Alleviating Hypertension by Selectively Targeting Angiotensin Receptor-Expressing Vagal Sensory Neurons.

Cardiovascular homeostasis is maintained, in part, by neural signals arising from arterial baroreceptors that apprise the brain of blood volume and pressure. Here, we test whether neurons within the nodose ganglia that express angiotensin type-1a receptors (referred to as NGAT1aR) serve as baroreceptors that differentially influence blood pressure (BP) in male and female mice. Using Agtr1a-Cre mice and Cre-dependent AAVs to direct tdTomato to NGAT1aR, neuroanatomical studies revealed that NGAT1aR receive input from the aortic arch, project to the caudal nucleus of the solitary tract (NTS), and synthesize mechanosensitive ion channels, Piezo1/2 To evaluate the functionality of NGAT1aR, we directed the fluorescent calcium indicator (GCaMP6s) or the light-sensitive channelrhodopsin-2 (ChR2) to Agtr1a-containing neurons. Two-photon intravital imaging in Agtr1a-GCaMP6s mice revealed that NGAT1aR couple their firing to elevated BP, induced by phenylephrine (i.v.). Furthermore, optical excitation of NGAT1aR at their soma or axon terminals within the caudal NTS of Agtr1a-ChR2 mice elicited robust frequency-dependent decreases in BP and heart rate, indicating that NGAT1aR are sufficient to elicit appropriate compensatory responses to vascular mechanosensation. Optical excitation also elicited hypotensive and bradycardic responses in ChR2-expressing mice that were subjected to deoxycorticosterone acetate (DOCA)-salt hypertension; however, the duration of these effects was altered, suggestive of hypertension-induced impairment of the baroreflex. Similarly, increased GCaMP6s fluorescence observed after administration of phenylephrine was delayed in mice subjected to DOCA-salt or chronic delivery of angiotensin II. Collectively, these results reveal the structure and function of NGAT1aR and suggest that such neurons may be exploited to discern and relieve hypertension.

Treatment of geographic atrophy: an update on data related to pegcetacoplan.

PURPOSE OF REVIEW: Geographic atrophy is an advanced and currently untreatable form of age-related macular degeneration (AMD), which leads to significant compromise of visual function and quality of life. Dysregulation of the complement cascade has been directly implicated in AMD pathogenesis. Pegcetacoplan is a pegylated highly selective bicyclic peptide that inhibits the cleavage of complement component 3 (C3), which represents a key step in propagation of the complement cascade. The phase 2 FILLY trial as well as the phase 3 OAKS and DERBY trials have evaluated the safety and efficacy of pegcetacoplan for the treatment of GA. RECENT FINDINGS: The FILLY, OAKS and DERBY trials have demonstrated that local inhibition of C3 cleavage with pegcetacoplan can reduce geographic atrophy lesion growth compared with sham with an effect size of approximately 11-35% depending on the specific trial and specific geographic atrophy phenotype considered. Overall pegcetacoplan has appeared to be well tolerated with the notable side effect of a dose-dependent increase in the rate of exudative AMD development in treated eyes. SUMMARY: The FILLY, OAKS and DERBY trials have demonstrated that pegcetacoplan is a potentially viable treatment for geographic atrophy. Additional data from the 2-year outcomes of DERBY and OAKS as well as data from the ongoing 3-year GALE extension study will provide additional insights into the potential therapeutic benefit of pegcetacoplan. Future studies assessing complement inhibition at earlier stages of AMD, with the goal of preventing geographic atrophy formation, are warranted.

Pathomolecular epidemiology, antimicrobial resistance, and virulence genes of Streptococcus dysgalactiae subsp. equisimilis isolates from slaughtered pigs in India.

AIMS: We aimed to investigate the prevalence, pathology, and characterization of Streptococcus dysgalactiae subsp. equisimilis (SDSE) in slaughtered pigs of India. METHODS AND RESULTS: We collected 1254 morbid tissues (lungs-627 and spleen-627) and 627 heart-blood from 627 slaughtered pigs. The bacterial isolation, antibiogram, virulence gene profiling, and mouse pathogenicity testing were performed for the detection and characterization of SDSE. A total of 177 isolates (heart-blood-160 and tissues-17) were recovered from 627 slaughtered pigs with higher isolation rate in heart-blood (25.51%). The prevalence of SDSE was 11% in morbid tissues by polymerase chain reaction. Majority of isolates showed higher detection of streptolysin O, followed by streptokinase and extracellular phospholipase A virulence genes with higher degree of resistance to azithromycin, clindamycin, erythromycin, and penicillin antibiotics. Mouse pathogenicity testing confirmed virulence based on histopathological lesions and re-isolation of SDSE. CONCLUSIONS: Our findings highlight the high prevalence of SDSE in slaughtered pigs. The presence of virulence genes and mouse pathogenicity testing confirm their pathogenic potential.

Unveiling piperazine-quinoline hybrids as potential multi-target directed anti-Alzheimer's agents: design, synthesis and biological evaluation.

Multi-target directed ligands (MTDLs) have recently been popularized due to their outstanding efficacy in combating the complicated features of Alzheimer's disease. This study details the synthesis of piperazine-quinoline-based MTDLs through a multicomponent Petasis reaction, targeting multiple factors such as AChE, BuChE, metal chelation to restore metal dyshomeostasis, and antioxidant activity. Some of the synthesized compounds exhibited notable inhibitory activity against AChE and BuChE enzymes at specific concentrations. Among the synthesized compounds compound (95) containing a 4-chloroaniline moiety and a 4-methoxybenzyl group displayed the most promising inhibitory activities against AChE (IC50 3.013 µM) and BuChE (IC50 = 3.144 µM). Compound (83) featuring 2-methoxyaniline and 4-fluorobenzyl substituents, exhibited the highest BuChE inhibition (IC50 1.888 µM). Notably, compound (79) demonstrated 93-times higher selectivity for BuChE over AChE. Molecular docking and molecular dynamics simulations were also performed to explore the binding modes and stability of these compounds with the AChE amd BuChE proteins. Further, kinetics study was performed against AChE for comounds (83 and 95) which indicated mixed inhibition of the enzyme by these compounds, Amongs the synthesized compounds, nine compounds were assessed for their antioxidant activity, displaying significant antioxidant properties with IC50 values ranging from 156 µM to 310 µM. Moreover, all the compounds demonstrated metal chelating tendency with Cu+2, Zn+2, Fe+2, Fe+3 and Al+3. This study provides insights into the design of novel MTDLs, highlighting compound (95) as a potential candidate for combating Alzheimer's disease.

Postoperative Delirium Screening Characteristics in Pediatric Intestinal, Liver, and Renal Transplant Recipients: Single-Center Retrospective Cohort Study.

OBJECTIVES: To describe and compare the results of delirium screening in the immediate post-transplant PICU admission for pediatric intestinal, liver, and renal transplant recipients. We also examined associations with known and suspected risk factors for pediatric delirium (PD). DESIGN: Retrospective analysis of a single-center cohort, 2016-2022. SETTING: Twenty-four-bed PICU in a high-volume transplant center. PATIENTS: All intestinal, liver, and renal transplant recipients under 23 years old admitted between July 2016 and August 2022. MEASUREMENTS AND MAIN RESULTS: We identified 211 pediatric transplant recipients: intestinal (n = 36), liver (n = 78), and renal (n = 97). Results of the Cornell Assessment for PD during the immediate post-transplant PICU admission were reviewed and patients were categorized into screen positive, screen negative, and unscreened. Corresponding data on known and suspected risk factors for PD were also collected. Data on delirium subtypes were not collected. Screens were available for 156 of 211 patients (74%) who were included in the final analysis. The prevalence of a positive screen by transplant category was: intestine 80% (24/30), liver 75% (47/63), and renal 14% (9/63). A positive screen was associated with younger age, greater duration of mechanical ventilation, and greater PICU length of stay (LOS) in bivariate analysis. In multivariable analysis, age and PICU LOS remained strongly correlated with a positive screen (p < 0.05). Deep sedation and agitation as categorized by the State Behavioral Scale was associated with a positive screen, as was significant iatrogenic withdrawal symptoms (p < 0.05). Most patients screened positive by post-transplant days 2 and 3 (58/80 [72%] and 64/80 [80%], respectively). CONCLUSIONS: In our 2016 to 2022 experience, we found a high prevalence of positive PD screens in pediatric intestinal and liver transplant recipients in the immediate post-transplant PICU admission. A positive screen was associated with younger age and greater PICU LOS.

MANAGEMENT OF LARGE FULL-THICKNESS MACULAR HOLES: Long-Term Outcomes of Internal Limiting Membrane Flaps and Internal Limiting Membrane Peels.

BACKGROUND/PURPOSE: To determine and compare the efficacy of a surgical internal limiting membrane (ILM) flap technique with the traditional ILM peel on long-term visual and anatomical outcomes for large (>400 µm) full-thickness macular holes. METHODS: From October 2016 to July 2022, patients undergoing initial full-thickness macular hole repair with the ILM flap or ILM peel technique were reviewed. Final outcomes were recorded and based on size in microns: 401 to 800, 801 to 1,200, and >1,200. RESULTS: Patients treated with ILM flap (n = 52, 94.2% closure rate) or ILM peel (n = 407, 93.6% closure rate) were followed with a mean follow-up time of 15.0 ± 10.2 and 20.0 ± 13.4 months, respectively. Success rates for ILM flaps and ILM peels were compared for full-thickness macular holes of 401 to 800 (100%, 95.8%, P = 0.39), 801 to 1,200 (95%, 93%, P = 0.74), and >1,200 (86.7%, 86.7%, P = 1.0) µm. Mean best-recorded logarithm of the minimal angle of resolution visual acuity for ILM flaps and ILM peels, respectively, was 1.02 ± 0.46 and 0.87 ± 0.47 preoperatively, with follow-up acuity of 0.48 ± 0.32 (P < 0.03) and 0.39 ± 0.42 (P < 0.01) at Year 3. CONCLUSION: Both techniques provide a similar anatomical closure rate and functional improvement in vision. Comparisons should be cautiously made based on difference in preoperative hole size.

Efficacy and Safety of Intrathecal Morphine for Cesarean Delivery: A Narrative Review.

PURPOSE OF REVIEW: Pain management is a critical aspect of care during and following a cesarean delivery. Without proper control of pain, individuals can experience poor mobility, increased thromboembolic events, and difficulty caring for the neonate in the postpartum period. There have been multiple methods for pain management for cesarean delivery and intrathecal morphine (ITM) has emerged as a prominent option for post-operative analgesia due to its efficacy, safety, and potential benefits over other treatments. This review analyzes data on efficacy, side effects, and safety of ITM and the pain control alternatives. RECENT FINDINGS: A comprehensive literature review was conducted to compare ITM with other analgesic techniques in post-cesarean patients. ITM was found to be as effective or better than other analgesic options, including bilateral quadratus lumborum block (QLB), opioid-free epidural analgesia (CSEA-EDA), and intravenous fentanyl. One study found that both ITM and oral analgesia were effective in pain control and that ITM caused fewer breakthrough pain events but had a longer duration and a greater rate of side effects than oral opioid analgesia. Commonly observed side effects of intrathecal opioids include nausea, vomiting, pruritus, and urinary retention, and it is thought that the adverse effects from intrathecal administration of opioids are short-lived. ITM may provide a decreased risk of DVT and coagulation by decreasing lower extremity weakness and numbness, thereby decreasing recovery time and increasing mobility. ITM is a safe and effective option for post-cesarean analgesia, with comparable pain relief to alternative forms of pain control, and side effects that are generally manageable. Further research is warranted to explore beneficial combinations with other methods of pain management and optimal dosing strategies.

Multiple independent recombinations led to hermaphroditism in grapevine.

Hermaphroditic (perfect) flowers were a key trait in grapevine domestication, enabling a drastic increase in yields due to the efficiency of self-pollination in the domesticated grapevine (Vitis vinifera L. ssp. vinifera). In contrast, all extant wild Vitis species are dioecious, each plant having only male or female flowers. In this study, we identified the male (M) and female (f) haplotypes of the sex-determining region (SDR) in the wild grapevine species V. cinerea and confirmed the boundaries of the SDR. We also demonstrated that the SDR and its boundaries are precisely conserved across the Vitis genus using shotgun resequencing data of 556 wild and domesticated accessions from North America, East Asia, and Europe. A high linkage disequilibrium was found at the SDR in all wild grape species, while different recombination signatures were observed along the hermaphrodite (H) haplotype of 363 cultivated accessions, revealing two distinct H haplotypes, named H1 and H2. To further examine the H2 haplotype, we sequenced the genome of two grapevine cultivars, 'Riesling' and 'Chardonnay'. By reconstructing the first two H2 haplotypes, we estimated the divergence time between H1 and H2 haplotypes at ∼6 million years ago, which predates the domestication of grapevine (∼8,000 y ago). Our findings emphasize the important role of recombination suppression in maintaining dioecy in wild grape species and lend additional support to the hypothesis that at least two independent recombination events led to the reversion to hermaphroditism in grapevine.

Impact of bortezomib-based versus lenalidomide maintenance therapy on outcomes of patients with high-risk multiple myeloma.

BACKGROUND: Lenalidomide maintenance after autologous stem cell transplant (ASCT) in multiple myeloma (MM) results in superior progression-free survival and overall survival. However, patients with high-risk multiple myeloma (HRMM) do not derive the same survival benefit from lenalidomide maintenance compared with standard-risk patients. The authors sought to determine the outcomes of bortezomib-based maintenance compared with lenalidomide maintenance in patients with HRMM undergoing ASCT. METHODS: In total, the authors identified 503 patients with HRMM who were undergoing ASCT within 12 months of diagnosis from January 2013 to December 2018 after receiving triplet novel-agent induction in the Center for International Blood and Marrow Transplant Research database. HRMM was defined as deletion 17p, t(14;16), t(4;14), t(14;20), or chromosome 1q gain. RESULTS: Three hundred fifty-seven patients (67%) received lenalidomide alone, and 146 (33%) received bortezomib-based maintenance (with bortezomib alone in 58%). Patients in the bortezomib-based maintenance group were more likely to harbor two or more high-risk abnormalities and International Staging System stage III disease (30% vs. 22%; p = .01) compared with the lenalidomide group (24% vs. 15%; p < .01). Patients who were receiving lenalidomide maintenance had superior progression-free survival at 2 years compared with those who were receiving either bortezomib monotherapy or combination therapy (75% vs. 63%; p = .009). Overall survival at 2 years was also superior in the lenalidomide group (93% vs. 84%; p = .001). CONCLUSIONS: No superior outcomes were observed in patients with HRMM who received bortezomib monotherapy or (to a lesser extent) in those who received bortezomib in combination as maintenance compared with lenalidomide alone. Until prospective data from randomized clinical trials are available, post-transplant therapy should be tailored to each patient with consideration for treating patients in clinical trials that target novel therapeutic strategies for HRMM, and lenalidomide should remain a cornerstone of treatment.

The mutational landscape in chronic myelomonocytic leukemia and its impact on allogeneic hematopoietic cell transplantation outcomes: a Center for Blood and Marrow Transplantation Research (CIBMTR) analysis.

Somatic mutations are recognized as an important prognostic factor in chronic myelomonocytic leukemia (CMML). However, limited data are available regarding their impact on outcomes after allogeneic hematopoietic cell transplantation (HCT). In this registry analysis conducted in collaboration with the Center for International Blood and Marrow Transplantation Registry database/sample repository, we identified 313 adult patients with CMML (median age: 64 years, range, 28- 77) who underwent allogeneic HCT during 2001-2017 and had an available biospecimen in the form of a peripheral blood sample obtained prior to the start of conditioning. In multivariate analysis, a CMML-specific prognostic scoring system (CPSS) score of intermediate-2 (HR=1.46, P=0.049) or high (HR=3.22, P=0.0004) correlated significantly with overall survival. When the molecularly informed CPSS-Mol prognostic model was applied, a high CPSS-Mol score (HR=2 P=0.0079) correlated significantly with overall survival. The most common somatic mutations were in ASXL1 (62%), TET2 (35%), KRAS/NRAS (33% combined), and SRSF2 (31%). DNMT3A and TP53 mutations were associated with decreased overall survival (HR=1.70 [95% CI: 1.11-2.60], P=0.0147 and HR=2.72 [95% CI: 1.37-5.39], P=0.0042, respectively) while DNMT3A, JAK2, and TP53 mutations were associated with decreased disease-free survival (HR=1.66 [95% CI: 1.11-2.49], P=0.0138, HR=1.79 [95% CI: 1.06-3.03], P=0.0293, and HR=2.94 [95% CI: 1.50-5.79], P=0.0018, respectively). The only mutation associated with increased relapse was TP53 (HR=2.94, P=0.0201). Nonetheless, the impact of TP53 mutations specifically should be interpreted cautiously given their rarity in CMML. We calculated the goodness of fit measured by Harrell's C-index for both the CPSS and CPSS-Mol, which were very similar. In summary, via registry data we have determined the mutational landscape in patients with CMML who underwent allogeneic HCT, and demonstrated an association between CPSS-Mol and transplant outcomes although without major improvement in the risk prediction beyond that provided by the CPSS.

Association between the choice of the conditioning regimen and outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/ busulfan n=166, fludarabine/melphalan n=327) and 379 using MAC (fludarabine/busulfan n=247, busulfan/cyclophosphamide n=132). In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (hazard ratio [HR]=1.80; 95% confidenec interval [CI]: 1.15-2.81; P=0.009), higher early non-relapse mortality (HR=1.81; 95% CI: 1.12-2.91; P=0.01) and higher acute graft-versus-host disease (GvHD) (grade 2-4 HR=1.45; 95% CI: 1.03-2.03; P=0.03; grade 3-4 HR=2.21; 95%CI: 1.28-3.83; P=0.004) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GvHD (grade 2-4 HR=2.33; 95% CI: 1.67-3.25; P<0.001; grade 3-4 HR=2.31; 95% CI: 1.52-3.52; P<0.001) and inferior GvHD-free relapse-free survival (GRFS) (HR=1.94; 95% CI: 1.49-2.53; P<0.001) as compared to fludarabine/busulfan. Hence, our study suggests that fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GvHD) and MAC (lower acute GvHD and better GRFS) in myelofibrosis.

Genotypic characterization of Japanese encephalitis virus circulating in swine population of India: Genotype-III still in dominance.

Swine is considered as a suitable sentinel to predict Japanese encephalitis virus (JEV) outbreaks in humans. The present study was undertaken to determine the circulating genotypes of JEV in swine population of India. A total of 702 swine serum samples from four states of western, northern, northern-temperate, and north-eastern zones of India were screened by real-time RT-PCR targeting envelope gene of JEV, which showed positivity of 35.33%. The viral copy number ranged from 3 copies to 6.3 × 104 copies/reaction. Subsequently, the capsid/prM structural gene region of JEV positive samples was amplified by nested RT-PCR, sequenced, and genetically characterized. The phylogenetic analysis of the partial sequences of the capsid gene of 42 JEV positive samples showed that they all belonged to genotype-III (G-III) of JEV. Notably, JEV positive swine samples showed high nucleotide identity with human isolates from China and Nepal which explains the probable spillover of infection between neighboring countries probably by migratory birds. The novel mutations were observed in JEV positive sample B8 at C54 position (Phe → Ser), and JEV positive sample K50 at C62 (Thr → Ala) and C65 (Leu → Pro) positions which were absent from other JEV isolates reported till now. The mutation at the C66 position (Leu → Ser) observed in live attenuated vaccine SA14-14-2 strain was not found in JEV positive samples of our study. The detection of the G-III JE virus from climatically diverse states of India reinforces the need to continue the ongoing human vaccination program in India by extending vaccine coverage in temperate states.

The Intersection of Prostate Cancer and Hypertension: a Call to Action.

OPINION STATEMENT: With improvements in treatment and survival from prostate cancer, comorbid cardiac conditions will significantly impact overall morbidity and mortality from prostate cancer. Hypertension is a well-established cardiovascular risk factor that increases the risk of heart failure, myocardial infarction, and stroke. Therapies used in the treatment of prostate cancer, including GnRH agonists, GnRH antagonists, enzalutamide, abiraterone, and others, can directly or indirectly increase the risk of hypertension. In this paper, we review the evidence available on the incidence and mechanism of hypertension in prostate cancer patients. In addition, we provide recommendations on the assessment, treatment, and future directions for hypertension management in the prostate cancer population. We propose an individualized goal for blood pressure in prostate cancer patients, balancing the target goal of 130/80 mmHg with common comorbidities of frailty, orthostatic symptoms, and imbalance in this population. The presence of additional comorbidities (myocardial infarction, heart failure, renal disease, diabetes) can assist in preference of anti-hypertensive drugs.

USE OF OPTICAL COHERENCE TOMOGRAPHY IN DETECTING RETINAL TEARS IN ACUTE, SYMPTOMATIC POSTERIOR VITREOUS DETACHMENT.

PURPOSE: To evaluate the association of posterior vitreous opacities (PVOs) on optical coherence tomography with retinal tears identified on examination in patients with acute, symptomatic posterior vitreous detachment (PVD). METHODS: Data were retrospectively collected from the medical records of 388 patients with acute, symptomatic PVD between January 1, 2021, and June 30, 2021. Included patients had received a primary diagnosis of PVD and presented with flashes and/or floaters. Optical coherence tomography scans were reviewed by two separate readers for the presence of PVOs. The primary outcome was the presence of retinal tear on fundus photograph and on examination. RESULTS: Of 388 patients who presented with acute PVD symptoms, 90 (23.2%) were found to have a retinal tear on dilated fundus examination. Among these patients, 78 (86.7%) were found to have PVOs on optical coherence tomography. Statistical analysis demonstrated a significant relationship between the presence of PVOs and retinal tear ( P < 0.01). The sensitivity and specificity of this finding was 86.7% and 72.5%, respectively. Further analysis included area under the curve from receiver operating characteristic curve which was found to be 0.80. CONCLUSION: The presence of PVOs on optical coherence tomography is suggestive of a retinal tear in patients with acute, symptomatic PVD.

Improvement in International Prostate Symptom Score after prostatic urethral lifts is dependent on prostatic volume.

INTRODUCTION: Prostatic urethral lifts (PUL) provide improvement in urinary symptoms for men with benign prostatic hyperplasia (BPH). The aim of this study is to determine operative factors associated with improvement in urinary symptoms after PUL in men with bothersome BPH. MATERIALS AND METHODS: Men with BPH undergoing PUL at a single, tertiary center were identified from 2019 to 2022. Inclusion criteria included documented prostate volume as well as preoperative and postoperative cystoscopic images of the prostatic urethra. Multivariate regression modeling was performed to determine the predictive factors-including prostate volume, number of implants, and degree of unobstructed prostatic urethral channel-for improvement in International Prostate Symptom Score (IPSS) after PUL. RESULTS: Of the 47 men, the distribution of prostate volume was 1 patient with < 30 grams, 33 patients with 30-79 grams, five patients with 80-100 grams, and six patients with > 100 grams. The mean number of implants used was six implants. The mean preoperative and postoperative IPSS were 23 and 14, respectively. The mean (standard error (SE)) change and percent change in IPSS score following PUL was 14 and 60%, respectively. The mean percent improvement in prostatic urethral channel after anterior clip placements was 67%. On multivariate analysis, larger prostate volume was associated with greater change in IPPS follow surgery (p = 0.0091) while number of implants and percent of prostatic urethral opening were not associated with change in IPSS (p = 0.3094 and p = 0.2249, respectively). CONCLUSION: Men with larger prostates are associated with greater improvement in urinary symptom after PUL regardless of number of implants utilized and degree of prostatic urethral channel opening after prostatic implants.

Rapid unpaired CBCT-based synthetic CT for CBCT-guided adaptive radiotherapy.

In this work, we demonstrate a method for rapid synthesis of high-quality CT images from unpaired, low-quality CBCT images, permitting CBCT-based adaptive radiotherapy. We adapt contrastive unpaired translation (CUT) to be used with medical images and evaluate the results on an institutional pelvic CT dataset. We compare the method against cycleGAN using mean absolute error, structural similarity index, root mean squared error, and Frèchet Inception Distance and show that CUT significantly outperforms cycleGAN while requiring less time and fewer resources. The investigated method improves the feasibility of online adaptive radiotherapy over the present state-of-the-art.

Absolute quantification of plasma mitochondrial DNA by droplet digital PCR marks COVID-19 severity over time during intensive care unit admissions.

Increased plasma mitochondrial DNA concentrations are associated with poor outcomes in multiple critical illnesses, including COVID-19. However, current methods of cell-free mitochondrial DNA quantification in plasma are time-consuming and lack reproducibility. Here, we used next-generation sequencing to characterize the size and genome location of circulating mitochondrial DNA in critically ill subjects with COVID-19 to develop a facile and optimal method of quantification by droplet digital PCR. Sequencing revealed a large percentage of small mitochondrial DNA fragments in plasma with wide variability in coverage by genome location. We identified probes for the mitochondrial DNA genes, cytochrome B and NADH dehydrogenase 1, in regions of relatively high coverage that target small sequences potentially missed by other methods. Serial assessments of absolute mitochondrial DNA concentrations were then determined in plasma from 20 critically ill subjects with COVID-19 without a DNA isolation step. Mitochondrial DNA concentrations on the day of enrollment were increased significantly in patients with moderate or severe acute respiratory distress syndrome (ARDS) compared with those with no or mild ARDS. Comparisons of mitochondrial DNA concentrations over time between patients with no/mild ARDS who survived, patients with moderate/severe ARDS who survived, and nonsurvivors showed the highest concentrations in patients with more severe disease. Absolute mitochondrial DNA quantification by droplet digital PCR is time-efficient and reproducible; thus, we provide a valuable tool and rationale for future studies evaluating mitochondrial DNA as a real-time biomarker to guide clinical decision-making in critically ill subjects with COVID-19.

Persistent leukocytosis in polycythemia vera is associated with disease evolution but not thrombosis.

There are unresolved questions regarding the association between persistent leukocytosis and risk of thrombosis and disease evolution in polycythemia vera (PV), as much of the published literature on the topic does not appropriately use repeated-measures data or time-dependent modeling to answer these questions. To address this knowledge gap, we analyzed a retrospective database of 520 PV patients seen at 10 academic institutions across the United States. Taking hematologic laboratory data at ∼3-month intervals (or as available) for all patients for duration of follow-up, we used group-based trajectory modeling to identify latent clusters of patients who follow distinct trajectories with regard to their leukocyte, hematocrit, and platelet counts over time. We then tested the association between trajectory membership and hazard of 2 major outcomes: thrombosis and disease evolution to myelofibrosis, myelodysplastic syndrome, or acute myeloid leukemia. Controlling for relevant covariates, we found that persistently elevated leukocyte trajectories were not associated with the hazard of a thrombotic event (P = .4163), but were significantly associated with increased hazard of disease evolution in an ascending stepwise manner (overall P = .0002). In addition, we found that neither hematocrit nor platelet count was significantly associated with the hazard of thrombosis or disease evolution.

Management of mammalian bites to the external genitalia: a scoping review.

OBJECTIVE: To review existing publications to determine the approaches for the medical and operative management of mammalian bites to the external genitalia. MATERIALS AND METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Scoping Review guidelines were followed. Four databases were searched. Articles were independently screened and analysed by two reviewers. Publications were included if detailed summaries of genitalia bites and management were documented. Discrepancies were resolved by a third reviewer. Data were extracted from the final article cohort. RESULTS: A total of 42 articles were included in this scoping review with 67 cases of mammalian bites to the genitalia reported in the cohort. The most common injury site was the penis (44.9%). Dog and human bites were the most common type of mammalian bites (61.2% and 26.9%, respectively). In all, 13.4% of cases were managed with medical therapy while 86.6% of cases required surgical intervention. The most common intervention was wound irrigation, debridement, and primary closure (32.8%). Although uncommon, other operative approaches included skin flaps (7.5%) and grafts (4.5%), re-implantation (4.5%), urethroplasty/repair (7.5%), penectomy (3.0%), scrotoplasty (3.0%), and perineal urethrostomy (1.5%). The reported complication rate was 19.4%. The mean follow-up time was 39.9 months. CONCLUSION: Trauma related to mammalian bites is associated with high utilisation of healthcare resources and cost. Although management of such bites to the genitalia is controversial, surgical intervention is often warranted ranging from simple debridement of devitalised tissue to complex reconstructive surgery. This review underscores the need for further investigation of mammalian bites to the genitalia to improve surgical options and monitor for long-term complication rates.

Impact of Comorbid Psychiatric Disorders on Healthcare Utilization in Patients with Inflammatory Bowel Disease: A Nationally Representative Cohort Study.

BACKGROUND AND AIMS: Patients with inflammatory bowel disease (IBD) frequently experience comorbid psychiatric disorders, which negatively impact quality of life. We characterized the longitudinal burden of hospitalization-related healthcare utilization in adults with IBD with and without comorbid anxiety, depression, or bipolar disorder. METHODS: In the 2017 Nationwide Readmissions Database (NRD), we identified 40,177 patients with IBD who were hospitalized between January 1, 2017 and June 30, 2017 and who were followed until December 31, 2017. In this cohort, we compared the annual burden (i.e., total days spent in hospital), costs, risk of readmission, inpatient mortality, and IBD-related surgery in patients with and without comorbid psychiatric disorders (anxiety, depression, or bipolar disorder). RESULTS: Of the 40,177 adults who were hospitalized for IBD, 25.7% had comorbid psychiatric disorders. Over a 10 month-long period of follow-up, patients with comorbid psychiatric disorders spent more days in the hospital (median, 7 days vs. 5 days, p < 0.01), experienced higher 30-day (31.3 vs. 25.4%; p < 0.01) and 90-day (42.6 vs. 35.3%, p < 0.01) readmission rates, and had higher hospitalization-related costs (median, $41,418 vs. $39,242, p < 0.01). However, they were less likely to undergo IBD-related procedures or surgeries. There were no differences in risk of mortality. On Cox proportional hazard analysis, the presence of comorbid psychiatric disorders was associated with a 16% higher risk of readmission (HR, 1.16; 95% CI, 1.13-1.20) and a 13% higher risk of severe IBD-related hospitalization (HR, 1.13; 95% CI, 1.08-1.16). CONCLUSIONS: In adults with IBD, comorbid psychiatric disorders were independently associated with a higher burden and cost of hospitalization, without an increase in the risk of IBD-related surgery or procedures. Population-based interventions aimed at treating psychiatric comorbidities may decrease the risk of unplanned healthcare utilization.