltration into brain tumors despite their immune suppressive microenvironment. Using a mouse genetic model for medulloblastoma, we found that T. gondii infection induced the infiltration of activatable T cells into the tumor mass and led to myeloid cell reprogramming toward a T cell-supportive state, without causing severe health issues in mice. The study provides a concrete foundation for future studies to take advantage of the immune modulatory capacity of T. gondii to facilitate brain tumor immunotherapy.

A Histone Methylation-MAPK Signaling Axis Drives Durable Epithelial-Mesenchymal Transition in Hypoxic Pancreatic Cancer.

The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) plays a key role in tumor progression and response to therapy. The dense PDAC stroma causes hypovascularity, which leads to hypoxia. Here, we showed that hypoxia drives long-lasting epithelial-mesenchymal transition (EMT) in PDAC primarily through a positive-feedback histone methylation-MAPK signaling axis. Transformed cells preferentially underwent EMT in hypoxic tumor regions in multiple model systems. Hypoxia drove a cell autonomous EMT in PDAC cells, which, unlike EMT in response to growth factors, could last for weeks. Furthermore, hypoxia reduced histone demethylase KDM2A activity, suppressed PP2 family phosphatase expression, and activated MAPKs to post-translationally stabilize histone methyltransferase NSD2, leading to an H3K36me2-dependent EMT in which hypoxia-inducible factors played only a supporting role. Hypoxia-driven EMT could be antagonized in vivo by combinations of MAPK inhibitors. Collectively, these results suggest that hypoxia promotes durable EMT in PDAC by inducing a histone methylation-MAPK axis that can be effectively targeted with multidrug therapies, providing a potential strategy for overcoming chemoresistance. SIGNIFICANCE: Integrated regulation of histone methylation and MAPK signaling by the low-oxygen environment of pancreatic cancer drives long-lasting EMT that promotes chemoresistance and shortens patient survival and that can be pharmacologically inhibited. See related commentary by Wirth and Schneider, p. 1739.

Association between Cystic Fibrosis exacerbations, lung function, T2 inflammation and microbiological colonization.

BACKGROUND: The Cystic Fibrosis Foundation Patient Registry (CFFPR) reports a high prevalence of asthma (34.6%) in people with Cystic Fibrosis (PwCF). While our current understanding of this relationship is limited, a type 2 inflammatory (T2) phenotype has often been identified in CF patients. RESEARCH QUESTION: This study aimed to evaluate the relationship between the eosinophilic CF T2 inflammatory phenotype and CF-related pulmonary outcomes and microbiological data. STUDY DESIGN AND METHODS: We conducted a retrospective chart review of adult patients with CF (18 and older; n = 93) receiving their care at University of Virginia Medical Center adult program from January, 2013 through December, 2018. Data collected included demographic data, CFTR (CF transmembrane conductance regulator) mutation, CF comorbidities, medications, Absolute Eosinophil Counts (AEC) in cells/µL and Immunoglobulin E (IgE) levels in IU/mL. RESULTS: Of 93 patients screened for study eligibility, 74 were included in the final analysis; 19 patients were excluded due to lack of longitudinal data across the study timeline. Lung function decline correlated with increased AEC (p < 0.001) and IgE (p < 0.001) even when adjusting for covariates: age, gender, presence of Pseudomonas spp., MRSA, other bacterial spp., Aspergillus spp., and other fungi (p < 0.001). Univariate analysis demonstrated that people with CF who experienced more than 2 exacerbations requiring hospitalizations and/or intravenous antibiotics a year were more likely to have high AEC (p = 0.018). Logistic regression showed that as AEC increases, the probability that the measurement was taken during a CF exacerbation increases (p = 0.0039). A linear mixed model showed that each additional annual exacerbation event increased on average the log IgE by 0.04. (p = 0.015). This finding remained stable in a multivariate model (p = 0.0145). When adjusted for atopy, log IgE increases as the number of exacerbation events increases (p = 0.022). There was no association between AEC and IgE and microbiological colonization. INTERPRETATION: This study has shown that in CF patients, T2 inflammation based on serum AEC and IgE correlated with pulmonary exacerbations requiring hospitalizations and/or intravenous antibiotics, independent of bacterial airway colonization. In addition, lung function decline correlated with increased IgE and AEC. Further studies are needed to explore these correlations and potential impact on treatment.

Novel online comprehensive pelvic floor therapy program following prostatectomy.

Background: Although pelvic floor muscle training (PFMT) is widely shown to improve post-prostatectomy incontinence (PPI), numerous barriers impede access to formal PFMT and include the limited availability of specialized therapists and financial or scheduling barriers. To address these barriers, we developed a novel online program delivering comprehensive long-term PFMT, pelvic floor education (PFE), and dietary/behavioral modification education. This study is a prospective interim analysis of online PFMT/PFE (oPFMT/PFE), with focus on feasibility, satisfaction, and continence outcomes. Methods: Patients anticipating robotic-assisted laparoscopic prostatectomy (RALP) were recruited (6/2021-9/2022) for oPFMT/PFE. oPFMT/PFE comprises a 12-month program of 3 phases, including multiple exercises with varied contraction types and duration, and comprehensive dietary and behavioral technique education. Incontinence and quality of life (QOL) outcomes are assessed at 3 weeks, 3, 6, and 12 months following RALP using validated International Consultation on Incontinence Questionnaire Male Lower Urinary Tract Symptoms (ICIQ-MLUTS) and Incontinence Impact Questionnaire (IIQ-7) questionnaires and additional items assessing satisfaction, improvement, and daily pad use. Primary study outcomes included ICIQ-MLUTS stress urinary incontinence (SUI) domain score (SDS) and SUI cure [ICIQ SUI domain score (SDS) =0]. Interim 6-month analysis was performed using mixed effects linear regression and mixed effects Poisson regression. Results: Analysis included 21 men (64±6 years). At 6-month follow-up, men undergoing oPFMT/PFE showed significant improvement in SDS compared to the 3-week time point [mean ± standard error (SE) =1.05±0.24 vs. 0.45±0.17, P=0.011], but still experienced higher scores than at baseline (P=0.017). Six-month patient-reported improvement averaged 7.42±0.74 (10-point Likert scale). All (100%) of 19 respondents (2 missing data) found the program easy to use, educational, and would recommend it to others, with 89% expressing satisfaction with the program. During patient interview at 6-month follow-up, no men reported inability to access the program online or any adverse events. Finally, IIQ-7 score improved significantly from the 3-week timepoint (4.47±1.10) at both time points (3-month 1.14±0.44, P<0.001 and 6-month 1.10±0.37, P<0.001), and neither 3- nor 6-month scores differed from baseline (P=0.808 and P=0.444, respectively). Conclusions: Our novel oPFMT/PFE yields significant improvements to validated urinary incontinence (UI) and QOL measures, providing a valuable and accessible treatment option for PPI.

Improved survival of SARS COV-2-infected K18-hACE2 mice treated with adenosine A2AR agonist.

A life-threatening manifestation of Covid-19 infection is a cytokine storm that requires hospitalization and supplemental oxygen. Various strategies to reduce inflammatory cytokines have had some success in limiting cytokine storm and improving survival. Agonists of adenosine A2A receptors (A2AR) reduce cytokine release from most immune cells. Apadenoson is a potent and selective anti-inflammatory adenosine analog that reduces inflammation. When administered by subcutaneous osmotic pumps to mice infected with SARS CoV-2, Apadenoson was found to improve the outcomes of infection as measured by a decrease in weight loss, improved clinical symptoms, reduced levels of proinflammatory cytokines and chemokines in bronchial lavage (BAL) fluid, and enhanced survival of K18-hACE2 transgenic mice. These results support further examination of A2AR agonists as therapies for treating cytokine storm due to COVID-19.

The Impact of CFTR Modulator Triple Therapy on Type 2 Inflammatory Response in Patients with Cystic Fibrosis.

Background Treatment of cystic fibrosis (CF) has been revolutionized by the use of cystic fibrosis transmembrane conductance regulator (CFTR) protein modulators such as elexacaftor/tezacaftor/ivacaftor (ETI) triple therapy. Prior studies support a role for type 2 (T2) inflammation in many people with CF (PwCF) and CF-asthma overlap syndrome (CFAOS) is considered a separate clinical entity. It is unknown whether initiation of ETI therapy impacts T2 inflammation in PwCF. We hypothesized that ETI initiation decreases T2 inflammation in PwCF. Methods A single center retrospective chart review was conducted for adult PwCF. As markers of T2 inflammation, absolute eosinophil count (AEC) and total immunoglobulin E (IgE) data were collected longitudinally 12 months prior to ETI therapy initiation and 12 months following therapy initiation. Multivariable analyses adjusted for the age, gender, CFTR mutation, disease severity, inhaled steroid use, and microbiological colonization. Results There was a statistically significant reduction (20.10%, p < 0.001) in 12-month mean IgE following ETI initiation; this change remained statistically significant in the multivariate model. The longitudinal analysis demonstrated no change in AEC following therapy initiation. Conclusion This study shows reduction in IgE but no change in AEC after ETI therapy initiation. We think that the lack of influence on AEC argues against an impact on previously established T2 inflammation and that the reduction in IgE is likely related to antigen load reduction post ETI. Further studies are warranted to determine the underlying mechanism of ETI impact on T2 inflammation and possible role for asthma immunomodulator therapy post ETI initiation in CFAOS.

The Ratings Game: Demographic and Practice Factors Affecting Yelp Ratings of Plastic Surgeons.

BACKGROUND: Review platforms such as Yelp are increasingly used by patients establishing care and may contain substantial information regarding patient preferences and potential biases. The authors' aims were to (1) analyze patient satisfaction through identifying factors associated with positive and negative patient reviews for plastic surgery providers across the United States, and (2) investigate the association between overall rating and different physician and practice factors based on gender and race. METHODS: Reviews of plastic surgery provider practices from cities across seven different regions within the United States were obtained from Yelp. Quantitative and qualitative analyses were performed. Chi-square tests were used to determine whether race or sex was associated with overall rating (of five stars) and qualitative themes. RESULTS: A total of 5210 reviews met inclusion criteria; 80.3% received a five-star rating and 13.5% received a one-star rating. Positive Yelp reviews and higher ratings were associated with positive comments regarding surgical and injectable outcomes, physical examination, communication, competency/knowledge base, temperament, scheduling, and staff interactions. When the following factors were mentioned negatively, the practice was more likely to receive a lower rating: temperament, communication, cost consciousness, surgical and injectable outcomes, physical examination, billing/insurance, scheduling, interactions with staff, and wait times. No association was identified in terms of overall physician rating based on sex or race; however, there were differences noted in distribution of positive and negative themes. CONCLUSIONS: Patient reviews on Yelp indicate that several physician and practice factors influence patient satisfaction. The themes reported in this study may be used by plastic surgery providers to identify areas for practice improvement to enhance the overall patient experience.

Extracellular Tau Oligomers Damage the Axon Initial Segment.

BACKGROUND: In Alzheimer's disease (AD) brain, neuronal polarity and synaptic connectivity are compromised. A key structure for regulating polarity and functions of neurons is the axon initial segment (AIS), which segregates somatodendritic from axonal proteins and initiates action potentials. Toxic tau species, including extracellular oligomers (xcTauOs), spread tau pathology from neuron to neuron by a prion-like process, but few other cell biological effects of xcTauOs have been described. OBJECTIVE: Test the hypothesis that AIS structure is sensitive to xcTauOs. METHODS: Cultured wild type (WT) and tau knockout (KO) mouse cortical neurons were exposed to xcTauOs, and quantitative western blotting and immunofluorescence microscopy with anti-TRIM46 monitored effects on the AIS. The same methods were used to compare TRIM46 and two other resident AIS proteins in human hippocampal tissue obtained from AD and age-matched non-AD donors. RESULTS: Without affecting total TRIM46 levels, xcTauOs reduce the concentration of TRIM46 within the AIS and cause AIS shortening in cultured WT, but not TKO neurons. Lentiviral-driven tau expression in tau KO neurons rescues AIS length sensitivity to xcTauOs. In human AD hippocampus, the overall protein levels of multiple resident AIS proteins are unchanged compared to non-AD brain, but TRIM46 concentration within the AIS and AIS length are reduced in neurons containing neurofibrillary tangles. CONCLUSION: xcTauOs cause partial AIS damage in cultured neurons by a mechanism dependent on intracellular tau, thereby raising the possibility that the observed AIS reduction in AD neurons in vivo is caused by xcTauOs working in concert with endogenous neuronal tau.

Knowledge, attitudes, and practices [KAP] toward COVID-19: A cross-sectional study in the New York Metropolitan Area and California Bay Area.

OBJECTIVE: The 2019 novel coronavirus [COVID-19] pandemic has necessitated the implementation of public health initiatives [PHI] to slow viral spread. We evaluated the effectiveness of PHI through a survey of COVID-19 knowledge, attitudes and practices [KAP]. METHODS: This cross-sectional study was conducted primarily during stay-at-home orders in New York and San Francisco. A volunteer sample of 675 U.S. participants completed a KAP questionnaire after electronic distribution. RESULTS: Participants had good knowledge and practices, but poor attitudes. Predictors of higher knowledge scores included white ethnicity, non-essential worker status, and healthcare worker status. Correlates with positive attitude included male gender, residence in California, higher annual income, and not utilizing radio or social media. Higher practice scores were predicted by female gender, non-essential and healthcare worker status, and information source. CONCLUSIONS: Differences in KAP were found among demographic variables. Determining what factors and sources of information drive reception of public health information can guide targeted intervention and advance equitable health education.

Impact of elexacaftor/tezacaftor/ivacaftor on depression and anxiety in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is associated with worsening of depression and anxiety symptoms. Elexacaftor/tezacaftor/ivacaftor (Trikafta®), a cystic fibrosis transmembrane regulator (CFTR) modulator approved in 2019, significantly improves lung function, decreases pulmonary exacerbations, and improves quality of life. Studies are needed to evaluate the effects of Trikafta on symptoms of anxiety and depression. RESEARCH QUESTION: Do adults with CF report a change in depression and anxiety symptoms after Trikafta initiation? STUDY DESIGN AND METHODS: A retrospective chart review was conducted of patients with CF (n = 127) receiving care from January 2015 through February 2022. Data collected included demographics, annual PHQ-9 and GAD-7 scores, FEV1 percent predicted at each visit, BMI, consistency and timeline of Trikafta use, mental health diagnoses, counseling/psychotherapy use, psychiatric medication use, prescriber of psychiatric medications, number of psychiatric emergency department visits and psychiatric hospital admissions, and sleep disturbances. RESULTS: Of the 127 patients screened for eligibility, 100 patients were included. Data collected yielded 563 PHQ-9, 563 GAD-7, and 560 ppFEV1 data points. No significant changes in average PHQ-9 or GAD-7 scores were found after Trikafta initiation or due to the COVID-19 pandemic. However, 22% of patients initiated or had a change in psychiatric medications, and patients with changes in psychiatric medications had significantly higher PHQ-9 and GAD-7 scores than patients not prescribed psychiatric medications. Trikafta use improved lung function by an average of 5.23% (p = 8.56e-08). Around a quarter (23%) of all patients reported sleep issues after initiating Trikafta. INTERPRETATION: No significant changes in average PHQ-9 and GAD-7 scores were found after Trikafta initiation. A quarter of patients required a change in psychiatric medications, and significant differences in depression and anxiety scores were found between patients with a change in psychiatric medications and those not prescribed medication. Twenty-three percent of patients reported a prevalence of sleep issues after Trikafta initiation.

Interest of the MGAP score on in-hospital trauma patients: Comparison with TRISS, ISS and NISS scores.

Trauma scoring systems were created to predict mortality and enhance triage capabilities. However, efficacy of scoring systems to predict mortality and accuracy of originally reported severity thresholds remains uncertain. A single-center, retrospective study was conducted at University of Virginia (UVA), an American College of Surgeons verified Level I trauma center. We compared four scoring systems: MGAP (Mechanism, Glasgow Coma Scale, Age, and arterial pressure), Injury Severity Score (ISS), New Injury Severity Score (NISS), and Trauma Related Injury Severity Score (TRISS) to predict in-hospital mortality and disposition from the emergency department to higher acuity level of care including mortality (i.e. operating room, intensive care unit, morgue) versus standard floor admission using area under the curve (AUC) for receiver operating characteristic analysis. Second, we examined sensitivity of these scores at standard thresholds to determine if adjustments were needed to minimize under-triage (sensitivity ≥95%). TRISS was the best predictor of mortality in a cohort of n = 16,265 with AUC of 0.920 (95% CI: 0.911-0.929, p<0.0001), followed by MGAP with AUC of 0.900 (95% CI: 0.889-0.911, p<0.0001), and finally ISS and NISS (0.830 (95% CI: 0.814-0.847) and 0.827 (95% CI: 0.809-0.844) respectively). NISS was the best predictor of high acuity disposition with an AUC of 0.729 (95% CI: 0.721-0.736, p<0.0001), followed by ISS with AUC of 0.714 (95% CI: 0.707-0.722, p<0.0001), and finally TRISS and MGAP (0.673 (95% CI: 0.665-0.682) and 0.613 (95% CI: 0.604-0.621) respectively (p<0.0001). At historic thresholds, no scoring system displayed adequate sensitivity to predict mortality, with values ranging from 73% for ISS to 80% for NISS. In conclusion, in the reported study cohort, TRISS was the best predictor of mortality while NISS was the best predictor of high acuity disposition. We also stress updating scoring system thresholds to achieve ideal sensitivity, and investigating how scoring systems derived to predict mortality perform when predicting indicators of morbidity such as disposition from the emergency department.

Scleroderma and Raynaud Phenomenon: The Cold Truth Regarding the Use of Operative Management.

BACKGROUND: Raynaud phenomenon, with and without scleroderma, is a common vasospastic condition that manifests with extremity pain and skin discoloration. When conservative management fails, complications such as ischemia, ulceration, and gangrene may warrant surgical intervention. The purpose of this study was to determine the risk factors and use of surgical intervention in this population. METHODS: A national insurance claims-based database with patient records from the Centers for Medicare and Medicaid Services was used for data collection. Patients with first diagnoses of Raynaud phenomenon, scleroderma, or both between 2005 and 2014 were identified. Primary outcomes included the presence of upper extremity amputation or vascular procedure, and history of amputation within 5 years of a vascular procedure. Secondary outcomes included hospital admissions, upper extremity wounds, and amputation within 1 year of diagnosis. RESULTS: The Raynaud phenomenon, scleroderma, and Raynaud phenomenon with scleroderma cohorts consisted of 161,300, 117,564, and 25,096 patients, respectively. A diagnosis of both Raynaud phenomenon and scleroderma increased the odds of upper extremity amputation by 5.4-fold, vascular procedure by 4.8-fold, and amputation within 5 years of a vascular procedure by 1.5-fold. Patients with Raynaud phenomenon or scleroderma alone were 3.1 and 5.6 times less likely to undergo amputation within 5 years of a vascular procedure, respectively. CONCLUSIONS: Patients with both Raynaud phenomenon and scleroderma have higher likelihoods of having upper extremity amputations, vascular procedures, and amputations following vascular procedures compared to each diagnosis alone. Vascular procedures are rarely being performed. Further research is necessary to establish a standard of care and determine whether early and more frequent intervention with vascular procedures can decrease amputation rates in this patient population. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.