bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Patient Demographics, Utilization Trends, and Costs of Treatment for Dupuytren’s Disease in the United States From 2012 to 2019
Authors: Gordon Adam M. , Nian Patrick P. , Miller Chaim , Schwartz Jake M. , Choueka Jack
Published: August 2023

Introduction

Dupuytren’s disease is a fibroproliferative disorder of the palm leading to flexion deformities of the digits that impair hand function. Studies have evaluated treatment trends for patients with Dupuytren’s disease; however, most conclude in 2012 shortly after collagenase clostridium histolyticum (CCH) injection was introduced to the market. It is unknown how provider preferences have been influenced since its introduction. We aimed to compare treatment options with regard to (1) patient demographics, (2) annual utilization rates, and (3) costs.

Methods

The PearlDiver nationwide administrative claims database from 2012 to 2019 was analyzed for patients diagnosed with Dupuytren’s disease (N = 47,813). Patients receiving procedural treatment were identified using codes for percutaneous needle aponeurotomy (PNA) (current procedural terminology [CPT] 26040), open fasciotomy (CPT 26045), open fasciectomy (CPT 26121, 26123, 26125), and CCH injection (CPT 20527). Fasciectomies were further analyzed by examining the number of patients receiving release of 1 or more digits (CPT 26123, 26125) versus palmar-only surgery (CPT 26121). Outcomes included comparing patient comorbidities comprising the Elixhauser Comorbidity Index (ECI), frequencies of each procedure annually, and costs. Linear regressions evaluated changes in utilization over time. Analysis of variance compared costs. P values less than 0.05 were significant.

Results

Patient demographics for each treatment differed with respect to age, sex, and the presence of multiple comorbidities comprising the ECI. Open fasciectomy (60.7%) was the predominant treatment, followed by CCH injection (22.9%), PNA (10.1%), and open fasciotomy (6.3%) (P < 0.001). Multiple patient comorbidities comprising the ECI differed for each treatment. Relative to total annual procedures from 2012 to 2019, PNA declined (10.2% to 9.5%, P = 0.037), open fasciotomy declined (6.8% to 5.6%, P = 0.007), palmar fasciectomy remained constant (14.5% to 14.2%, P = 0.710), fasciectomy of digits increased (46.3% to 47.5%, P = 0.030), and CCH injection remained constant (22.2% to 23.3%, P = 0.623). Day of procedure costs were significantly different for PNA ($573), open fasciotomy ($1176), palmar open fasciectomy ($1410), open fasciectomy digits ($1560), and CCH injection ($1250) (P < 0.001).

Conclusions

The overall annual Dupuytren’s disease treatment did not change over time. Treatment with open fasciectomy continues to be preferred. Collagenase clostridium histolyticum utilization has remained constant since its introduction. This study may assist hand surgeons in educating patients on the treatment and costs related to Dupuytren’s disease.
A Vessel Wall MRI Investigation in Patients With Moyamoya or Quasi-Moyamoya Disease: Diagnosis, Features, and Outcomes
Authors: Yu Le-Bao , Shen Mi , Zhang Qian , Zhang Dong
Published: August 2023

Background and Purpose:

None of the previous studies have investigated the pathologic authenticity of affected arteries in moyamoya disease (MMD) and Quasi-MMD diagnosed by angiography. This study aimed to confirm the angiographic diagnosis of moyamoya as well as investigate the pathologic mechanisms in angiographically proven MMD and Quasi-MMD using high-resolution magnetic resonance imaging (MRI) in a large sample.

Methods:

We prospectively studied 116 patients who had angiographically proven MMD and Quasi-MMD. Each affected internal carotid artery, and middle cerebral artery was independently evaluated. In addition, clinical features and postoperative outcomes were compared between hemispheres with MMD and moyamoya syndrome (MMS).

Results:

Among 116 patients analyzed, 88 and 22 patients had angiographically proven MMD and Quasi-MMD, respectively. high-resolution magnetic resonance imaging confirmed bilateral MMD in 73 (83.0%) patients, 1 hemisphere with MMD and the other with intracranial atherosclerotic disease (ICAD) in 10 (11.4%) patients, and bilateral hemispheres with different vasculopathies in 5 (5.7%) patients. Detailed analysis of 204 affected hemispheres showed that several combinations of different vasculopathies were observed in the internal carotid artery and middle cerebral artery of the same hemisphere, such as ICAD-ICAD, ICAD-MMD, dissection-ICAD, and dissection-MMD. Hemispheres were assigned to MMD and MMS groups according to their vasculopathies. Transient ischemic attack occurred more frequently in hemispheres with MMD (48.1% versus 21.1%, P=0.024), whereas symptomatic ischemia was more common in hemispheres with MMS (57.9% versus 24.9%, P=0.002). However, postoperative cerebral infarction, symptom improvement and neo-formative collaterals showed no significant difference between hemispheres with MMD and MMS (P>0.05).

Conclusions:

Patients with angiographically proven MMD or Quasi-MMD needed more accurate evaluation combined with high-resolution magnetic resonance imaging. Highly selected patients with MMS might also obtain benefits from surgical revascularization.
Benefit of higher blood pressure target in severe acute kidney injury (AKI) treated by continuous renal replacement therapy (CRRT)
Authors: Matsuura Ryo , Komaru Yohei , Hamasaki Yoshifumi , Nangaku Masaomi , Doi Kent
Published: August 2023

Introduction

The optimal target of mean arterial pressure (MAP) during CRRT is unknown.

Method

We retrospectively collected the hourly MAP data in AKI patients requiring CRRT who admitted to the intensive care unit in the University of Tokyo hospital during 2011-2019. Patients who died within 48 hours of CRRT start and whose average value of hourly MAPs during the first 48 hours was <65 mmHg were excluded. When the average value of MAP was≤75 mmHg or > 75 mmHg, patients were allocated to the low or high target group. We estimated the effect of MAP on mortality and RRT independence at 90-day, using multivariable Cox regression model and Fine and Gray model.

Result

Of 275 patients we analyzed, 95 patients were in the low group. There are no differences in gender, baseline kidney function, disease severity. At 90 day, the low target group had higher mortality with 38 deaths (40.0%) compared with 57 deaths (31.7%) in the high target group (p < 0.05). The adjusted hazard ratio of the low target group (≤75 mmHg) for mortality was 1.72 (95%CI, 1.08-2.74). In addition, the low target group had lower rate of RRT independence, with 60 (63.2%) patients compared with 136 (75.6%) patients in the high target group (p < 0.05). The multivariable analysis revealed that adjusted hazard ratio of the low target group for RRT independence was 0.74 (95%CI, 0.54-1.01).

Conclusion

This study found the association with low MAP and mortality. The association with low MAP and delayed renal recovery was not revealed.
THE ACCURACY OF INFERIOR VENA CAVA DISTENSIBILITY THROUGH THE TRANSHEPATIC APPROACH TO PREDICT FLUID RESPONSIVENESS IN PATIENTS WITH SEPTIC SHOCK AFTER EMERGENCY LAPAROTOMY
Authors: Hasanin Ahmed , Karam Nadia , Mostafa Maha , Abdelnasser Amr , Hamimy Waleed , Fouad Ahmed Z. , Eladawy Akram , Lotfy Ahmed
Published: August 2023

Background: We aimed to evaluate the ability of inferior vena cava (IVC) distensibility using the transhepatic approach to predict fluid responsiveness in mechanically ventilated patients with septic shock after emergency laparotomy. Methods: This prospective observational study included mechanically ventilated paralyzed adult who had septic shock after emergency laparotomy. The IVC dimensions were measured through the transhepatic and subxiphoid approaches. The fluid responsiveness was confirmed with >15% increase in cardiac output after 500 mL of fluid bolus. The outcomes were the ability of transhepatic (primary outcome) and subxiphoid approach to predict fluid responders using the area under the receiver operating characteristics curve analysis. The gray zone for the two approaches was calculated. Results: Data from 51 patients were analyzed, and the number of fluid responders was 30 of 52 (58%). The transhepatic approach was feasible in all patients, whereas the subxiphoid approach was only feasible in 42 patients. The area under the receiver operating characteristics curve (95% confidence interval) for the transhepatic IVC distensibility was 0.88 (0.76–0.95), and it was comparable with that of the subxiphoid approach (0.81 [0.66–0.92], P = 0.417). The gray zone for the transhepatic IVC distensibility was 17% to 35% including 24 of 51 patients (47%), whereas the gray zone for the subxiphoid IVC distensibility was 13% to 34% including 18 of 42 patients (43%). Conclusion: In conclusion, the transhepatic approach for evaluation of IVC distensibility showed good accuracy in predicting fluid responsiveness in patients with septic shock after emergency laparotomy. The transhepatic approach showed the same accuracy as the subxiphoid approach with the advantage of being feasible in larger number of patients.
RHINOORBITAL CEREBRAL MYCOSIS: A CASE SERIES OF NON-MUCORALES IN COVID PATIENTS
Authors: Patil Rajashri , Ajagunde Jyoti , KHAN SAMEENA , KANNURI SRIRAM , Gandham Nageswari , Mukhida Sahjid
Published: August 2023

Introduction: Rhinocerebral mycoses are not only caused by Aspergillus spp. and Zygomycetes spp. but also can be associated with other rare species like Neurospora spp., Cladosporium spp, and Fusarium spp. Mucormycosis is caused due to immunocompromised state like patients with comorbidities like Diabetes Mellitus. Clinical symptoms of COVID and Mucormycosis are a critical and relentless situation without a saving grace even with treatment.
Case series: We are reporting 3 patients with COVID-19 infection, who during the course of the treatment, developed rhino-orbital-cerebral mycosis including oral cavity involvement.Rhinocerebral mycosis along with Oral cavity involvement was diagnosed by radiological investigations and preliminary screening for fungal infection (KOH mount) in all three cases. Empirical treatment was started but patients were not responding to treatment. All patients succumbed even after debridement and Maxillectomy type crucial surgical procedures. On culture, rare species of fungi were isolated in all three cases which were identified with the help of a reference laboratory. Neurospora is considered nonpathogenic to humans. Cladosporium is a dematiaceous fungus found in soil in all climates, associated with disseminated or cerebral infections; and Fusarium though considered a saprophytic colonizer of skin and respiratory mucosa along with other bacteria, it is a common cause of mycotic keratitis worldwide.
Conclusion: Immune system modifications due to COVID-19 with/without other risk factors result in fungal co-infections proving to be fatal for the patients. It is vital to be aware that COVID-19 patients, particularly those who are critically ill, may acquire secondary fungal infections and early detection is critical
Design and validation of a PCR screen for γ-butyrolactone-like regulatory systems in Streptomyces
Authors: Waschulin Valentin , Borsetto Chiara , Corre Christophe , Wellington Elizabeth M.
Published: August 2023

γ-butyrolactone and related signalling systems are found in Streptomyces and other actinobacteria where they control the production of secondary or specialised metabolites such as antibiotics. Genetic manipulation of these regulatory systems therefore leads to changes in the secondary metabolite profile of a strain and has been used to activate previously silent secondary metabolite gene clusters. However, there is no easy way to assess the presence of γ-butyrolactone-like systems in Streptomyces strains without whole genome sequencing. We have therefore developed and tested a PCR screen that is able to detect homologs of the commonly co-located butenolide synthase and γ-butyrolactone receptor genes. This PCR screen could be employed for the screening of strain libraries to detect signalling systems without the necessity for whole genome sequencing.
A meta-analysis of tissue microbial biomarkers for recurrence and metastasis in multiple cancer types
Authors: Li Xuebo , Yuan Xuelian , Zhu Xiumin , Li Changjun , Ji Lei , Lv Kebo , Tian Geng , Ning Kang , Yang Jialiang
Published: August 2023

Background. Local recurrence and distant metastasis are the main causes of death in patients with cancer. Only considering species abundance changes when identifying markers of recurrence and metastasis in patients hinders finding solutions.

Hypothesis. Consideration of microbial abundance changes and microbial interactions facilitates the identification of microbial markers of tumour recurrence and metastasis.

Aim. This study aims to simultaneously consider microbial abundance changes and microbial interactions to identify microbial markers of recurrence and metastasis in multiple cancer types.

Method. One thousand one hundred and six non-RM (patients without recurrence and metastasis within 3 years after initial surgery) tissue samples and 912 RM (patients with recurrence or metastasis within 3 years after initial surgery) tissue samples representing 11 cancer types were collected from The Cancer Genome Atlas (TCGA).

Results. Tumour tissue bacterial composition differed significantly among 11 cancers. Among them, the tissue microbiome of four cancers, head and neck squamous cell carcinoma (HNSC), lung squamous cell carcinoma (LUSC), stomach adenocarcinoma (STAD) and uterine corpus endometrial carcinoma (UCEC), showed relatively good performance in predicting recurrence and metastasis in patients, with areas under the receiver operating characteristic curve (AUCs) of 0.78, 0.74, 0.91 and 0.93, respectively. Considering both species abundance changes and microbial interactions for the four cancers, a combination of nine genera (

Niastella

,

Schlesneria

,

Thioalkalivibrio

,

Phaeobacter

,

Sphaerotilus

,

Thiomonas

,

Lawsonia

,

Actinobacillus

and

Spiroplasma

) performed best in predicting patient survival.

Conclusion. Taken together, our results imply that comprehensive consideration of microbial abundance changes and microbial interactions is helpful for mining bacterial markers that carry prognostic information.
Molecular characterization and genotyping of isolates from cancer patients with Clostridioides difficile infection or asymptomatic colonization
Authors: de-la-Rosa-Martinez Daniel , Bobadilla Del Valle Miriam , Esteban-Kenel Veronica , Zinser Peniche Paola , Ponce De León Garduño Alfredo , Cornejo Juárez Patricia , Sánchez Cruz María Nancy , Camacho-Ortiz Adrian , Vilar-Compte Diana
Published: August 2023

Introduction. Cancer patients with

Clostridioides difficile

infection (CDI) are at a higher risk for adverse outcomes. In addition, a high prevalence of

Clostridioides difficile

asymptomatic colonization (CDAC) has been reported in this vulnerable population.

Gap Statement. The molecular characteristics and potential role of CDAC in healthcare-related transmission in the cancer population have been poorly explored.

Aim. We aimed to compare the molecular and genotypic characteristics of

C. difficile

isolates from cancer patients with CDAC and CDI.

Method. We conducted a prospective cohort study of cancer patients with CDAC or CDI from a referral centre. Molecular characterization, typification and tcdC gene expression of isolates were performed.

Results. The hospital-onset and community-onset healthcare facility-associated CDI rates were 4.5 cases/10 000 patient-days and 1.4 cases/1 000 admissions during the study period. Fifty-one

C. difficile

strains were isolated: 37 (72 %) and 14 (28 %) from patients with CDI or CDAC, respectively. All isolates from symptomatic patients were tcdA+/tcdB+, and four (10 %) were ctdA+/ctdB+. In the CDAC group, 10 (71 %) isolates were toxigenic, and none were ctdA+/ctdB+. The Δ18 in-frame tcdC deletion and two transition mutations were found in five isolates. After bacterial typing, 60 % of toxigenic isolates from asymptomatic carriers were clonal to those from patients with

C. difficile

-associated diarrhoea. No NAP1/027/BI strains were detected.

Conclusions. We found a clonal association between

C. difficile

isolates from patients with CDAC and CDI. Studies are needed to evaluate the potential role of asymptomatic carriers in the dynamics of nosocomial transmission to support infection control measures and reduce the burden of CDI in high-risk groups.
Respiratory symptoms after coalmine fire and pandemic: a longitudinal analysis of the Hazelwood Health Study adult cohort
Authors: Lane Tyler J , Carroll Matthew , Borg Brigitte , McCaffrey Tracy , Smith Catherine L , Gao Caroline X , Brown David , Johnson Amanda , Poland David , Allgood Shantelle , Ikin Jill F , Abramson Michael J
Published: August 2023

Objectives Extreme but discrete fine particle <2.5μm (PM2.5) exposure is associated with higher prevalence of respiratory symptoms. It was unknown whether these effects abate, persist, or worsen over time, nor whether they are exacerbated by COVID-19. Methods We analysed longitudinal survey data from a cohort residing near a 2014 coalmine fire in regional Australia. A 2016/2017 survey included 4,056 participants, of whom 612 were followed-up in 2022. Items included questions on respiratory symptoms, history of COVID-19, and time-location diaries that were combined with geospatial and temporal models of fire-related PM2.5. Associations were examined using logistic and mixed-effects logistic regressions. Results PM2.5exposure predicted higher prevalence of chronic cough and current wheeze 2-3 years post-fire. At the 2022 follow-up, PM2.5exposure was associated with worsening prevalence of chronic cough and possibly current wheeze. While there were no detectable interaction effects between PM2.5and COVID-19, PM2.5exposure was associated with additional respiratory symptoms among participants who reported a history of COVID-19. Conclusion Short-term but extreme PM2.5may increase the long-term prevalence of chronic cough, while COVID-19 may exacerbate the effect on additional respiratory symptoms.
Nitroglycerin use preceding primary percutaneous coronary intervention is associated with adverse clinical outcomes in elderly patients with acute coronary syndrome
Authors: Komaki Soichi , Matsuura Yunosuke , Tanaka Hiroki , Moribayashi Kohei , Yamamura Yoshimasa , Kurogi Kazumasa , Ideguchi Takeshi , Yamamoto Nobuyasu , Nakai Michikazu , Tsuruda Toshihiro , Kaikita Koichi
Published: August 2023

Background

The primary care for acute coronary syndrome (ACS) includes the administration of nitroglycerin (GTN). This study aimed to investigate the association between the use of GTN before percutaneous coronary intervention (PCI) for ACS and clinical outcomes.

Methods and Results

Nine-hundred and forty-seven patients who underwent PCI for ACS were examined and classified into two groups: those who were treated with GTN before PCI (GTN group) and those who were not (non-GTN group). The incidence of major adverse cardiovascular events (MACE), which consist of all-cause mortality, myocardial infarction, stroke, and rehospitalization for heart failure at 1 year, was compared between the two groups. This study identified 289 patients with ACS who used GTN preceding PCI. Pre-PCI systolic blood pressure was significantly lower in the GTN group than in the non-GTN group (median (interquartile range); 130.0 (112.5-144.2) mmHg vs. 142.0 (115.0-160.0) mmHg, respectively, p = 0.03). Multivariate Cox regression analysis indicated that GTN use preceding PCI was an independent determinant for the incidence of MACE (hazard ratio, 1.64; 95% confidence interval, 1.17-2.31; p = 0.004). Overall, the incidence of MACE 1 year after PCI for ACS was significantly higher in the GTN group than in the non-GTN group (log-rank test, p = 0.02); however, this trend was consistently found in elderly patients aged ≥ 75 years (p = 0.002) but not in non-elderly patients aged < 75 years (p = 0.77).

Conclusions

GTN use preceding PCI for ACS is associated with lower blood pressure and adverse clinical outcomes in elderly patients.
Association between Dysphagia and Symptoms of Depression and Anxiety after Ischemic Stroke
Authors: Karisik Anel , Dejakum Benjamin , Moelgg Kurt , Komarek Silvia , Toell Thomas , Mayer-Suess Lukas , Pechlaner Raimund , Kostner Stefanie , Sollereder Simon , Kiechl Sophia , Rossi Sonja , Schoenherr Gudrun , Lang Wilfried , Kiechl Stefan , Knoflach Michael , Boehme Christian ,   the STROKE-CARD Registry study group.
Published: August 2023

BACKGROUND

Dysphagia after stroke is associated not only with poor outcome and higher mortality, but also with reduced quality of life and social isolation. We aimed to investigate the potential relationship between swallowing impairment and symptoms of anxiety and depression after ischemic stroke.

METHODS

Consecutive patients with ischemic stroke participating in the prospective STROKE-CARD Registry study at the study center Innsbruck, Austria from 2020 to 2022 were assessed for presence of dysphagia on hospital admission (clinical swallowing assessment) as well as for persistence until hospital discharge and a 3-month follow-up (SINGER Independency Index). Symptoms of anxiety and depression were recorded using Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HADS) at 3-month follow-up.

RESULTS

Of 648 patients (36.6% female), 19.3% had dysphagia at hospital admission which persisted in 14.8% (hospital discharge) and 6.8% (3-month follow-up). With the presence or duration of dysphagia (no dysphagia, dysphagia at baseline, discharge or at 3 months), score points (mean±SD) increased in the BDI (7.9±6.7, 12.5±8.7, 13.5±9.0, 16.5±10.2), HADS-D (4.4±3.7, 7.1±4.2, 7.7±4.4, 9.8±4.3) and HADS-A (4.4±3.5, 5.4±3.6, 6.0±3.6, 7.0±3.6). In linear regression analysis adjusting for age, sex and functional disability, BDI and HADS-D but not HADS-A scores were significantly higher in patients with dysphagia when compared to those without dysphagia at baseline or who recovered to discharge and follow-up. Moreover, patients with swallowing impairment were more likely to receive antidepressants, antipsychotics or benzodiazepines at discharge and 3-month follow-up.

CONCLUSIONS

Dysphagia after stroke is common and severely affects psychosocial functioning of individuals. Our results highlight swallowing impairment as an independent predictor of depressive symptoms after stroke.
Dietary Intake Is Associated With the Prevalence of Uterine Leiomyoma in Korean Women: A Retrospective Cohort Study
Authors: Kim Min-Jeong , Kim Sunmie , Kim Jin Ju , Kim Young Sun , Song Ji Hyun , Lee Jung Eun , Youn Jiyoung , Yang Sun Young
Published: August 2023

Objective

Uterine leiomyoma (UL), the most prevalent benign gynecologic tumor among reproductive-aged women, lacks sufficient research on the potential association between dietary intake and its occurrence in Korean women. Addressing this research gap, this study aims to evaluate the potential link between dietary intake and the prevalence of UL in Korean women.

Methods

In this cross-sectional study, a cohort of 672 women, aged 25 to 65, were enrolled, with 383 (57%) being premenopausal. Dietary intake was assessed using a validated food frequency questionnaire (FFQ), and UL presence was determined through ultrasonography. The analysis focused exclusively on items within ten categories, including vegetables/fruit, vegetables, fruits, red meat, processed meat, poultry, fish, dairy product, milk, and alcohol. Multiple logistic regression models were employed to explore the relationship between dietary intake and the prevalence of UL, calculating odds ratios (ORs) and 95 % confidence intervals (CIs) while adjusting for confounding factors.

Results

Within the total cohort, 219 (32.6%) women were diagnosed with UL. High intakes of fish and poultry showed an association with higher UL prevalence. Odds ratios (95% CIs) for the upper quartiles compared to the lower quartiles were 1.70 (1.02-2.84; p trend = 0.049) for fish intake and 1.85 (1.09 -3.14; p trend = 0.07) for poultry intake. Conversely, an inverse relationship emerged between dairy product intake and UL prevalence, with an odds ratio of 0.59 (95% CI 0.36–0.98; p trend = 0.06). Stratifying the analysis by menopausal status revealed a parallel pattern, with heightened UL prevalence with fish intake and reduced prevalence with dairy product intake. However, the link between poultry intake and UL prevalence was primarily observed among postmenopausal women. Among premenopausal women, elevated vegetable intake was linked to a decreased UL prevalence (OR 0.47, 95% CI 0.22-1.01 for top vs. bottom quartiles; p trend = 0.01).

Conclusion

We found that high consumption of fish and poultry, coupled with low intake of dairy products, correlated with an elevated prevalence of UL. Furthermore, vegetable intake exhibited an inverse relationship with UL prevalence, particularly among premenopausal women.
Bat RNA viruses employ viral RHIMs orchestrating species-specific cell death programs linked to Z-RNA sensing and ZBP1-RIPK3 signaling
Authors: Mishra Sanchita , Jain Disha , Dey Ayushi Amin , Nagaraja Sahana , Srivastava Mansi , Khatun Oyahida , Balamurugan Keerthana , Anand Micky , Tripathi Shashank , Ganji Mahipal , Kesavardhana Sannula
Published: August 2023

RHIM is a protein motif in cell death proteins that assembles higher-order signaling complexes and triggers regulated cell death, which in itself limits virus spread and additionally triggers inflammation for mounting immune responses. A few DNA viruses employ viral RHIMs mimicking host RHIMs. However, these viral RHIMs counteract host cell death by interacting with host RHIM proteins and blocking complex formation to alleviate antiviral defenses. Whether RNA viruses operate such viral RHIMs remains unknown. RHIM-protein signaling promotes lung damage and cytokine storm in respiratory RNA virus infections, arguing the presence of viral RHIMs. Here, we report the novel viral RHIMs in Nsp13 and Nsp14 of SARS-CoV-2 and other bat RNA viruses, providing the basis for bats as the hosts for their evolution. Nsp13 promoted cell death in bat and human cells, however, viral RHIM of Nsp13 is more critical for human cell death than bat cells, suggesting species-specific regulation. The conformation of RNA-binding channel in Nsp13 is critical for cell death in bat and human cells. Nsp13 showed RHIM-dependent interactions with ZBP1 and RIPK3 and promoted the formation of large insoluble complexes of ZBP1 and RIPK3. Also, Nsp13 promoted ZBP1-RIPK3 signaling-mediated cell death dependent on intracellular RNA ligands. Intriguingly, the SARS-CoV-2 genome consists of bona fide Z-RNA-forming segments. These SARS-CoV-2 Z-RNA segments promoted Nsp13-dependent cell death, further revealing Nsp13’s association with Z-RNA sensing and ZBP1-RIPK3 signaling. Our findings reveal the functional viral RHIMs of bat-originated RNA viruses regulating host cell death associated with Z-RNA sensing and ZBP1-RIPK3 signaling activation. These observations allow the understanding of mechanisms of cellular damage and cytokine storm in SARS-CoV-2 and other bat-originated RNA virus infections.

GRAPHICAL ABSTRACT

One-sentence summary

Bat-associated RNA viruses employ viral RHIMs and regulate host cell death.
Temporal weighting of cortical and subcortical spikes reveals stimulus dependent differences in their contributions to behavior
Authors: Cone Jackson J. , Mitchell Autumn O. , Parker Rachel K. , Maunsell John H.R.
Published: August 2023

The primary visual cortex (V1) and the superior colliculus (SC) both occupy stations early in the processing of visual information. They have long been thought to perform distinct functions, with V1 supporting perception of visual features and the SC regulating orienting to visual inputs. However, growing evidence suggests that the SC supports perception of many of the same visual features traditionally associated with V1. To distinguish V1 and SC contributions to visual processing, it is critical to determine whether both areas causally contribute to perception of specific visual stimuli. Here, mice reported changes in visual contrast or luminance near perceptual threshold while we presented white noise patterns of optogenetic stimulation to V1 or SC inhibitory neurons. We then performed a reverse correlation analysis on the optogenetic stimuli to estimate a neuronal-behavioral kernel (NBK), a moment-to-moment estimate of the impact of V1 or SC inhibition on stimulus detection. We show that the earliest moments of stimulus-evoked activity in SC are critical for detection of both luminance or contrast changes. Strikingly, there was a robust stimulus-aligned modulation in the V1 contrast-detection NBK, but no sign of a comparable modulation for luminance detection. The data suggest that perception of visual contrast depends on both V1 and SC spiking, whereas mice preferentially use SC activity to detect changes in luminance. Electrophysiological recordings showed that neurons in both SC and V1 responded strongly to both visual stimulus types, while the reverse correlation analysis reveals when these neuronal signals actually contribute to visually-guided behaviors.
Copy number variation and population-specific immune genes in the model vertebrate zebrafish
Authors: Schäfer Yannick , Palitzsch Katja , Leptin Maria , Whiteley Andrew R. , Wiehe Thomas , Suurväli Jaanus
Published: August 2023

Many species have hundreds of immune genes from the NLR family (Nucleotide-binding domain Leucine-rich Repeat containing). In plants they have a considerable amount of within-species variation, but not much is known about their variability in fishes. Here we captured and analysed the diversity of NLRs in zebrafish (Danio rerio) by sequencing 93 individuals from four wild and two laboratory strains. We found 1,560 unique NLR genes, and theoretical modelling revealed each wild population to have around 2,000. Only 100-550 were detected in each individual fish, and the observed variance of copy numbers differed among populations. Laboratory strains were found to have three times less NLRs than wild populations, and their genetic diversity was lower in general. Many NLRs showed no single nucleotide variation, but those that did showed evidence of purifying selection. Our study lays the groundwork for unraveling mechanisms driving the evolution of this large gene family in vertebrates.

Significance statement

We show here that the gene repertoires of vertebrates can be extremely variable, with different individuals having different genes. By sequencing one large family of immune receptors from 93 wild and laboratory zebrafish we found hundreds of novel gene copies, each only present in specific strains or specific individuals. Our observations can be explained by a combination of complex patterns of inheritance and a high rate of gene birth and death.
PROTEIN-O-MANNOSYLATION BY NON-SEC/TAT SECRETION TRANSLOCONS IN ACTINOBACTERIA
Authors: Saxena Hirak , Patel Rucha , Kelly John , Wakarchuk Warren
Published: August 2023

Protein-O-mannosylation (POM) is a form ofO-glycosylation that is ubiquitous throughout all domains of life and has been extensively characterized in eukaryotic systems. However, in prokaryotes this process has only been investigated in terms of pathogenicity (inMycobacterium tuberculosis) even though there are many non-pathogenic bacteria that are known to regularly carry out POM. To date, there is no consensus on what benefit POM imparts to the non-pathogenic bacteria that can perform it. Though the generation of a POM deficient mutant ofCorynebacterium glutamicum– a widely utilized and known mannosylating actinobacteria – this work shows that even closely related actinobacterial GT-39s (the enzymes responsible for the initiation of POM) can potentially have different activities and substrate specificities for targets of POM. Moreover, presented here is evidence that POM does not only occur in a SEC-dependent manner; POM also occurs with TAT and non-SEC secreted substrates in a specific and likely tightly regulated manner. Together these results highlight the need for further biochemical characterization of POM in these and other bacterial species to help elucidate the true nature of its biological functions.

Importance

Both the mechanism and overall cellular function of protein-O-mannosylation, a ubiquitous subset ofO-glycosylation, is poorly understood in bacterial systems. InMycobacterium tuberculosisand other pathogenic actinobacteria, numerous secreted virulence factors were identified as mannoproteins, with protein-O-mannosylation deficient mutants displaying a less virulent phenotype due to these proteins lacking the modification. However, these findings do not offer any explanations as to why non-pathogenic strains of actinobacteria also perform this modification as in these organisms it is seemingly dispensable.Corynebacterium glutamicumis a widely utilized, industrially relevant actinobacteria that also performs protein-O-mannosylation. This manuscript describes the utilization ofC. glutamicumas a Gram-positive recombinant host for thein vivostudy of actinobacterial protein-O-mannosylation and demonstrates the distinct lack of first-hand biochemical data of the process in prokaryotes.
Mutation ofmltGincreases peptidoglycan fragment release, cell size, and antibiotic susceptibility inNeisseria gonorrhoeae
Authors: Harris-Jones Tiffany N. , Pérez Medina Krizia M. , Hackett Kathleen T. , Schave Melanie A. , Schaub Ryan E. , Dillard Joseph P.
Published: August 2023

Infection with the Gram-negative speciesNeisseria gonorrhoeaeleads to inflammation that is responsible for the disease symptoms of gonococcal urethritis, cervicitis, and pelvic inflammatory disease. During growth these bacteria release significant amounts of peptidoglycan (PG) fragments which elicit inflammatory responses in the human host. To better understand the mechanisms involved in PG synthesis and breakdown inN. gonorrhoeae, we characterized the effects of mutation ofmltG. MltG has been identified in other bacterial species as a terminase that stops PG strand growth by cleaving the growing glycan. Mutation ofmltGinN. gonorrhoeaedid not affect bacterial growth rate but resulted in increased PG turnover, more cells of large size, decreased autolysis under non-growth conditions, and increased sensitivity to antibiotics that affect PG crosslinking. AnmltGmutant released greatly increased amounts of PG monomers, PG dimers, and larger oligomers. In themltGbackground, mutation of eitherltgAorltgD, encoding the lytic transglycosylases responsible for PG monomer liberation, resulted in wild-type levels of PG monomer release. Bacterial two-hybrid assays identified positive interactions of MltG with synthetic penicillin-binding proteins PBP1 and PBP2 and the PG-degrading endopeptidase PBP4 (PbpG). These data are consistent with MltG acting as a terminase inN. gonorrhoeaeand suggest that absence of MltG activity results in excessive PG growth and extra PG in the sacculus that must be degraded by lytic transglycosylases including LtgA and LtgD. Furthermore, absence of MltG causes a cell wall defect that is manifested as large cell size and antibiotic sensitivity.

Importance

Neisseria gonorrhoeaeis unusual in that the bacteria release larger amounts of cell wall material as they grow as compared to related bacteria, and the released cell wall fragments induce inflammation that leads to tissue damage in infected people. The study of MltG revealed the importance of this enzyme for controlling cell wall growth, cell wall fragment production, and bacterial cell size and suggest a role for MltG in a cell wall synthesis and degradation complex. The increased antibiotic sensitivities of anmltGmutant suggest that an antimicrobial drug inhibiting MltG would be useful in combination therapy to restore the sensitivity of the bacteria to cell wall targeting antibiotics to which the bacteria are currently resistant.
Using network control theory to study the dynamics of the structural connectome
Authors: Parkes Linden , Kim Jason Z. , Stiso Jennifer , Brynildsen Julia K. , Cieslak Matthew , Covitz Sydney , Gur Raquel E. , Gur Ruben C. , Pasqualetti Fabio , Shinohara Russell T. , Zhou Dale , Satterthwaite Theodore D. , Bassett Dani S.
Published: August 2023

Network control theory (NCT) is a simple and powerful tool for studying how network topology informs and constrains dynamics. Compared to other structure-function coupling approaches, the strength of NCT lies in its capacity to predict the patterns of external control signals that may alter dynamics in a desired way. We have extensively developed and validated the application of NCT to the human structural connectome. Through these efforts, we have studied (i) how different aspects of connectome topology affect neural dynamics, (ii) whether NCT outputs cohere with empirical data on brain function and stimulation, and (iii) how NCT outputs vary across development and correlate with behavior and mental health symptoms. In this protocol, we introduce a framework for applying NCT to structural connectomes following two main pathways. Our primary pathway focuses on computing thecontrol energyassociated with transitioning between specific neural activity states. Our second pathway focuses on computingaverage controllability, which indexes nodes’ general capacity to control dynamics. We also provide recommendations for comparing NCT outputs against null network models. Finally, we support this protocol with a Python-based software package callednetwork control theory for python (nctpy).
Immune memory shapes human polyclonal antibody responses to H2N2 vaccination
Authors: Yang Yuhe R. , Han Julianna , Perrett Hailee R. , Richey Sara T. , Jackson Abigail M. , Rodriguez Alesandra J. , Gillespie Rebecca A. , O’Connell Sarah , Raab Julie E. , Cominsky Lauren Y. , Chopde Ankita , Kanekiyo Masaru , Houser Katherine V. , Chen Grace L. , McDermott Adrian B. , Andrews Sarah F. , Ward Andrew B.
Published: August 2023

Influenza A virus subtype H2N2, which caused the 1957 influenza pandemic, remains a global threat. A recent phase I clinical trial investigating a ferritin nanoparticle displaying H2 hemagglutinin in H2-naïve and H2-exposed adults. Therefore, we could perform comprehensive structural and biochemical characterization of immune memory on the breadth and diversity of the polyclonal serum antibody response elicited after H2 vaccination. We temporally map the epitopes targeted by serum antibodies after first and second vaccinations and show previous H2 exposure results in higher responses to the variable head domain of hemagglutinin while initial responses in H2-naïve participants are dominated by antibodies targeting conserved epitopes. We use cryo-EM and monoclonal B cell isolation to describe the molecular details of cross-reactive antibodies targeting conserved epitopes on the hemagglutinin head including the receptor binding site and a new site of vulnerability deemed the medial junction. Our findings accentuate the impact of pre-existing influenza exposure on serum antibody responses.

Highlights

Serum Abs after first H2-F vaccination in H2-exposed donors bound variable HA head epitopes

Serum Abs after first H2-F vaccination in H2-naïve donors bound conserved HA head and stem epitopes

RBS-targeting VH1-69 cross-reactive antibodies were induced in H2-naïve individuals

The medial junction is a previously uncharacterized conserved epitope on the HA head
Deep proteome analysis of time-series human plasma samples applied to Covid-19 antibody test
Authors: Fukuda Tetsuya , Nakayama Aya , Chikaoka Yoko , Bando Yasuhiko , Kawamura Takeshi
Published: August 2023

For the purpose of Covid-19 antibody testing, the human plasma samples acquired over a period of 310 days from August 18, 2021, to June 22, 2022, were subjected to DIA LC-MS proteome analysis. This process led to the acquisition of a quantitative protein profile and allowed for the validation of the temporal behavior of expressed proteins within the samples. A total of 1502 proteins were identified from the plasma samples. Before vaccination, after the first dose, after the second dose, and during the period after contracting the novel coronavirus, protein quantification values during each event interval were compared. Despite minimal changes observed before and after Covid-19 vaccination, notable proteins exhibiting distinct high-expression and low-expression patterns were identified after contracting the novel coronavirus infection.
Collective Almost Synchronization Modeling Used for Motor Imagery EEG Classification
Authors: Phuong Nguyen Thi Mai , Phan Minh Khanh , Hayashi Yoshikatsu , Baptista Murilo S. , Kondo Toshiyuki
Published: August 2023

Classification based on feature extraction is a crucial technique to develop Brain Computer Interface (BCI) systems. The human brain can be considered as a dynamical system, and its behavior measured by EEG signals can be modeled by a group of nonlinear oscillators. Exploring the dynamical nature of EEG signals along with model based approach may improve classification accuracy in BCI. This study proposes a novel feature extraction method for the classification of Motor Imagery (MI) EEG using a dynamical network model operating in a special collective state, so called Collective Almost Synchronization (CAS). The CAS, the nonlinear oscillators set to operate in a weakly coupled regime, can be used to model an EEG. Purpose of this study is to investigate the performance of the CAS model to identify features for the classification of MI states. To achieve this goal, a linear regression method is used and linear coefficients are extracted as feature vectors. Our approach boils down to identifying patterns in the MI-EEG by associating them to the coefficients of a linear regression (or weights of an output function) constructed to model the MI-EEG signals from simulated time-series generated by a dynamical neural network. The dataset 2b from BCI Competition-IV was used to evaluate the performance of the proposed method. Results indicate that the CAS-based classification method is more robust in extracting distinguishable features from EEG signals as compared with other state-of-the-art methods. The proposed method achieved better performance on two-class MI classification. Moreover, the method developed in this study for MI classification across subjects is effective with 74.03% of the accuracy.
Hypertension Trends and Disparities over Twelve Years in a Large Health System: Leveraging the Electronic Health Records
Authors: Brush John E. , Lu Yuan , Liu Yuntian , Asher Jordan R. , Li Shu-Xia , Sawano Mitsuaki , Young Patrick , Schulz Wade L. , Anderson Mark , Burrows John S. , Krumholz Harlan M.
Published: August 2023

Background

The digital transformation of medical data enables health systems to leverage real-world data (RWD) from electronic health records (EHR) to gain actionable insights for improving hypertension care.

Methods

We performed a serial cross-sectional analysis of outpatients of a large regional health system from 2010 to 2021. Hypertension was defined by systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg) or recorded treatment with anti-hypertension medications. We evaluated four methods of using blood pressure measurements in the EHR to define hypertension.

The primary outcomes were age-adjusted prevalence rates and age-adjusted control rates. Secondary outcomes were age-adjusted mean SBP and DBP and age-adjusted proportion of patients with a searchable diagnosis code of hypertension in the EHR.

Results

Hypertension prevalence varied depending on the definition used, ranging from 36.5% to 50.9% initially and increasing over time by approximately 5%, regardless of the definition used. Control rates ranged from 61.2% to 71.3% initially, rose during 2018-2019 and fell during 2020-2021. The proportion of patients with a hypertension diagnosis ranged from 45.5% to 60.2% initially and improved during the study period. Non-Hispanic Black patients represented 25% of our regional population and consistently had higher prevalence rates, higher mean SBP and DBP and lower control rates compared with other racial and ethnic groups.

Conclusion

In a large regional health system, we leveraged the EHR to provide real-world insights. The findings largely reflected national trends but showed distinctive regional demographics and findings. The findings have provided opportunities for improvement, with prevalence increasing, a quarter of the patients not controlled, and marked disparities. This approach could be emulated by regional health systems seeking to improve hypertension care.

Key Points

Question:Can a large regional health system leverage the electronic health record to analyze hypertension trends and disparities to drive improvement?

Findings:We analyzed 1,376,325 patients over 12 years and found that age-adjusted hypertension prevalence increased by approximately 5%. Age-adjusted hypertension control rates were in the 70% range and remained stable. Non-Hispanic Black patients represented 25% of our specific regional population and had 12-14% higher hypertension prevalence rates, higher mean age-adjusted systolic and diastolic blood pressure, and lower hypertension control rates compared with other racial groups.

Meaning:Real world data can provide actionable insights about hypertension and disparities in a specific region that could inform regional system strategies and initiatives for improvement.
Exploring the gut virome in fecal immunochemical test stool samples reveals novel associations with lifestyle in a large population-based study
Authors: Istvan Paula , Birkeland Einar , Avershina Ekaterina , Kværner Ane S , Bemanian Vahid , de Vos Willem M. , Rognes Torbjørn , Berstad Paula , Rounge Trine B
Published: August 2023

Stool samples for fecal immunochemical tests (FIT) are collected in large numbers worldwide as part of colorectal cancer screening programs, but to our knowledge, the utility of these samples for virome studies is still unexplored. Employing FIT samples from 1034 CRCbiome participants, recruited from a Norwegian colorectal cancer screening study, we identified and annotated more than 18000 virus clusters (vOTUs), using shotgun metagenome sequencing. Only six percent of vOTUs were assigned to a known taxonomic family, withMicroviridaebeing the most prevalent viral family. Genome integration state was family-associated, and the majority of identified viruses were unintegrated. Linking individual profiles to comprehensive lifestyle and demographic data showed 17/25 of the variables to be associated with the gut virome. Physical activity, smoking, and dietary fiber consumption exhibited strong and consistent associations with both diversity and relative abundance of individual vOTUs, as well as with enrichment for auxiliary metabolic genes.

We demonstrate the suitability of FIT samples for virome analysis, opening an opportunity for large-scale studies of this yet enigmatic part of the gut microbiome. The diverse viral populations and their connections to the individual lifestyle uncovered herein paves the way for further exploration of the role of the gut virome in health and disease.