bluuebunny/crossref_metadata_2025 huggingface dataset:
Electrocardiographic Changes at the Early Stage of Status Epilepticus: First Insights From the ICTAL Registry*
Authors: Chinardet Paul , Gilles Floriane , Cochet Helene , Chelly Jonathan , Quenot Jean-Pierre , Jacq Gwenaelle , Soulier Pauline , Lesieur Olivier , Beuret Pascal , Holleville Mathilde , Bruel Cedric , Bailly Pierre , Sauneuf Bertrand , Sejourne Caroline , Galbois Arnaud , Fontaine Candice , Perier François , Pichon Nicolas , Arrayago Marine , Mongardon Nicolas , Schnell David , Lascarrou Jean-Baptiste , Convers Raphaële , Legriel Stephane
Published: December 2022

Objectives:

To describe early electrocardiogram (ECG) abnormalities after status epilepticus (SE) and evaluate their association with 90-day neurological outcomes.

Design:

Retrospective analysis of a multicenter, national prospective registry between February 2018 and June 2020.

Setting:

Sixteen ICUs in France, IctalGroup Research Network.

Patients:

Adults with available ECG performed less than or equal to 24 hours after the onset of SE and less than or equal to 12 hours after its resolution.

Intervention:

Double-blinded review of all ECGs was performed by two independent cardiologists. ECGs were categorized as normal/abnormal and then with minor/major early ECG abnormalities according to the Novacode ECG Classification system.

Measurements and Main Results:

Among 155 critically ill patients with SE, early ECG abnormalities were encountered in 145 (93.5%), categorized as major in 91 of 145 (62.8%). In addition to sinus tachycardia, the main abnormalities were in the ST segment (elevation [16.6%] or depression [17.9%]) or negative T waves (42.1%). Major early ECG abnormalities were significantly associated with respiratory distress and sinus tachycardia at the scene and hyperlactatemia at ICU admission. By multivariable analysis, three variables were significantly associated with 90-day poor outcome: age, preexisting ultimately fatal comorbidity, and cerebral insult as the cause of SE. Early major ECG abnormalities were not independently associated with 90-day functional outcome.

Conclusions:

In our study, early ECG abnormalities in the acute phase of SE were frequent, often unrecognized and were associated with clinical and biological stigma of hypoxemia. Although they were not independently associated with 90-day functional outcome, ECG changes at the early stage of SE should be systematically evaluated.

TRIAL REGISTRATION:

https://clinicaltrials.gov/ct2/show/NCT03457831.
Switching between eltrombopag and recombinant human thrombopoietin in patients with immune thrombocytopenia: an observational study
Authors: Cai Xuan , Fu Haixia , Zhao Xiangyu , Lu Jin , Jiang Qian , Chang Yingjun , Huang Xiaojun , Zhang Xiaohui
Published: December 2022

Background:

Recombinant human thrombopoietin (rh-TPO) and eltrombopag are two distinct TPO receptor agonists (TPO-RAs) with different mechanisms. During the pandemic, when immunosuppressive medications are controversial, switching to another TPO-RA may be worth exploring in patients who do not benefit from their first TPO-RA. We investigated the outcomes of switching from rh-TPO to eltrombopag or vice versa in immune thrombocytopenia (ITP) patients.

Methods:

This prospective, open-label, observational investigation included 96 adult ITP patients who needed to switch between rh-TPO and eltrombopag between January 2020 and January 2021 at Peking University People's Hospital in China. The study evaluated response rates and platelet counts at different time points after the switch, bleeding events, time to response, duration of response, and adverse events.

Results:

At 6 weeks after switching, response was observed in 21/49 patients (43%) who switched for inefficacy and 34/47 patients (72%) who switched for non-efficacy-related issues. In the inefficacy group, 9/27 patients (33%) responded to eltrombopag, and 12/22 patients (55%) responded to rh-TPO. In the non-efficacy-related group, 21/26 (81%) and 13/21 (62%) patients in the eltrombopag and rh-TPO groups maintained their response rates at 6 weeks after switching, respectively. Response at 6 months was achieved in 24/49 patients (49%) switching for inefficacy and 37/47 patients (79%) switching for non-efficacy issues. In the inefficacy group, 13/27 patients (48%) responded to eltrombopag, and 11/22 patients (50%) responded to rh-TPO. In the non-efficacy-related group, 22/26 patients (85%) and 15/21 patients (71%) in the eltrombopag and rh-TPO groups maintained their response rates at 6 months after switching, respectively. Both eltrombopag and rh-TPO were well tolerated.

Conclusions:

Our study confirmed the safety and effectiveness of switching between rh-TPO and eltrombopag for ITP patients who had no response to or experienced adverse events with their first TPO-RA. When the switch was motivated by other reasons, including patient preference and platelet count fluctuations, the probability of response was high.

Registration:

ClinicalTrials.gov, NCT04214951.
Safety of Reduction Mammaplasty and Mastopexy After Breast Conservation Therapy and Radiation Therapy
Authors: Prasidha Ines , Boyages John , Lam Thomas C.
Published: December 2022

Background

Conservative surgery and radiotherapy (CS + RT) have become the standard of care for early-stage breast cancer as an alternative to mastectomy. With the increasing rate of obesity and incidence of macromastia, surgeons increasingly encounter patients with a history of breast radiation desiring breast reduction. However, elective breast surgery after irradiation remains to be controversial due to known adverse effects of radiation, especially on wound healing, and unknown effects of lumpectomy on traditional pedicle choices. Herein, we present our experiences and outcomes of reduction mammaplasties and mastopexies in patients with breast cancer previously treated with CS + RT.

Methods

Between 2009 and 2020, 13 patients undergoing reduction mammaplasty or mastopexy, who have previously underwent CS + RT with or without axillary surgery, were included in this study. Surgical techniques and complications, including delayed wound healing, infection, fat necrosis, and nipple-areolar necrosis, were recorded and analyzed based on the irradiated versus nonirradiated sides.

Results

Of the 13 patients, delayed wound healing occurred in 7% on the irradiated side and 15% on the nonirradiated sides (P > 0.05). No significant correlation was observed between the number of complications and time of elective breast surgery from the last radiation therapy. Complications between irradiated and nonirradiated breasts did not significantly differ in both the reduction mammaplasty and mastopexy groups.

Conclusions

Reduction mammaplasty and mastopexy in patients with a history of lumpectomy and breast irradiation can be safely performed and should be considered in those experiencing macromastia or asymmetry post-CS + RT.
Breast Morphological Comparison Between Anatomic and Round Implant Augmentation
Authors: Liu Yue , Zhang Xiaoyu , Luan Jie
Published: December 2022

Background

The choice of implant shape (anatomic or round) is one of the most critical issues for breast augmentation. Determining whether there are differences in the postoperative breast morphology of the 2 implants is pivotal for surgical planning. This issue has been controversial and lacking in evidence. The aim of this study was to provide reference for implant selection by comparing breast morphology after dual-plane augmentation with anatomic and round implants using 3-dimensional scanning technology.

Methods

Patients with implant volume less than 300 mL who underwent transaxillary dual-plane augmentation were included in this study and were grouped according to implant shape. Three-dimensional scans were performed preoperatively and 6 months postoperatively. Postoperative breast height (BH), breast width (BW), BH of upper pole (BHUP), BH of lower pole (BHLP), breast projection (BP), BP of upper pole (BPUP), and BP of lower pole (BPLP) were measured separately, resulting in corresponding ratios (BH/BW, BHUP/BHLP, BP/BH, BPUP/BPLP). Breast volume, and the volumes of each pole (breast volume of upper pole [BVUP], breast volume of lower pole [BVLP]) and its ratio (BVUP/BVLP) were calculated. Correlation and regression analysis on the influencing factors of breast volume were performed.

Results

Thirty patients with anatomic implants and 26 with round implants were enrolled in this study. The mean volumes of anatomic and round implants were 260.5 ± 26.7 and 267.9 ± 21.7 mL (P = 0.192). The ratios of BH/BW in the 2 groups were 1.39 ± 0.12 and 1.37 ± 0.19, respectively (P = 0.582). The BHUP/BHLP values of 2 groups were 1.35 ± 0.22 and 1.41 ± 0.25 (P = 0.160). Two sets of BPUP/BPLP were 0.68 ± 0.19 and 0.73 ± 0.17 (P = 0.133). The ratios of BP/BH in the 2 groups were 0.39 ± 0.08 and 0.39 ± 0.06 (P = 0.830). The BVUP/BVLP ratios for both groups were 0.75 ± 0.11 and 0.77 ± 0.12 (P = 0.287). There was a volume loss rate of 13.3% ± 3.9% and 13.9% ± 5% (P = 0.489). The postoperative volume showed a positive correlation with both the preoperative volume and the implant volume.

Conclusions

For patients with breast dysplasia undergoing transaxillary dual-plane augmentation with anatomic or round implants less than 300 mL, the difference in postoperative breast morphology is not obvious. Using these 2 shapes of implants results in a similar degree of volume loss.
Trial of antibiotic restraint in presumed pneumonia: A Surgical Infection Society multicenter pilot
Authors: Guidry Christopher A. , Beyene Robel T. , Watson Christopher M. , Sawyer Robert G. , Chollet-Hinton Lynn , Simpson Steven Q. , Atchison Leanne , Derickson Michael , Cooper Lindsey C. , Pennington G. Patton , VandenBerg Sheri , Halimeh Bachar N. , O'Dell Jacob C.
Published: December 2022

BACKGROUND

Pneumonia is the most common intensive care unit–acquired infection in the trauma and emergency general surgery population. Despite guidelines urging rapid antibiotic use, data supporting immediate antibiotic initiation in cases of suspected infection are limited. Our hypothesis was that a protocol of specimen-initiated antibiotic initiation would have similar compliance and outcomes to an immediate initiation protocol.

METHODS

We devised a pragmatic cluster-randomized crossover pilot trial. Four surgical and trauma intensive care units were randomized to either an immediate initiation or specimen-initiated antibiotic protocol for intubated patients with suspected pneumonia and bronchoscopically obtained cultures who did not require vasopressors. In the immediate initiation arm, antibiotics were started immediately after the culture regardless of patient status. In the specimen-initiated arm, antibiotics were delayed until objective Gram stain or culture results suggested infection. Each site participated in both arms after a washout period and crossover. Outcomes were protocol compliance, all-cause 30-day mortality, and ventilator-free alive days at 30 days. Standard statistical techniques were applied.

RESULTS

A total of 186 patients had 244 total cultures, of which only the first was analyzed. Ninety-three patients (50%) were enrolled in each arm, and 94.6% were trauma patients (84.4% blunt trauma). The median age was 50.5 years, and 21% of the cohort was female. There were no differences in demographics, comorbidities, sequential organ failure assessment, Acute Physiology and Chronic Health Evaluation II, or Injury Severity Scores. Antibiotics were started significantly later in the specimen-initiated arm (0 vs. 9.3 hours; p < 0.0001) with 19.4% avoiding antibiotics completely for that episode. There were no differences in the rate of protocol adherence, 30-day mortality, or ventilator-free alive days at 30 days.

CONCLUSION

In this cluster-randomized crossover trial, we found similar compliance rates between immediate and specimen-initiated antibiotic strategies. Specimen-initiated antibiotic protocol in patients with a suspected hospital-acquired pneumonia did not result in worse clinical outcomes compared with immediate initiation.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level II.
Pathophysiological Changes in the Hemostatic System and Antithrombotic Management in Kidney Transplant Recipients
Authors: van den Berg Tamar A.J. , Nieuwenhuijs-Moeke Gertrude J. , Lisman Ton , Moers Cyril , Bakker Stephan J.L. , Pol Robert A.
Published: December 2022

Nowadays, the main cause for early graft loss is renal graft thrombosis because kidney transplant outcomes have improved drastically owing to advances in immunological techniques and immunosuppression. However, data regarding the efficacy of antithrombotic therapy in the prevention of renal graft thrombosis are scarce. Adequate antithrombotic management requires a good understanding of the pathophysiological changes in the hemostatic system in patients with end-stage kidney disease (ESKD). Specifically, ESKD and dialysis disrupt the fine balance between pro- and anticoagulation in the body, and further changes in the hemostatic system occur during kidney transplantation. Consequently, kidney transplant recipients paradoxically are at risk for both thrombosis and bleeding. This overview focuses on the pathophysiological changes in hemostasis in ESKD and kidney transplantation and provides a comprehensive summary of the current evidence for antithrombotic management in (adult) kidney transplant recipients.
Faunimonas pinastri gen. nov., sp. nov., an endophyte from a pine tree of the family Pleomorphomonadaceae, class Alphaproteobacteria
Authors: Proença Diogo N. , Whitman William B. , Shapiro Nicole , Woyke Tanja , Kyrpides Nikos C. , Morais Paula V.
Published: December 2022

Bacterial strain A52C2T was isolated from the endophytic microbial community of a Pinus pinaster tree trunk and characterized. Strain A52C2T stained Gram-negative and formed rod-shaped cells that grew optimally at 30 °C and at pH 6.0–7.0. The G+C content of the DNA was 65.1 mol %. The respiratory quinone was ubiquinone 10, and the major fatty acids were cyclo-C19:0
ω8c and C18:0, representing 70.1 % of the total fatty acids. Phylogenetic analyses based on the 16S rRNA gene sequences placed strain A52C2T in a distinct lineage within the order

Hyphomicrobiales

, family

Pleomorphomonadaceae

. The 16S rRNA gene sequence similarities of A52C2T to that of

Mongoliimonas terrestris

and

Oharaeibacter diazotrophicus

were 93.15 and 93.2 %, respectively. The draft genome sequence of strain A52C2T comprises 4 196 045 bases with a 195-fold mapped coverage of the genome. The assembled genome consists of 43 contigs of more than 1 000 bp (N50 contig size was 209 720 bp). The genome encodes 4033 putative coding sequences. The phylogenetic, phenotypic and chemotaxonomic data showed that strain A52C2T (=UCCCB 130T=CECT 8949T=LMG 29042T) represents the type of a novel species and genus, for which we propose the name Faunimonas pinastri gen. nov., sp. nov.
Judicial Opinions 123–127
Authors: Arahal David R. , Bull Carolee T. , Busse Hans-Jürgen , Christensen Henrik , Chuvochina Maria , Dedysh Svetlana N. , Fournier Pierre-Edouard , Konstantinidis Konstantinos T. , Parker Charles T. , Rossello-Mora Ramon , Ventosa Antonio , Göker Markus
Published: December 2022

Opinion 123 places the epithet of the name

Aeromonas punctata

on the list of rejected epithets and clarifies the citation of authors of selected names within the genus

Aeromonas

. Opinion 124 denies the request to place

Borreliella

on the list of rejected names because the request is based on a misinterpretation of the Code, which is clarified. There are alternative ways to solve the perceived problem. Opinion 125 denies the request to place

Lactobacillus fornicalis

on the list of rejected names because the provided information does not yield a reason for rejection. Opinion 126 denies the request to place

Prolinoborus

and

Prolinoborus fasciculus

on the list of rejected names because a relevant type strain deposit was not examined. Opinion 127 grants the request to assign the strain deposited as ATCC 4720 as the type strain of

Agrobacterium tumefaciens

, thereby correcting the Approved Lists. These Opinions were ratified by the voting members of the International Committee on Systematics of Prokaryotes.
Development of an in vitro homeostasis model between airway epithelial cells, bacteria and bacteriophages: a time-lapsed observation of cell viability and inflammatory response
Authors: Tzani-Tzanopoulou Panagiota , Rozumbetov Ramazan , Taka Styliani , Doudoulakakis Anastassios , Lebessi Evangelia , Chanishvili Nina , Kakabadze Elene , Bakuradze Nata , Grdzelishvili Nino , Goderdzishvili Marina , Legaki Evangelia , Andreakos Evangelos , Papadaki Maria , Megremis Spyridon , Xepapadaki Paraskevi , Kaltsas Grigoris , Akdis Cezmi A. , Papadopoulos Nikolaos G.
Published: December 2022

Bacteriophages represent the most extensive group of viruses within the human virome and have a significant impact on general health and well-being by regulating bacterial population dynamics.

Staphylococcus aureus

, found in the anterior nostrils, throat and skin, is an opportunistic pathobiont that can cause a wide range of diseases, from chronic inflammation to severe and acute infections. In this study, we developed a human cell-based homeostasis model between a clinically isolated strain of

S. aureus

141 and active phages for this strain (PYOSa141) isolated from the commercial Pyophage cocktail (PYO). The cocktail is produced by Eliava BioPreparations Ltd. (Tbilisi, Georgia) and is used as an add-on therapy for bacterial infections, mainly in Georgia. The triptych interaction model was evaluated by time-dependent analysis of cell death and inflammatory response of the nasal and bronchial epithelial cells. Inflammatory mediators (IL-8, CCL5/RANTES, IL-6 and IL-1β) in the culture supernatants were measured by enzyme-linked immunosorbent assay and cell viability was determined by crystal violet staining. By measuring trans-epithelial electrical resistance, we assessed the epithelial integrity of nasal cells that had differentiated under air-liquid interface conditions. PYOSa141 was found to have a prophylactic effect on airway epithelial cells exposed to

S. aureus

141 by effectively down-regulating bacterial-induced inflammation, cell death and epithelial barrier disruption in a time-dependent manner. Overall, the proposed model represents an advance in the way multi-component biological systems can be simulated in vitro.
An efficient CRISPR interference-based prediction method for synergistic/additive effects of novel combinations of anti-tuberculosis drugs
Authors: Samukawa Noriaki , Yamaguchi Takehiro , Ozeki Yuriko , Matsumoto Sohkichi , Igarashi Masayuki , Kinoshita Naoko , Hatano Masaki , Tokudome Kentaro , Matsunaga Shinji , Tomita Shuhei
Published: December 2022

Tuberculosis (TB) is treated by chemotherapy with multiple anti-TB drugs for a long period, spanning 6 months even in a standard course. In perspective, to prevent the emergence of antimicrobial resistance, novel drugs that act synergistically or additively in combination with major anti-TB drugs and, if possible, shorten the duration of TB therapy are needed. However, their combinatorial effect cannot be predicted until the lead identification phase of the drug development. Clustered regularly interspaced short palindromic repeats interference (CRISPRi) is a powerful genetic tool that enables high-throughput screening of novel drug targets. The development of anti-TB drugs promises to be accelerated by CRISPRi. This study determined whether CRISPRi could be applicable for predictive screening of the combinatorial effect between major anti-TB drugs and an inhibitor of a novel target. In the checkerboard assay, isoniazid killed

Mycobacterium smegmatis

synergistically or additively in combinations with rifampicin or ethambutol, respectively. The susceptibility to rifampicin and ethambutol was increased by knockdown of inhA, which encodes a target molecule of isoniazid. Additionally, knockdown of rpoB, which encodes a target molecule of rifampicin, increased the susceptibility to isoniazid and ethambutol, which act synergistically with rifampicin in the checkerboard assay. Moreover, CRISPRi could successfully predict the synergistic action of cyclomarin A, a novel TB drug candidate, with isoniazid or rifampicin. These results demonstrate that CRISPRi is a useful tool not only for drug target exploration but also for screening the combinatorial effects of novel combinations of anti-TB drugs. This study provides a rationale for anti-TB drug development using CRISPRi.
State-dependent photocrosslinking unveiled the role of intersubunit interfaces on Ca2+activating mechanisms of the BK channel
Authors: Gonzalez-Hernandez Alberto J. , Rivero-Pérez Belinda , Bartolomé-Martín David , de la Rosa Diego Álvarez , Plested Andrew J.R. , Giraldez Teresa
Published: December 2022

BK channels are high-conductance potassium channels that are activated by voltage and Ca2+. The pore-forming α-subunits form homotetramers including a membrane-spanning domain and a cytosolic domain with a tandem of RCK-like domains (RCK1 and RCK2) per subunit. The eight RCKs compose high affinity Ca2+-binding sites that drive channel activation. Full-length Cryo-EM structures revealed intersubunit interactions between the RCK domains. Asparagine 449 (N449, human BK channel) is located at the RCK1 domain and coordinates Ca2+in the RCK2 of the adjacent subunit. In addition, two Arginines (R786 and R790) of one RCK2 and Glutamate 955 of the adjacent subunit constitute an additional interaction interface. Functional studies on these residues showed that these two interfaces are crucial in Ca2+sensitivity. To detect structural rearrangements induced by Ca2+during channel activation, we took advantage of the photoactivatable unnatural amino acid p-benzoyl-L-phenylalanine (BzF). Functional channels were obtained with this amino acid inserted at 11 positions. N449 and R786 positions (N449BzF and R786BzF respectively). UV-induced photocrosslinking led to Ca2+dependent and voltage-independent effects in both mutants. N449BzF showed a steady-state current reduction at saturating Ca2+concentrations. Our data shows that this effect mainly relies on full occupancy of the RCK1 Ca2+binding site, since mutation of this site abolished the effect. The R786BzF construct showed a substantial potentiation of the current in the absence of Ca2+. In this case, photocrosslinking seems to favor the activation of the channel by voltage. Overall, these results suggest mobile interfaces between RCK domains are key to BK channel activation.
Co-evolution of human influenza A and Epstein Barr virus-specific CD8 ex vivo memory T cell receptor BV repertoires with increasing age
Authors: Clark Fransenio , Gil Anna , Aslan Nuray , Ghersi Dario , Selin Liisa K.
Published: December 2022

CD8 memory T cells are generated during primary infection with intracellular pathogens, such as viruses. These cells play an important role in the protection of the host upon re-infection with the same pathogen. In this study, we compare CD8 memory T cell receptor (TCR) BV repertoires directly ex vivo for two common human viruses, influenza A virus (IAV), an RNA virus that frequently re-infects due to a high rate of genetic mutation, and Epstein-Barr virus (EBV), a DNA virus, which persists in B cells for life, in the 95% of people that become infected. In cross- sectional and longitudinal studies of EBV seropositive, HLA-A2+, young (18-22 years), middle age (25-59 years), and older (>60 years) donors, we demonstrate that CD8 memory TCR repertoires to three immunodominant epitopes, known to have cross-reactive responses, IAV- M158-66(M1), EBV-BMLF1280-288(BM), and EBV-BRLF109-117(BR) co-evolve as individuals age. Cross-sectional studies showed that IAV-M1- and both EBV-specific repertoires narrowed their TRBV usage with increasing age manifesting to different degrees for each epitope. In fact, narrowing of EBV-BM and EBV-BR-specific TRBV usage correlated with increasing age. IAV- M1-specific TRBV usage was significantly narrowed by middle-age. There was evidence that TRBV usage was changing with increasing age. For instance, IAV-M1-specific dominant BV19 usage appeared to become bimodal showing either high or low frequency of usage in the older age group, while BV30 usage frequency directly correlated with age. For the EBV epitope-specific responses there was preferential usage of particular TRBV and changes in the hierarchy of BV family usage in the different age groups. There appeared to be focusing of the TRBV repertoire by all 3 epitopes to three common BV in the older donors, which would be consistent with retention of crossreactive TCR suggesting co-evolution. Longitudinal studies tracking two donors over 14- 15 years (middle age to older) showed that there were continuous modulations in the TCR repertoire of IAV-M1, EBV-BM and EBV-BR-specific responses over time. There was evidence that acute IAV infection could contribute to these changes in TCR repertoire. This could be occurring by the TCR cross-reactivity that is known to exist between these 3 epitopes, and which appeared to be enhanced during acute IAV infection based on increased usage of common shared TRBV. These studies suggest that virus-specific TCR repertoires change over time as individuals’ age leading to narrowing of the repertoire favoring retention of potentially crossreactive TCR.
Heritability and pre-adult survivorship costs of ectoparasite resistance in the naturally occurringDrosophila-Gamasodesmite system
Authors: Polak Michal , Bose Joy , Benoit Joshua B. , Singh Harmanpreet
Published: December 2022

Our understanding of the evolutionary significance of ectoparasites in natural communities is limited by a paucity of information concerning the mechanisms and heritability of resistance to this ubiquitous and diverse assemblage of organisms. Here, we report the results of artificial selection for increasing ectoparasite resistance in replicate lines ofDrosophila melanogasterderived from a field-fresh population. Resistance, as ability to avoid infestation by naturally occurringGamasodes queenslandicusmites, increased significantly in response to selection, and realized heritability (s.e.) was estimated to be 0.11 (0.0090). Ability to deploy energetically expensive bursts of flight from the substrate was a main mechanism of resistance that responded to selection, aligning with previously documented metabolic costs of fly behavioral defenses. Host body size, which affects parasitism rate in some fly-mite systems, was not shifted by selection. In contrast, resistant lines expressed significant reductions in larva-to-adult survivorship with increasing toxic (ammonia) stress, identifying an environmentally modulated pre-adult cost of resistance. Flies resistant toG. queenslandicuswere also more resistant to a different mite,Macrocheles subbadius, suggesting that we documented genetic variation and a pleiotropic cost of broad-spectrum behavioral immunity against ectoparasites. This study demonstrates significant evolutionary potential of an ecologically important trait.
Genome-wide association study reveals loci with sex-specific effects on plasma bile acids
Authors: Landini Arianna , Ghasemi-Semeskandeh Dariush , Johansson Åsa , Ahmad Shahzad , Liebisch Gerhard , Gnewuch Carsten ,   Regeneron Genetics Center, Tzoneva Gannie , Shuldiner Alan R. , Hicks Andrew A. , Pramstaller Peter , Pattaro Cristian , Campbell Harry , Polašek Ozren , Pirastu Nicola , Hayward Caroline , Ghanbari Mohsen , Gyllensten Ulf , Fuchsberger Christian , Wilson James F. , Klarić Lucija
Published: December 2022

Bile acids are essential for food digestion and nutrient absorption, but also act as signalling molecules involved in hepatobiliary diseases, gastrointestinal disorders and carcinogenesis. While many studies have focused on the genetic determinants of blood metabolites, research focusing specifically on genetic regulation of bile acids in the general population is currently lacking. Here we investigate the genetic architecture of primary and secondary bile acids in blood plasma, reporting associations with both common and rare variants. By performing genome-wide association analysis (GWAS) of plasma blood levels of 18 bile acids (N = 4923) we identify two significantly associated loci, a common variant mapping toSLCO1B1(encoding a liver bilirubin and drug transporter) and a rare variant inPRKG1(encoding soluble cyclic GMP-dependent protein kinase). For these loci, in the sex-stratified GWAS (N♂ = 820, N♀ = 1088), we observe sex-specific effects (SLCO1B1β ♂ = -0.51,P= 2.30×10−13, β♀ = -0.3,P= 9.90×10−07;PRKG1β ♂ = -0.18,P= 1.80×10−01, β ♀ = -0.79,P= 8.30×10−11), corroborating the contribution of sex to bile acid variability. Using gene-based aggregate tests and whole exome sequencing, we identify rare pLoF and missense variants potentially associated with bile acid levels in 3 genes (OR1G1, SART1andSORCS2), some of which have been linked with liver diseases.
COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data From Five Randomized Trials
Authors: Levine Adam C. , Fukuta Yuriko , Huaman Moises A. , Ou Jiangda , Meisenberg Barry R. , Patel Bela , Paxton James H. , Hanley Daniel F. , Rijnders Bart JA , Gharbharan Arvind , Rokx Casper , Zwaginga Jaap Jan , Alemany Andrea , Mitjà Oriol , Ouchi Dan , Millat-Martinez Pere , Durkalski-Mauldin Valerie , Korley Frederick K. , Dumont Larry J. , Callaway Clifton W. , Libster Romina , Marc Gonzalo Perez , Wappner Diego , Esteban Ignacio , Polack Fernando , Sullivan David J.
Published: December 2022

Background

Monoclonal antibody and antiviral treatments for COVID-19 disease remain largely unavailable worldwide, and existing monoclonal antibodies may be less active against circulating omicron variants. Although treatment with COVID-19 convalescent plasma (CCP) is promising, randomized clinical trials (RCTs) among outpatients have shown mixed results.

Methods

We conducted an individual participant data meta-analysis from all outpatient CCP RCTs to assess the overall risk reduction for all-cause hospitalizations by day 28 in all participants who had transfusion initiated. Relevant trials were identified by searching MEDLINE, Embase, MedRxiv, WHO, Cochrane Library, and Web of Science from January 2020 to September 2022.

Results

Five included studies from four countries enrolled and transfused 2,620 adult patients. Comorbidities were present in 1,795 (69%). The anti-Spike or virus neutralizing antibody titer range across all trials was broad. 160 (12.2%) of 1315 control patients were hospitalized, versus 111 (8.5%) of 1305 CCP-treated patients, yielding a 3.7% (95%CI: 1.3%-6.0%; p=.001) ARR and 30.1% RRR for all-cause hospitalization. The effect size was greatest in those with both early transfusion and high titer with a 7.6% ARR (95%CI: 4.0%-11.1%; p=.0001) accompanied by at 51.4% RRR. No significant reduction in hospitalization was seen with treatment > 5 days after symptom onset or in those receiving CCP with antibody titers below the median titer.

Conclusions

Among outpatients with COVID-19, treatment with CCP reduced the rate of all-cause hospitalization. CCP may be most effective when given within 5 days of symptom onset and when antibody titer is higher.

Key Points

While the outpatient COVID-19 randomized controlled trial meta-analysis indicated heterogeneity in participant risk factors and convalescent plasma, the combined CCP efficacy for reducing hospitalization was significant, improving with transfusion within 5 days of symptom onset and high antibody neutralization levels.
A versatile and interoperable computational framework for the analysis and modeling of COVID-19 disease mechanisms
Authors: Niarakis Anna , Ostaszewski Marek , Mazein Alexander , Kuperstein Inna , Kutmon Martina , Gillespie Marc E. , Funahashi Akira , Acencio Marcio Luis , Hemedan Ahmed , Aichem Michael , Klein Karsten , Czauderna Tobias , Burtscher Felicia , Yamada Takahiro G. , Hiki Yusuke , Hiroi Noriko F. , Hu Finterly , Pham Nhung , Ehrhart Friederike , Willighagen Egon L. , Valdeolivas Alberto , Dugourd Aurelien , Messina Francesco , Esteban-Medina Marina , Peña-Chilet Maria , Rian Kinza , Soliman Sylvain , Aghamiri Sara Sadat , Puniya Bhanwar Lal , Naldi Aurélien , Helikar Tomáš , Singh Vidisha , Fernández Marco Fariñas , Bermudez Viviam , Tsirvouli Eirini , Montagud Arnau , Noël Vincent , de Leon Miguel Ponce , Maier Dieter , Bauch Angela , Gyori Benjamin M. , Bachman John A. , Luna Augustin , Pinero Janet , Furlong Laura I. , Balaur Irina , Rougny Adrien , Jarosz Yohan , Overall Rupert W. , Phair Robert , Perfetto Livia , Matthews Lisa , Rex Devasahayam Arokia Balaya , Orlic-Milacic Marija , Cristobal Monraz Gomez Luis , De Meulder Bertrand , Ravel Jean Marie , Jassal Bijay , Satagopam Venkata , Wu Guanming , Golebiewski Martin , Gawron Piotr , Calzone Laurence , Beckmann Jacques S. , Evelo Chris T. , D’Eustachio Peter , Schreiber Falk , Saez-Rodriguez Julio , Dopazo Joaquin , Kuiper Martin , Valencia Alfonso , Wolkenhauer Olaf , Kitano Hiroaki , Barillot Emmanuel , Auffray Charles , Balling Rudi , Schneider Reinhard ,   the COVID-19 Disease Map Community
Published: December 2022

The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing. Community-driven and highly interdisciplinary, the project is collaborative and supports community standards, open access, and the FAIR data principles. The coordination of community work allowed for an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework links key molecules highlighted from broad omics data analysis and computational modeling to dysregulated pathways in a cell-, tissue- or patient-specific manner. We also employ text mining and AI-assisted analysis to identify potential drugs and drug targets and use topological analysis to reveal interesting structural features of the map. The proposed framework is versatile and expandable, offering a significant upgrade in the arsenal used to understand virus-host interactions and other complex pathologies.
Dynamic interplay between target search and recognition for the Cascade surveillance complex of type I-E CRISPR-Cas systems
Authors: Aldag Pierre , Rutkauskas Marius , Madariaga-Marcos Julene , Songailiene Inga , Sinkunas Tomas , Kemmerich Felix E , Kauert Dominik J , Siksnys Virginijus , Seidel Ralf
Published: December 2022

CRISPR-Cas effector complexes enable the defense against foreign nucleic acids and have recently been exploited as molecular tools for precise genome editing at a target locus. To bind and cleave their target, the CRISPR-Cas effectors first have to interrogate the entire genome for the presence of a matching sequence. Matching is achieved by base-pairing between the crRNA of the complexes and the DNA target strand such that an R-loop is formed. R-loop formation starts at a specific PAM motif and progresses reversibly in single base-pair steps until mismatches stop further progression or until the full target is recognized and destroyed. The reversible nature of this process entails that even a fully matching target should only become recognized with a low probability per target encounter. The details of this process, which directly affect the effectiveness of the target search, remain unresolved.

Here we dissect the target search process of the Type I CRISPR-Cas complex Cascade by simultaneously monitoring DNA binding and R-loop formation by the complex. We directly quantify the low target recognition probabilities and show that they increase with increasing negative supercoiling. Furthermore, we demonstrate that Cascade uses a combination of three-dimensional and limited one-dimensional diffusion along the DNA contour for its target search. The latter allows for rapidly scanning the PAM sequences in a given region and, importantly, significantly increasing the overall efficiency of the target search by repeatedly revisiting the sites. Overall we show that target search and target recognition are tightly linked and that DNA supercoiling and limited 1D diffusion need to be considered when understanding target recognition and target search by CRISPR-Cas enzymes and engineering more efficient and precise variants.
Genetic relationships and causality between overall and central adiposity and breast, prostate, lung and colorectal cancer
Authors: Maina Jared G , Pascat Vincent , Zudina Liudmila , Ulrich Anna , Pupko Igor , Demirkan Ayse , Bonnefond Amélie , Balkhiyarova Zhanna , Kaakinen Marika , Froguel Philippe , Prokopenko Inga
Published: December 2022

OBJECTIVE

Diverse measures of obesity relate to cancer risk differently. Here we assess the relationship between overall and central adiposity and cancer.

METHODS

We constructed z-score weighted polygenic scores (PGS) for two obesity-related phenotypes; body mass index (BMI) and BMI adjusted waist-to-hip ratio (WHRadjBMI) and tested for their association with five cancers in the UK Biobank: overall breast (BrC), post-menopausal breast (PostBrC), prostate (PrC), colorectal (CrC) and lung (LungC) cancer. We utilised publicly available data to perform bi-directional Mendelian randomization (MR) between BMI/WHRadjBMI and BrC, PrC and CrC.

RESULTS

PGSBMIhad significant multiple testing-corrected inverse association with PrC (OR[95%CI]=0.97[0.95-0.99],P=0.0012) but PGSWHRadjBMIwas not associated with PrC. PGSBMIwas associated with PostBrC (OR[95%CI]=0.97[0.96-0.99],P=0.00203) while PGSWHRadjBMIhad nominal association with BrC. PGSBMIhad nominal positive association with LungC. MR analyses showed significant multiple testing-corrected protective causal effect of BMI on PrC (OR[95%CI]=0.993[0.988-0.998],P=4.19×10−3). WHRadjBMI had a nominal causal effect on higher PrC risk (OR[95%CI]=1.022[1.0067-1.038],P=0.0053). We also report nominal causal protective effect of WHRadjBMI on breast cancer (OR[95%CI]=0.99[0.98-0.997],P=0.0068). Neither PGS nor MR analyses were significant for CrC.

CONCLUSIONS

Higher overall adiposity appears protective from PrC while higher central adiposity is a potential risk factor for PrC but protective from BrC.

STUDY IMPORTANCE

What is already known about this subject?

Observational studies suggest obesity is associated with higher risk of certain cancers and at the same time is protective of other cancers. The direction of association is in part influenced by the anthropometric trait used to assess obesity.

Higher BMI appears protective from prostate, breast and lung cancers but is a risk factor for post-menopausal breast, pancreatic and colorectal cancers.

What are the new findings in your manuscript?

We implement Mendelian randomization approach using large scale datasets and show a protective causal effect of higher BMI from prostate cancer but suggest that higher WHRadjBMI is causal for prostate cancer.

We also show nominal evidence of WHRadjBMI being causally protective from breast cancer.

How might your results change the direction of research or the focus of clinical practice?

We demonstrate the importance of partitioning obesity into discrete types depending on the area of fat deposition rather than using an overall measure.

Our results show that diverse measures of obesity relate differently to cancer risk. In fact, even for the same type of cancer, overall and central obesity measures may impact in opposite direction in terms of risk to cancer.
Automated 4D BIM development: the resource specification and optimization approach
Authors: Fazeli Abdulwahed , Banihashemi Saeed , Hajirasouli Aso , Mohandes Saeed Reza
Published: December 2022

Purpose

This research aims to develop an automated and optimization algorithms (OAs)-integrated 4D building information modeling (BIM) approach and a prototype and enable construction managers and practitioners to estimate the time of compound elements in building projects using the resource specification technique.

Design/methodology/approach

A 4D BIM estimation process was first developed by applying the resource specification and geometric information from the BIM model. A suite of OA including particle swarm optimization, ant colony, differential evolution and genetic algorithm were developed and compared in order to facilitate and automate the estimation process. The developed processes and porotypes were linked and integrated.

Findings

The OA-based automated 4D BIM estimation prototype was developed and validated through a real-life construction project. Different OAs were applied and compared, and the genetic algorithm was found as the best performing one. The prototype was successfully linked with BIM timeliner application. By using this approach, the start and finish dates of all object-based activities are developed, and the project completion time is automatically estimated.

Originality/value

Unlike conventional construction estimation methods which need various tools and are error prone and time-consuming, the developed method bypasses the existing time estimation tools and provides the integrated and automated process with BIM and machine learning algorithms. Furthermore, this approach integrates 4D BIM applications into construction design procedures, connected with OA automation.
The interaction effect of government non-financial support and firm's regulatory compliance on firm innovativeness in Sub-Saharan Africa
Authors: Njinyah Sam , Asongu Simplice , Adeleye Ngozi
Published: December 2022

Purpose

The purpose of this study is to assess the interaction effect of government non-financial support and firms' regulatory compliance on firms' innovativeness. Firms' regulatory compliance with environmental and safety issues has been suggested as one of the reasons why firms innovate. Such compliance provides legitimacy, improves reputation and corporate image, and enhances customer loyalty and competitive advantages, which influence firm innovativeness. However, regulatory compliance is costly and with limited resources, the role of government support is crucial as a moderator, to help firms become more compliant and influence their innovativeness.

Design/methodology/approach

The study uses data from the World Bank Enterprise Innovation Survey for seven countries in Sub-Saharan Africa.

Findings

Regulatory compliance has a positive and significant effect on firm innovativeness. Increased use of government non-financial support enhances the level of firm regulatory compliance and the effect of regulatory compliance on firm innovativeness.

Originality/value

The study contributes to the literature on compliance and firm innovativeness in Africa by showing how the positive effect of regulatory compliance on firm innovativeness is stronger when firms benefit from government non-financial support.
A new era of the music industry? Blockchain and value co-creation: the Bitsong case study
Authors: Centorrino Giovanna , Naciti Valeria , Rupo Daniela
Published: December 2022

Purpose

The study aims to investigate the impact of technological innovation, such as blockchain, in the music field from a value co-creation perspective, highlighting how it is determining a radical change in the business model and value creation process.

Design/methodology/approach

To shed light on how blockchain adoption is reconfiguring the music industry, the authors adopted a qualitative-based approach based on a case study, allowing us to investigate value co-creation at three levels (macro, meso and micro) through exchange and integration of multi-actor resources.

Findings

The authors found that blockchain adoption in the music industry can singularly shape the business model, representing a powerful tool to enhance inter-organizational cooperation in value creation. It effectively deals with operational and business issues, besides financial transactions, profoundly impacting both the creation and distribution of value within the supply chain.

Research limitations/implications

The research contributes to a better understanding of innovation adoption in a specific setting, the music industry, giving support and guidance for players working in this ecosystem. The blockchain-music link helps close the gap between music and society through technology, thus providing a foundation for future research.

Originality/value

The paper provides new insights into the antecedents and mechanisms of value co-creation, spanning macro-, meso-, and micro-levels of context. It also illustrates the factors underpinning Bitsong viability to embed the value co-creation perspective in designing the business model within a value network.
The corruption and sustainable development nexus in Africa: a contemporary review and analysis
Authors: Hope, Sr. Kempe Ronald
Published: December 2022

Purpose

This study aims to re-examine the corruption and sustainable development nexus in Africa and offer a contemporary analytical review and analysis of that relationship in the region.

Design/methodology/approach

Drawing on the available and accessible relevant data from credible sources, this work quantifies, outlines and analyses the nexus between corruption and sustainable development, as it applies primarily to sub-Saharan Africa. It uses the relevant disaggregated data and also complements that with the results of reliable empirical studies to further cross-reference and demonstrate the corruption and sustainable development nexus.

Findings

It is shown that corruption in Africa continues to be negatively associated with sustainable development objectives and that, in turn, will continue to affect the continent’s progress in achieving sustainable development. Undoubtedly, corruption is very damaging to economies across all nations and regions. However, in Africa, this impact on sustainable development has been particularly severe and ongoing. Consequently, the views expressed several decades ago of corruption being able to grease the wheels and potentially contribute to economic development is not valid and, in fact, has been severally discredited over the years.

Originality/value

The main value of the paper is the insights it provides, and with cross-reference to the empirical literature and time series data, on the corruption and sustainable development nexus in Africa.
Improving the waste to energy supply chain through increased overall equipment effectiveness
Authors: Wijesinghe Prashan Bandara , Illankoon Prasanna
Published: December 2022

Purpose

The purpose of this study was to improve the overall equipment effectiveness (OEE) of the production process of the shredder operation of ABC company, an industrial waste management company which supplies pre-processed industrial waste as alternative fuel to a cement plant.

Design/methodology/approach

This case study investigated all possible availability and performance losses that caused the shredder system’s OEE and various problem-solving techniques, such as root cause analysis and Pareto analysis, were used to find the root cause of the reduced OEE.

Findings

After analysing this case study, three significant loss factors were identified from all the availability and performance losses, which caused the shredder system’s OEE losses. Practical solutions were found for the effect of those loss factors to improve the machine’s OEE and productivity.

Research limitations/implications

This case study has been concentrated on only analysing of losses and improvement of OEE in the production process and not about cost analysis between loss and improvements.

Originality/value

This paper shows how to improve the OEE of a production process through various problem-solving techniques by identifying its losses and how to achieve the best solutions for those losses in a practical manner.