Electrochemistry at the Edge of a van der Waals Heterostructure.

Artificial van der Waals heterostructures, obtained by stacking two-dimensional (2D) materials, represent a novel platform for investigating physicochemical phenomena and applications. Here, the electrochemistry at the one-dimensional (1D) edge of a graphene sheet, sandwiched between two hexagonal boron nitride (hBN) flakes, is reported. When such an hBN/graphene/hBN heterostructure is immersed in a solution, the basal plane of graphene is encapsulated by hBN, and the graphene edge is exclusively available in the solution. This forms an electrochemical nanoelectrode, enabling the investigation of electron transfer using several redox probes, e.g., ferrocene(di)methanol, hexaammineruthenium, methylene blue, dopamine and ferrocyanide. The low capacitance of the van der Waals edge electrode facilitates cyclic voltammetry at very high scan rates (up to 1000 V s-1), allowing voltammetric detection of redox species down to micromolar concentrations with sub-second time resolution. The nanoband nature of the edge electrode allows operation in water without added electrolyte. Finally, two adjacent edge electrodes are realized in a redox-cycling format. All the above-mentioned phenomena can be investigated at the edge, demonstrating that nanoscale electrochemistry is a new application avenue for van der Waals heterostructures. Such an edge electrode will be useful for studying electron transfer mechanisms and the detection of analyte species in ultralow sample volumes.

Rising Rates of Severe Obesity in Adults Younger Than 50 Correspond to Rise in Hospitalizations for Non-malignant Gastrointestinal Disease.

BACKGROUND: Colorectal cancer incidence is rising in adults < 50 years old, possibly due to obesity. Non-malignant colorectal conditions are understudied in this population. We hypothesize that developing severe obesity in young adulthood also corresponds with increased hospitalization rates for non-malignant colorectal conditions. METHODS: We examined annual percent change (APC) in the prevalence of obesity in adults < 50 using the 2009-2014 National Health and Nutrition Examination Survey. Using the 2010-2014 Nationwide Readmission Database, we then compared yearly hospitalization trends for various gastrointestinal conditions and their outcomes in adults < 50 with severe obesity vs. no obesity. RESULTS: The prevalence of obesity increased in adults < 50 years in 2009-2014. This increase was most pronounced for severe obesity (APC of + 12.8%). The rate of patients with severe obesity < 50 who were admitted for gastrointestinal diseases has increased by 7.76% per year in 2010-2014 (p < 0.001). This increase was > 10% per year for colorectal conditions such Clostridium difficile infections (APC + 17.3%, p = 0.002), inflammatory bowel disease (APC + 13.1%, p = 0.001), and diverticulitis (APC + 12.7%, p = 0.002). The hospitalization rate for chronic liver diseases and acute pancreatitis also increased by 12.2% and 10.0% per year, respectively (p < 0.01). In contrast, young adults without obesity had lower hospitalization rate for most gastrointestinal diseases. Furthermore, adults with no obesity had lower mortality rates for appendicitis, diverticulitis, pancreatitis and chronic liver diseases than adults with severe obesity. CONCLUSION: Our data suggest that increased adiposity in young adults is associated with more hospitalization and worse outcomes for infectious/inflammatory gastrointestinal conditions. Future prevention strategies are warranted to ameliorate these trends.

INJECTABLE FLUOCINOLONE IMPLANT FOR THE MANAGEMENT OF CHRONIC POSTSURGICAL CYSTOID MACULAR EDEMA IN VITRECTOMIZED EYES.

PURPOSE: Long-acting injectable steroids are changing the treatment paradigm for patients with chronic intraocular inflammation and cystoid macular edema (CME). We report the use of the fluocinolone implant 0.18 mg in patients with chronic postsurgical CME after pars plana vitrectomy. METHODS: This is a retrospective case series of 24 vitrectomized eyes which received fluocinolone implant for the management postsurgical CME. Clinical outcomes and requirement for rescue therapy were studied. RESULTS: Median length of follow-up was 19.3 months (range 8.3-23.2 months). There was an improvement in median central subfield thickness from 412 µ m (range 167-806 µ m) to 311 µ m (range 157-686 µ m) after fluocinolone implant ( P < 0.001). The injection burden decreased significantly after study treatment ( P < 0.001); however, there was no significant change in visual acuity ( P = 0.334). Eighteen eyes had control of CME that did not require additional intravitreal therapy. Four eyes had initially controlled but recurrent CME requiring intravitreal steroid therapy at median of 7.8 months (range 7.6-15.4 months). One eye never attained sufficient inflammatory control despite rescue therapy. CONCLUSION: Fluocinolone implant can be an effective treatment in vitrectomized patients with chronic postsurgical CME and can help decrease the overall injection burden.

IL-12p40 promotes secondary damage and functional impairment after spinal cord contusional injury.

Secondary damage obstructs functional recovery for individuals who have sustained a spinal cord injury (SCI). Two processes significantly contributing to tissue damage after trauma are spinal cord hemorrhage and inflammation: more specifically, the recruitment and activation of immune cells, frequently driven by pro-inflammatory factors. Cytokines are inflammatory mediators capable of modulating the immune response. While cytokines are necessary to elicit inflammation for proper healing, excessive inflammation can result in destructive processes. The pro-inflammatory cytokines IL-12 and IL-23 are pathogenic in multiple autoimmune diseases. The cytokine subunit IL-12p40 is necessary to form bioactive IL-12 and IL-23. In this study, we examined the relationship between spinal cord hemorrhage and IL-12-related factors, as well as the impact of IL-12p40 (IL-12/IL-23) on secondary damage and functional recovery after SCI. Using in vivo magnetic resonance imaging and protein tissue analyses, we demonstrated a positive correlation between IL-12 and tissue hemorrhage. Receptor and ligand subunits of IL-12 were significantly upregulated after injury and colocalized with astrocytes, demonstrating a myriad of opportunities for IL-12 to induce an inflammatory response. IL-12p40-/- mice demonstrated significantly improved functional recovery and reduced lesion sizes compared to wild-type mice. Targeted gene array analysis in wild-type and IL-12p40-/- female mice after SCI revealed an upregulation of genes associated with worsened recovery after SCI. Taken together, our data reveal a pathogenic role of IL-12p40 in the secondary damage after SCI, hindering functional recovery. IL-12p40 (IL-12/IL-23) is thus an enticing neuroinflammatory target for further study as a potential therapeutic target to benefit recovery in acute SCI.

Cost-effectiveness of first-line vs third-line ibrutinib in patients with untreated chronic lymphocytic leukemia.

The ALLIANCE A041202 trial found that continuously administered ibrutinib in the first-line setting significantly prolonged progression-free survival compared with a fixed-duration treatment of rituximab and bendamustine in older adults with chronic lymphocytic leukemia (CLL). In this study, we created a Markov model to assess the cost-effectiveness of ibrutinib in the first-line setting, compared with a strategy of using ibrutinib in the third-line after failure of time-limited bendamustine and venetoclax-based regimens. We estimated transition probabilities from randomized trials using parametric survival modeling. Lifetime direct health care costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated from a US payer perspective. First-line ibrutinib was associated with an improvement of 0.26 QALYs and 0.40 life-years compared with using ibrutinib in the third-line setting. However, using ibrutinib in the first-line led to significantly higher health care costs (incremental cost of $612 700), resulting in an ICER of $2 350 041 per QALY. The monthly cost of ibrutinib would need to be decreased by 72% for first-line ibrutinib therapy to be cost-effective at a willingness-to-pay threshold of $150 000 per QALY. In a scenario analysis where ibrutinib was used in the second-line in the delayed ibrutinib arm, first-line ibrutinib had an incremental cost of $478 823, an incremental effectiveness of 0.05 QALYs, and an ICER of $9 810 360 per QALY when compared with second-line use. These data suggest that first-line ibrutinib for unselected older adults with CLL is unlikely to be cost-effective under current pricing. Delaying ibrutinib for most patients with CLL until later lines of therapy may be a reasonable strategy to limit health care costs without compromising clinical outcomes.

Rectal screening for azole non-susceptible Candida species in patients undergoing liver transplantation.

INTRODUCTION: Candidiasis is the most common invasive fungal infection in solid organ transplant recipients, and liver transplant (LT) recipients are at heightened risk. We hypothesized that pre-transplant screening for azole non-susceptible Candida (ANSC) allows for tailored antifungal prophylaxis to reduce the incidence of post-LT ANSC infection. METHODS: We performed a retrospective chart review of adult (age ≥18 years) patients who underwent LT at Yale New Haven Hospital from April 2019 to March 2021. Screening for ANSC, defined as Candida glabrata or Candida krusei, was performed using a rectal swab prior to or at the time of LT. RESULTS: During the study period, ANSC screening was performed in 47 patients who underwent a total of 48 LTs, with 46/48 (96%) primary LTs and two re-transplantations. Ten of 48 screened cases (21%) had ANSC-positive rectal swabs. Only seven of 10 ANSC-colonized patients received appropriate antifungal prophylaxis (i.e., anidulafungin), and one of these seven patients developed candidemia within 30 days of LT. The median number of candidiasis risk factors was one, and 29% of the cohort had two or more risk factors. DISCUSSION: Routine ANSC screening of LT candidates may assist in selecting appropriate antifungal prophylaxis but may be insufficient to prevent infection in those with multiple risk factors for Candida infection.

Distinct effects of volatile and intravenous anaesthetics on presynaptic calcium dynamics in mouse hippocampal GABAergic neurones.

BACKGROUND: General anaesthetics have marked effects on synaptic transmission, but their neuronal and circuit-level effects remain unclear. The volatile anaesthetic isoflurane differentially inhibits synaptic vesicle exocytosis in specific neuronal subtypes, but whether other common anaesthetics also have neurone-subtype-specific actions is unknown. METHODS: We used the genetically encoded fluorescent Ca2+ sensor GCaMP6f to compare the pharmacological effects of isoflurane, sevoflurane, propofol, and ketamine on presynaptic excitability in hippocampal glutamatergic neurones and in hippocampal parvalbumin-, somatostatin-, and vasoactive intestinal peptide-expressing (PV+, SST+, and VIP+, respectively) GABAergic interneurones. RESULTS: Isoflurane and sevoflurane depressed activity-driven presynaptic Ca2+ transients in a neurone-type-specific manner, with greater potency for inhibition of glutamate and SST+ compared with PV+ and VIP+ neurone presynaptic activation. In contrast, clinical concentrations of propofol (1 µM) or ketamine (15 µM) had no significant effects on presynaptic activation. Propofol potentiated evoked Ca2+ entry in PV+ interneurones but only at a supraclinical concentration (3 µM). CONCLUSIONS: Anaesthetic-agent-selective effects on presynaptic Ca2+ entry have functional implications for hippocampal circuit function during i.v. or volatile anaesthetic-mediated anaesthesia. Hippocampal interneurones have distinct subtype-specific sensitivities to volatile anaesthetic actions on presynaptic Ca2+, which are similar between isoflurane and sevoflurane.

Roles for GADD45 in Development and Cancer.

The Growth Arrest and DNA Damage-inducible 45 (GADD45) family of proteins are critical stress sensors that mediate various cellular responses, including DNA repair, cell cycle arrest, and apoptosis. Here, we review current literature investigating GADD45 family members as they relate to normal development and carcinogenesis. We first describe how modulation of GADD45 in model organisms has facilitated our understanding of roles for GADD45 family members in development and homeostasis. We then review current literature exploring roles for GADD45 in human cancer, describing cancer-associated alterations in expression of GADD45 family members; tumor suppressive and tumor promoting functions attributed to GADD5; and roles for GADD45 in cancer therapy. In exploring roles for GADD45 in development, homeostasis, and carcinogenesis, we aim to provide an informational resource that both highlighst current knowledge on this topic while also noting key gaps in our understanding of the biology of GADD45 that may be filled in order to best guide the development of novel approaches to improve diagnosis, monitoring, and therapy of human malignancies.

Thalamic Stimulation Improves Postictal Cortical Arousal and Behavior.

The postictal state following seizures is characterized by impaired consciousness and has a major negative impact on individuals with epilepsy. Previous work in disorders of consciousness including the postictal state suggests that bilateral deep brain stimulation (DBS) of the thalamic intralaminar central lateral nucleus (CL) may improve level of arousal. We tested the effects of postictal thalamic CL DBS in a rat model of secondarily generalized seizures elicited by electrical hippocampal stimulation. Thalamic CL DBS was delivered at 100 Hz during the postictal period in 21 female rats while measuring cortical electrophysiology and behavior. The postictal period was characterized by frontal cortical slow waves, like other states of depressed consciousness. In addition, rats exhibited severely impaired responses on two different behavioral tasks in the postictal state. Thalamic CL stimulation prevented postictal cortical slow wave activity but produced only modest behavioral improvement on a spontaneous licking sucrose reward task. We therefore also tested responses using a lever-press shock escape/avoidance (E/A) task. Rats achieved high success rates responding to the sound warning on the E/A task even during natural slow wave sleep but were severely impaired in the postictal state. Unlike the spontaneous licking task, thalamic CL DBS during the E/A task produced a marked improvement in behavior, with significant increases in lever-press shock avoidance with DBS compared with sham controls. These findings support the idea that DBS of subcortical arousal structures may be a novel therapeutic strategy benefitting patients with medically and surgically refractory epilepsy.SIGNIFICANCE STATEMENT The postictal state following seizures is characterized by impaired consciousness and has a major negative impact on individuals with epilepsy. For the first time, we developed two behavioral tasks and demonstrate that bilateral deep brain stimulation (DBS) of the thalamic intralaminar central lateral nucleus (CL) decreased cortical slow wave activity and improved task performance in the postictal period. Because preclinical task performance studies are crucial to explore the effectiveness and safety of DBS treatment, our work is clinically relevant as it could support and help set the foundations for a human neurostimulation trial to improve postictal responsiveness in patients with medically and surgically refractory epilepsy.

TWENTY-FIVE AND TWENTY-SEVEN-GAUGE SUTURELESS INTRASCLERAL FIXATION OF INTRAOCULAR LENSES: Clinical Outcomes and Comparative Effectiveness of Haptic Flanging in a Large Single-Surgeon Series of 488 Eyes.

PURPOSE: To describe the clinical outcomes and surgical technique in transconjunctival sutureless intrascleral fixation of intraocular lenses, including the effectiveness of haptic flanging and peripheral iridotomy. METHOD: Retrospective series of patients who underwent sutureless intrascleral fixation of three-piece intraocular lenses by a single surgeon. RESULTS: A total of 488 eyes were included in this study. Mean follow-up was 444 days. Mean preoperative best-corrected visual acuity was 20/355, and mean postoperative best-corrected visual acuity was 20/39 (P < 0.001). Intraocular lens dislocation occurred during the postoperative period in 67 (13.7%), with the majority (65.7%) occurring within 3 months after surgery. Dislocation occurred in 13 of 196 (6.6%) flanged haptics versus 54 of 292 (18.5%) unflanged haptics (P < 0.001). Reverse pupillary block occurred in 7 of 231 eyes (3.0%) without intraoperative peripheral iridotomy but only in 1 of 257 eyes (0.4%) with iridotomy (P = 0.0297). Other complications included haptic exposure (1.2%), retinal detachment (1.0%), and endophthalmitis (0.4%). CONCLUSION: This is the largest reported series of sutureless intrascleral fixation of intraocular lenses using trocar cannulas. This technique is an effective surgical option with low complication rates. The authors recommend that haptic flanging and peripheral iridotomy be performed in all cases.

Trends and patterns of thoracic intervertebral disc degeneration in symptomatic subjects: a magnetic resonance imaging analysis.

PURPOSE: This study aimed to analyse the trends and patterns of IVD degeneration in different age groups at each level of the thoracic spine. METHODS: This cross-sectional MRI study included 1000 symptomatic patients who had undergone upright thoracic spine MRI. A total of 13,000 thoracic IVDs from C7/T1 to T12/L1 were classified into five grades using Pfirrmann classification. Patients were divided according to their ages into five groups (n = 200/group). The severity and pattern of IVD degeneration were analysed in each age group. A predictive model of the severity and pattern of IVD degeneration in each age group was proposed. RESULTS: The total grade of IVD degeneration and the number of degenerated levels increased with increasing age (P < 0.001). The most common degenerated level was T6/7 (13.3%), while the least common degenerated level was T12/L1 (1.8%). The most common grades were grade I in group 1 (60.5%), grade II in groups 2 (39%) and 3 (37.3%), and grade III in groups 4 (42.5%) and 5 (44.6%). Adjacent-level degenerations were more common than skip-level degenerations. Severe disc degeneration (Pfirrmann grades IV or V) could be predicted to occur more in group 5 (patients with 60 years and above) (margin = 0.79, 95% CI = 0.73-0.84, P < 0.001). CONCLUSIONS: The severity of thoracic IVD degeneration and the number of degenerated levels increased with age. Disc degeneration was more accelerated in the mid-thoracic spine. Adjacent-level degeneration was more common than skip-level degenerations.

Transmission of SARS-CoV-2: an update of current literature.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent for the 2019 coronavirus disease (COVID-19) pandemic, has caused a public health emergency. The need for additional research in viral pathogenesis is essential as the number of cases and deaths rise. Understanding the virus and its ability to cause disease has been the main focus of current literature; however, there is much unknown. Studies have revealed new findings related to the full transmission potential of SARS-CoV-2 and its subsequent ability to cause infection by different means. The virus is hypothesized to be of increased virulence compared with previous coronavirus that caused epidemics, in part due to its overall structural integrity and resilience to inactivation. To date, many studies have discussed that the rationale behind its transmission potential is that viral RNA has unexpectedly been detected in multiple bodily fluids, with some samples having remained positive for extended periods of time. Additionally, the receptor by which the virus gains cellular entry, ACE2, has been found to be expressed in different human body systems, thereby potentiating its infection in those locations. In this evidence-based comprehensive review, we discuss various potential routes of transmission of SARS-CoV-2-respiratory/droplet, indirect, fecal-oral, vertical, sexual, and ocular. Understanding these different routes is important as they pertain to clinical practice, especially in taking preventative measures to mitigate the spread of SARS-CoV-2.

Anti-inflammatory effects of haptoglobin on LPS-stimulated macrophages: Role of HMGB1 signaling and implications in chronic wound healing.

Nonhealing wounds possess elevated numbers of pro-inflammatory M1 macrophages, which fail to transition to anti-inflammatory M2 phenotypes that promote healing. Hemoglobin (Hb) and haptoglobin (Hp) proteins, when complexed (Hb-Hp), can elicit M2-like macrophages through the heme oxygenase-1 (HO-1) pathway. Despite the fact that nonhealing wounds are chronically inflamed, previous studies have focused on non-inflammatory systems, and do not thoroughly compare the effects of complexed vs individual proteins. We aimed to investigate the effect of Hb/Hp treatments on macrophage phenotype in an inflammatory, lipopolysaccharide (LPS)-stimulated environment, similar to chronic wounds. Human M1 macrophages were cultured in vitro and stimulated with LPS. Concurrently, Hp, Hb, or Hb-Hp complexes were delivered. The next day, 27 proteins related to inflammation were measured in the supernatants. Hp treatment decreased a majority of inflammatory factors, Hb increased many, and Hb-Hp had intermediate trends, indicating that Hp attenuated overall inflammation to the greatest extent. From this data, Ingenuity Pathway Analysis software identified high motility group box 1 (HMGB1) as a key canonical pathway-strongly down-regulated from Hp, strongly up-regulated from Hb, and slightly activated from Hb-Hp. HMGB1 measurements in macrophage supernatants confirmed this trend. In vivo results in diabetic mice with biopsy punch wounds demonstrated accelerated wound closure with Hp treatment, and delayed wound closure with Hb treatment. This work specifically studied Hb/Hp effects on macrophages in a highly inflammatory environment relevant to chronic wound healing. Results show that Hp-and not Hb-Hp, which is known to be superior in noninflammatory conditions-reduces inflammation in LPS-stimulated macrophages, and HMGB1 signaling is also implicated. Overall, Hp treatment on M1 macrophages in vitro reduced the inflammatory secretion profile, and also exhibited benefits in in silico and in vivo wound-healing models.

Index admission cholecystectomy for acute biliary pancreatitis favorably impacts outcomes of hospitalization in cirrhosis.

BACKGROUND AND AIM: Despite higher rates of gallstones in patients with cirrhosis, there are no population-based studies evaluating outcomes of acute biliary pancreatitis (ABP). Therefore, we sought to evaluate the predictors of early readmission and mortality in this high-risk population. METHODS: We utilized the Nationwide Readmission Database (2011-2014) to evaluate all adults admitted with ABP. Multivariable logistic regression models were used to assess independent predictors for 30-day readmission, index admission mortality, and calendar year mortality. RESULTS: Among 184 611 index admissions with ABP, 4344 (2.4%) subjects had cirrhosis (1649 with decompensation). Subjects with cirrhosis, when compared with those without, incurred higher rates of 30-day readmission (20.9% vs 11.2%; P < 0.001), index mortality (2.0% vs 1.0%; P < 0.001), and calendar year mortality (4.2% vs 0.9%; P < 0.001). Decompensation in cirrhosis was associated with significantly fewer cholecystectomies (26.7% vs 60.2%; P < 0.001) and endoscopic retrograde cholangiopancreatographies (23.3% vs 29.9%; P < 0.001). Multivariate analysis revealed that severe acute pancreatitis (odds ratio [OR]: 14.8; 95% confidence interval [CI]: 5.3, 41.2), sepsis (OR: 12.6; 95% CI: 5.8, 27.4), and decompensation (OR: 3.1; 96% CI: 1.4, 6.6) were associated with increased index admission mortality. Decompensated cirrhosis (OR: 1.8; 95% CI: 1.1, 3.0) and 30-day readmission (OR: 5.6; 95% CI: 3.3, 9.5) were predictors of calendar year mortality. However, index admission cholecystectomy was associated with decreased 30-day readmissions (OR: 0.6; 95% CI: 0.4, 0.7) and calendar year mortality (OR: 0.44; 95% CI: 0.25, 0.78). CONCLUSIONS: The presence of cirrhosis adversely impacts hospital outcomes of patients with ABP. Among modifiable factors, index admission cholecystectomy portends favorable prognosis by reducing risk of early readmission and consequent calendar year mortality.

Novel carbazole-stilbene hybrids as multifunctional anti-Alzheimer agents.

Molecules capable of engaging with multiple targets associated with pathological condition of Alzheimer's disease have proved to be potential anti-Alzheimer's agents. In our goal to develop multitarget-directed ligands for the treatment of Alzheimer's disease, a novel series of carbazole-based stilbene derivatives were designed by the fusion of carbazole ring with stilbene scaffold. The designed compounds were synthesized and evaluated for their anti-AD activities including cholinesterase inhibition, Aß aggregation inhibition, antioxidant and metal chelation properties. Amongst them, (E)-1-(4-(2-(9-ethyl-9H-carbazol-3-yl)vinyl)phenyl)-3-(2-(pyrrolidin-1-yl)ethyl)thiourea (50) appeared to be the best candidate with good inhibitory activities against AChE (IC50 value of 2.64 µM) and BuChE (IC50 value of 1.29 µM), and significant inhibition of self-mediated Aß1-42 aggregation (51.29% at 25 µM concentration). The metal chelation study showed that compound (50) possessed specific copper ion chelating property. Additionally, compound (50) exhibited moderate antioxidant activity. To understand the binding mode of 50, molecular docking studies were performed, and the results indicated strong non-covalent interactions of 50 with the enzymes in the active sites of AChE, BuChE as well as of the Aß1-42 peptide. Additionally, it showed promising in silico ADMET properties. Putting together, these findings evidently showed compound (50) as a potential multitarget-directed ligand in the course of developing novel anti-AD drugs.

Diverticulitis in Morbidly Obese Adults: A Rise in Hospitalizations with Worse Outcomes According to National US Data.

BACKGROUND AND AIMS: Obesity is a known risk factor for diverticulitis. Our objective was to examine the less investigated impact of morbid obesity (MO) on admissions and clinical course of diverticulitis in a US representative database. METHODS: We retrospectively queried the 2010-2014 Nationwide Readmission Database to compare diverticulitis hospitalizations in 48,651 MO and 841,381 non-obese patients. Outcomes of mortality, clinical course, surgical events, and readmissions were compared using multivariable and propensity-score-matched analyses. RESULTS: The number of MO patients admitted with diverticulitis increased annually from 7570 in 2010 to 11,935 in 2014, while the total number of patients admitted with diverticulitis decreased (p = 0.003). Multivariable analysis demonstrates that MO was associated with increased mortality (adjusted odds ratio [aOR] 1.54; 95% confidence internal [CI]: 1.16, 2.05), intensive care admissions (aOR = 1.92; 95% CI: 1.61, 2.31), emergent surgery (aOR = 1.20; 95% CI: 1.11, 1.30), colectomy (aOR = 1.13; 95% CI: 1.08, 1.18), open laparotomy (aOR = 1.28; 95% CI: 1.21, 1.34), and colostomy (aOR = 1.34; 95% CI: 1.25, 1.43). Additionally, MO was associated with higher risk for multiple readmissions for diverticulitis within 30 days (aOR = 1.45; 95% CI: 1.08, 1.96) and 6 months (aOR = 1.21; 95% CI: 1.03, 1.42). A one-to-one matched propensity-score analysis confirmed our multivariable analysis findings. CONCLUSIONS: Analysis of national data demonstrates an increasing trend of MO patients' admissions for diverticulitis, with a presentation at a younger age. Furthermore, MO is associated with an increased risk of adverse outcomes and readmissions of diverticulitis. Future strategies are needed to ameliorate these outcomes.

Blood Pressure after Endovascular Therapy for Ischemic Stroke (BEST): A Multicenter Prospective Cohort Study.

Background and Purpose- To identify the specific post-endovascular stroke therapy (EVT) peak systolic blood pressure (SBP) threshold that best discriminates good from bad functional outcomes (a priori hypothesized to be 160 mm Hg), we conducted a prospective, multicenter, cohort study with a prespecified analysis plan. Methods- Consecutive adult patients treated with EVT for an anterior ischemic stroke were enrolled from November 2017 to July 2018 at 12 comprehensive stroke centers accross the United States. All SBP values within 24 hours post-EVT were recorded. Using Youden index, the threshold of peak SBP that best discriminated primary outcome of dichotomized 90-day modified Rankin Scale score (0-2 versus 3-6) was identified. Association of this SBP threshold with the outcomes was quantified using multiple logistic regression. Results- Among 485 enrolled patients (median age, 69 [interquartile range, 57-79] years; 51% females), a peak SBP of 158 mm Hg was associated with the largest difference in the dichotomous modified Rankin Scale score (absolute risk reduction of 19%). Having a peak SBP >158 mm Hg resulted in an increased likelihood of modified Rankin Scale score 3 to 6 (odds ratio, 2.24 [1.52-3.29], P<0.01; adjusted odds ratio, 1.29 [0.81-2.06], P=0.28, after adjustment for prespecified variables). Conclusions- A peak post-EVT SBP of 158 mm Hg was prospectively identified to best discriminate good from bad functional outcome. Those with a peak SBP >158 had an increased likelihood of having a bad outcome in unadjusted, but not in adjusted analysis. The observed effect size was similar to prior studies. This finding should undergo further testing in a future randomized trial of goal-targeted post-EVT antihypertensive treatment.

HIV-1 Vif's Capacity To Manipulate the Cell Cycle Is Species Specific.

Cells derived from mice and other rodents exhibit profound blocks to HIV-1 virion production, reflecting species-specific incompatibilities between viral Tat and Rev proteins and essential host factors cyclin T1 (CCNT1) and exportin-1 (XPO1, also known as CRM1), respectively. To determine if mouse cell blocks other than CCNT1 and XPO1 affect HIV's postintegration stages, we studied HIV-1NL4-3 gene expression in mouse NIH 3T3 cells modified to constitutively express HIV-1-compatible versions of CCNT1 and XPO1 (3T3.CX cells). 3T3.CX cells supported both Rev-independent and Rev-dependent viral gene expression and produced relatively robust levels of virus particles, confirming that CCNT1 and XPO1 represent the predominant blocks to these stages. Unexpectedly, however, 3T3.CX cells were remarkably resistant to virus-induced cytopathic effects observed in human cell lines, which we mapped to the viral protein Vif and its apparent species-specific capacity to induce G2/M cell cycle arrest. Vif was able to mediate rapid degradation of human APOBEC3G and the PPP2R5D regulatory B56 subunit of the PP2A phosphatase holoenzyme in mouse cells, thus demonstrating that VifNL4-3's modulation of the cell cycle can be functionally uncoupled from some of its other defined roles in CUL5-dependent protein degradation. Vif was also unable to induce G2/M cell cycle arrest in other nonhuman cell types, including cells derived from nonhuman primates, leading us to propose that one or more human-specific cofactors underpin Vif's ability to modulate the cell cycle.IMPORTANCE Cells derived from mice and other rodents exhibit profound blocks to HIV-1 replication, thus hindering the development of a low-cost small-animal model for studying HIV/AIDS. Here, we engineered otherwise-nonpermissive mouse cells to express HIV-1-compatible versions of two species-specific host dependency factors, cyclin T1 (CCNT1) and exportin-1 (XPO1) (3T3.CX cells). We show that 3T3.CX cells rescue HIV-1 particle production but, unexpectedly, are completely resistant to virus-induced cytopathic effects. We mapped these effects to the viral accessory protein Vif, which induces a prolonged G2/M cell cycle arrest followed by apoptosis in human cells. Combined, our results indicate that one or more additional human-specific cofactors govern HIV-1's capacity to modulate the cell cycle, with potential relevance to viral pathogenesis in people and existing animal models.