bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist for vasomotor symptoms: a dose-finding clinical trial (SWITCH-1)
Authors: Simon James A. , Anderson Richard A. , Ballantyne Elizabeth , Bolognese James , Caetano Cecilia , Joffe Hadine , Kerr Mary , Panay Nick , Seitz Christian , Seymore Susan , Trower Mike , Zuurman Lineke , Pawsey Steve
Published: January 2023

Objective

Neurokinin (NK)-3 and NK-1 receptors have been implicated in the etiology of vasomotor symptoms (VMS) and sleep disturbances associated with menopause. This phase 2b, adaptive, dose-range finding study aimed to assess the efficacy and safety of multiple doses of elinzanetant (NT-814), a selective NK-1,3 receptor antagonist, in women experiencing VMS associated with menopause, and investigate the impact of elinzanetant on sleep and quality of life.

Methods

Postmenopausal women aged 40 to 65 years who experienced seven or more moderate-to-severe VMS per day were randomized to receive elinzanetant 40, 80, 120, or 160 mg or placebo once daily using an adaptive design algorithm. Coprimary endpoints were reduction in mean frequency and severity of moderate-to-severe VMS at weeks 4 and 12. Secondary endpoints included patient-reported assessments of sleep and quality of life.

Results

Elinzanetant 120 mg and 160 mg achieved reductions in VMS frequency versus placebo from week 1 throughout 12 weeks of treatment. Least square mean reductions were statistically significant versus placebo at both primary endpoint time points for elinzanetant 120 mg (week 4: −3.93 [SE, 1.02], P < 0.001; week 12: −2.95 [1.15], P = 0.01) and at week 4 for elinzanetant 160 mg (−2.63 [1.03]; P = 0.01). Both doses also led to clinically meaningful improvements in measures of sleep and quality of life. All doses of elinzanetant were well tolerated.

Conclusions

Elinzanetant is an effective and well-tolerated nonhormone treatment option for postmenopausal women with VMS and associated sleep disturbance. Elinzanetant also improves quality of life in women with VMS.
Racial and ethnic differences in aortic stenosis: the tip of the iceberg
Authors: Hassan Syed M. Ali , Ghunaim Abdullah , Verma Raj , Sicilia Amanda , Yanagawa Bobby
Published: January 2023

Purpose of review

There is a lack of data on the epidemiology and management of severe aortic stenosis (AS) in diverse populations. We summarize the contemporary literature on the racial and ethnic differences in AS prevalence, treatment and outcomes and discuss possible explanations for these disparities to inform future research and improve the delivery of care to under-represented patient groups.

Recent findings

African American (AA) patients have significantly less prevalence of severe AS than White patients whereas paradoxically having higher traditional risk factors for severe AS. Non-White patients have less referral for aortic valve replacement (AVR) after adjusting for clinical and echocardiographic parameters. Surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) are both underutilized in non-White patients. Differences in race and ethnicity have not shown to result in worse in-hospital and long-term survival outcomes after either SAVR or TAVR.

Much research is warranted to explore the epidemiology, true prevalence and treatment outcomes of severe AS in diverse populations. Greater inclusion of non-White ethnic groups in the primary analysis of prospective trials is needed. Lastly, further research is warranted to explore the complex causes of racial and ethnic disparities in utilization of surgical and transcatheter interventions.
Radio-adaptive Response Induced by Low-dose Ionizing Radiation in Innate Immunity for Radiotherapy
Authors: Hussien Soha M.
Published: January 2023

Radio-adaptive response (RAR) is a mechanism by which low doses of ionizing radiation (IR) protect cells from subsequent high doses. This study aimed to compare the immuno-radiological effects of 0.25, 0.5, and 5 Gy to 0.25 or 0.5 Gy as priming and 5 Gy as challenging doses. Thirty-five rats were irradiated whole-body with 0.25 and 0.5 Gy followed by 5 Gy, and the same single IR doses with non-irradiated animals serving as controls. Serum interferon-gamma (INF-γ), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), and malondialdehyde (MDA) levels were measured 4 d post both priming and challenge doses. A 0.25-Gy priming dose significantly (P< 0.05) reduced serum TNF-α, MDA, and NO levels compared to all single-irradiated groups. Surprisingly, there was no difference in IFN-γ serum levels between the RAR-induced and non-irradiated groups (P≥ 0.05). Compared to the same low priming dose (0.25 and 0.5 Gy), the effect of the challenging dose (5 Gy) remains unchanged or decreases. Serum IFN-γ, MDA, and NO concentrations, on the other hand, were significantly (P< 0.05) lower in the 0.5 Gy pre-challenging dose, whereas IL1β had no effect (P≥ 0.05) compared to 5 Gy alone. The post-RAR group had significantly (P< 0.05) lower oxidative stress indicators than the other irradiation groups. The findings suggested that priming with low IR could help mitigate the negative effects on the hematopoietic system. Finally, RAR has significantly impacted endogenous cytokines, oxidative stress biomarkers, and lipid peroxidation parameters. RAR can improve patients' radiological safety profiles by mitigating adverse radiotherapy effects.
Electron Paramagnetic Resonance Measurements of Lifetime Doses in Teeth of Durham Region Residents, Ontario
Authors: Ghimire Lekhnath , Waller Edward
Published: January 2023

The Canadian Nuclear Safety Commission (CNSC) and Ontario Power Generation (OPG) determined the total dose contribution of nuclear power plants in Durham Region populations by analyzing environmental samples from the surrounding areas of both nuclear generating stations (Pickering and Darlington). However, the total doses from the various sources were unknown in Durham Region populations, Ontario. Electron paramagnetic resonance (EPR) dosimetry with tooth enamel has been successfully established as an effective tool for gamma dose assessment for chronic and acute exposures in individuals, groups, or populations to reconstruct the absorbed dose down to 30 mGy. This study collected the extracted teeth from people of different ages in Durham Region, Ontario, and analyzed them using the x-band continuous wave (CW) EPR spectrometer. The total dose rate from the natural and anthropogenic sources was 1.9721 mSv y−1. The anthropogenic dose rate from the various sources was 0.6341 mSv y−1, about 47.39% of the natural background dose (1.338 mSv y−1) in Durham Region, Ontario. The combined anthropogenic doses from these sources were lower than the local background dose in Durham Region and lower than the regulatory annual effective dose limit of 1 mSv y−1 in Canada. Based on these data, this study concluded that the anthropogenic dose contribution was lower than the regulatory limit to the local populations.
The Dose Spiking Technique for Measuring Low Doses in Deciduous Teeth Enamel Using EPR Spectroscopy for Retrospective and Accident Dosimetry
Authors: Ghimire Lekhnath , Waller Edward
Published: January 2023

Dose estimation by electron paramagnetic resonance (EPR) has been accomplished using the standard EPR dosimetry technique (ISO protocol 13304-1 for EPR retrospective dosimetry). However, different studies showed that these techniques have high measurement errors in measuring the low doses (10–100 mGy) in enamel. This work proposes a new method to make a dosimetric signal visible and measurable at low doses. The sample was purified using both chemical and mechanical processes. The pure sample mass and position and the EPR acquisition parameters were optimized to enhance the spectrometer's sensitivity for the quantitative low dose measurements. At the same time to reduce errors from the sample and spectrum anisotropy, the total doses (low plus spike) and the spike dose (4 Gy) were measured by rotating 0 to 360 degrees (i.e., 40 degrees at a time) relative to constant magnetic field direction using a goniometer. Subsequently, the spectra were averaged after their g-factor normalization. However, at low doses (<30 mGy), the radiation induced signal (RIS) was obscured by the background signal (BGS). So, the dose spiking technique was used as an alternative method. Ten low-dose deciduous molar tooth enamel (10–100 mGy) samples were spiked to the higher doses by delivering 4 Gy and measured using the X-band continuous wave (CW) EPR (Bruker EMXmicro) spectrometer. The total dose EPR signal was distinctly visible, and the peak-to-peak (P2P) amplitude height was measured. Then, the total dose was subtracted with the spike, often called a reference sample, to determine the initial low doses. The measurement errors using this method were lower than the previous methods. These results demonstrated that this method could be promising for solving low dose measurement problems in EPR dosimetry with deciduous and permanent tooth enamel.
Hematopoietic Cell Autonomous Disruption of Hematopoiesis in a Germline Loss-of-function Mouse Model of RUNX1-FPD
Authors: Ernst Martijn P. T. , Pronk Eline , van Dijk Claire , van Strien Paulina M. H. , van Tienhoven Tim V. D. , Wevers Michiel J. W. , Sanders Mathijs A. , Bindels Eric M. J. , Speck Nancy A. , Raaijmakers Marc H. G. P.
Published: January 2023

RUNX1 familial platelet disorder (RUNX1-FPD) is a hematopoietic disorder caused by germline loss-of-function mutations in the RUNX1 gene and characterized by thrombocytopathy, thrombocytopenia, and an increased risk of developing hematologic malignancies, mostly of myeloid origin. Disease pathophysiology has remained incompletely understood, in part because of a shortage of in vivo models recapitulating the germline RUNX1 loss of function found in humans, precluding the study of potential contributions of non-hematopoietic cells to disease pathogenesis. Here, we studied mice harboring a germline hypomorphic mutation of one Runx1 allele with a loss-of-function mutation in the other Runx1 allele (Runx1

L148A/−
mice), which display many hematologic characteristics found in human RUNX1-FPD patients. Runx1

L148A/−
mice displayed robust and pronounced thrombocytopenia and myeloid-biased hematopoiesis, associated with an HSC intrinsic reconstitution defect in lymphopoiesis and expansion of myeloid progenitor cell pools. We demonstrate that specific deletion of Runx1 from bone marrow stromal cells in Prrx1-cre;Runx1

fl/fl
mice did not recapitulate these abnormalities, indicating that the hematopoietic abnormalities are intrinsic to the hematopoietic lineage, and arguing against a driving role of the bone marrow microenvironment. In conclusion, we report a RUNX1-FPD mouse model faithfully recapitulating key characteristics of human disease. Findings do not support a driving role of ancillary, non-hematopoietic cells in the disruption of hematopoiesis under homeostatic conditions.
Vision rehabilitation in glaucoma patients
Authors: Shi Angell , Salim Sarwat
Published: January 2023

Purpose of review

Vision rehabilitation services are important but underutilized resources for patients with glaucoma. Glaucoma and its impact on vision can affect patients’ abilities to read and drive, two activities of daily living that are associated with quality of life and functional independence. In this review, we provide an overview of low vision, discuss barriers to vision rehabilitation, and outline various strategies and interventions to optimize visual function and quality of life in patients with glaucoma.

Recent findings

Studies have shown that glaucoma negatively impacts reading, driving and overall quality of life. Decreased visual acuity, visual field loss and reduced contrast sensitivity play a role. Low vision services and interventions can help patients maximize visual function and improve their quality of life. Barriers to receiving these services exist at multiple levels and an increased awareness and integration into routine ophthalmic care are needed to deliver comprehensive care.

Glaucoma is one of the leading causes of low vision. Ophthalmologists who treat glaucoma often tend to focus on objective measures to monitor progression and disease severity, but the functional impact of glaucoma should also be addressed. Low vision services can benefit patients, particularly for reading and driving, and should be considered as an essential component of patient care.
Mitochondrial-linked de novo pyrimidine synthesis as a regulator of T cell responses
Authors: Peeters Marlies J. W. , Desler Claus , thor Straten Per
Published: January 2023

It has been well established that the metabolism of T cells is integral to their functionality. If a T cell cannot generate enough energy or building blocks, it will not be able to exert its cytotoxic properties to eliminate pathogens and cancer cells. Impairment of mitochondrial oxidative phosphorylation is a well-known disruptor of T cell activation. Dihydroorotate dehydrogenase (DHODH) is a rate-limiting component of the de novo synthesis of pyrimidines and its activity is dependent on functional mitochondrial oxidative phosphorylation. In this regard, DHODH inhibitors have long been used in clinical settings for the treatment of autoimmune diseases, as they potently inhibit lymphocyte proliferation. The exact mode-of-action of these inhibitors in T lymphocytes is not yet exactly understood. In this review, we briefly discuss the critical role of mitochondria in T cell functionality. We also describe how de novo pyrimidine biosynthesis is linked to mitochondrial activity. Finally, we summarize our current knowledge of how mitochondrial-linked de novo pyrimidine biosynthesis modulates T cell responses.
Artificial iris: state of the art
Authors: Gius Irene , Tozzi Luigi , De Biasi Chiara Sofia , Pizzolon Tobia , Parolini Barbara , Frisina Rino
Published: January 2023

Surgical correction of traumatic aniridia aims to improve quality of vision, compartmentalize anterior and posterior chamber, re-establish a satisfying cosmetic appearance. Various types of prosthetic iris devices (PIDs) are available, that differ in technical difficulty of implant and design: artificial iris-intraocular lens (AI-IOL) prosthesis, endocapsular capsular tension ring based PID, and customized AI. The choice depends to the pre-existing clinical condition after severe ocular trauma and on patient’s functional and cosmetic expectations. This systematic review of literature compared anatomical and functional outcomes of various types of PIDs. Of 185 articles found in literature, 70 fulfilled the eligibility criteria. 5 subgroups of PIDs were: Opthech, Artificial Iris from the Ophtec, Morcher, Humanoptics and ‘other prosthesis’. Both glare and aesthetic outcome improved after surgery; in comparison to other PIDs, intraocular pressure (IOP) rise incidence was higher in the Morcher group (40%), whereas prosthesis dislocation incidence was higher in the Ophtech group (39%).
Placebo effects on cutaneous pain and itch: a systematic review and meta-analysis of experimental results and methodology
Authors: Blythe Joseph S. , Thomaidou Mia A. , Peerdeman Kaya J. , van Laarhoven Antoinette I.M. , van Schothorst Myrthe M.E. , Veldhuijzen Dieuwke S. , Evers Andrea W.M.
Published: January 2023

Placebo effects, positive treatment outcomes that go beyond treatment processes, can alter sensations through learning mechanisms. Understanding how methodological factors contribute to the magnitude of placebo effects will help define the mechanisms by which these effects occur. We conducted a systematic review and meta-analysis of experimental placebo studies in cutaneous pain and itch in healthy samples, focused on how differences in methodology contribute to the resulting placebo effect magnitude. We conducted meta-analyses by learning mechanism and sensation, namely, for classical conditioning with verbal suggestion, verbal suggestion alone, and observational learning, separately for pain and itch. We conducted subgroup analyses and meta-regression on the type of sensory stimuli, placebo treatment, number of acquisition and evocation trials, differences in calibrated intensities for placebo and control stimuli during acquisition, age, and sex. We replicated findings showing that a combination of classical conditioning with verbal suggestion induced larger placebo effects on pain (k = 68, g = 0.59) than verbal suggestion alone (k = 39, g = 0.38) and found a smaller effect for itch with verbal suggestion alone (k = 7, g = 0.14). Using sham electrodes as placebo treatments corresponded with larger placebo effects on pain than when topical gels were used. Other methodological and demographic factors did not significantly affect placebo magnitudes. Placebo effects on pain and itch reliably occur in experimental settings with varied methods, and conditioning with verbal suggestion produced the strongest effects. Although methods may shape the placebo effect to some extent, these effects appear robust overall, and their underlying learning mechanisms may be harnessed for applications outside the laboratory.
The impact of neutrophil extracellular traps in coronavirus disease - 2019 pathophysiology
Authors: Shahidi Minoo , Amirzargar Mohammad Reza
Published: January 2023

Coronavirus disease 2019 (COVID-19), which is caused by novel coronavirus-2019 (nCoV-2019), is a highly contagious disease with high mortality and morbidity risk. Infected people may suffer from respiratory infections, which may be more progressive in patients with a defective immune system and underlying medical problems. In this regard, the cells involved in the innate immune system, play a decisive role in disease progression and complication development. Pathogen entrapment is the critical role of neutrophil extracellular traps (NETosis). This process involves the widespread release of fibrous structures by the stimulant-activated neutrophils. These fibrous structures are composed of cytosolic proteins and granular contents brought together by a network of released chromatins. This network can inhibit the spread of pathogens by their entrapment. Moreover, NETosis damage the host by producing toxic agents and triggering thrombosis. Therefore, this phenomenon may act as a double-edged sword. Regarding the rapid expansion of COVID-19, it is crucial to examine the involvement of NETosis in infected patients. This study aims to discuss NETosis participation to show its probable association with increased risk of thrombogenicity and help develop new therapeutic approaches in the battle against this viral disease.
Performance evaluation of the Sysmex CN-6000-automated coagulation analyzers for routine coagulation tests
Authors: Kim Hyerim , Jo Su-Yeon , Kim In-Suk
Published: January 2023

The Sysmex CN-6000 is a novel automated multiparameter coagulometer that performs clotting, chromogenic and immunological assays, and platelet aggregation tests in a single system. Here we evaluated its performance of routine coagulation assays. The precision, linearity, carryover and establishment of reference ranges of the CN-6000, as well as correlations between it and the currently used Diagnostica Stago STA-R Max were determined according to Clinical and Laboratory Standards Institute guidelines. The evaluated parameters included prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FBG), antithrombin (AT), d-dimers (DDi), and fibrin and FBG degradation products (FDP). The intra-run and inter-run precisions of the six tests were determined using normal and pathological control materials; all coefficients of variation were acceptable and within the allowable ranges. The CN-6000 showed excellent linearity for FBG, AT, DDi, and FDP (R = 0.999–1.00). Passing-Bablok regression (R
2 > 0.95) demonstrated good agreement between the analyzers. In the carryover study, APTT, PT, FBG, AT, DDi, and FDP values were all acceptable. The establishing reference intervals revealed that each manufacturer's range was acceptable. Significant differences were observed in the APTT reference range because of using different detection systems and reagents. The CN-6000 analyzer showed reliable performance and good correlation with the currently used STA-R Max automated hemostatic analyzer. As CN-6000 uses an optical clot-detection method, its reference ranges for PT and APTT are lower than those of the STA-R Max; thus, the difference should be considered before its use.
Adrenal insufficiency revealing bilateral adrenal hemorrhage related to JAK2 V617F-positive essential thrombocythemia: about two cases
Authors: Gensous Noémie , Jourde Wendy , Salles Kévin , James Chloé , Guy Alexandre , Duffau Pierre
Published: January 2023

Bilateral adrenal hemorrhage is a rare cause of adrenal insufficiency which has been rarely associated with myeloproliferative neoplasms. Here, we report two cases of bilateral adrenal hemorrhage revealed by abdominal pain, malaise, and fatigue in two octogenarian males previously diagnosed with JAK2 V617F-positive essential thrombocythemia. Both patients were on long-term direct oral anticoagulant treatment for atrial fibrillation. Evolution was favorable under steroid replacement therapy, associated with cytoreduction, aspirin, and switch of direct oral anticoagulants for vitamin K antagonists.
Statin can reduce the risk of hepatocellular carcinoma among patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis
Authors: Zhang Jie , Fu Shifeng , Liu Deliang , Wang Yongjun , Tan Yuyong
Published: January 2023

Currently, nonalcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease and liver-related mortality worldwide. Hepatocellular carcinoma (HCC) is a fatal complication in patients with NAFLD. However, whether statins can reduce the risk of HCC in patients with NAFLD remains controversial. We aimed to determine the relationship between statin use and HCC occurrence among patients with NAFLD. We independently retrieved related studies from PubMed, EMBASE, Cochrane Library, Web of Science, and ClinicalTrial.gov (from 1 January 2000 to 27 February 2022). The main outcome was the development of HCC. A fixed-effects model was used to merge odds ratio (OR) in the meta-analysis. Five studies involving 684 363 patients were included. The results of the meta-analysis suggested a significantly lower risk of HCC among statin users with NAFLD [OR = 0.59; 95% confidence interval (CI), 0.39–0.89; I
2 = 87.90%]. Additionally, a lower risk of HCC was observed among patients with NAFLD aged less than 65 years (OR = 0.59; 95% CI, 0.46–0.77; I
2 = 20.50%). Statins can reduce the risk of HCC in patients aged less than 65 years with NAFLD.
Epidemiology of geriatric patients presenting to emergency departments in Europe: EGERS study
Authors: Karamercan Mehmet A. , Dündar Defne Z. , Slagman Ana , Ergin Mehmet , Janssens Kelly Ann C. , Fabbri Andrea , Bjornsen Lars P. , Somodi Sándor , Adam Visnja N. , Polyzogopoulou Effie , Demir Hüseyin A. , Laribi Said ,   on behalf of the EGERS study investigators
Published: January 2023

Background and importance

Patients aged 65 and above constitute a large and growing part of emergency department (ED) visits in western countries.

Objective

The primary aim of this European prospective study was to determine the epidemiologic characteristics of elderly patients presenting to EDs across Europe. Our secondary objective was to determine the hospitalization rate, characteristics, and in-hospital mortality rates of geriatric patients presenting to EDs.

Design setting and participants

An observational prospective cohort study over seven consecutive days between 19 October and 30 November 2020, in 36 EDs from nine European countries. Patients aged 65 years and older presenting to EDs with any complaint during a period of seven consecutive days were included.

Outcome measures

Data were collected on demographics, the major presenting complaint, the presenting vital signs, comorbidities, usual medication, and outcomes after the ED, including disposition, in-hospital outcome, and the final hospital diagnosis. The patients were stratified into three groups: old (65–74 years), older (75–84 years), and oldest age (>85 years).

Main results

A total of 5767 patients were included in the study. The median age of the patients was 77 (interquartile range: 71–84) years. The majority presented with a non-traumatic complaint (81%) and about 90% of the patients had at least one comorbid disease and were on chronic medication. An ED visit resulted in subsequent hospital admission in 51% of cases, with 9% of patients admitted to an intensive care unit. Overall in-hospital mortality was 8%, and ED mortality was 1%. Older age was associated with a higher female proportion, comorbidities, need for home care service, history of previous falls, admission rates, length of ED, and hospital stay.

Conclusion

The characteristics of ED elderly patients and their subsequent hospital stay are reported in this prospective study.
The Association of Antimicrobial Prophylaxis With Return Visits After Dog Bites in Children
Authors: Davis Ashley , Fullerton Lynne , Hill Deirdre A. , Snow Harry , Dehority Walter
Published: January 2023

Objectives

Dog bites occur frequently in the United States, yet there are no clear guidelines for prescribing antibiotic prophylaxis in healthy children after a dog bite. The aim of our study was to assess antibiotic prophylaxis and subsequent rates of infection after dog bites in children. We hypothesized a negative association between prophylactic prescription of any antimicrobial and return visit within 14 days for infection.

Methods

In this retrospective cohort study, we assessed the frequency of antibiotic prophylaxis prescribed after dog bite injuries in patients 0 to 18 years old and subsequent return visits for infection using 2016 to 2017 medical and pharmacy claims derived from the IBM MarketScan Research Databases. We used the International Classification of Diseases-10 code W54 for dog bites then used keyword searches to find diagnoses (including infection), wound descriptions, and medications.

Results

Over the 2-year period, 22,911 patients were seen for dog bites that were not coded as infected. The majority, 13,043 (56.9%), were prescribed an antibiotic at the initial visit and 9868 (43.1%) were not. Of those prescribed antibiotics, 98 (0.75%; 95% confidence interval [CI], 0.60–0.90) returned with an infection, compared with 59 (0.60%; 95% CI, 0.44–0.75) of those not prescribed antibiotics. Receiving an antibiotic prescription at the initial visit was associated with a reduced rate of return for wound infection only among children whose wounds were repaired or closed. Children not receiving a prescription whose wounds were repaired were more than twice as likely to return with an infection in the subsequent 14 days as children whose wounds were not repaired (odds ratio, 2.2; 95% CI, 1.2–4.0).

Conclusions

Most children are prescribed antibiotics at an initial emergency department visit after a dog bite. However, very few return for infection independent of antimicrobial prophylaxis, which suggests antibiotics are overprescribed in this setting.
Update on drug treatments for multidrug resistant tuberculosis
Authors: Davies Geraint R. , Aston Stephen
Published: January 2023

Purpose of the review

To describe important recent developments in the treatment of multidrug resistant tuberculosis (MDR-TB)

Recent findings

In the last decade, novel and repurposed antituberculosis drugs have transformed MDR-TB treatment with improved rates of treatment success, better tolerability and safety and reduced duration. As recently as 2016, standard care relied on up to seven drugs for 24 months with treatment success no better than 70%. Seven drug shorter so-called “Bangladesh” style regimens subsequently achieved similar or better results at a duration of 9–12 months but concerns about first-line resistance additional to rifampicin hampered global uptake. After conditional approval in 2012, the novel agent bedaquiline was demonstrated to improve outcomes and reduce mortality when used in longer and shorter regimens, resulting in the replacement of injectable agents. In the last 2 years, clinical trials of all-oral 6-month three or four drug regimens containing bedaquiline, pretomanid and linezolid have shown superior efficacy against both longer and shorter traditional regimens, resulting in major changes in WHO guidance.

Although some concerns around safety and emergent bedaquiline resistance remain to be fully addressed, 6-month all oral regimens promise to transform the treatment of people with MDR-TB worldwide.
Skin and soft tissue infections in the elderly
Authors: Falcone Marco , Tiseo Giusy
Published: January 2023

Purpose of review

To highlight the peculiarity of skin and soft tissue infections (SSTIs) in elderly patients and to provide useful elements for their optimal management.

Recent findings

In the COVID-19 era, early discharge from the hospital and implementation of outpatient management is of key importance.

Elderly patients are at high risk of SSTIs due to several factors, including presence of multiple comorbidities and skin factors predisposing to infections. Clinical presentation may be atypical and some signs of severity, such as fever and increase in C-reactive protein, may be absent or aspecific in this patients population. An appropriate diagnosis of SSTIs in the elderly is crucial to avoid antibiotic overtreatment. Further studies should explore factors associated with bacterial superinfections in patients with pressure ulcers or lower limb erythema. Since several risk factors for methicillin-resistant Staphylococcus aureus (MRSA) may coexist in elderly patients, these subjects should be carefully screened for MRSA risk factors and those with high risk of resistant etiology should receive early antibiotic therapy active against MRSA. Physicians should aim to several objectives, including clinical cure, patient safety, early discharge and return to community. SSTIs in the elderly may be managed using long-acting antibiotics, but clinical follow-up is needed.
Tactile sensorimotor training does not alter short- and long-latency afferent inhibition
Authors: Adams Faith C. , Pickersgill Jacob W. , Turco Claudia V. , Foglia Stevie D. , Toepp Stephen L. , Rehsi Ravjot R. , Ramdeo Karishma R. , Salman Maria , Nelson Aimee J.
Published: January 2023

Sensorimotor integration refers to the process of combining incoming sensory information with outgoing motor commands to control movement. Short-latency afferent inhibition (SAI), and long-latency afferent inhibition (LAI) are neurophysiological measures of sensorimotor integration collected using transcranial magnetic stimulation. No studies to date have investigated the influence of tactile discrimination training on these measures. This study aimed to determine whether SAI and LAI are modulated following training on a custom-designed tactile discrimination maze task. Participants performed a ‘high difficulty’ and ‘low difficulty’ maze training condition on separate visits. On an additional visit, no maze training was performed to serve as a control condition. Despite evidence of performance improvements during training, there were no significant changes in SAI or LAI following training in either condition. The total number of errors during maze training was significantly greater in the high-difficulty condition compared with the low-difficulty condition. These findings suggest that sensorimotor maze training for 30 min is insufficient to modify the magnitude of SAI and LAI.
Cortical oscillatory changes during thermal grill illusion
Authors: Uragami Shinji , Osumi Michihiro
Published: January 2023

Objective

The thermal grill illusion (TGI) can cause a burning pain sensation when the skin is subjected to simultaneously harmless hot and cold stimuli, and the pain is reported to be similar to central neuropathic pain. Although electroencephalography (EEG) is commonly used in pain research, no reports have revealed EEG activity during TGI.

Methods

One healthy subject was enrolled, and EEG activity was recorded during the experience of the TGI and a warm sensation. Independent component analysis (ICA) was applied to preprocessed EEG data, which was divided into several clusters.

Results

Theta and alpha bands in the insular cortex and parietal operculum clusters were significantly more desynchronized under the TGI condition than under the warm condition (P < 0.05). Additionally, theta, alpha and beta bands in the frontal (middle and inferior frontal gyrus) cluster showed significantly more desynchronization under the TGI condition than under the warm condition (P < 0.05).

Conclusion

EEG oscillations in these brain areas could be useful markers of central neuropathic pain.
Real-Time Quantification of Cell Mechanics and Functions by Double Resonator Piezoelectric Cytometry — Theory and Study of Cellular Adhesion of HUVECs
Authors: Zhou Tiean , Huang Jingyuan , Xiong Lun , Shen Haibo , Huang Fushen , Li Wenwei , Peng Hange , Su Zhaohong , Pan Weison , Zhao Jia , Zhou Zhen , Bao Dongqin , Deng Linhong
Published: January 2023

Cell mechanics is closely associated with cellular structure and function. However, the inability to measure both cellular force and viscoelasticity of statistically significant number of cells noninvasively remains a challenge for quantitative characterizations of various cellular functions and practical applications. Here a double resonator piezoelectric cytometry (DRPC), using AT and BT cut quartz crystals of the same frequency and surface morphology is developed to simultaneously quantify the cells-generated forces (ΔS) and viscoelastic moduli (G′, G″) of a population of isolated single cells or cells with different degrees of cell-cell interactions in a non-invasive and real time manner. DRPC captures the dynamic mechanical parameters ΔS and G′, G″ during the adhesions of human umbilical vein endothelial cells (HUVECs) under different ligand densities of adhesion molecules fibronectin or Arg-Gly-Asp (RGD) modified on the gold surfaces of 9 MHz AT and BT cut quartz crystals, and different seeding densities of HUVECs. It is found that both the ligand density and cell seeding density affect the magnitudes of ΔS and G′, G″ and their correlations are revealed for the first time by DRPC. The validity of DRPC is further verified by mechanical changes of the cells in response to treatments with cytoskeleton regulators.
movedesign: Shiny R app to evaluate sampling design for animal movement studies
Authors: Silva Inês , Fleming Christen H. , Noonan Michael J. , Fagan William F. , Calabrese Justin M.
Published: January 2023

Projects focused on movement behavior and home range are commonplace, but beyond a focus on choosing appropriate research questions, there are no clear guidelines for such studies. Without these guidelines, designing an animal tracking study to produce reliable estimates of space-use and movement properties (necessary to answer basic movement ecology questions), is often done in anad hocmanner.

We developed ‘movedesign’, a user-friendly Shiny application, which can be utilized to investigate the precision of three estimates regularly reported in movement and spatial ecology studies: home range area, speed, and distance traveled. Conceptually similar to statistical power analysis, this application enables users to assess the degree of estimate precision that may be achieved with a given sampling design;i.e., the choices regarding data resolution (sampling interval) and battery life (sampling duration).

Leveraging the ‘ctmm’Rpackage, we utilize two methods proven to handle many common biases in animal movement datasets: autocorrelated Kernel Density Estimators (AKDE) and continuous-time speed and distance (CTSD) estimators. Longer sampling durations are required to reliably estimate home range areas via the detection of a sufficient number of home range crossings. In contrast, speed and distance estimation requires a sampling interval short enough to ensure that a statistically significant signature of the animal’s velocity remains in the data.

This application addresses key challenges faced by researchers when designing tracking studies, including the trade-off between long battery life and high resolution of GPS locations collected by the devices, which may result in a compromise between reliably estimating home range or speed and distance. ‘movedesign’ has broad applications for researchers and decision-makers, supporting them to focus efforts and resources in achieving the optimal sampling design strategy for their research questions, prioritizing the correct deployment decisions for insightful and reliable outputs, while understanding the trade-off associated with these choices.
Lumbar endplate microfracture injury induces Modic-like changes, intervertebral disc degeneration and spinal cord sensitization – An In Vivo Rat Model
Authors: Wang Dalin , Lai Alon , Gansau Jennifer , Seifert Alan C. , Munitz Jazz , Zaheer Kashaf , Bhadouria Neharika , Lee Yunsoo , Nasser Philip , Laudier Damien M. , Holguin Nilsson , Hecht Andrew C. , Iatridis James C.
Published: January 2023

BACKGROUND CONTEXT: Endplate (EP) injury plays critical roles in painful IVD degeneration since Modic changes (MCs) are highly associated with pain. Models of EP microfracture that progress to painful conditions are needed to better understand pathophysiological mechanisms and screen therapeutics.

PURPOSE: Establish in vivo rat lumbar EP microfracture model with painful phenotype.

STUDY DESIGN/SETTING: In vivo rat study to characterize EP-injury model with characterization of IVD degeneration, vertebral bone marrow remodeling, spinal cord sensitization, and pain-related behaviors.

METHODS: EP-driven degeneration was induced in 5-month-old male Sprague-Dawley rats L4-5 and L5-6 IVDs through the proximal vertebral body injury with intradiscal injections of TNFα (n=7) or PBS (n=6), compared to Sham (surgery without EP-injury, n=6). The EP-driven model was assessed for IVD height, histological degeneration, pain-like behaviors (hindpaw von Frey and forepaw grip test), lumbar spine MRI and μCT analyses, and spinal cord substance P (SubP).

RESULTS: EP injuries induced IVD degeneration with decreased IVD height and MRI T2 values. EP injury with PBS and TNFα both showed MC type1-like changes on T1 and T2-weighted MRI, trabecular bone remodeling on μCT, and damage in cartilage EP adjacent to the injury. EP injuries caused significantly decreased paw withdrawal threshold and reduced grip forces, suggesting increased pain sensitivity and axial spinal discomfort. Spinal cord dorsal horn SubP was significantly increased, indicating spinal cord sensitization.

CONCLUSIONS: EP microfracture can induce crosstalk between vertebral bone marrow, IVD and spinal cord with chronic pain-like conditions.

CLINICAL SIGNIFICANCE: This rat EP microfracture model of IVD degeneration was validated to induce MC-like changes and pain-like behaviors that we hope will be useful to screen therapies and improve treatment for EP-drive pain.
Assessing the impact of successive soil cultivation onMeloidogyne enterolobiiinfection and on soil bacterial assemblages
Authors: Pasche Josephine , Brito Janete A. , Vallad Gary E. , Brawner Jeremy , Snyder Samantha L. , Fleming Ellen A. , Yang Jingya , Terra Willian C. , Martins Samuel J.
Published: January 2023

Soil cultivation may change the soil microbiome and alter interactions between plants and parasites. The objective of this work was to evaluate temporal changes in plant health, microbiome abundance, bacterial diversity and the plant-parasitic nematode,Meloidogyne enterolobiiincidence in two soil fields with different agricultural uses. Soil samples were collected from a commercial tomato production field (agricultural soil) and a single-cultivation strawberry field (native soil). Samples for the second experiment were collected from the same fields the following year. Tomato plants cv. Yearly Girl were grown in a greenhouse and inoculated withM. enterolobii. After 45 days, plants were evaluated for the plant growth parameters, nematode reproduction, and soil bacterial assemblages were assessed using cultivation-independent sequencing methods (V3/V4 region of the rRNA 16S). Overall the average of fruit fresh weight in the second experiment was 2.4-fold to 14-fold higher than the first experiment. Moreover, there was a 80.5% decrease in eggs present per root system from the first experiment to the second. The relative abundance of bacterial assemblages from Experiment 1 to Experiment 2 changed for most of the top phyla (eg.Actinobacteria, Bacteroidetes, andChloroflexi) and genera (eg.Bacillus, Streptomyces, andFlavisolibacter) and there was no change in microbial diversity between the two experiments. This study suggests that soil management can lead to an overall decrease in nematode reproduction and better crop yield, as well as a shift in the overall bacterial assemblages.

Graphical Abstract
Causal inference during closed-loop navigation: parsing of self- and object-motion
Authors: Noel Jean-Paul , Bill Johannes , Ding Haoran , Vastola John , DeAngelis Gregory C. , Angelaki Dora E. , Drugowitsch Jan
Published: January 2023

A key computation in building adaptive internal models of the external world is to ascribe sensory signals to their likely cause(s), a process of Bayesian Causal Inference (CI). CI is well studied within the framework of two-alternative forced-choice tasks, but less well understood within the cadre of naturalistic action-perception loops. Here, we examine the process of disambiguating retinal motion caused by self- and/or object-motion during closed-loop navigation. First, we derive a normative account specifying how observers ought to intercept hidden and moving targets given their belief over (i) whether retinal motion was caused by the target moving, and (ii) if so, with what velocity. Next, in line with the modeling results, we show that humans report targets as stationary and steer toward their initial rather than final position more often when they are themselves moving, suggesting a misattribution of object-motion to the self. Further, we predict that observers should misattribute retinal motion more often: (i) during passive rather than active self-motion (given the lack of an efference copy informing self-motion estimates in the former), and (ii) when targets are presented eccentrically rather than centrally (given that lateral self-motion flow vectors are larger at eccentric locations during forward self-motion). Results confirm both of these predictions. Lastly, analysis of eye-movements show that, while initial saccades toward targets are largely accurate regardless of the self-motion condition, subsequent gaze pursuit was modulated by target velocity during object-only motion, but not during concurrent object- and self-motion. These results demonstrate CI within action-perception loops, and suggest a protracted temporal unfolding of the computations characterizing CI.
Competition between bottom-up visual input and internal inhibition generates error neurons in a model of the mouse primary visual cortex
Authors: Fraile J. Galván , Scherr Franz , Ramasco José J. , Arkhipov Anton , Maass Wolfgang , Mirasso Claudio R.
Published: January 2023

The predictive coding theory, although attractive, is far from being proven. Supporters of this theory agree that bottom-up sensory inputs and top-down predictions of these inputs must be compared in certain types of neurons called error neurons. Excitatory neurons in layer 2/3 (E2/3) of the primary visual cortex (V1) are ideal candidates to act as error neurons, although how these error neurons are generated is poorly understood. In this study, we aimed to gain insight into how the genetically encoded structure of canonical microcircuits in the neocortex implements the emergence of error neurons. To this end, we used a biologically realistic computational model of V1, developed by the Allen Institute, to study the effect that sudden changes in bottom-up input had on the dynamics of E2/3 neurons. We found that the responses of these neurons can be divided into two main classes: one that depolarized (reporting positive errors; dVf neurons) and one that hyperpolarized (reporting negative errors; hVf neurons). Detailed analysis of both network and effective connectivity allowed us to uncover the mechanism that led to the dynamic segregation of these neurons. This mechanism was found to be the competition between the external visual input, originating in the thalamus, and the recurrent inhibition, originating mainly in layers 2/3 and 4. In contrast, we found no evidence of similar division and responses in excitatory infragranular neurons of layers 5 and 6. Our results are in agreement with recent experimental findings and shed light on the mechanisms responsible for the emergence of error neurons.
Marching with ants to a new nest
Authors: Annagiri Sumana , Halder Eshika
Published: January 2023

In this review, we journey withDiacamma indicuma Ponerine ant over the last decade as they relocate to new nests and discover the challenges they face along the way and how they solve them. Colony relocation is a goal oriented dynamic task that involves all the colony members and impacts the colonies’ fitness. After explaining how I initiated this journey, we examine colony composition of this species by analysing data from 1200 colonies collected over the last 13 years. On average colonies are constituted with 89.35 adult females, 0.29 males and 56.6 brood items of different development stages and these were significantly impacted by seasonality with Pre monsoon having the highest numbers. After explaining how colonies are collected and maintained in the lab, we explore the architectural components of the subterrain nests built by this species in the natural habitat. Colonies live in relatively simple single chambered nest that does not change significantly across seasons and consists of an entrance tunnel and a secondary runoff tunnel. All members of the colony are recruited to the new nest through tandem running and this species shows the highest documented tandem running speeds at 4.35 body lengths per second and a path efficiency of 83.95% with only 2.4% of tandem runs being unsuccessful in the natural habitat. Even in lab conditions, when colonies are given defined paths of different lengths, colonies showed significant preference to travel through short paths, highlighting their ability to optimizes their path even in the absence of chemical trails. A combination of experiments in the natural habitat and controlled experiments in the lab which are anchored in theumweltof the organism has enabled us to understand howD. indicumfunctions and reveals the selection forces that are operating on the organization and performances of relocation. Our journey has brought to light several answers but has opened several more avenues for exploration branching out in different directions. With time and dedicated minds, we hope to continue on this route to marvel at the achievements of these superorganisms.