bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting Extent of Microsurgical Resection of Sporadic Vestibular Schwannoma
Authors: Macielak Robert J. , Lohse Christine M. , Wallerius Katherine P. , Lawlor Skye K. , Neff Brian A. , Van Gompel Jamie J. , Driscoll Colin L.W. , Link Michael J. , Carlson Matthew L.
Published: August 2022

Objective

Develop a predictive model for incomplete microsurgical resection of sporadic vestibular schwannoma (VS).

Study Design

Historical cohort.

Setting

Tertiary referral center.

Patients

Patients with sporadic VS.

Interventions

Microsurgery with preoperative intent of gross total resection.

Main Outcome Measures

Patient and tumor characteristics that influence extent of resection.

Results

Among 603 patients, 101 (17%) had intracanalicular tumors and 502 (83%) had tumors with cerebellopontine angle (CPA) extension. For patients with CPA tumors, 331 (66%) underwent gross total resection and 171 (34%) underwent near-total or subtotal resection (NTR-STR). Multivariable modeling identified older age at surgery, larger linear tumor size, and absence of a fundal fluid cap as predictive of NTR-STR (p < 0.001). From this model, one can estimate that a 20-year-old with a tumor that has less than 10 mm of CPA extension and a present fundal fluid cap has a predicted probability of NTR-STR of 0.01 (or 1%), whereas a 70-year-old with a tumor that has 30 mm or greater CPA extension and absence of a fundal fluid cap has a predicted probability of NTR-STR of 0.91 (or 91%). Among the 171 patients who underwent NTR-STR, 24 required secondary treatment at the time of last follow-up.

Conclusion

The primary predictors of incomplete microsurgical resection of VS include older age at surgery, larger linear tumor size, and absence of a fundal fluid cap. These factors can be used to estimate the likelihood of NTR-STR, aiding in preoperative discussions regarding future surveillance and potential need of secondary treatment, as well as shared clinical decision making.
Early Translabyrinthine Surgery for Small- and Medium-Sized Vestibular Schwannomas: Consecutive Cohort Analysis of Outcomes
Authors: Zanoletti Elisabetta , Mazzoni Antonio , Chiumenti Francesca Angela , d’Avella Domenico , Cazzador Diego
Published: August 2022

Objective

Reappraisal of the role of translabyrinthine (TLAB) surgery in small- and medium-sized vestibular schwannomas (VSs).

Study Design

Retrospective study.

Setting

Tertiary referral center.

Patients

A total of 330 consecutive patients diagnosed between 1973 and 2019 with small- and medium-sized VS up to 20 mm in the extrameatal portion submitted to surgical treatment.

Interventions

VS removal through microscopic TLAB approach.

Main Outcome Measures

Facial nerve function according to the House-Brackmann scale at 12-month follow-up, postoperative complications and entity of tumor resection assessed with postoperative MRI. A comparative analysis of outcomes between two groups of patients was further conducted, according to tumor size: Group A, small-sized (intrameatal or ≤10 mm extrameatal tumors) and Group B, medium-sized VSs (extrameatal between 11 and 20 mm).

Results

Complete tumor removal was achieved in all cases. The overall complication rate was 5.5%, being cerebrospinal fluid leak the most frequent. Patients with small-sized VS (n = 121) presented a significantly better facial nerve function than patients with medium-sized tumors (n = 209), showing House-Brackmann Grades I to II in 92.6% versus 73.6% of cases, respectively (p < 0.001). A nearly 4.5-fold higher risk of poor facial nerve function at 12 months affects patients with medium-sized tumors (odds ratio, 4.473; 95% confidence interval, 2.122–9.430; p < 0.001).

Conclusion

In the current scenario of multioptional VS management, when hearing preservation is not feasible, early TLAB approach as first-line treatment for small-sized VSs showed favorable results. Factors supporting such proactive surgical treatment include long-term definitive cure, no major complications, good facial nerve outcomes, and the possibility of simultaneous hearing rehabilitation with a cochlear implant.
Acute myocardial infarction in young adults with chronic kidney disease
Authors: Gyurjian Karo , Schweis Franz , Patel Sej , Hammershaimb Bryant , Chiu Sarah , Nadadur Malini , Chen Aiyu , Wu Yi-Lin , Lee Ming-Sum
Published: August 2022

Objective

The goal of this study was to evaluate the prevalence of chronic kidney disease (CKD) in young patients with acute myocardial infarction (AMI) and to report their characteristics and clinical outcomes.

Background

Underlying renal dysfunction is a risk factor for poor cardiovascular outcomes in older patients. The implication of CKD in young patients with AMI is not well studied.

Methods

This is a retrospective population-based cohort study of patients aged 18–50 who presented with AMI between 2006 and 2016. Medical records were reviewed to confirm diagnosis and to identify treatment and long-term outcomes. Cox regression models were used to evaluate the association of CKD with mortality.

Results

Among 1753 young patients with type 1 AMI (median age 45 years, 85.3% male), CKD was present in 112 (6.8%) patients. A higher proportion of CKD patients had concomitant hypertension, hyperlipidemia, diabetes, and obesity. Use of statin and P2Y12 inhibitors post-AMI was lower in CKD patients. Over a median follow-up of 7.2 years, CKD was associated with higher all-cause mortality [hazard ratio (HR), 9.3; 95% CI, 6.3–13.8]. This association persisted after adjusting for demographics, comorbidities, and treatment (adjusted HR, 3.6; 95% CI, 2.2–6.0).

Conclusion

Presence of CKD was associated with 3.6-fold higher mortality over a median follow-up of 7.2 years. A lower proportion of CKD patients were treated with statin therapy and P2Y12 inhibitors. These findings highlight the need for intensive risk factor modification and optimal use of guideline-directed medical therapies in this high-risk population.
Subphenotypes of acute kidney injury in adults
Authors: Vaara Suvi T. , Forni Lui G. , Joannidis Michael
Published: August 2022

Purpose of review

Acute kidney injury is a heterogeneous syndrome and as such is associated with multiple predisposing conditions and causes all of which affect outcomes. Such heterogeneity may conceal the potential benefit of therapies when generally applied to patients with acute kidney injury (AKI). The discovery of pathophysiology-based subphenotypes could be of benefit in allocating current and future therapies to specific groups.

Recent findings

Clinical subphenotypes group patients into categories according to predisposing factors, disease severity, and trajectory. These may be helpful in assessing patient outcomes. Analyses of existing databases have revealed biological subphenotypes that are characterized by levels of biomarkers indicative of hyperinflammation and endothelial injury. Patients with increased levels of these biomarkers display higher mortality rates compared with those with lower levels and there is potential that this group might respond differently to therapies. However, challenges remain in the validation, generalizability, and application of these subphenotypes.

Subphenotyping may help reduce heterogeneity under the umbrella term of acute kidney injury. Despite challenges remain, the identification of AKI subphenotypes has opened the potential of AKI research focused on better targeted therapies.
Alternating hemiplegia of childhood: a distinct clinical entity and ATP1A3-related disorders: A narrative review
Authors: Pavone Piero , Pappalardo Xena Giada , Ruggieri Martino , Falsaperla Raffaele , Parano Enrico
Published: August 2022

Alternating Hemiplegia of Childhood (AHC) is a rare disorder with onset in the first 18 months of life characterized by stereotyped paroxysmal manifestations of tonic and dystonic attacks, nystagmus with other oculomotor abnormalities, respiratory and autonomic dysfunctions. AHC is often associated with epileptic seizures and developmental delay. Hemiplegic paroxysm is the most remarkable symptom, although AHC includes a large series of clinical manifestations that interfere with the disease course. No cure is available and the treatment involves many specialists and therapies. Flunarizine is the most commonly used drug for reducing the frequency and intensity of paroxysmal events. Mutations in ATP1A2, particularly in ATP1A3, are the main genes responsible for AHC. Some disorders caused by ATP1A3 variants have been defined as ATP1A3-related disorders, including rapid-onset dystonia-parkinsonism, cerebellar ataxia, pes cavus, optic atrophy, sensorineural hearing loss, early infant epileptic encephalopathy, child rapid-onset ataxia, and relapsing encephalopathy with cerebellar ataxia. Recently, the term ATP1A3 syndrome has been identified as a fever-induced paroxysmal weakness and encephalopathy, slowly progressive cerebellar ataxia, childhood–onset schizophrenia/autistic spectrum disorder, paroxysmal dyskinesia, cerebral palsy/spastic paraparesis, dystonia, dysmorphism, encephalopathy, MRI abnormalities without hemiplegia, and congenital hydrocephalus. Herewith, we discussed about historical annotations of AHC, symptoms, signs and associated morbidities, diagnosis and differential diagnosis, treatment, prognosis, and genetics. We also reported on the ATP1A3-related disorders and ATP1A3 syndrome, as 2 recently established and expanded genetic clinical entities.
Global trends of ERCP research in the last 25 years: A bibliometrics study
Authors: Yang Huai-Yu , Wang Dan , Lin Xi , Han Chao , Lv Yan-Wei , Huang Ren-Qian , Zhang Jie , Li Zhao-Shen , Liao Zhuan , Hu Liang-Hao
Published: August 2022

Purpose:

Endoscopic retrograde cholangiopancreatography (ERCP) has been used in clinical practice for over 50 years. This study aims to investigate the current state of research in the field of ERCP.

Methods:

Web of Science database was searched using the term “ERCP” for articles published between 1994 and 2018. The total number of articles from the top 20 countries with the most published articles was determined. The top 5 countries were compared in terms of output per capita, number of articles published in top journals, cumulative impact factor (IF), and average IF. All annual data were subjected to time-trend analysis. The frequently used terms in the titles and abstracts of all articles were retrieved to conduct co-occurrence analysis to determine the research focus of ERCP.

Results:

A total of 9960 articles on ERCP were published between 1994 and 2018, of which 8778 articles were from the top 20 producing countries. There was a significant positive correlation between the output and GDP of each country (R = 0.870, P = .001). The United States of America (USA), Japan, Germany, Italy, and China were the top 5 producing countries with 3190 (32.0%), 868 (8.7%), 658 (6.6%), 512 (5.1%) and 488 (4.9%) articles published, respectively. The USA, Japan, Italy, and China were trending upwards in the total outputs and outputs per capita, while Germany were trending downwards. For average IF, Germany had a downwards trend, while the other 4 countries remained stable. Overall, the USA had the highest output per capita (97.5/10 million) and the highest average IF (6.454). China had the lowest output per capita (3.5/10 million) and average IF (3.125). The ERCP procedures for sphincter of Oddi dysfunction, the combination of ERCP, and laparoscopic cholecystectomy have been the research focus of ERCP.

Conclusions:

Except for Germany, research on ERCP will continue to increase in the top-producing countries. The outputs per capita and quality of articles from developed countries are higher than those from developing countries.
Ultra-low dose computed tomography of the chest in an emergency setting: A prospective agreement study
Authors: Kristjánsdóttir Björg , Taekker Maria , Andersen Michael B. , Bentsen Lasse P. , Berntsen Mikkel H. , Dahlin Jan , Fransen Maja L. , Gosvig Kristina , Greisen Pernille W. , Laursen Christian B. , Mussmann Bo , Posth Stefan , Rasmussen Claus-Henrik , Sjölander Hannes , Graumann Ole
Published: August 2022

Ultra-low dose computed tomography (ULD-CT) assessed by non-radiologists in a medical Emergency Department (ED) has not been examined in previous studies. To (i) investigate intragroup agreement among attending physicians caring for ED patients (i.e., radiologists, senior- and junior clinicians) and medical students for the detection of acute lung conditions on ULD-CT and supine chest X-ray (sCXR), and (ii) evaluate the accuracy of interpretation compared to the reference standard. In this prospective study, non-traumatic patients presenting to the ED, who received an sCXR were included. Between February and July 2019, 91 patients who underwent 93 consecutive examinations were enrolled. Subsequently, a ULD-CT and non-contrast CT were performed. The ULD-CT and sCXR were assessed by 3 radiologists, 3 senior clinicians, 3 junior clinicians, and 3 medical students for pneumonia, pneumothorax, pleural effusion, and pulmonary edema. The non-contrast CT, assessed by a chest radiologist, was used as the reference standard. The results of the assessments were compared within each group (intragroup agreement) and with the reference standard (accuracy) using kappa statistics. Accuracy and intragroup agreement improved for pneumothorax on ULD-CT compared with the sCXR for all groups. Accuracy and intragroup agreement improved for pneumonia on ULD-CT when assessed by radiologists and for pleural effusion when assessed by medical students. In patients with acute lung conditions ULD-CT offers improvement in the detection of pneumonia by radiologists and the detection of pneumothorax by radiologists as well as non-radiologists compared to sCXR. Therefore, ULD-CT may be considered as an alternative first-line imaging modality to sCXR for non-traumatic patients who present to EDs.
Joint hypermobility and preschool-age flexible flatfoot
Authors: Tsai Chia-Chun , Chih Yu-Chia , Shih Chia-Lung , Chen Shu-Jung , Shen Po-Chih , Tien Yin-Chun
Published: August 2022

Flexible flatfoot is the most common condition seen in pediatric orthopedic practice and generalized joint hypermobility is widely regarded as one of the predisposing factors. However, in previous studies, the flatfoot was defined by observers’ subjective evaluation of the eversion of the bare foot in the standing position; and the joint hypermobility was defined by the Beighton score. The objective of this study is to evaluate the correlation between preschool-age flexible flatfoot and joint hypermobility in preschool-age children objectively.

Footprints were measured on a Harris and Beath footprint mat. Flatfoot flexibility was assessed by Staheli Plantar Arch Index (PAI). Other than the Beighton score, 2 new measurement methods, the thumb-to-forearm test and the thumb-thrust test were developed to evaluate joint hypermobility.

Of the 291 preschool children from 4 different kindergarten schools included in this study, 156 were boys and 135 were girls. The mean age was 64.18 ± 9.33 months (range 35–88 months). Pearson correlation analysis demonstrated PAI was not associated with the Beighton score (R = 0.020, P = .735), thumb-to-forearm grade (R = 0.109, P = .066), and thumb-thrust grade (R = 0.027, P = .642). Two-sample t-test results showed that the normal and flatfoot groups did not differ significantly in the Beighton score (P = .404), thumb-to-forearm grade (P = .063), and thumb-thrust grade (P = .449).

The results demonstrated no correlation between joint hypermobility and preschool-age flexible flatfoot when flatfoot was defined with Staheli PAI and joint hypermobility with the Beighton score. Even with 2 new methods, the thumb-to-forearm test and thumb-thrust test, to define joint hypermobility, we still found no correlation between preschool-age flexible flatfoot and joint hypermobility.
Development of an International Competency Framework for Nurses in the Provision of Self-management Support to Cancer Populations
Authors: Chan Raymond J. , Agbejule Oluwaseyifunmi Andi , Crawford-Williams Fiona , Yates Patsy M. , Koczwara Bogda , Erickson Jeanne , So Winnie K. W. , Howell Doris ,   on behalf of the ISNCC Knowledge Development and Dissemination Committee
Published: August 2022

Background

Cancer survivors are required to manage their health, healthcare, and a myriad of symptoms through self-management.

Objective

The aim of this study was to develop a comprehensive framework of competencies and performance criteria that identifies the requisite knowledge and skills for nursing practice in the provision of self-management support for cancer survivors and their families.

Methods

The competency framework was developed using the following 3-stage consensus building approach: (1) development of a preliminary list of self-management support competencies and performance criteria informed by relevant literature, (2) a 2-round modified Delphi conducted with a panel of cancer nurse experts, and (3) a research team consensus meeting to finalize framework components.

Results

Seventy-one items, comprising 13 core competencies and 58 performance criteria, across 6 domains were generated. In round 1 of the modified Delphi, a panel of 21 oncology nurses produced consensus on retaining 28 items for inclusion in the final framework. Thirty-one items (including new items generated in round 1) were sent to round 2 for further rating. A panel of 19 nurses produced consensus on retaining a further 20 items in the framework in round 2. Of the 11 items that did not reach consensus, the research team proposed to include 7 in the final framework. Fifty-nine items were included in the final framework.

Conclusions

This study provides a comprehensive, self-management support competency framework for oncology nurses.

Implications for Practice

This framework is the first step toward the development of training program curricula that prepares nurses in self-management for cancer and associated coaching knowledge and skills.
The Utility of Assessing Alexithymia, in Addition to Coping, in the Context of Posttraumatic Stress
Authors: Bowen Mya E. , McDevitt-Murphy Meghan E. , Olin Cecilia C. , Buckley Brooke E.
Published: August 2022

The distinction between alexithymia and coping in relation to posttraumatic stress has not been fully explored. The present study examined the extent to which alexithymia explained unique variance in posttraumatic stress, beyond the variance explained by coping, in a sample of trauma-exposed adults (N = 706; Mage
= 19.41 years, SD = 1.5; 77.1% female). Then, we explored the effect of race on these associations, comparing participants who identified as Black (n = 275) to those who identified as White (n = 337). Avoidant-emotional coping showed stronger correlations (compared with problem-focused and active-emotional coping) with total alexithymia, difficulty identifying feelings, and difficulty describing feelings. In regression analyses, we found alexithymia explained unique variance in posttraumatic stress severity beyond the effect of coping. Results did not differ by racial identity. These findings suggest that despite some overlap between alexithymia and coping, each shows unique relations with posttraumatic stress.
Orientation of the Cochlea From a Surgeon’s Perspective
Authors: Matsumoto Nozomu , Akagi-Tsuchihashi Nana , Noda Teppei , Komune Noritaka , Nakagawa Takashi
Published: August 2022

Background:

One of the mechanisms that cause tip fold-over is a misalignment between the electrode array’s coiling direction and the cochlea’s curving direction.

Objectives:

We reviewed surgical videos and computed tomography (CT) datasets of the patients who underwent cochlear implantation procedures from January 2010 to December 2021, paying particular attention to the cochlea’s orientation in the surgeon’s microscopic view.

Methods:

CT dataset and video recordings were analyzed to measure the “slope angle,” which is the angle between the cochlea’s coiling plane and the horizontal plane.

Results:

There were 220 cases that met the criteria and completed the analysis. The mean slope angle was 12.1° ± 9.5°, with a minimum of −9.4° and maximum of 44.6°. However, each surgeon had a favored slope angle range.

Conclusion:

Understanding the slope angle and making an effort to reduce the chance of misalignment during electrode insertion may help prevent tip fold-over of slim perimodiolar electrode arrays.
Associations between single-question Visual Analogue Scale pain score and weight-bearing and non–weight-bearing domains of Western Ontario and McMaster Universities Arthritis Index pain: data from 2 phase 3 clinical trials
Authors: Bjerre-Bastos Jonathan J. , Miller Claire P. , Li Yanqi , Andersen Jeppe R. , Karsdal Morten , Bihlet Asger R.
Published: August 2022

Introduction:

Visual Analogue Scale (VAS) and the pain subscale of the Western Ontario and McMaster Universities Arthritis Index (WOMAC) are commonly used measuring tools of osteoarthritis (OA) pain.

Objectives:

The objective of this cross-sectional study was to explore the associations between single-question VAS pain and the weight-bearing and non–weight-bearing domains of WOMAC pain.

Methods:

Data from 2093 patients with OA participating in 2 phase 3 clinical trials were included for post hoc analyses. Univariate Pearson correlations and comparison of r values were made using z statistics obtained using the Fisher r to z test for all items of the VAS pain scale, the WOMAC pain subscale, the weight-bearing and non–weight-bearing constructs of WOMAC pain subscale, and by subgroups of WOMAC pain quintiles and Kellgren–Lawrence grades.

Results:

The correlations between VAS pain and WOMAC pain were significant (r = 0.67, P < 0.001) with a slope of 0.57 (95% confidence interval [CI]: 0.54–0.61). A similar correlation was found for weight-bearing pain (r = 0.68, P < 0.001, slope: 0.62 (95% CI: 0.59–0.65) but significantly lower for non–weight-bearing pain (r = 0.55, P < 0.001, slope: 0.49 (95% CI: 0.46–0.52). The degree of disagreement between the 2 instruments seemed to be lesser in the extreme ends of the scales, and the observed association between Kellgren–Lawrence grade and disagreement between VAS and WOMAC was driven by non–weight-bearing pain.

Conclusion:

In conclusion, VAS pain and WOMAC pain subscale correlation was found to be moderate and the VAS pain scale correlated more accurately with the WOMAC pain weight-bearing questions. This constitutes novel insight into patient with OA pain reporting.
Brief Report: HIV-Positive and Breastfeeding in High-Income Settings: 5-Year Experience From a Perinatal Center in Germany
Authors: Weiss Fabian , von Both Ulrich , Rack-Hoch Anita , Sollinger Franz , Eberle Josef , Mahner Sven , Kaestner Ralph , Alba Alejandre Irene
Published: August 2022

Background:

Exclusive breastfeeding is recommended for women living with HIV (WLWH) in low-income—but not in high-income—countries, where milk substitutes are preferred. Some guidelines for high-income countries opted for a shared decision-making process regarding breastfeeding in optimal scenarios with adherence to antiretroviral therapy (cART), suppressed maternal viral load (mVL), and clinical monitoring. Although vertical transmission (VT) risk under cART is estimated below 1% in low-income settings, data from high-income countries are rare.

Methods:

We retrospectively analyzed all 181 live births from WLWH at the LMU Munich university hospital perinatal center in Germany between January 2016 and December 2020. We focused on VT, suppressed mVL and optimal scenario rates, breastfeeding frequency, cART regimens, and infant prophylaxis. All women were counseled according to current guidelines, foremost recommending avoidance of breastfeeding.

Results:

In the 5-year cohort, no VT was observed. One hundred fifty-one WLWH (83.4%) decided not to breastfeed, even in optimal scenarios. Thrity infants (16.6%) were nursed, of which 25 were within an optimal scenario, whereas in 5 cases, breastfeeding was performed with a detectable VL in pregnancy or the postpartum period. All WLWH were treated with cART at delivery, and 91.7% sustained suppressed mVL. Zidovudine infant prophylaxis was given between 2 and 8 weeks but not necessarily over the whole breastfeeding duration and was declined from 5 breastfeeding WLWH.

Conclusions:

Although the cohort is too small to assess VT risk through breastfeeding with cART-suppressed mVL, breastfeeding might be an alternative even in high-income countries, but further studies are needed.
Diagnostic Performance of Superb Microvascular Imaging in Differentiating Benign and Malignant Axillary Lymph Nodes
Authors: Kurt Seda Aladag , Eryurekli Ali Ergun , Kayadibi Yasemin , Samanci Cesur , Velidedeoglu Mehmet , Onur Irem , Arslan Serdar , Taskin Fusun
Published: August 2022

The aim was to evaluate the effectiveness of superb microvascular imaging (SMI) in axillary lymph nodes (LNs).

Benign and malignant LNs diagnosed via histopathological examination constituted the study subgroups. In addition to grayscale findings for morphological evaluation, vascular patterns and appearance of internal vessels were analyzed by both power Doppler ultrasound (PDUS) and SMI. The number of vascular branches was counted, and a vascularity index (VI) was calculated by SMI.

Fifty-two LNs with suspicious findings in terms of metastasis (33 malignant and 19 benign) were evaluated. Diagnostic accuracy according to vascular patterns was 82% for PDUS and 92% for SMI. In the presence of asymmetric cortical thickening, there was a significant difference between benign and malignant LNs in the number of vascular branches of both thin and thick cortical sides (P < 0.01). Mean VI was significantly higher in the malignant group (P < 0.05). In differentiating malignancy, when a cutoff VI value was set to 9%, sensitivity was 69.7%, and specificity was 63.2%.

Evaluating the vascularity of axillary LNs by SMI is a useful tool in determining the potential of axillary metastasis, especially in the absence of typical sonographic findings. Superb microvascular imaging can beneficially be used to select the most suspicious LN and suspicious area of the LN to sample.
Acute Antibody-mediated Rejection Coexisting With T Cell–mediated Rejection in Pediatric ABO-incompatible Transplantation
Authors: Yanagi Yusuke , Sakamoto Seisuke , Yamada Masaki , Mimori Koutaro , Nakao Toshimasa , Kodama Tasuku , Uchida Hajime , Shimizu Seiichi , Fukuda Akinari , Nakano Noriyuki , Haga Chiduko , Yoshioka Takako , Kasahara Mureo
Published: August 2022

Background.

The management and outcome of ABO-incompatible (ABO-I) liver transplantation (LT) has been improving over the past few decades. Recently, the introduction of a pathological evaluation of acute antibody-mediated rejection (AMR) for liver allograft has provided a new recognition of allograft rejection in LT.

Methods.

One hundred and one pediatric ABO-I LTs performed in our institute were retrospectively analyzed. We assessed the clinical manifestations, diagnosis, and treatment of acute AMR, focusing on the recipient age and pathological findings.

Results.

Twelve cases (11.9%) of acute AMR related to ABO-I were observed. Nine cases developed mixed T cell–mediated rejection (TCMR)/AMR. These consisted of 6 patients in the younger age group for whom the preconditioning treatment was not indicated and 4 patients in the older age group to whom rituximab was administered as planned. Two patients in the older age group to whom preoperative rituximab was not administered as planned developed isolated AMR. Acute AMR in the older group required plasma exchange for treatment, regardless of the coexistence of TCMR. In contrast, those in the younger group were successfully treated by intravenous methylprednisolone pulse and intravenous immunoglobulin without plasma exchange, accounting for mild immune reaction.

Conclusions.

Acute ABO-I AMR can develop simultaneously with TCMR, even in young patients with a compromised humoral immune response following ABO-I LT. Establishing the accurate diagnosis of AMR with a pathological examination, including component 4d staining, is crucial for optimizing treatment.
Update on genetics of amyotrophic lateral sclerosis
Authors: Brenner David , Freischmidt Axel
Published: August 2022

Purpose of review

ALS genetics are highly dynamic and of great interest for the ALS research community. Each year, by using ever-growing datasets and cutting-edge methodology, an array of novel ALS-associated genes and downstream pathomechanisms are discovered. The increasing plenty and complexity of insights warrants regular summary by-reviews.

Recent findings

Most recent disease gene discoveries constitute the candidate and risk genes SPTLC1, KANK1, CAV1, HTT, and WDR7, as well as seven novel risk loci. Cell type and functional enrichment analyses enlighten the genetic basis of selective motor neuron vulnerability in ALS demonstrating high expression of ALS-associated genes in cortical motor neurons and highlight the pathogenic significance of cell-autonomous processes. Major pathomechanistic insights have been gained regarding known ALS genes/proteins, specifically C9orf72, TDP43, ANXA11, and KIF5A. The first ASO-based gene-specific therapy trials in familial forms of ALS have yielded equivocal results stressing the re-evaluation of pathomechanisms linked to SOD1 and C9orf72 mutations.

The genetic and molecular basis of ALS is increasingly examined on single-cell resolution. In the past 2 years, the understanding of the downstream mechanisms of several ALS genes and TDP-43 proteinopathy has been considerably extended. These insights will result in novel gene specific therapy approaches for sporadic ALS and genetic subtypes.
Biomarkers for amyotrophic lateral sclerosis
Authors: Witzel Simon , Mayer Kristina , Oeckl Patrick
Published: August 2022

Purpose of review

Amyotrophic lateral sclerosis (ALS) is an incurable, devastating neurodegenerative disease. Still, the diagnosis is mainly based on clinical symptoms, and the treatment options are strongly limited. However, the pipeline of potential treatments currently tested in clinical trials is promising. This review will discuss developments in ALS biomarker research and applications within the last 2 years and suggest future directions and needs.

Recent findings

The diagnostic and prognostic utility of neurofilaments, a general marker for axoneuronal degeneration, has been confirmed by further studies in patients with ALS, and neurofilaments are finding their way into routine diagnostic and clinical trials. Additionally, there have been advancements in developing and implementing disease-specific biomarkers, especially in patients with a genetic variant, such as SOD1 or C9orf72. Here, biomarkers have already been used as target markers and outcome parameters for novel treatment approaches. In addition, several novel biomarkers have shown encouraging results but should be discussed in the context of their early stage of assay and clinical establishment.

The first biomarkers have found their way into clinical routine in ALS. In light of an increasing pipeline of potential treatments, further progress in discovering and implementing novel and existing biomarkers is crucial.
Recent advances in our understanding of genetic rhabdomyolysis
Authors: Cabrera-Serrano Macarena , Ravenscroft Gianina
Published: August 2022

Purpose of review

This review summarizes recent advances in our understanding of the genetics of rhabdomyolysis.

Recent findings

Rhabdomyolysis is the acute breakdown of myofibres resulting in systemic changes that can be life-threatening. Environmental triggers, including trauma, exercise, toxins and infections, and/or gene defects can precipitate rhabdomyolysis. A schema (aptly titled RHABDO) has been suggested for evaluating whether a patient with rhabdomyolysis is likely to harbour an underlying genetic defect. It is becoming increasingly recognized that defects in muscular dystrophy and myopathy genes can trigger rhabdomyolysis, even as the sole or presenting feature. Variants in genes not previously associated with human disease have been identified recently as causative of rhabdomyolysis, MLIP, MYH1 and OBSCN. Our understanding of the pathomechanisms contributing to rhabdomyolysis have also improved with an increased awareness of the role of mitochondrial dysfunction in LPIN1, FDX2, ISCU and TANGO2-mediated disease.

An accurate genetic diagnosis is important for optimal clinical management of the patient, avoiding associated triggers and genetic counselling and cascade screening. Despite recent advances in our understanding of the genetics contributing to rhabdomyolysis, many patients remain without an accurate genetic diagnosis, suggesting there are many more causative genes, variants and disease mechanisms to uncover.
Education-based grant programmes for bottom-up distance learning and project catalysis: Antimicrobial Resistance in Sub-Saharan Africa
Authors: Graham Chris LB , Akligoh Harry , Ori Joy King , Adzaho Gameli , Salekwa Linda , Campbell Patrick , Saba Courage KS , Landrain Thomas E. , Santolini Marc
Published: August 2022

International development and aid are often conducted through the allocation of funding determined by decisions of non-locals, especially in the west for those in the global south. In addition, such funding is often disassociated from local expertise, therefore providing little long-term developmental impact and generating distrust. This is particularly true for conservation, as well as environmental and educational programmes. We hypothesise that by granting local people the educational tools and the necessary funding to develop their own projects through the use of an applicant driven peer-review approach, it is possible to relocalize the decision-making process to the programme participants, with the potential to generate and select more relevant projects with developmental outcomes of higher quality. Here we created an online curriculum for antimicrobial resistance (AMR) education that was followed by 89 participants across Ghana, Tanzania, Nigeria, and Uganda. We then created an open research programme that facilitated the creation of eight de novo projects on AMR. Finally, we organised an applicant-driven grant round to allocate funding to the “Neonatal Sepsis in Nigeria” project to conduct a pilot study and awareness campaign. This work opens perspectives for the design of frugal educational programmes and the funding of context-specific, community-driven projects aimed at empowering local stakeholders in the global South.
The biogenesis of β-lactamase enzymes
Authors: Kaderabkova Nikol , Bharathwaj Manasa , Furniss R. Christopher D. , Gonzalez Diego , Palmer Tracy , Mavridou Despoina A.I.
Published: August 2022

The discovery of penicillin by Alexander Fleming marked a new era for modern medicine, allowing not only the treatment of infectious diseases, but also the safe performance of life-saving interventions, like surgery and chemotherapy. Unfortunately, resistance against penicillin, as well as more complex β-lactam antibiotics, has rapidly emerged since the introduction of these drugs in the clinic, and is largely driven by a single type of extra-cytoplasmic proteins, hydrolytic enzymes called β-lactamases. While the structures, biochemistry and epidemiology of these resistance determinants have been extensively characterized, their biogenesis, a complex process including multiple steps and involving several fundamental biochemical pathways, is rarely discussed. In this review, we provide a comprehensive overview of the journey of β-lactamases, from the moment they exit the ribosomal channel until they reach their final cellular destination as folded and active enzymes.
Flnc: Machine Learning Improves the Identification of Novel Full-length Long Noncoding RNAs from RNA Sequencing Data Without Transcriptional Initiation Profiles
Authors: Li Zixiu , Zhou Peng , Kwon Euijin , Fitzgerald Katherine , Weng Zhiping , Zhou Chan
Published: August 2022

Long noncoding RNAs (lncRNAs) play critical regulatory roles in human development and disease. However, many lncRNAs have yet to be annotated. The conventional approach to identifying novel lncRNAs from RNA sequencing (RNA-seq) data is to find transcripts without coding potential. This approach has a false discovery rate of 30-75%. The majority of these misidentified lncRNAs are RNA fragments or transcriptional noise and lack defined transcription start sites, which are marked by H3K4me3 histone modifications. Therefore, the accuracy of lncRNA identification can be improved by incorporating H3K4me3 chromatin immunoprecipitation sequencing (ChIP-seq) data. However, because of cost, time, and limited sample availability, most RNA-seq data lacks such data. This paucity of H3K4me3 data greatly hinders the efforts to accurately identify novel lncRNAs. To address this problem, we have developed software, Flnc, to identify both novel and annotated full-length lncRNAs from RNA-seq data without H3K4me3 profiles. Flnc integrates machine learning models built incorporating four types of features: transcript length, promoter signature, multiple exons, and genomic location. Flnc achieves state-of-the-art prediction power with an AUROC score over 0.92. Flnc significantly improves the prediction accuracy from less than 50% using the conventional approach to over 85%. Flnc is available via https://github.com/CZhouLab/Flnc.
Short communication: automatic real-time monitoring of fungal spores: the case of Alternaria spp
Authors: Erb Sophie , Berne Alexis , Burgdorfer Nina , Clot Bernard , Graber Marie-José , Lieberherr Gian , Sallin Christine , Tummon Fiona , Crouzy Benoît
Published: August 2022

We present the first implementation of the monitoring of airborne fungal spores in real-time using digital holography. To obtain observations of Alternaria spp. spores representative of their airborne stage, we collected events measured in the air during crop harvesting in a contaminated potato field, using a Swisens Poleno device. The classification algorithm used by MeteoSwiss for operational pollen monitoring was extended by training the system using this additional dataset. The quality of the retrieved concentrations is evaluated by comparison with parallel measurements made with a manual Hirst-type trap. Correlations between the two measurements are high, especially over the main dispersion period of Alternaria spp., demonstrating the potential for automatic real-time monitoring of fungal spores.
A multi-modal fitting approach to construct single-neuron models with patch clamp and high-density microelectrode arrays
Authors: Buccino Alessio Paolo , Damart Tanguy , Bartram Julian , Mandge Darshan , Xue Xiaohan , Zbili Mickael , Gänswein Tobias , Jaquier Aurélien , Emmenegger Vishalini , Markram Henry , Hierlemann Andreas , Van Geit Werner
Published: August 2022

In computational neuroscience, multicompartment models are among the most biophysically realistic representations of single neurons. Constructing such models usually involves the use of the patch-clamp technique to record somatic voltage signals under different experimental conditions. The experimental data are then used to fit the many parameters of the model. While patching of the soma is currently the gold-standard approach to build multicompartment models, several studies have also evidenced a richness of dynamics in dendritic and axonal sections. Recording from the soma alone makes it hard to observe and correctly parameterize the activity of non-somatic compartments.

In order to provide a richer set of data as input to multicompartment models, we here investigate the combination of somatic patch-clamp recordings with recordings of high-density micro-electrode arrays (HD-MEAs). HD-MEAs enable the observation of extracellular potentials and neural activity of neuronal compartments at sub-cellular resolution.

In this work, we introduce a novel framework to combine patch-clamp and HD-MEA data to construct multicompartment models. We first validate our method on a ground-truth model with known parameters and show that the use of features extracted from extracellular signals, in addition to intracellular ones, yields models enabling better fits than using intracellular features alone. We also demonstrate our procedure using experimental data by constructing cell models from in vitro cell cultures.

The proposed multi-modal fitting procedure has the potential to augment the modeling efforts of the computational neuroscience community and to provide the field with neuronal models that are more realistic and can be better validated.

Author Summary

Multicompartment models are one of the most biophysically detailed representations of single neurons. The vast majority of these models are built using experimental data from somatic recordings. However, neurons are much more than just their soma and one needs recordings from distal neurites to build an accurate model. In this article, we combine the patch-clamp technique with extracellular high-density microelectrode arrays (HD-MEAs) to compensate this shortcoming. In fact, HD-MEAs readouts allow one to record the neuronal signal in the entire axonal arbor. We show that the proposed multi-modal strategy is superior to the use of patch clamp alone using an existing model as ground-truth. Finally, we show an application of this strategy on experimental data from cultured neurons.
Facilitating CG simulations with MAD: the MArtini Database Server
Authors: Hilpert Cécile , Beranger Louis , Souza Paulo C.T. , Vainikka Petteri A. , Nieto Vincent , Marrink Siewert J. , Monticelli Luca , Launay Guillaume
Published: August 2022

The MArtini Database (MAD - www.mad.ibcp.fr) is a web server designed for the sharing structures and topologies of molecules parameterized with the Martini coarse-grained (CG) force field. MAD can also convert atomistic structures into CG structures and prepare complex systems (including proteins, lipids etc.) for molecular dynamics (MD) simulations at the CG level. It is dedicated to the generation of input files for Martini 3, the most recent version of this popular CG force field. Specifically, the MAD server currently includes tools to submit or retrieve CG models of a wide range of molecules (lipids, carbohydrates, nanoparticles, etc.), transform atomistic protein structures into CG structures and topologies, with fine control on the process and assemble biomolecules into large systems and deliver all files necessary to start simulations in the GROMACS MD engine.
Multienzyme deep learning models improve peptide de novo sequencing by mass spectrometry proteomics
Authors: Gueto-Tettay Carlos , Tang Di , Happonen Lotta , Heusel Moritz , Khakzad Hamed , Malmström Johan , Malmström Lars
Published: August 2022

Generating and analyzing overlapping peptides through multienzymatic digestion is an efficient procedure for de novo protein using from bottom-up mass spectrometry (MS). Despite improved instrumentation and software, de novo MS data analysis remains challenging. In recent years, deep learning models have represented a performance breakthrough. Incorporating that technology into de novo protein sequencing workflows require machine-learning models capable of handling highly diverse MS data. In this study, we analyzed the requirements for assembling such generalizable deep learning models by systematically varying the composition and size of the training set. We assessed the generated models’ performances using two test sets composed of peptides originating from the multienzyme digestion of samples from various species. The peptide recall values on the test sets showed that the deep learning models generated from a collection of highly N- and C-termini diverse peptides generalized 76% more over the termini-restricted ones. Moreover, expanding the training set’s size by adding peptides from the multienzymatic digestion with five proteases of several species samples led to a 2-3 fold generalizability gain. Furthermore, we tested the applicability of these multienzyme deep learning (MEM) models by fully de novo sequencing the heavy and light monomeric chains of five commercial antibodies (mAbs). MEM models extracted over 10000 matching and overlapped peptides across six different proteases mAb samples, achieving a 100% sequence coverage for 8 of the ten polypeptide chains. We foretell that the MEM models’ proven improvements to de novo analysis will positively impact several applications, such as analyzing samples of high complexity, unknown nature, or the peptidomics field.
Training the next generation of researchers in the Organ-on-Chip field
Authors: Moruzzi Alessia , Shroff Tanvi , Keller Silke , Loskill Peter , Cipriano Madalena
Published: August 2022

Organ-on-chip (OoC) technology bridges the principles of biology and engineering to create a new generation of in vitro models and involves highly interdisciplinary collaboration across STEM disciplines. Training the next generation of scientists, technicians and policy makers is a challenge that requires a tailored effort. To promote the qualification, usability, uptake and long-term development of OoC technology, we designed a questionnaire to evaluate the key aspects for training, identify the major stakeholders to be trained, their professional level and specific skillset. The 151 respondents unanimously agreed on the need to train the next generation of OoC researchers and that the training should be provided early, in interdisciplinary subjects and throughout the researchers’ career. We identified two key training priorities: (i) training scientists with a biology background in microfabrication and microfluidics principles and (ii) training OoC developers in pharmacology/toxicology. This makes training in OoC a transdisciplinary challenge rather than an interdisciplinary one. The data acquired and analyzed here serves to guide training initiatives for preparing competent and transdisciplinary researchers, capable of assuring the successful development and application of OoC technologies in academic research, pharmaceutical/chemical/cosmetic industries, personalized medicine and clinical trials on chip.
Does the paradigm of genotype-environment associations need to be re-assessed? The paradox of adaptive phenotypic clines with non-clinal patterns in causal alleles
Authors: Lotterhos Katie E
Published: August 2022

Multivariate climate change presents an urgent need to understand how species adapt to complex environments. Population genetic theory predicts that loci under selection will form monotonic allele frequency clines with their selective environment, which has led to the wide use of genotype-environment associations (GEAs). This study elucidates the conditions under which allele frequency clines are more or less likely to evolve as multiple quantitative traits adapt to a multivariate environment. A novel set of simulations was created that all evolved similar phenotypic clines, but with varying proportions of causal alleles with clines. Phenotypic clines evolved mostly without clines in the causal allele frequencies under conditions that promoted unique combinations of mutations to achieve the multivariate optimum in different parts of the landscape. Although univariate and multivariate GEA methods failed to accurately infer the genetic basis of adaptation under a range of scenarios, individual multivariate traits could be accurately predicted from genotype and environmental data without any knowledge of the genetic architecture. This research challenges the utility of GEAs for understanding the genetic basis of adaptation to the environment, and instead suggests that multivariate trait predictions are a more fruitful approach for genomic forecasting and assisted gene flow efforts.