bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effectiveness of Serial Casting in the Treatment of Recurrent Equinovarus in Children With Arthrogryposis
Authors: Church Chris , Bourantas Christina , Butler Stephanie , Salazar-Torres Jose J. , Henley John , Donohoe Maureen , Miller Freeman , Nichols L. Reid Boyce
Published: January 2023

Background:

Arthrogryposis multiplex congenita (AMC) is characterized by joint contractures in 2 or more body areas, often resulting in clubfoot deformities that are typically stiffer than those seen in idiopathic clubfoot deformities. While surgery is routinely used to treat clubfoot in AMC, it has a high rate of recurrence and complications. Current literature suggests serial casting (SC) could be useful in treating clubfoot in AMC, though evidence of its effectiveness is limited.

Methods:

Passive range of motion (PROM), dynamic foot pressure, parent-reported Pediatric Outcomes Data Collection Instrument, brace tolerance, and the need for post-casting surgery were evaluated retrospectively in children with AMC treated with SC to address clubfoot deformities. Analysis of variance or paired t tests were used as appropriate on pre-casting, short-term (within 6 mo after SC) and/or longer-term (6 to 18 mo after SC) parameters to determine the effectiveness of SC. Brace tolerance before and after SC was analyzed using the Global Test for Symmetry, and medical records were reviewed to determine the need for surgery post-SC.

Results:

Forty-six children (6.1±3.1 y old) were cast an average of 2.5±1.9 times, resulting in 206 SC episodes. PROM showed improvement in ankle dorsiflexion and forefoot abduction in the short term (P<0.05), returning to baseline measurements in the long term (P=0.09). Brace tolerance improved after casting (P<0.05). Only 15% of feet required surgery at follow-up at 10.3±5.5 years. There were no significant changes in dynamic foot pressure or Pediatric Outcomes Data Collection Instrument results after SC, except for an increase in the pain subtest (P<0.05).

Conclusions:

Serial casting in children with AMC can be effective in temporarily improving PROM and improving brace tolerance, but it does not impact dynamic barefoot position. Positive impact of conservative management in children with AMC can potentially delay or reduce the need for invasive surgical intervention by improving PROM and brace tolerance.

Level of Evidence:

Level III, Retrospective Comparative Study.
Surgical Management of Severe Equinus Deformity in Ambulatory Children With Cerebral Palsy
Authors: Soufi Khadija , Bagley Anita , Brown Sean A. , Westberry David E. , Kulkarni Vedant A. , Saraswat Prabhav , Davids Jon R.
Published: January 2023

Background:

Tendo Achilles lengthening (TAL) for the management of equinus contractures in ambulatory children with cerebral palsy (CP) is generally not recommended due to concerns of over-lengthening, resulting in weakness and plantar flexor insufficiency. However, in some cases, surgical correction of severe equinus deformities can only be achieved by TAL. The goal of this study is to assess the outcomes following TAL in these cases.

Methods:

A retrospective cohort study of children with CP with severe equinus contractures (ankle dorsiflexion with the knee extended of -20 degrees or worse) who underwent TAL as part of a single event multilevel surgery, with preoperative and postoperative gait analysis studies. Continuous data were analyzed by paired t test, and categorical data by McNemar Test.

Results:

There were 60 subjects: 42 unilateral, 18 bilateral CP; 41 GMFCS II, 17 GMFCS I; mean age at surgery was 10.6 years, mean follow-up was 1.3 years. Ankle dorsiflexion with the knee extended improved from −28 to 5 degrees (P<0.001). The ankle Gait Variable Score improved from 34.4 to 8.6 (P<0.001). The ankle moment in terminal stance improved from 0.43 to 0.97 Nm/kg (P<0.001). Significant improvements (P<0.001) were seen in radiographic measures of foot alignment following surgery. There were few significant differences in the outcome parameters between subjects with unilateral versus bilateral CP (eg, only the bilateral group showed improved but persistent increased knee flexion in mid-stance).

Conclusions:

The outcomes following TAL for the management of severe equinus deformity in ambulatory children with CP were favorable 1 year after surgery, with significant improvements in all domains measured.

Significance:

This study does not advocate for the widespread use of TAL to correct equinus deformity in children with CP. However, it does show that good short-term outcomes following TAL are possible in properly selected subjects with severe contractures when the dosing of the surgery is optimal (correction of contracture to between 0 and 5 degrees of dorsiflexion with the knee extended) and the procedure is performed in the setting of single event multilevel surgery with subsequent proper orthotic management and rehabilitation.
Gait Analysis Characteristics in Relapsed Clubfoot
Authors: Bent Melissa , Hauschild Maia , Rethlefsen Susan A. , Wren Tishya A.L. , Liang Adriana , Goldstein Rachel Y. , Kay Robert M.
Published: January 2023

Background:

Relapse rates of clubfoot deformity after initial correction range between 19% and 68% regardless of treatment approach. Most studies focus on relapse before age 4. Little research has focused on late clubfoot relapse. The purpose of this study was to compare the gait characteristics of children with late clubfoot relapse (age ≥5 y) following treatment with the Ponseti method only compared with intra-articular and extra-articular surgeries.

Methods:

A retrospective review was conducted of all patients with idiopathic clubfoot ≥5 years old who underwent computerized gait analysis for clubfoot relapse between 2001 and 2021. Joint range of motion, muscle strength, gait kinematics, and kinetics were compared among 3 groups based on prior clubfoot treatment: (1) Ponseti casting, (2) Extra-articular (EA) surgery, and (3) Intra-articular (IA) surgery.

Results:

Sixty-eight subjects (107 feet) were included (39 bilateral). Thirty-one percent of feet had been treated with Ponseti casting alone; 57% had IA surgery, and 12% had EA surgery. The average age when presenting with late relapse was 8.2 years, 9.0 years and 10.7 years for the Ponseti, and IA and EA groups, respectively. The IA group had greater passive dorsiflexion than the other 2 groups (P<0.002), greater inversion weakness than the other 2 groups (P<0.0001), greater dorsiflexion during the stance phase of gait compared with the Ponseti group (P=0.001), and lower maximum power production at push-off compared with the other 2 groups (P=0.009).

Conclusion:

Late relapse can occur after all types of clubfoot correction. Consistent with existing literature, patients who have undergone posteromedial release surgery have significantly greater plantarflexor weakness resulting in poorer plantarflexor moment and power production during gait.

Level of Evidence:

Level III, retrospective comparative study.
Subjective Ratings of Mental and Physical Health Correlate With EQ-5D-5L Index Values in Survivors of Critical Illness: A Construct Validity Study*
Authors: Paul Nicolas , Cittadino Jonas , Weiss Björn , Krampe Henning , Denke Claudia , Spies Claudia D.
Published: January 2023

Objectives:

Survivors of critical illness commonly show impaired health-related quality of life (HrQoL). We investigated if HrQoL can be approximated by brief, easily applicable items to be used in primary care.

Design:

Secondary analysis of data from the multicenter, cluster-randomized controlled Enhanced Recovery after Intensive Care trial (ClinicalTrials.gov: NCT03671447) and construct validity study.

Setting:

Ten participating clusters of ICUs in the metropolitan area of Berlin, Germany.

Patients:

Eight hundred fifty ICU survivors enrolled in a mixed, medical or surgical ICU when they had an expected ICU length of stay of at least 24 hours, were at least 18 years old, and had statutory health insurance coverage.

Interventions:

None.

Measurements and Main Results:

Patients received follow-ups scheduled 3 and 6 months after ICU discharge. HrQoL was assessed with the EuroQol 5-Dimension 5-Level (EQ-5D-5L), and patients were asked to rate their current mental and physical health state from 0 (worst) to 10 (best). We fitted prediction models for the EQ-5D-5L index value using these two items and additional covariates, applying stepwise regression and adaptive lasso. Subjective mental health (Spearman: 0.59) and subjective physical health (Spearman: 0.68) correlated with EQ-5D-5L index values and were better predictors of EQ-5D-5L index values in the two-item regression (normalized root mean squared error [nRMSE] 0.164; normalized mean absolute error [nMAE] 0.118; R
2
adj 0.43) than the EQ-5D Visual Analog Scale (nRMSE 0.175; nMAE 0.124; R
2
adj 0.35). Stepwise regression with additional covariates further increased prediction performance (nRMSE 0.133; nMAE 0.1; R
2
adj 0.51).

Conclusions:

Asking patients to rate their subjective mental and physical health can be an easily applicable tool for a first impression of the HrQoL in primary care settings.
A Review of Radon Exposure in Non-uranium Mines—Estimation of Potential Radon Exposure in Canadian Mines
Authors: Chen Jing
Published: January 2023

A worldwide review of radon exposure in non-uranium mines was conducted. Based on the reported radon measurements in a total of 474 underground non-uranium mines, the average radon concentration in underground non-uranium mines was calculated to be 570 Bq m−3 (varied from below detection limit to above 10,000 Bq m−3), and the average equilibrium factor between radon and its short-lived progeny was 0.34 (varied from 0.02 to 0.9). Using the average values from the review, annual effective radon doses to workers in Canadian non-uranium mines were estimated. For underground workers, the estimated annual effective radon dose to non-uranium miners was 3.8 mSv with the possibility of varying from 0.22 to 10 mSv depending on ventilation and other operation conditions. In Canada, the majority of mines are open-pit surface mines; only a small portion of the workforce in non-uranium mines physically work underground where radon concentration can be elevated. Averaged over the entire mining workforce, occupational exposure to radon in non-uranium mines is estimated to be 0.9 mSv. The results of this study indicate that there is potential for workers in non-uranium mines to reach or exceed Canadian thresholds for mandatory monitoring and reporting radiation doses, at least for underground operations.
Clinical Implications of the Neurosteroid Allopregnanolone in Reproductive Depression
Authors: Susser Leah C.
Published: January 2023

Certain women develop depression with fluctuations in hormone levels whereas other women do not; this hormonally driven depression has been termed reproductive depression. The pathophysiology of reproductive depression differs from that of major depressive disorder, and this distinction has important clinical—including treatment—implications. Recent advances have revealed that the neurosteroid, allopregnanolone, plays a central role in reproductive depression. Appreciation of allopregnanolone’s role in reproductive depression aids in selecting targeted treatments and in predicting symptom worsening during subsequent reproductive stages, and it can be used to reduce risk of relapse. This knowledge is also guiding the development of new pharmacologic treatments for reproductive depression.
Sleep Variability in UK Long Distance Heavy Goods Vehicle Drivers
Authors: Sherry Aron Peter , Clemes Stacy A. , Chen Yu-Ling , Edwardson Charlotte L. , Gray Laura J. , Guest Amber , King James A. , Rowlands Alex V. , Ruettger Katharina , Sayyah Mohsen , Varela-Mato Veronica , Hartescu Iuliana
Published: January 2023

Objectives

Sleep variability levels are unknown in heavy goods vehicle (HGV) drivers yet are associated with adverse health outcomes and reduced driver vigilance when high.

Methods

Two hundred and thirty-three HGV drivers recruited across 25 UK depots provided sleep variability, sleep duration, and sleep efficiency data via wrist-worn accelerometry (GENEActiv) over 8 days. Sleep variability indicators included social jetlag (the difference in midpoint of the sleep window between work and nonworkdays) and intraindividual variability of sleep window onset time, out-of-bed time, and sleep duration.

Results

Fifty-three percent of drivers experienced social jetlag (≥1 hour), and 27% experienced high (>2 hours) social jetlag. Drivers with the highest sleep variability had the shortest sleep duration and lowest sleep efficiency during workdays.

Conclusions

Drivers with high sleep variability may experience more fatigue when driving given the poor sleep outcomes during workdays observed.
Population attributable fraction estimates of cardiovascular diseases in different blood pressure levels in a large-scale cross-sectional study: a focus on prevention strategies and treatment coverage
Authors: Keykhaei Mohammad , Rezaei Negar , Roshani Shahin , Montazeri Fateme , Nasserinejad Maryam , Azadnajafabad Sina , Mohammadi Esmaeil , Ghasemi Erfan , Rezaei Nazila , Farrokhpour Hossein , Foroumadi Roham , Bagheri Sayna , Moghimi Mana , Larijani Bagher , Farzadfar Farshad
Published: January 2023

Objective

Hypertension is one of the major modifiable risk factors in developing cardiovascular diseases (CVD). Hence, we aimed to ascertain age- and sex-specific population attributable fraction (PAF) for CVD in different blood pressure levels to implement efficient preventive strategies at the population level.

Methods

Participants’ data were obtained from the Iranian stepwise approach for surveillance of noncommunicable disease risk factors (STEPs) survey to calculate PAF in four subsequent phases. In phase 0, PAF was measured, irrespective of the diagnosis status. In phase 1, the theoretical minimum range of 115 ≤SBP less than 130 mmHg was considered as the low-risk and measurements equal to or higher than 130 mmHg as the high-risk group. Across phase 2, patients were divided into normal and hypertensive groups based on the American College of Cardiology/American Heart Association guideline. In phase 3, patients were divided into two categories based on treatment coverage.

Results

A total number of 27 165 participants aged ≥25 years had valid blood pressure measurements and were enrolled. Phase 0: PAF generally had an upward trend with age advancing. Phase 1: participants with BP ≥130 mmHg comprised the largest PAF, extending from 0.31 (0.25–0.37) in older male individuals to 0.85 (0.79–0.91) in younger females. Phase 2: higher values were found in younger ages for hypertension. Phase 3 represented that attributable fractions among hypertensive patients who received treatment were much lower than drug-naïve hypertensive participants.

Conclusion

Our study enlightens the necessity for implementing effective screening strategies for the younger generation and providing adequate access to antihypertensive medications for the low-risk population.
Variability of blood pressure response to orthostatism and reproducibility of orthostatic hypotension in hospitalized patients with acute ischemic stroke
Authors: Huang Hui , Wu Bin , Liu Li , Tang Xianbi , Yi Ziwei , Zeng Ling , Jing Kaiquan , Pan Chuzheng
Published: January 2023

Objective

Orthostatic hypotension (OH) which diagnosis is based on the measurement of the blood pressure response to orthostatism (BPRO) is a common condition associated with adverse cerebrovascular and cognitive prognosis. It is likely that the single measurement might underestimate the true prevalence of OH. This study investigated the prevalence and reproducibility of the diagnosis of OH and related risk factors in hospitalized acute ischemic stroke (AIS) patients with multiple measurements.

Materials and methods

This study was a prospective cohort analysis of consecutive AIS patients admitted to the hospital. A total of 211 patients were included. BPRO was assessed five times at the same time on different days.

Results

OH was found in 33 cases (15.6%) in the initial set of measurements of the first day. A cumulative diagnosis of OH after five BPRO tests was found in 75 cases (35.5%). The reproducibility of the diagnosis of OH was mild or poor. In patients with a cumulative diagnosis of OH, 29 (38.7%) patients had orthostatic hypertension (OHTN). In multivariate analysis, the Fazekas scale (odds radio = 1.28, 95% confidence interval (CI), 1.04–1.59, P = 0.023) and extracranial carotid stenosis (≥70%) (odds radio = 3.64, 95% CI, 1.19–11.13, P = 0.023) were independent risk factors for OH.

Conclusion:

The reproducibility of OH is poor and the concurrent appearance of OH and OHTN is common in hospitalized AIS patients. Multiple measurements should be taken in hospitalized AIS patients when screening for OH especially patients with higher Fazekas scale and extracranial carotid stenosis (≥70%).
Efficacy of Low-Dose Versus Traditional Buprenorphine Induction in the Hospital: A Quantitative and Qualitative Study
Authors: Sulakvelidze Nika , Ronan Clare , Peterkin Alyssa F. , Weinstein Zoe M.
Published: January 2023

Background:

Emerging evidence suggests low-dose buprenorphine (LDB) induction can expand opportunities for buprenorphine induction in patients who are taking taking methadone, short-acting opioid agonists, or who have anxiety about opioid withdrawal.

Study Question:

How is a rapid LDB protocol using transdermal buprenorphine tolerated in the hospital?

Study Design:

A prospective study of 20 patient encounters (n = 20 patients) with traditional buprenorphine induction before implementation of study protocol (control group) and 37 patient encounters (n = 34 patients) with LDB induction protocol (pilot group). Summary statistics were used to describe demographics, clinical opioid withdrawal scale and pain scores within 24 hours preprotocol and within 24 hours postprotocol initiation, hospital length of stay after protocol initiation, receipt of a buprenorphine prescription at discharge, and prescription activity at 30 days. T test and chi-square tests were used to analyze comparisons. A subset of pilot group patients completed a survey about their experience.

Results:

There were no statistically significant differences in pain and clinical opioid withdrawal scale scores between the pilot and control groups. There were 5 instances of precipitated withdrawal in the pilot group. There was no statistically significant difference in mean discharge time after protocol initiation between the pilot and control groups (P = 0.60). Most patients surveyed described a positive experience with LDB induction.

Conclusion:

Hospitalization is a critical time to initiate buprenorphine for patients with opioid use disorder. Our data adds to the growing evidence that LDB induction is feasible for patients taking methadone and short-acting opioid agonists, and that a more rapid induction protocol is generally well-tolerated by patients although precipitated withdrawal is a risk. Finally, our rapid induction protocol did not seem to increase hospital length of stay compared with traditional induction.
What is the cost, impact, and willingness to pay for an Amputee Peer Support Program?
Authors: Brusco Natasha K. , Foster Sarah , Noonan Melissa , Waugh Fiona , Warren Narelle
Published: January 2023

Background:

The provision of peer support from those who have already made positive adjustments to amputation is recommended for people incurring a major limb amputation; however, few receive this service.

Objective:

From a program perspective, determine the cost, impact, and willingness to pay for an Amputee Peer Support Program.

Study design:

Cost analysis.

Methods:

Cost of the Amputee Peer Support Program included a cost analysis of program data over a 5-year time horizon (2013–2018) reported in Australian Dollars 2018/2019. Impact and willingness to pay for an Amputee Peer Support Program was determined through surveys of the 3 participant groups: referring health professionals, program volunteers, and program participants.

Results:

Over 5 years, there were 793 program participants, serviced by 256 program volunteers, for a cost of $631,497. The cost per program participant was $796. Thirty-eight health professionals, 86 program volunteers, and 12 program participants reported on impact and willingness to pay. The Program was reported to have a positive impact on all participant groups. The themes of access to resources and information and the provision of social and emotional well-being were identified across all 3 groups as being important. All 3 groups reported a higher willingness to pay for the health service (range $113–$450), National Disability Insurance Scheme ($156–$432), and private health insurance ($153–$347), and a lower willingness to pay for the program participant ($23–$49).

Conclusion:

Amputee peer support had a positive impact on those receiving and providing the service. Amputee peer support is likely to be a powerful yet inexpensive addition to routine care.
Inverted FDG Uptake Pattern in Subcutaneous Panniculitis-Like T-Cell Lymphoma
Authors: Koyasu Sho , Sugimoto Akihiko , Nakamoto Yuji
Published: January 2023

A 47-year-old woman presented with a 2-month history of subcutaneous nodules, erythema, and fever. 18F-FDG PET images demonstrated inverted FDG uptake pattern corresponding to the subcutaneous lesion against lymph nodes. The specimen of the inguinal lesion showed massive infiltration of small lymphocytes in the adipose tissue with rimming adipocytes, whereas very few tumor cells infiltrated the lymph nodes. Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) was diagnosed. SPTCL normally shows quite interesting distribution of tumor cells, that is, lymph node involvement is usually absent. Therefore, this case highlighted the importance of the inverted accumulation pattern on FDG PET to suspect SPTCL.
Unintentional Intra-arterial Injection of 177Lu-PSMA-1 in a Patient With a Peritoneal Carcinosis Secondary to a Metastatic Prostate Cancer
Authors: Kryza David , Moreau Aurélie , Badel Jean Noël , Mognetti Thomas , Giraudet Anne Laure
Published: January 2023

We report the case of an 81-year-old man presenting with peritoneal carcinosis secondary to a metastatic castrate-resistant prostate cancer addressed for 177Lu-PSMA-1 therapy. During the second cycle, a diffuse uptake in his left forearm was observed on the 1-hour postinjection scintigraphy, typical for an accidental intra-arterial injection. Less than 24 hours postinjection, a full removal of the intra-arterial injection was observed in the man, without any pain or symptoms. Moreover, the man demonstrated an 85% PSA reduction and a CT OR following the RECIST 1.1 criteria after 3 cycles.
Progressive Transformation of Germinal Centers Simulating Malignant Axillary Lymphadenopathy in a Breast Cancer Patient on FDG PET/CT
Authors: Hod Nir , Nalbandyan Karen , Porges Tzvika , Lantsberg Sophie
Published: January 2023

A 64-year-old woman with breast cancer underwent FDG PET/CT for follow-up. The study revealed highly increased FDG uptake in newly diagnosed enlarged axillary lymph nodes, which were worrisome for malignancy. Histopathology revealed a rarely diagnosed benign disease of progressive transformation of germinal centers mimicking malignant lymphadenopathy. As imaging findings of this entity, which usually involves the axillary and cervical areas, have been reported in very few studies, nuclear medicine physicians should be familiar with this potential “false-positive” FDG uptake representing an interpretative pitfall, especially during evaluation of breast cancer patients.
68Ga-DOTAGA-IAC PET/CT for Imaging Metastatic and Recurrent Adrenocortical Carcinoma
Authors: Pandey Somit , Walia Rama , Kumar Rajender , Chopra Sejal , Rana Nivedita , Chatterjee Debajyoti , Satz Stanley , Mittal Bhagwant Rai , Shukla Jaya
Published: January 2023

Adrenocortical carcinoma (ACC) is a rare malignancy with a prevalence of 1 to 2 cases/million/year. The diagnosis depends upon endocrine workup followed by imaging with CT, MRI, and 18F-FDG PET/CT. The treatment includes surgical resection, debulking surgery, chemotherapy, and radiotherapy. However, patients do not respond well to any of the available therapies. We present noninvasive imaging of histopathology-proven ACC patients using 68Ga-DOTAGA-IAC PET/CT, specific for integrin αvβ3. 68Ga-DOTAGA-IAC PET/CT 45 minutes after IV injection showed a decent tumor-to-background ratio and could be used as a promising radiotracer for metastatic and recurrent ACC.
Aortitis PET Imaging in VEXAS Syndrome
Authors: Grambow-Velilla Julia , Braun Thorsten , Pop Gabriel , Louzoun Astrid , Soussan Michael
Published: January 2023

VEXAS (vacuoles, E1 enzyme, X-LINKED, autoinflammatory, somatic) syndrome is a complex inflammatory disease associated with somatic mutations of the ubiquitin-like modifier activating enzyme 1 (UBA1) gene. A 75-year-old man with a medical history of thrombophlebitis, leukocytoclastic vasculitis, chronic inflammatory arthralgia, elevated inflammatory markers, and anemia was diagnosed with VEXAS syndrome. 18F-FDG PET/CT showed thoracic aortitis, a rare involvement during VEXAS syndrome. Corticosteroid therapy monitored with 18F-FDG PET/CT led to a complete metabolic response.
Allopurinol and ellagic acid decrease epileptiform activity and the severity of convulsive behavior in a model of status epilepticus
Authors: Pardo-Peña Kenia , Medina-Ceja Laura , Martínez-Gallegos Salvador , Sánchez-Lira Ana
Published: January 2023

Background

During status epilepticus, severe seizures can occur, generating recurrent cycles of excitotoxicity and oxidative stress that cause neuronal damage and cell death. The administration of agents with antioxidant properties represents a therapeutic alternative aimed at reducing the severity of status epilepticus and mitigating the neurobiological consequences that precede them.

Objective

The objective of this work was to evaluate the antiseizure effect of the antioxidants allopurinol (ALL) and ellagic acid during status epilepticus induced by pilocarpine (PILO).

Methods

Male Wistar rats (200–250 g) were injected with ALL (50 mg/kg) or ellagic acid (50 mg/kg), 30 min before PILO administration (pretreatment) or 60 min after the beginning of status epilepticus, to evaluate the antiseizure effect of these drugs on epileptiform activity and convulsive behavior.

Results

ALL or ellagic acid administration before or after PILO significantly decreased the epileptiform activity and the severity of convulsive behavior. Better efficacy was observed when the drugs were administered as a pretreatment, increasing the latency time of the appearance of status epilepticus from 27.2 ± 2.6 to 45.8 ± 3.31 min, and significantly reducing the amplitude of epileptiform discharges by 53.5% with ALL and 68.9% with ellagic acid.

Conclusion

The antioxidants ALL and ellagic acid showed an antiseizure effect, representing an alternative to reduce epileptiform activity and severity of convulsive behavior during status epilepticus, an effect that may be used as adjuvants to mitigate or reduce oxidative damage processes.
Artificial nanovesicles for dsRNA delivery in spray induced gene silencing for crop protection
Authors: Qiao Lulu , Niño-Sánchez Jonatan , Hamby Rachael , Capriotti Luca , Chen Angela , Mezzetti Bruno , Jin Hailing
Published: January 2023

Spray-Induced Gene Silencing (SIGS) is an innovative and eco-friendly technology where topical application of pathogen gene-targeting RNAs to plant material can enable disease control. SIGS applications remain limited because of the instability of dsRNA, which can be rapidly degraded when exposed to various environmental conditions. Inspired by the natural mechanism of crosskingdom RNAi through extracellular vesicle trafficking, we describe herein the use of artificial nanovesicles (AVs) for dsRNA encapsulation and control against the fungal pathogen,Botrytis cinerea. AVs were synthesized using three different cationic lipid formulations, DOTAP + PEG, DOTAP, and DODMA, and examined for their ability to protect and deliver dsRNA. All three formulations enabled dsRNA delivery and uptake byB. cinerea. Further, encapsulating dsRNA in AVs provided strong protection from nuclease degradation and from removal by leaf washing. This improved stability led to prolonged RNAi-mediated protection againstB. cinereaboth on pre- and post-harvest plant material using AVs. Specifically, the AVs extended the protection duration conferred by dsRNA to 10 days on tomato and grape fruits and to 21 days on grape leaves. The results of this work demonstrate how AVs can be used as a new nanocarrier to overcome dsRNA instability in SIGS for crop protection.
Oral Azvudine (FNC) Tablets in Patients infected with SARS-CoV-2 Omicron Variant: A Retrospective Cohort Study
Authors: Chen Wenmei , Xu Honggang , Hong Lei , Yang Ran , Peng Caiqiu , Wang Guiqiang , Li Wei
Published: January 2023

Background

There is a lack of data on the efficacy of oral Azvudine in Coronavirus Disease treatment. This study aimed to assess the association between Azvudine treatment and clinical outcomes in a cohort of patients infected with the SARS-CoV-2 Omicron variant.

Methods

This is a retrospective study conducted in two mobile cabin hospitals. All consecutive patients with a diagnosis of COVID-19 admitted from August to October 2022 were included in the study. Linear regression models and Cox proportional hazards models were used to assess the association between Azvudine treatment and time to obtain the first negative nucleic acid test results.

Results

A total of 207 patients were analyzed, of whom 166 patients (80.2%) received Azvudine treatment after hospitalization, and the rest did not. Linear regression models showed that Azvudine treatment was associated with reduced time to obtain the first negative nucleic acid test results after adjusting for age and gender [mean difference = −1.658; 95% CI: −2.772 to −0.544, P = 0.0039]. The multivariable Cox analysis conforms to the results from the linear regression model (hazard ratio = 1.461; 95% CI: 1.01 to 2.11, P = 0.044).

Conclusion

Azvudine treatment was associated with reduced virus shedding time. Further studies are needed to confirm our findings.
The impact of central and obstructive respiratory events on cerebral oxygenation in adults with sleep disordered breathing
Authors: Khatami Ramin , Gnaiger Dominik , Hügli Gordana , Qi Ming , Zhang Zhongxing
Published: January 2023

Obstructive (OSA) and central sleep apnea (CSA) are two main types of sleep disordered breathing (SDB). While the changes in cerebral hemodynamics triggered by OSA events have been well studied using near-infrared spectroscopy (NIRS), they are essentially unknown in CSA in adults. Therefore, in this study we compared the changes in cerebral oxygenation between OSA and CSA events in adult patients using NIRS. Cerebral tissue oxygen saturation (StO2) in 13 severe SDB patients who had both CSA and OSA events was measured using frequency-domain NIRS. The changes in cerebral StO2 desaturation and blood volume (BV) in the first hour of natural sleep were compared between different types of respiratory events (i.e., 277 sleep hypopneas, 161 OSAs and 113 CSAs) with linear mixed-effect models controlling for confounders. All respiratory events occurred during non-rapid eye movement (NREM) sleep. We found that apneas events induced greater cerebral desaturations and BV fluctuations compared to hypopneas, but there was no difference between OSA and CSA. These results suggest that cerebral autoregulation in our patients are still capable to counteract the pathomechanisms of apneas, in particularly the negative intrathoracic pressure (ITP) caused by OSA events. Otherwise larger BV fluctuations in OSA compared to CSA should be observed due to the negative ITP that reduces cardiac stroke volume and leads to lower systematic blood supply. Our study suggests that OSA and CSA may have similar impact on cerebral oxygenation during NREM sleep in adult patients with SDB.
Collagen remodeling leads to inflammation-free expansion of periprostatic adipose tissue and promotes prostate cancer progression
Authors: Estève David , Toulet Aurélie , Roumiguié Mathieu , Bu Dawei , Pericart Sarah , Belles Chloé , Manceau Cécile , Houël Cynthia , Ducoux-Petit Manuelle , Van Acker Nathalie , Dauvillier Stéphanie , Jia Yiyue , Franchet Camille , Doumerc Nicolas , Thoulouzan Mathieu , Le Gonidec Sophie , Valet Philippe , Malavaud Bernard , Burlet-Schiltz Odile , Bouloumié Anne , Scherer Philipp E. , Milhas Delphine , Muller Catherine
Published: January 2023

Periprostatic adipose tissue (PPAT) abundance correlates with prostate cancer progression, but the mechanism remains unexplained. Here, we used a statistical approach to define abundant PPAT by normalizing PPAT volume to prostate volume in a cohort of 351 patients with a linear regression model. Applying this definition, we find tumors specifically from patients with abundant PPAT exhibit several hallmarks of aggressiveness, suggesting that PPAT abundance might be used to improve risk stratification. We show that abundant PPAT expands by adipocyte hypertrophy but this does not result in inflammation. Extensive extracellular matrix remodeling, notably of the collagen network, and decreased expression of mechano-sensing proteins in adipocytes explains this inflammation-free expansion by decreasing the mechanical constraints on the adipocytes. Moreover, collagen VI degradation in abundant PPAT is associated with production of endotrophin, a matrikine that promotes cancer progression. We find high levels of endotrophin specifically in the urine of patients with abundant PPAT, indicating the clinical relevance of our findings.

The abundance of periprostatic adipose tissue favors prostate cancer aggressiveness. The increase in extracellular matrix remodeling that occurs in expanded periprostatic fat allows adipocyte hypertrophy without tissue inflammation and generates a matrikine, endotrophin, which favors tumor progression.
The Effects of Histone H2B ubiquitylations and H3K79me3on Transcription Elongation
Authors: Huynh Mai T. , Sengupta Bhaswati , Krajewski Wladyslaw A. , Lee Tae-Hee
Published: January 2023

Post-translational modifications of histone proteins often mediate gene regulation by altering the global and local stability of the nucleosome, the basic gene-packing unit of eukaryotes. We employed semi-synthetic approaches to introduce histone H2B ubiquitylations at K34 (H2BK34ub) and K120 (H2BK120ub) and H3 K79 trimethylation (H3K79me3). With these modified histones, we investigated their effects on the kinetics of transcription elongation by RNA Polymerase II (Pol II) using single-molecule FRET. Pol II pauses at several locations within the nucleosome for a few seconds to minutes, which governs the overall transcription efficiency. We found that H2B ubiquitylations suppress pauses and shorten the pause durations near the nucleosome entry while H3K79me3 shortens the pause durations and increases the rate of RNA elongation near the center of the nucleosome. We also found that H2BK34ub facilitates partial rewrapping of the nucleosome upon Pol II passage. These observations suggest that H2B ubiquitylations promote transcription elongation and help maintain the chromatin structure by inducing and stabilizing nucleosome intermediates and that H3K79me3 facilitates Pol II progression possibly by destabilizing the local structure of the nucleosome. Our results provide the mechanisms of how these modifications coupled by a network of regulatory proteins facilitate transcription in two different regions of the nucleosome and help maintain the chromatin structure during active transcription.
Chronic Changes In Oligodendrocyte Sub-Populations After Middle Cerebral Artery Occlusion in Neonatal Mice
Authors: Frazier Alexandra P. , Mitchell Danae N. , Given Katherine S. , Hunn Genevieve , Burch Amelia M. , Childs Christine R. , Moreno-Garcia Myriam , Corigilano Michael R. , Quillinan Nidia , Macklin Wendy B. , Herson Paco S. , Dingman Andra L.
Published: January 2023

Background

Neonatal stroke is common and causes life-long motor and cognitive sequelae. Because neonates with stroke are not diagnosed until days-months after the injury, chronic targets for repair are needed. We evaluated oligodendrocyte maturity and myelination and assessed oligodendrocyte gene expression changes using single cell RNA sequencing (scRNA seq) at chronic timepoints in a mouse model of neonatal arterial ischemic stroke.

Methods

Mice underwent sixty minutes of transient right middle cerebral artery occlusion (MCAO) on postnatal day 10 (p10) and received 5-ethynyl-2’-deoxyuridine (EdU) on post-MCAO days 3-7 to label dividing cells. Animals were sacrificed 14 and 28-30 days post-MCAO for immunohistochemistry and electron microscopy. Oligodendrocytes were isolated from striatum 14 days post-MCAO for scRNA seq and differential gene expression analysis.

Results

The density of Olig2+EdU+cells was significantly increased in ipsilateral striatum 14 days post-MCAO and the majority of oligodendrocytes were immature. Density of Olig2+EdU+cells declined significantly between 14 and 28 days post-MCAO without a concurrent increase in mature Olig2+EdU+cells. By 28 days post-MCAO there were significantly fewer myelinated axons in ipsilateral striatum. scRNA seq identified a cluster of “disease associated oligodendrocytes (DOLs)” specific to the ischemic striatum, with increased expression of MHC class I genes. Gene ontology analysis suggested decreased enrichment of pathways involved in myelin production in the reactive cluster.

Conclusions

Oligodendrocytes proliferate 3-7 days post-MCAO and persist at 14 days, but fail to mature by 28 days. MCAO induces a subset of oligodendrocytes with reactive phenotype, which may be a therapeutic target to promote white matter repair.
Functional connectivity favors aberrant visual network c-Fos expression accompanied by cortical synapse loss in a mouse model of Alzheimer’s disease
Authors: L’Esperance Oliver J. , McGhee Josh , Davidson Garett , Niraula Suraj , Smith Adam , Sosunov Alexandre A , Yan Shirley Shidu , Subramanian Jaichandar
Published: January 2023

While Alzheimer’s disease (AD) has been extensively studied with a focus on cognitive networks, sensory network dysfunction has received comparatively less attention despite compelling evidence of its significance in both Alzheimer’s disease patients and mouse models. We recently found that neurons in the primary visual cortex of an AD mouse model expressing human amyloid protein precursor with the Swedish and Indiana mutations (hAPP mutations) exhibit aberrant c-Fos expression and altered synaptic structures at a pre-amyloid plaque stage. However, it is unclear whether aberrant c-Fos expression and synaptic pathology vary across the broader visual network and to what extent c-Fos abnormality in the cortex is inherited through functional connectivity. Using both sexes of 4-6-month AD model mice with hAPP mutations (J20[PDGF-APPSw, Ind]), we found that cortical regions of the visual network show aberrant c-Fos expression and impaired experience-dependent modulation while subcortical regions do not. Interestingly, the average network-wide functional connectivity strength of a brain region in wild type (WT) mice significantly predicts its aberrant c-Fos expression, which in turn correlates with impaired experience-dependent modulation in the AD model. Usingin vivotwo-photon andex vivoimaging of presynaptic termini, we observed a subtle yet selective weakening of excitatory cortical synapses in the visual cortex. Intriguingly, the change in the size distribution of cortical boutons in the AD model is downscaled relative to those in WT mice, suggesting that synaptic weakening may reflect an adaptation to aberrant activity. Our observations suggest that cellular and synaptic abnormalities in the AD model represent a maladaptive transformation of the baseline physiological state seen in WT conditions rather than entirely novel and unrelated manifestations.
Prenatal benzene exposure alters offspring hypothalamic development predisposing to metabolic disease in later life
Authors: Koshko Lisa , Scofield Sydney , Debarba Lucas , Stilgenbauer Lukas , Sacla Mikaela , Fakhoury Patrick , Jayarathne Hashan , Perez-Mojica J. Eduardo , Griggs Ellen , Lempradl Adelheid , Sadagurski Marianna
Published: January 2023

The hypothalamus is essential in the regulation of metabolism, notably during critical windows of development. An abnormal hormonal and inflammatory milieu during development can trigger persistent changes in the function of hypothalamic circuits, leading to long-lasting effects on the body’s energy homeostasis and metabolism. We recently demonstrated that gestational exposure to benzene at smoking levels induces severe metabolic dysregulation in the offspring. Given the central role of the hypothalamus in metabolic control, we hypothesized that prenatal exposure to benzene impacts hypothalamic development, contributing to the adverse metabolic effects in the offspring. C57BL/6JB dams were exposed to benzene in the inhalation chambers exclusively during pregnancy (from E0.5 to E19). The transcriptome analysis of the offspring hypothalamus at postnatal day 21 (P21) revealed changes in genes related to metabolic regulation, inflammation, and neurodevelopment exclusively in benzene-exposed male offspring. Moreover, the hypothalamus of prenatally benzene-exposed male offspring displayed alterations in orexigenic and anorexigenic projections, impairments in leptin signaling, and increased microgliosis. Additional exposure to benzene during lactation did not promote further microgliosis or astrogliosis in the offspring, while the high-fat diet (HFD) challenge in adulthood exacerbated glucose metabolism and hypothalamic inflammation in benzene-exposed offspring of both sexes. These findings reveal the persistent impact of prenatal benzene exposure on hypothalamic circuits and neuroinflammation, predisposing the offspring to long-lasting metabolic health conditions.
Goldilocks meets Polycomb
Authors: Verrijzer C. Peter
Published: January 2023

The Polycomb system modulates chromatin structure to maintain gene repression during cell differentiation. Polycomb repression involves methylation of histone H3K27 (H3K27me3) by Polycomb repressive complex 2 (PRC2), monoubiquitylation of H2A (H2Aub1) by noncanonical PRC1 (ncPRC1), and chromatin compaction by canonical PRC1 (cPRC1), which is independent of its enzymatic activity. Puzzlingly, Polycomb repression also requires deubiquitylation of H2Aub1 by Polycomb repressive deubiquitinase (PR-DUB). In this issue ofGenes & Development, Bonnet and colleagues (pp. 1046–1061) resolve this paradox by showing that high levels of H2Aub1 inDrosophilalacking PR-DUB activity promotes open chromatin and gene expression in spite of normal H3K27me3 levels and PRC binding. Pertinently, gene repression is restored by concomitant loss of PRC1 E3 ubiquitin ligase activity but depends on its chromatin compaction activity. These findings suggest that PR-DUB ensures just-right levels of H2Aub1 to allow chromatin compaction by cPRC1.
Whole-genome characterization of myoepithelial carcinomas of the soft tissue
Authors: Cyrta Joanna , Rosiene Joel , Bareja Rohan , Kudman Sarah , Al Zoughbi Wael , Motanagh Samaneh , Wilkes David C. , Eng Kenneth , Zhang Tuo , Sticca Evan , Mathew Susan , Rubin Mark A. , Sboner Andrea , Elemento Olivier , Rubin Brian P. , Imielinski Marcin , Mosquera Juan Miguel
Published: January 2023

Myoepithelial carcinomas (MECs) of soft tissue are rare and aggressive tumors affecting young adults and children, but their molecular landscape has not been comprehensively explored through genome sequencing. Here, we present the whole-exome sequencing (WES), whole-genome sequencing (WGS), and RNA sequencing findings of two MECs. Patients 1 and 2 (P1, P2), both male, were diagnosed at 27 and 37 yr of age, respectively, with shoulder (P1) and inguinal (P2) soft tissue tumors. Both patients developed metastatic disease, and P2 died of disease. P1 tumor showed a rhabdoid cytomorphology and a complete loss of INI1 (SMARCB1) expression, associated with a homozygousSMARCB1deletion. The tumor from P2 showed a clear cell/small cell morphology, retained INI1 expression and strong S100 positivity. By WES and WGS, tumors from both patients displayed low tumor mutation burdens, and no targetable alterations in cancer genes were detected. P2's tumor harbored anEWSR1::KLF15rearrangement, whereas the tumor from P1 showed a novelASCC2::GGNBP2fusion. WGS evidenced a complex genomic event involving mainly Chromosomes 17 and 22 in the tumor from P1, which was consistent with chromoplexy. These findings are consistent with previous reports ofEWSR1rearrangements (50% of cases) in MECs and provide a genetic basis for the loss of SMARCB1 protein expression observed through immunohistochemistry in 10% of 40% of MEC cases. The lack of additional driver mutations in these tumors supports the hypothesis that these alterations are the key molecular events in MEC evolution. Furthermore, the presence of complex structural variant patterns, invisible to WES, highlights the novel biological insights that can be gained through the application of WGS to rare cancers.
Rapid genome sequencing identifies novel variants in complement factor I
Authors: Rodriguez Katherine M. , Vaught Jordan , Dilley Michelle , Ellsworth Kataryzna , Heinen Alaina , Abud Edsel M. , Zhang Yuzhou , Smith Richard J.H. , Sheets Robert , Geng Bob , Hoffman Hal M. , Worthen H. Michael , Dimmock David , Coufal Nicole G.
Published: January 2023

Complement factor I deficiency (CFID; OMIM #610984) is a rare immunodeficiency caused by deficiencies in the serine protease complement factor I (CFI). CFID is characterized by predisposition to severe pneumococcal infection, often in infancy. We report a previously healthy adolescent male who presented with respiratory failure secondary to pneumococcal pneumonia and severe systemic inflammatory response. Rapid genome sequencing (rGS) identified compound heterozygous variants inCFIin the proband, with a novel maternally inherited likely pathogenic variant, a single nucleotide deletion resulting in premature stop (c.1646del; p.Asn549ThrfsTer25) and a paternally inherited novel likely pathogenic deletion (Chr 4:110685580–110692197del).
Molecular Sexing ofNothobranchius furzeriEmbryos and Larvae
Authors: Richter Annekatrin , Krug Johannes , Englert Christoph
Published: January 2023

Differences between the sexes are of increasing interest in basic and applied research with regard to development, behavior, aging, and diseases. Although the African turquoise killifishNothobranchius furzeri, a model for aging research well known for its remarkably short life span, develops strong sexual dimorphism in adulthood, there is no visible indicator of its sex in embryonic and juvenile stages. To address this issue, we developed a molecular sexing assay exploiting two large sequence polymorphisms in the minimal sex-determining region (SDR) ofN. furzeri. These polymorphisms are sequence deletions on the Y chromosome that involve the lack or truncation of one or multiple microsatellites. The simple polymerase chain reaction (PCR) readout of the assays described here allows the sexing ofN. furzeriembryos and larvae in a medium- to high-throughput and cost-efficient manner.
Isolation and Sequencing of NovelVibrioSpecies
Authors: Camilli Andrew
Published: January 2023

Whole-genome sequencing of bacteria facilitates their genotypic analysis and expands our understanding of the tree of life on Earth. TheVibriogenus comprises many halophilic species of bacteria, including some that are pathogenic to humans and other animals. Here I describe methods for isolating and sequencing both known and novel species ofVibriofrom saltwater environments. The first section outlines methods of isolating and phenotypically characterizing strains, followed by purification of their total DNA. The second and third sections outline methods of whole-genome sequencing and assembly, annotation, and phylogenetic analysis.