bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary Targeted Muscle Reinnervation after Below Knee Amputation is Not Associated with An Increased Risk of Major or Minor Surgical Complications: A Multi-Institutional, Propensity Score-Matched Analysis
Authors: Shammas Ronnie L. , Azoury Said C. , Sergesketter Amanda R. , Lee Hui-Jie , Poehlein Emily , Othman Sammy E. , Cason Roger W. , Levinson Howard , Kovach Stephen J. , Mithani Suhail K.
Published: July 2022

BACKGROUND:

Targeted muscle reinnervation (TMR) has emerged as a technique to reduce neuroma and phantom limb pain after below knee amputation (BKA); however, the incidence of post-operative complications remains unknown. This multi-institutional study assessed the risk of post-operative complications among patients who underwent TMR at the time of BKA (BKA+TMR).

STUDY DESIGN:

Patients who underwent BKA+TMR were propensity score-matched 1:3 to patients who underwent BKA only. Study outcomes included the incidence of major or minor complications within 60 days. Regression models were utilized to estimate the relative risk (RR) of major and minor complications.

RESULTS:

Overall, 96 patients were matched including 31 BKA+TMR and 65 BKA only. In the matched sample, a higher incidence of major complications (29% vs. 24.6%), readmission (25.8% vs. 18.5%) and reoperation (19.4% vs. 10.8%) was seen after BKA+TMR compared to BKA only. Furthermore, patients who underwent BKA+TMR displayed a higher incidence of minor complications (25.8% versus 20.0%), blood transfusion (22.6% vs. 18.5%), wound healing complications (45.2% vs. 33.8%), and longer operative time (mean [standard deviation] 188.5 [63.6] vs. 88 [28.2] minutes). However, there was no statistically significant difference in the risk of major (RR:1.20, 90% confidence interval (CI):0.68, 2.11) or minor (RR:1.21, 90% CI:0.61, 2.41) complications between the two cohorts.

CONCLUSION:

Despite an increased incidence of post-operative complications, undergoing BKA+TMR does not confer a statistically significant increased risk of major or minor complications. Future studies are needed to delineate patient selection criteria when assessing the suitability of TMR at the time of major limb amputation.
“Negative Pressure Wound Therapy (NPWT) Yields Lower Wound Complication and Surgical Site Infection Rates Compared to Standard Surgical Dressings (SSDs) after Resection of a Malignancy: A Systematic Review and Meta-Analysis”
Authors: Hays Thomas R. , Singh Gurtej , Saragossi Jamie , Park Jason , Shekar Shruthi , Marquez Jocellie E. , Dagum Alexander B. , Khan Sami U. , Khan Fazel A. , Bui Duc T.
Published: July 2022

Background–

Negative Pressure Wound Therapy (NPWT) offers many advantages over Standard Surgical Dressings (SSDs) in the treatment of open wounds including accelerated wound healing (72.3% vs 30.8%), cost savings (up to $1,607), and reduced complication rates (35% vs 53%).2-4 Contraindicated by device manufacturers in malignancy-resected wounds for hypothesized risk of tumor recurrence, NPWT is still applied post-operatively due to limited clinical support. A systematic review with meta-analysis was performed to compare NPWT outcomes with SSDs on open wounds with our null hypotheses stating there would be no outcome differences.

Methods–

A systematic review of the literature on NPWT and SSDs on malignancy-resected wounds was conducted following PRISMA guidelines using PubMed, EMBASE, CINAHL, and Cochrane Central databases. Meta-analysis compared group outcomes, including malignancy recurrence, wound complication, and surgical site infection (SSI) rates, with random effects model.

Results–

1,634 studies were identified and 27 met eligibility criteria, including 4 randomized control trials (RCTs), 4 prospective cohort studies, and 19 retrospective reviews. Eighty-one percent of papers (n = 22) recommended NPWT use in malignancy-resected wounds. Meta-analysis determined NPWT yielded significantly lower overall SSI (P = 0.004) and wound complication rates (P = 0.01) than SSDs; however, there were no statistically significant differences found for other outcomes between the two groups.

Conclusions–

This review demonstrates favorable outcomes of NPWT over SSDs for malignancy-resected wounds without an increased risk of malignancy recurrence. However, with limited RCTs (detailing only incisional wounds for limited malignancies and anatomic regions), additional high-power RCTs are recommended.
OLDER PATIENTS AND PATIENTS WITH SEVERE ARTERIOSCLEROSIS ARE LESS LIKELY TO DEVELOP KELOIDS AND HYPERTROPHIC SCARS AFTER THORACIC MIDLINE INCISION: A SURVEY-BASED ANALYSIS OF 328 CASES
Authors: Sugimoto Atsuko , Ono Shinpei , Usami Satoshi , Nitta Takashi , Ogawa Rei
Published: July 2022

BACKGROUND:

Surgery is a well-known trigger of keloid and hypertrophic scarring. Sternotomy scars are subject to high skin tension, which is also known to promote pathological scarring. This suggests that sternotomies in adults associate with high pathological-scarring rates, which is also our anecdotal experience. However, this notion has never been formally examined. Therefore, we conducted a survey-based cohort study of patients who had undergone a sternotomy.

STUDY DESIGN:

All consecutive Japanese adults (≥18 years) who underwent cardiovascular surgery with sternotomy in 2014–2017 were identified in 2019 by chart review and sent a questionnaire. Respondents formed the study cohort. The questionnaire presented randomly-ordered photos of representative mature, keloid, and hypertrophic scars and asked the patients to choose the image that best resembled their midline scar when it was particularly noticeable. The incidence of self-reported pathological scarring (keloids and hypertrophic scars were grouped together) and the patient demographic (age and sex) and clinical characteristics (e.g. intima media thickness of the left and right common and internal carotid arteries) that associated with pathological scarring were determined.

RESULTS:

Of the 548 sternotomy patients, 328 (mean age, 67 years; 68.0% male) responded (60% response rate). Of these, 195 (59.5%) reported they had a pathological scar. Compared to mature-scar patients, pathological-scar patients had lower mean age (65 vs. 69 years, p=0.0002) and intima-media thickness (0.92 vs. 1.05 mm, p=0.028).

CONCLUSION:

Sternotomy was associated with a high rate of pathological scarring. An older age and arteriosclerosis were associated with less pathological scarring.
“An Algorithm for Reconstruction of Electrical Injuries of the Scalp”
Authors: Khalid Farrukh A. , Ahmed Omar A. , Rabbani Muhammad Jibran , Saleem Muhammad , Amin Muhammad , Mujahid Abdul Malik , Mehrose Muhammad Younas , Tarar Moazzam N , Shahzad Farooq
Published: July 2022

Background:

Electrical Injuries of the scalp are a frequent occurrence in underdeveloped countries. Burns can be contact or conductive and result in extensive tissue damage. We present our experience with treatment of scalp and calvarial electrical injuries and propose a management algorithm.

Methods:

This is a retrospective cohort study comprising of all patients with electrical injuries of the scalp treated at our center between January 2010 and December 2016. Non-contrast computed tomography scan was obtained to assess viability of the calvarium in patients who presented more than 2 weeks after injury. Single stage debridement and reconstruction was performed. All non-viable soft tissue and bone was removed. Soft tissue reconstruction was performed with skin grafts, local scalp flaps, pedicled trapezius flaps, and free flaps (anterolateral thigh, latissimus dorsi and scapular). Cranioplasty was performed in a delayed manner with autologous bone grafts.

Results:

Over a 7-year period, a total of 52 patients underwent scalp reconstruction for high voltage (44 patients) and low voltage (8 patients) electrical injury All patients underwent successful soft tissue reconstruction. Osteomyelitis with draining sinuses developed in 3 patients; these patients underwent flap re-elevation and bone debridement, which resulted in a healed wound and stable reconstruction. Cranioplasty was performed with split calvarial grafts in 2 patients and split rib grafts in 4 patients. One patient underwent scalp tissue expansion for hair restoration.

Conclusions:

We propose an algorithm for reconstruction of electrical injuries of the scalp. Thorough debridement of the calvarium is the most important determinant of a successful outcome.
Refined concept of motor supply to the medial periorbital area relevant to periorbital surgery
Authors: Choi Yeop , Kim In-Beom
Published: July 2022

Background:

Mimetic muscles in the medial periorbital area were thought to be innervated solely by the angular nerve. Recently however, the upper medial palpebral branch and lower palpebral branch were reported as additional motor suppliers in this area. This study aimed to define all the motor nerve systems passing through the medial canthal area.

Methods:

Motor nerve branches that passed through the medial canthal region were identified and traced thoroughly from the parotid gland to their destinations under a surgical microscopic field in 74 hemifaces. The courses, anatomical positions of, and anatomical relationships between the angular nerve and the upper medial palpebral branch were observed.

Results:

The upper medial palpebral branch and the angular nerve were found in all samples within a 3-6 mm area lateral to the intersecting point of the medial orbital rim and medial canthal ligament. The upper medial palpebral branch supplied the upper eyelid, whereas the angular nerve supplied the extra-orbicularis muscles in the medial periorbital area. The medial pretarsal area of the upper eyelid was supplied solely by the pretarsal branches of the upper medial palpebral branch, which was formed by uniting three or four minor branches that traveled throughout the anterior cheek.

Conclusion:

wo separate motor nerve systems, the upper medial palpebral branch and the angular nerve, exist in the medial canthal area. The upper medial palpebral branch course along the medial orbital rim is considered as a facial nerve danger zone.
Impact of orthodontic gap closure versus prosthetic replacement of missing maxillary lateral incisor on dental arch relationships and symmetry on 212 cleft patients: a retrospective study Missing lateral incisor gap in cleft patients (39/40 characters max)
Authors: QUENEL Léonie , KERIBIN Pierre , DURAND Thomas , SALAGNAC Jean-Michel , PERRIN Jean-Philippe , DELAIRE Jean , MERCIER Jacques , TALMANT Jean-Claude , CORRE Pierre , BERTIN Helios
Published: July 2022

Background:

Maxillary lateral incisors (MLI) are frequently missing in cleft patients. The aim of this study was to assess how orthodontic gap closure or prosthetic rehabilitation of the missing MLI affected the dental arch relationships and symmetry at the end of treatment. We also aimed to determine the impact of the level of oral hygiene on the decision made to manage the missing MLI gap.

Methods:

A descriptive, retrospective cohort study including all cleft patients born between 1980 and 1999 treated at Nantes Cleft Center was performed. Patients presenting unilateral or bilateral missing MLI were reviewed. Data about management of the missing MLI gap, dental arch relationships, symmetry and level of oral hygiene were collected.

Results:

Four hundred and eighty-six cleft patients were reviewed, including 212 patients with unilateral or bilateral missing MLI. When compared to orthodontic gap closure, prosthetic replacement of the MLI gap was associated with better final dental arch relationships (59.8% vs. 10.3%; p<0.01) and better dental arch symmetry (88.1% vs. 44.0%; p<0.01) for unilateral missing MLI cases but not for bilateral missing MLI cases. A better level of oral hygiene was associated with more cases with prosthetic replacement for unilateral missing MLI cases (p=0.03) and had no impact for bilateral missing MLI cases.

Conclusion:

Prosthetic replacement of the missing MLI gap provided better functional and esthetic results for cleft patients presenting with unilateral missing MLI.
Prospective evaluation of the selective nonoperative management of abdominal stab wounds: When is it safe to discharge?
Authors: Owattanapanich Natthida , Cremonini Camilla , Schellenberg Morgan A. , Matsushima Kazuhide , Lewis Meghan R. , Lam Lydia , Martin Matthew J. , Inaba Kenji
Published: July 2022

BACKGROUND

The optimal observation time required to exclude hollow viscus injury in patients undergoing selective nonoperative management (SNOM) for abdominal stab wounds (SWs) remains unclear. The aim of this study was to determine the safe period of observation required before discharge.

METHODS

In this prospective observational study, all patients who sustained an abdominal SW were screened for study inclusion (July 2018 to May 2021). The primary study outcome was time to SNOM failure, defined as the need for surgical intervention after an initial period of observation.

RESULTS

During the study period, 256 consecutive patients with an abdominal SW met the study criteria. The mean age was 33 (26–46) years, and 89% were male. Of all patients, 77% had single SW, and 154 (60%) had an anterior abdominal SW (most common site right upper quadrant, 31%). Forty-six (18%) underwent immediate laparotomy because of evisceration (59%), hemodynamic instability (33%), or peritonitis (24%). The remaining 210 patients (82%) were taken for computed tomography scan (n = 208 [99%]) or underwent clinical observation only (n = 2 [<1%]). Of the patients undergoing computed tomography scan, 27 (13%) triggered operative intervention, and 9 (4%) triggered angioembolization. The remaining 174 patients (83%) underwent SNOM. Of these, three patients (2%) failed SNOM and underwent laparotomy: two developed peritonitis at 10 and 20 hours after arrival, respectively, and at laparotomy had small bowel and gastric injuries. The third patient developed increasing leukocytosis but had nontherapeutic laparotomy.

CONCLUSION

Selective nonoperative management of stab wounds to the abdomen commonly avoids nontherapeutic operative intervention and its resultant complications. A small percentage of patients will fail SNOM, and therefore, close clinical observation of these patients in hospital is critical. All patients in this series who failed SNOM did so within 24 hours of presentation. Therefore, we recommend a period of 24 hours of close clinical monitoring to exclude a hollow viscus injury before discharge of patients with abdominal stab wounds who do not meet the criteria for immediate operative intervention.

LEVEL OF EVIDENCE

Prognostic/Epidemiological; Level III.
Postsecondary Education and Late-life Cognitive Outcomes Among Black and White Participants in the Project Talent Aging Study
Authors: Thomas Marilyn D. , Calmasini Camilla , Seblova Dominika , Lapham Susan , Peters Kelly , Prescott Carol A. , Mangurian Christina , Glymour Medellena Maria , Manly Jennifer J.
Published: July 2022

Background:

Higher education consistently predicts improved late-life cognition. Racial differences in educational attainment likely contribute to inequities in dementia risk. However, few studies of education and cognition have controlled for prospectively measured early-life confounders or evaluated whether the education late-life cognition association is modified by race/ethnicity.

Methods:

Among 2343 Black and White Project Talent Aging Study participants who completed telephone cognitive assessments, we evaluated whether the association between years of education and cognition (verbal fluency, memory/recall, attention, and a composite cognitive measure) differed by race, and whether these differences persisted when adjusting for childhood factors, including the cognitive ability.

Results:

In fully adjusted linear regression models, each additional year of education was associated with higher composite cognitive scores for Black [β=0.137; 95% confidence interval (CI)=0.068, 0.206] and White respondents (β=0.056; CI=0.034, 0.078) with an interaction with race (P=0.03). Associations between education and memory/recall among Black adults (β=0.036; CI=−0.037, 0.109) and attention among White adults (β=0.022; CI=−0.002, 0.046) were nonsignificant. However, there were significant race-education interactions for the composite (P=0.03) and attention measures (P<0.001) but not verbal fluency (P=0.61) or memory/recall (P=0.95).

Conclusion:

Education predicted better overall cognition for both Black and White adults, even with stringent control for prospectively measured early-life confounders.
Lesion network mapping for symptom localization: recent developments and future directions
Authors: Joutsa Juho , Corp Daniel T. , Fox Michael D.
Published: July 2022

Purpose of review

Focal lesions causing specific neurological or psychiatric symptoms can occur in multiple different brain locations, complicating symptom localization. Here, we review lesion network mapping, a technique used to aid localization by mapping lesion-induced symptoms to brain circuits rather than individual brain regions. We highlight recent examples of how this technique is being used to investigate clinical entities and identify therapeutic targets.

Recent findings

To date, lesion network mapping has successfully been applied to more than 40 different symptoms or symptom complexes. In each case, lesion locations were combined with an atlas of human brain connections (the human connectome) to map heterogeneous lesion locations causing the same symptom to a common brain circuit. This approach has lent insight into symptoms that have been difficult to localize using other techniques, such as hallucinations, tics, blindsight, and pathological laughter and crying. Further, lesion network mapping has recently been applied to lesions that improve symptoms, such as tremor and addiction, which may translate into new therapeutic targets.

Lesion network mapping can be used to map lesion-induced symptoms to brain circuits rather than single brain regions. Recent findings have provided insight into long-standing clinical mysteries and identified testable treatment targets for circuit-based and symptom-based neuromodulation.
Temporally auto-correlated predator attacks structure ecological communities
Authors: Schreiber Sebastian J.
Published: July 2022

For species primarily regulated by a common predator, the
P
* rule of Holt & Lawton (Holt & Lawton, 1993.
Am. Nat.
142
, 623–645. (
doi:10.1086/285561
)) predicts that the prey species that supports the highest mean predator density (
P
*) excludes the other prey species. This prediction is re-examined in the presence of temporal fluctuations in the vital rates of the interacting species including predator attack rates. When the fluctuations in predator attack rates are temporally uncorrelated, the
P
* rule still holds even when the other vital rates are temporally auto-correlated. However, when temporal auto-correlations in attack rates are positive but not too strong, the prey species can coexist due to the emergence of a positive covariance between predator density and prey vulnerability. This coexistence mechanism is similar to the storage effect for species regulated by a common resource. Negative or strongly positive auto-correlations in attack rates generate a negative covariance between predator density and prey vulnerability and a stochastic priority effect can emerge: with non-zero probability either prey species is excluded. These results highlight how temporally auto-correlated species’ interaction rates impact the structure and dynamics of ecological communities.
Neural underpinnings of action adaptation in the subthalamic nucleus
Authors: Herz Damian M. , Bange Manuel , Gonzalez-Escamilla Gabriel , Auer Miriam , Muthuraman Muthuraman , Bogacz Rafal , Groppa Sergiu , Brown Peter
Published: July 2022

Adapting our actions to changing goals and environments is central to intelligent behavior. There is substantial evidence that the basal ganglia play a crucial role in reinforcing actions that have led to favorable outcomes. However, little is known about the neural mechanisms underlying action adaptation following unfavorable outcomes when change is warranted. Here, we recorded electrophysiological activity and applied bursts of electrical stimulation to the subthalamic nucleus (STN), a core area of the basal ganglia, in patients with Parkinson’s disease using deep brain stimulation electrodes. During a task where patients continuously had to adapt their force depending on changing action-value associations, decreases in STN beta (13-30 Hz) activity in two critical time windows were associated with poorer outcomes and stronger action adaptation. STN stimulation reduced beta activity and led to stronger action adaptation if applied within the time windows when STN activity reflected action evaluation and adaptation. These results suggest that dynamic modulation of STN activity facilitates adaptive behavior.
Major Histocompatibility Complex (MHC) I-induced Endoplasmic Reticulum (ER) Stress mediates the secretion of pro-inflammatory muscle-derived cytokines
Authors: Thoma Anastasia , Earl Kate E. , Cooper Robert G. , Goljanek-Whysall Katarzyna , Lightfoot Adam P.
Published: July 2022

Major histocompatibility complex (MHC) I is an important component of intracellular antigen presentation. However, improper expression of MHC I upon the cell surface has been associated with several autoimmune diseases. Myositis is a rare acquired autoimmune diseases which targets skeletal muscle, and MHC I overexpression on the surface of muscle fibres and immune cell infiltration are clinical hallmarks. MHC I overexpression may have an important pathogenic role, mediated by the activation of the endoplasmic reticulum (ER) stress response. Given the evidence that muscle is a diverse source of cytokines, we aimed to investigate whether MHC I overexpression can modify the profile of muscle-derived cytokines and what role the ER stress pathway may play. Using C2C12 myoblasts we overexpressed MHC I with a H-2kb vector in the presence or absence of salubrinal an ER stress pathway modifying compound. MHC I overexpression induced ER stress pathway activation and elevated cytokine gene expression. MHC I overexpression caused significant release of cytokines and chemokines, which was attenuated in the presence of salubrinal. Conditioned media from MHC I overexpressing cells induced in vitro T-cell chemotaxis, atrophy of healthy myotubes and modified mitochondrial function, features which were attenuated in the presence of salubrinal. Collectively, these data suggest that MHC I overexpression can induce pro-inflammatory cytokine/chemokine release from C2C12 myoblasts, a process which appears to be mediated in-part by the ER stress pathway.
Genome-wide determination of barriers to horizontal gene transfer
Authors: Burch Christina L. , Romanchuk Artur , Kelly Michael , Wu Yingfang , Jones Corbin D.
Published: July 2022

Horizontal gene transfer (HGT) is a major contributor to bacterial genome evolution, generating phenotypic diversity, driving the expansion of protein families, and facilitating the evolution of new phenotypes, new metabolic pathways, and new species. Comparative studies of gene gain in bacteria suggest that the frequency with which individual genes successfully undergo HGT varies considerably and may be associated with the number of protein-protein interactions in which the gene participates—its connectivity. Two non-exclusive hypotheses have emerged to explain why transferability should decrease with connectivity: the Complexity Hypothesis (Jain, Rivera, & Lake, 1999) and the Balance Hypothesis (Papp, Pál, & Hurst, 2003). These hypotheses predict that the functional costs of HGT arise from a failure of divergent homologues to make normal protein-protein interactions or from gene mis-expression, respectively. Here we describe genome-wide assessments of these hypotheses in which we used 74 existing prokaryotic whole genome shotgun libraries to estimate rates of horizontal transfer of genes from taxonomically diverse prokaryotic donors into E. coli. We show that transferability declines as connectivity increases, but that this effect is driven primarily by the ribosomal genes. We also show that transferability declines as the divergence (% amino acid difference) between donor and recipient orthologs increases and that this effect of divergence increases with connectivity. We explain how these results, even the stronger effect of connectivity on the transferability of ribosomal compared to non-ribosomal genes, provide strong support for both the Balance and Complexity Hypotheses.

Significance Statement

Comparisons between prokaryotic genomes consistently show that genes with informational functions, e.g. in genome replication, transcription, and translation, have been subject to horizontal gene transfer between species more often than genes with operational functions, e.g. in metabolism and environmental sensing. In this study, we use a genome wide analysis of transferability data obtained from 74 genomes to provide the first experimental evidence that this pattern results from differences between informational and operational genes in the number of other proteins with which they interact, i.e., their connectivity, rather than from their functional differences. The importance of our exceptionally large dataset to the detection of connectivity effects on transferability explains why past experimental studies failed to replicate the consistent finding from comparative genomic studies.
Evaluating a Human/Machine Interface with Redundant Motor Modalities for Trajectory-Tracking
Authors: Chou Amber H.Y. , Yamagami Momona , Burden Samuel A.
Published: July 2022

In human/machine interfaces (HMI), humans can interact with dynamic machines through a variety of sensory and motor modalities. Redundant motor modalities are known to have advantages in both human sensorimotor control and human-computer interaction: motor redundancy in sensorimotor control provides abundant solutions to achieve tasks; and incorporating diverse features from different modalities has improved the performance of movement-, gesture-, and brain-controlled computer interfaces. Our objective is to investigate whether redundant motor modalities enhance performance for a continuous trajectory-tracking task. We designed a multimodal human/machine interface with combined manual (joystick) and muscle (surface electromyography, sEMG) inputs and evaluated its closed-loop performance for tracking trajectories through second-order machine dynamics. In a human subjects experiment with 15 participants, we found that the multimodal interface outperformed the manual-only interface while performing comparably to the muscle-only interface; and that the multimodal interface enabled users to coordinate individual modalities to attenuate noise. Multimodal human/machine interfaces could be beneficial in systems that require stability and robustness against perturbations such as motor rehabilitation and robotic manipulation.
Mid-life leukocyte telomere length and dementia risk: a prospective cohort study of 435,046 UK Biobank participants
Authors: Liu Rui , Xiang Meiruo , Pilling Luke C. , Melzer David , Wang Lihong , Manning Kevin J. , Steffens David C. , Bowden Jack , Fortinsky Richard H. , Kuchel George A. , Rhee Taeho G , Diniz Breno S. , Kuo Chia-Ling
Published: July 2022

Importance

Telomere attribution is one of biological aging hallmarks and may be intervened to target multiple aging-related diseases, including Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD).

Objective

To assess associations of leukocyte telomere length (TL) with AD/ADRD and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging (MRI) phenotypes.

Design, Setting, and Participants

Data from European-ancestry participants in the UK Biobank (n=435,046) were used to evaluate whether mid-life leukocyte TL is associated with incident AD/ADRD over a mean follow-up of 12.2 years. In a subsample without AD/ADRD and with brain imaging data (n=43,390), we associated TL with brain MRI phenotypes related to AD or vascular dementia pathology.

Exposures

Relative mean leukocyte TL at baseline was measured in T/S ratio, using a multiplex quantitative polymerase chain reaction technique by comparing the amount of the telomere amplification product (T) to that of a single-copy gene (S).

Main Outcomes and Measures

AD/ADRD was confirmed by mapping multi-source data to 3-charcter ICD codes (G30; F00; F01; F03; G31), excluding other-cause dementias (F02).

Results

Longer TL was associated with a lower risk of incident AD/ADRD (adjusted HR [aHR] per SD=0.93, 95% CI 0.90 to 0.96, P=3.37×10−7). Longer TL also was associated with better cognitive performance in specific cognitive domains, larger hippocampus volume (adjusted standardized β [aβ] per SD=0.012, 95% CI 0.003 to 0.021, P=0.012), lower total volume of white matter hyperintensities (aβ per SD= -0.015, 95% CI -0.024 to -0.006, P=0.002), and higher fractional anisotropy (FA; aβ per SD=0.018, 95% CI 0.009 to 0.027, P=9.44×10−5) and lower mean diffusivity (MD; aβ per SD=0.045, 95% CI 0.035 to 0.056, P=1.07×10−17) in the fornix.

Conclusions and Relevance

Longer TL is a protective factor against AD/ADRD, cognitive impairment, and brain structural lesions toward the development of AD/ADRD. A better understanding of underlying mechanisms may help improve diagnosis and management of AD/ADRD in older adults.

Key Points

Question

Is leukocyte telomere length (TL) associated with Alzheimer’s disease (AD) and AD related dementias (AD/ADRD) and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging phenotypes?

Findings

Longer TL was associated with a lower risk of incident AD/ADRD, larger hippocampus volume, lower total volume of white matter hyperintensities, higher fractional anisotropy and lower mean diffusivity in the fornix.

Meaning

Longer TL in midlife may play a protective role against AD/ADRD, and a better understanding of underlying mechanisms may help improve diagnosis and management of AD/ADRD in older adults.
Long-range communication between transmembrane- and nucleotide-binding domains does not depend on drug binding to mutant P-glycoprotein
Authors: Bonito Cátia A. , Ferreira Ricardo J. , Ferreira Maria-José.U. , Gillet Jean-Pierre , Cordeiro M. Natália D. S. , dos Santos Daniel J. V. A.
Published: July 2022

The modulation of drug efflux by P-glycoprotein (P-gp, ABCB1) represents one of the most promising approaches to overcome multidrug resistance (MDR) in cancer cells, however the mechanisms of drug specificity and signal-transmission are still poorly understood, hampering the development of more selective and efficient P-gp modulators. In this study, the impact of four P-gp mutations (G185V, G830V, F978A and ΔF335) on drug-binding and efflux-related signal-transmission mechanism was comprehensively evaluated in the presence of ligands within the drug-binding pocket (DBP), which are experimentally related with changes in their drug efflux profiles. The severe repacking of the transmembrane helices (TMH), induced by mutations and exacerbated by the presence of ligands, indicates that P-gp is sensitive to perturbations in the transmembrane region. Alterations on drug-binding were also observed as a consequence of the TMH repacking, but were not always correlated with alterations on ligands binding mode and/or binding affinity. Finally, and although all P-gp variantsholosystems showed considerable changes in the intracellular coupling helices/nucleotide-binding domain (ICH-NBD) interactions, they seem to be primarily induced by the mutation itself rather than by the presence of ligands within the DBP. The data further suggest that the changes in drug efflux experimentally reported are mostly related with changes on drug specificity rather than effects on signal-transmission mechanism. We also hypothesize that an increase in the drug-binding affinity may also be related with the decreased drug efflux, while minor changes in binding affinities are possibly related with the increased drug efflux observed in transfected cells.
Serotyping Salmonella Enteritidis and Typhimurium Using Whole Cell Matrix Assisted Laser Desorption Ionization – Time of Flight Mass Spectrometry (MALDI-TOF MS) through Multivariate Analysis and Artificial Intelligence
Authors: Gao Anli , Fischer-Jenssen Jennifer , Slavic Durda , Rutherford Kimani , Lippert Sarah , Wilson Emily , Chen Shu , Leon-Velarde Carlos G. , Martos Perry
Published: July 2022

Salmonella is one of the most frequent food-borne zoonoses, while Salmonella Typhimurium and Enteritidis are the major serovars of concern in public health. 113 Salmonella strains including 38 S. Enteritidis (SE), 38 S. Typhimurium (ST) and 37 strains of 32 other Salmonella serovars (SG) were tested in quadruplicate by whole-cell MALDI-TOF MS. Ions were studied and aligned from the raw data of mzXML files using Mass-Up (http://www.sing-group.org/mass-up), resulting in 1,741 aligned peaks. Datasets of ions (presence/absence) selected using a home-developed criteria on their specificity and detectability were subjected to multivariate analyses and artificial intelligence tools. Principle Component Analysis based on 88 selected ions separated SE, ST and SG without overlap on the first three principle components. The network and forest based deep learning tools were more sophisticated than the decision tree-based models. Neural Network carried out consistently well in training model, but no advantage was gained over the other models in validation results. HP (high performance) Neural, Support Vector Machine, HP Forest and Gradient Boasting were able to identify SE, ST and SG up to 100% correctly in both training and validation when 88 selected ions were used in analysis. Among them, HP Neural seemed to perform slightly better and relatively stable. Selection of serovar specific ions helps develop serotyping by increasing signal to noise. MALDI-TOF MS used with appropriate data processing strategies and classification tools could be applied to quickly alert when Salmonella serotypes of concern are suspected among routinely processed samples.
Targeting C5aR1 signaling reduced neutrophil extracellular traps and ameliorates COVID-19 pathology
Authors: Silva Bruna M. , Veras Flavio P. , Gomes Giovanni F. , Cambier Seppe , Silva Gabriel V. L. , Quadros Andreza U. , Caetité Diego B. , Nascimento Daniele C. , Silva Camilla M. , Silva Juliana C. , Damasceno Samara , Schneider Ayda H. , Beretta Fabio , Batah Sabrina S. , Castro Icaro M. S. , Paiva Isadora M. , Rodrigues Tamara , Salina Ana , Martins Ronaldo , Cebinelli Guilherme C.M. , Bibo Naira L. , Jorge Daniel M. , Nakaya Helder I. , Zamboni Dario S. , Leiria Luiz O. , Fabro Alexandre T. , Alves-Filho José C. , Arruda Eurico , Louzada-Junior Paulo , Oliveira Renê D. , Cunha Larissa D. , Mol Pierre Van , Vanderbeke Lore , Feys Simon , Wauters Els , Brandolini Laura , Cunha Fernando Q. , Köhl Jörg , Allegretti Marcello , Lambrechts Diether , Wauters Joost , Proost Paul , Cunha Thiago M.
Published: July 2022

Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions, and plays immunopathological roles in inflammatory diseases, we investigated whether C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill COVID-19 patients compared to patients with influenza infection, as well as in the lung tissue of K18-hACE2 Tg mice (Tg mice) infected with SARS-CoV-2. Genetic and pharmacological inhibition of C5aR1 signaling ameliorated lung immunopathology in Tg-infected mice. Mechanistically, we found that C5aR1 signaling drives neutrophil extracellular trap (NET)s-dependent immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonist of C5aR1 could be useful for COVID-19 treatment.
The contrasted impacts of grasshoppers on soil microbial activities in function of primary production and herbivore diet
Authors: Ibanez Sébastien , Foulquier Arnaud , Brun Charles , Colace Marie-Pascale , Piton Gabin , Bernard Lionel , Gallet Christiane , Clément Jean-Christophe
Published: July 2022

Herbivory can have contrasted impacts on soil microbes and nutrient cycling, which has stimulated the development of conceptual frameworks exploring the links between below- and aboveground processes. The “productivity model” predicts that herbivores stimulate microbial activities and accelerate nutrient mineralization in productive ecosystems, while they have an opposite effect in less productive ecosystems. In parallel, the “diet model” predicts that herbivores feeding on conservative plants accelerate nutrient cycling while those feeding on exploitative plants decelerate nutrient cycling, due to changes in litter inputs. Since these two frameworks can lead to conflicting predictions in some cases, experimental evidence combining herbivore diet and plant productivity is required.

During two consecutive years, we conducted an experiment controlling the presence of three grasshopper species consuming either grasses, forbs or both in twelve natural and managed alpine grasslands with contrasted productivities. In order to assess the effects of herbivory on soil microbes, we measured their extracellular enzymatic activities, biomass and potential nitrogen mineralization (PNM). Soil and vegetation were also characterized to test how much they modulated the effects of herbivory on microbes.

Contrary to the predictions of the diet model, the effects of herbivory on microbial characteristics did not depend on the herbivores diet, but were influenced by primary production, though in a way that differed from the productivity model. The most productive sites were constituted by exploitative plant species which depleted N resources in the soil, and by microbes producing relatively few extracellular enzymes, leading to a lower PNM. Herbivory increased microbial biomass and decreased the production of extracellular enzymes in those sites, possibly through the stimulation of root exudates produced by exploitative species. The least productive sites were characterized by conservative plants, high soil C content, and by microbes having a resource acquisition strategy (more extracellular enzymes, higher PNM). Herbivory decreased microbial biomass and increased the production of extracellular enzymes in those sites. This pattern can be explained by the loss of carbon associated with insect respiration, which increases the resource requirements of microbes and by a lower production of root exudates by conservative species. Therefore, the effects of two years of herbivory on soil microbes were at odds with the productivity model, which focuses instead on longer term effects corresponding to herbivory-induced changes in plant species composition. This highlights the multidimensional feature of the impacts of herbivory on ecosystem functioning, both in space and time.
A species-specific lncRNA modulates the reproductive ability of the Asian tiger mosquito
Authors: Belavilas-Trovas Alexandros , Gregoriou Maria-Eleni , Tastsoglou Spyros , Soukia Olga , Giakountis Antonis , Mathiopoulos Kostas
Published: July 2022

Long non-coding RNA (lncRNA) research has emerged as an independent scientific field in recent years. Despite their association with critical cellular and metabolic processes in plenty of organisms, lncRNAs are still a largely unexplored area in mosquito research. We propose that they could serve as exceptional tools for pest management due to unique features they possess. These include low inter-species sequence conservation and high tissue specificity. In the present study, we investigated the role of ovary-specific lncRNAs in the reproductive ability of the Asian tiger mosquito,Aedes albopictus. Through the analysis of transcriptomic data, we identified several lncRNAs that were differentially expressed upon blood feeding; we called these genes Norma (NOn-codingRNA inMosquito ovAries). We observed that silencing some of these Normas resulted in significant impact on mosquito fecundity and fertility. We further focused on Norma3 whose silencing resulted in 43% oviposition reduction and 53% hatching reduction of the laid eggs, compared to anti-GFP controls. Moreover, a significant downregulation of a neighboring (∼100 Kb) mucins cluster was observed in smaller anti-Norma3 ovaries, indicating a potential mechanism of in-cisregulation between Norma3 and the mucins. Our work constitutes the first experimental proof-of-evidence connecting lncRNAs with mosquito reproduction and opens a novel path for pest management.
Power spectrum and critical exponents in the 2D stochastic Wilson Cowan model
Authors: Apicella I. , Scarpetta S. , de Arcangelis L. , Sarracino A. , de Candia A.
Published: July 2022

The power spectrum of brain activity is composed by peaks at characteristic frequencies superimposed to a background that decays as a power law of the frequency, f-β, with an exponent β close to 1 (pink noise). This exponent is predicted to be connected with the exponent γ related to the scaling of the average size with the duration of avalanches of activity. “Mean field” models of neural dynamics predict exponents β and γ equal or near 2 at criticality (brown noise), including the simple branching model and the fully connected stochastic Wilson Cowan model. We here show that a 2D version of the stochastic Wilson Cowan model, where neuron connections decay exponentially with the distance, is characterized by exponents β and γ markedly different from those of mean field, respectively around 1 and 1.3. The exponents α and τ of avalanche size and duration distributions, equal to 1.5 and 2 in mean field, decrease respectively to 1.29 ± 0.01 and 1.37 ± 0.01. This seems to suggest the possibility of a different universality class for the model in finite dimension.
Noninvasive cancer detection by extracting and integrating multi-modal data from whole-methylome sequencing of plasma cell-free DNA
Authors: Bie Fenglong , Wang Zhijie , Li Yulong , Hong Yuanyuan , Han Tiancheng , Lv Fang , Yang Shunli , Li Suxing , Li Xi , Nie Peiyao , Zang Ruochuan , Zhang Moyan , Song Peng , Feng Feiyue , Guo Wei , Duan Jianchun , Bai Guangyu , Li Yuan , Huai Qilin , Zhou Bolun , Huang Yu , Chen Weizhi , Tan Fengwei , Gao Shugeng
Published: July 2022

Abstract

Plasma cell-free DNA (cfDNA) methylation and fragmentation signatures have been shown to be valid biomarkers for blood-based cancer detection. However, conventional methylation sequencing assays are inapplicable for fragmentomic profiling due to bisulfite-induced DNA damage. Here using enzymatic conversion-based low-pass whole-methylome sequencing (WMS), we developed a novel approach to comprehensively interrogate the genome-wide plasma methylation, fragmentation, and copy number profiles for sensitive and noninvasive multi-cancer detection. With plasma WMS data from a clinical cohort comprising 497 healthy controls and 780 patients with both early- and advanced-stage cancers of the breast, colorectum, esophagus, stomach, liver, lung, or pancreas, genomic features including methylation, fragmentation size, copy number alteration, and fragment end motif were extracted individually and subsequently integrated to develop an ensemble cancer classifier, called THEMIS, using machine learning algorithms. THEMIS outperformed individual biomarkers for differentiating cancer patients of all seven types from healthy individuals and achieved a combined area under the curve value of 0.971 in the independent test cohort, translating to a sensitivity of 86% and early-stage (I and II) sensitivity of 77% at 99% specificity. In addition, we built a cancer signal origin classifier with true-positive cancer samples at 100% specificity based on methylation and fragmentation profiling of tissue-specific accessible regulatory elements, which localized cancer-like signal to a limited number of clinically informative sites with 66% accuracy. Overall, this proof-of-concept work demonstrates the feasibility of extracting and integrating multi-modal biomarkers from a single WMS run for noninvasive detection and localization of common cancers across stages.
A comprehensive study of the microbiome and resistome of chicken waste from intensive farms
Authors: Błażejewska Aleksandra , Zalewska Magdalena , Grudniak Anna , Popowska Magdalena
Published: July 2022

The application of chicken waste to farmland could be detrimental to public health. It may contribute to the dissemination of antibiotic resistance genes (ARG) and antibiotic-resistant bacteria (ARB) from feces and their subsequent entry to the food chain. The present study analyzes the metagenome and resistome of chicken manure and litter obtained from a commercial chicken farm in Poland. ARB were isolated, identified and screened for antibiogram fingerprints using standard microbiological and molecular methods. The physicochemical properties of the chicken waste were also determined. ARG, integrons, and mobile genetic elements (MGE) in chicken waste were analyzed by high-throughput SmartChip qPCR. The results confirm the presence of many ARGs, probably located in MGE, which can be transferred to other bacteria. Potentially pathogenic or opportunistic microorganisms and phytopathogens were isolated. More than 50% of the isolated strains were classified as multi-drug resistant, and the remainder were resistant to at least one antibiotic class; these pose a real risk of entering groundwater and contaminating the surrounding environment. Our results indicate that while chicken manure can be sufficient sources of the nutrients essential for plant growth, its microbiological aspects make this material highly dangerous to the environment.
Negative regulation of p53 by the poliovirus receptor PVR is a target of a human cytomegalovirus immune evasion molecule
Authors: Odell Adam F. , Mannion Aarren J. , Jones Pamela F. , Cook Graham P.
Published: July 2022

Initially characterised for its role in maintaining genome integrity, p53 has emerged as a critical hub for coordinating cellular responses to diverse types of stress. Here we identify cell surface receptor loss as a signal for p53 induction. The poliovirus receptor (PVR) regulates angiogenesis, leucocyte adhesion and immune surveillance. We demonstrate that loss of PVR from endothelial cells also promotes cell cycle arrest through the induction of a p53 transcriptional programme. The p53 induction is post-translational and, despite remaining associated with MDM2, p53 exhibits reduced ubiquitination, aiding its stabilisation. Increased expression of PVR marks malignant or infected cells, and retention of PVR in the endoplasmic reticulum by human cytomegalovirus (HCMV) UL141 protein allows HCMV infected cells to evade immunity. We show that intracellular retention of PVR by UL141 prevents p53 induction, allowing HCMV to escape both the immune- and p53-mediated surveillance functions of PVR. These data reveal that p53 coordinates responses to changes in cell surface composition and that the cell intrinsic PVR-p53 pathway coupled with PVR-mediated immune surveillance functions provide a sensor mechanism to maintain expression of this multi-functional cell surface molecule.