bluuebunny/crossref_metadata_2025 huggingface dataset:
Corneal Toxicity After Stinging by a Sea Anemone, Anthopleura uchidai: A Case Report With Confirmation by In Vitro Study
Authors: Ono Takashi , Iwasaki Takuya , Terada Yukiko , Miyai Takashi , Mori Yosai , Nejima Ryohei , Honma Tomohiro , Aihara Makoto , Miyata Kazunori
Published: September 2021

Purpose:

This study aimed to present a case of transient corneal damage after exposure to the effluent squirting from a sea anemone, Anthopleura uchidai, and to experimentally confirm the presence of toxic substances from an A. uchidai in the tissue culture.

Methods:

We reviewed the clinical course of a 51-year-old man who complained of decreased vision in his left eye after the stinging of a sea anemone, A. uchidai. The toxicity of the effluents from an A. uchidai in immortalized human corneal endothelial cells (HCEnC-21T) and human corneal epithelial cells in vitro were evaluated.

Results:

Corneal edema was observed, and his best-corrected visual acuity was 0.2. Corneal endothelial cell density decreased to 1435 cells/mm2. Although his corneal edema and visual acuity recovered after topical instillation with a topical steroid and 5% NaCl, corneal endothelial cell density did not recover for 3 years after the injury. The in vitro study revealed fractioned effluence from the sea anemone, by size-exclusion chromatography, containing a substance toxic to HCEnC-21T with cytoplasmic swelling and nuclear dislocation.

Conclusions:

It is necessary to be cautious of effluents from sea anemones along the coast, and ophthalmologists should be aware that sea anemones can cause corneal endothelial dysfunction.
Corneal Perforation in Patients Under Treatment With Dupilumab for Atopic Dermatitis
Authors: Phylactou Maria , Jabbour Samir , Ahmad Sajjad , Vasquez-Perez Alfonso
Published: September 2021

Purpose:

We report, for the first time, 2 cases of corneal ulceration and perforation after treatment with dupilumab for atopic dermatitis.

Methods:

A 30-year-old woman and a 44-year-old man developed unilateral severe corneal ulceration and perforation while on dupilumab therapy after 3 and 9 months, respectively.

Results:

Corneal cultures were negative in both cases except for scanty growth of Staphylococcus species on enrichment. Both cases progressed to perforation despite intensive topical antibiotic treatment. The first case required a tectonic keratoplasty to restore globe integrity after failed attempts of corneal gluing and multilayer amniotic membrane transplantation, and the second case was managed successfully with a cyanoacrylate glue patch.

Conclusions:

Although there have been previous reports of conjunctival injection and dry eye after dupilumab, these are the first 2 reports of corneal ulceration with rapid progression to perforation in patients under treatment with dupilumab. The underlying pathophysiology for ulcerative keratitis in these cases remains unknown, but there is no doubt that cessation of dupilumab prevented progression of the melting. Severe ocular symptoms while on dupilumab require a prompt discussion with the dermatology team to potentially switch treatment and halt further keratitis progression.
Neuropathic pain and neurocognitive functioning in children treated for acute lymphoblastic leukemia
Authors: Partanen Marita , Alberts Nicole M. , Conklin Heather M. , Krull Kevin R. , Pui Ching-Hon , Anghelescu Doralina A. , Jacola Lisa M.
Published: September 2021

Children with acute lymphoblastic leukemia (ALL) often experience treatment-related neurocognitive deficits and significant pain. Pain may exacerbate these cognitive impairments. This study examined neuropathic pain and neurocognitive outcomes in survivors of childhood ALL treated with contemporary therapy on a clinical trial (NCT00137111). There were 345 survivors (45% female, M = 6.9 years at diagnosis) who completed neurocognitive assessments including measures of sustained attention, learning and memory, and parent ratings of attention during at least one of 4 time points: on-therapy (Induction and Reinduction), end of therapy, and 2 years post-therapy. At-risk performance was defined as a score at least 1SD below the age-adjusted mean. Data on neuropathic pain (events, duration, and severity according NCI Common Toxicity Criteria) and pharmacologic pain management (opioids and gabapentin) were ascertained. Results showed that 135 survivors (39%) experienced neuropathic pain during treatment. Compared with those without pain, survivors with pain had greater memory impairments at end of therapy (California Verbal Learning Test [CVLT]-Total, 24% vs 12%, P = 0.046). Within the pain group, survivors who experienced a greater number of pain events (CVLT-Total = −0.88, P = 0.023) and those who were treated with opioids (versus gabapentin) had poorer learning and memory performance (CVLT-Total = −0.73, P = 0.011; Short Delay = −0.57, P = 0.024; Long Delay = −0.62, P = 0.012; and Learning Slope = −0.45, P = 0.042) across time points. These are considered medium-to-large effects (SD = 0.45-0.88). Neuropathic pain may be a risk factor for learning problems after therapy completion, and treatment for pain with opioids may also adversely affect neurocognitive performance. Therefore, patients who experience pain may require closer monitoring and additional intervention for neurocognitive impairment.
Exploring sex differences in alpha brain activity as a potential neuromarker associated with neuropathic pain
Authors: Fauchon Camille , Kim Junseok A. , El-Sayed Rima , Osborne Natalie R. , Rogachov Anton , Cheng Joshua C. , Hemington Kasey S. , Bosma Rachael L. , Dunkley Benjamin T. , Oh Jiwon , Bhatia Anuj , Inman Robert D. , Davis Karen D.
Published: September 2021

Alpha oscillatory activity (8-13 Hz) is the dominant rhythm in the awake brain and is known to play an important role in pain states. Previous studies have identified alpha band slowing and increased power in the dynamic pain connectome (DPC) of people with chronic neuropathic pain. However, a link between alpha-band abnormalities and sex differences in brain organization in healthy individuals and those with chronic pain is not known. Here, we used resting-state magnetoencephalography to test the hypothesis that peak alpha frequency (PAF) abnormalities are general features across chronic central and peripheral conditions causing neuropathic pain but exhibit sex-specific differences in networks of the DPC (ascending nociceptive pathway [ANP], default mode network, salience network [SN], and subgenual anterior cingulate cortex). We found that neuropathic pain (N = 25 men and 25 women) was associated with increased PAF power in the DPC compared with 50 age- and sex-matched healthy controls, whereas slower PAF in nodes of the SN (temporoparietal junction) and the ANP (posterior insula) was associated with higher trait pain intensity. In the neuropathic pain group, women exhibited lower PAF power in the subgenual anterior cingulate cortex and faster PAF in the ANP and SN than men. The within-sex analyses indicated that women had neuropathic pain-related increased PAF power in the ANP, SN, and default mode network, whereas men with neuropathic pain had increased PAF power restricted to the ANP. These findings highlight neuropathic pain-related and sex-specific abnormalities in alpha oscillations across the DPC that could underlie aberrant neuronal communication in nociceptive processing and modulation.
A multicenter, randomized, double-blind, placebo-controlled, comparative study to evaluate the efficacy and safety of newly developed diclofenac patches in patients with cancer pain
Authors: Yamaguchi Shigeki , Terahara Takaaki , Okawa Koji , Inakura Hiroshi
Published: September 2021

This phase III multicenter randomized double-blind placebo-controlled comparative study evaluated the efficacy and safety of diclofenac sodium patches for the treatment of cancer pain. The study consisted of a 2-week to 4-week open-label dose-titration phase and a 4-week double-blind phase. In the double-blind phase, patients who were expected to continue treatment of cancer pain with nonopioid analgesics alone were randomized to the diclofenac sodium patch or placebo group. Once-daily diclofenac sodium patches were started at 150 mg/day (2 patches) and could be increased up to 225 mg/day (3 patches). The primary efficacy endpoint was the time to insufficient analgesic response. Statistical analysis of the double-blind phase included data from 120 patients of the diclofenac sodium patch group and 118 patients of the placebo group. Time to insufficient analgesic response was significantly longer with diclofenac sodium patches than with placebo (P = 0.0016). The hazard ratio for insufficient response for diclofenac sodium patch vs placebo was 0.459 (95% confidence interval, 0.275-0.768). Regarding sleep quality during the double-blind phase, the proportion of patients with “very good sleep” or “good sleep” in the diclofenac sodium patch and placebo groups was 90.8% and 88.1% at the start of the double-blind phase and 81.4% and 78.6% at the final assessment, respectively. The incidence of adverse events was 60.8% (73/120) in the diclofenac sodium patch group and 60.2% (71/118) in the placebo group. Once-daily diclofenac sodium patches are effective in treating cancer pain and are well tolerated.
A peripheral CB2 cannabinoid receptor mechanism suppresses chemotherapy-induced peripheral neuropathy: evidence from a CB2 reporter mouse
Authors: Lin Xiaoyan , Xu Zhili , Carey Lawrence , Romero Julian , Makriyannis Alexandros , Hillard Cecilia J. , Ruggiero Elizabeth , Dockum Marilyn , Houk George , Mackie Ken , Albrecht Phillip J. , Rice Frank L. , Hohmann Andrea G.
Published: September 2021

CB2 cannabinoid receptors (CB2) are a promising therapeutic target that lacks unwanted side effects of CB1 activation. However, the cell types expressing CB2 that mediate these effects remain poorly understood. We used transgenic mice with CB2 promoter–driven expression of enhanced green fluorescent protein (EGFP) to study cell types that express CB2 and suppress neuropathic nociception in a mouse model of chemotherapy-induced peripheral neuropathy. Structurally distinct CB2 agonists (AM1710 and LY2828360) suppressed paclitaxel-induced mechanical and cold allodynia in CB2
EGFP reporter mice with established neuropathy. Antiallodynic effects of AM1710 were blocked by SR144528, a CB2 antagonist with limited CNS penetration. Intraplantar AM1710 administration suppressed paclitaxel-induced neuropathic nociception in CB2
EGFP but not CB2 knockout mice, consistent with a local site of antiallodynic action. mRNA expression levels of the anti-inflammatory cytokine interleukin-10 were elevated in the lumbar spinal cord after intraplantar AM1710 injection along with the proinflammatory cytokine tumor necrosis factor alpha and chemokine monocyte chemoattractant protein-1. CB2
EGFP, but not wildtype mice, exhibited anti-GFP immunoreactivity in the spleen. However, the anti-GFP signal was below the threshold for detection in the spinal cord and brain of either vehicle-treated or paclitaxel-treated CB2
EGFP mice. EGFP fluorescence was coexpressed with CB2 immunolabeling in stratified patterns among epidermal keratinocytes. EGFP fluorescence was also expressed in dendritic cells in the dermis, Langerhans cells in the epidermis, and Merkel cells. Quantification of the EGFP signal revealed that Langerhans cells were dynamically increased in the epidermis after paclitaxel treatment. Our studies implicate CB2 expressed in previously unrecognized populations of skin cells as a potential target for suppressing chemotherapy-induced neuropathic nociception.
Biomechanical Measures for Fall Risk Assessment and Fall Detection in People with Transfemoral Amputations for the Next-Generation Prostheses: A Scoping Review
Authors: Monaco Vito , Aprigliano Federica , Palmerini Luca , Palumbo Pierpaolo , Chiari Lorenzo , Micera Silvestro
Published: September 2021

Introduction

Transfemoral amputations are known to compromise balance control capabilities, thus increasing the probability of falling. Current research in robotic prostheses is exploring novel strategies to assess the risk of fall and, if required, enable assistive strategies to promote balance recovery.

Objectives

The aim of this study was to identify a set of biomechanical variables associated with fall risk and fall detection in people with transfemoral amputation (pwTFA), which can be potentially assessed through the next generation of sensorized powered prostheses.

Study Design

The study design was scoping review.

Methods

Screening of the literature (CINAHL, PubMed, Scopus, and Web of Science) carried out in February 2020 (quality assessment of retained articles through Downs and Black checklist; retrieved information: measurement tests and biomechanical variables).

Results

From the initial 595 documents, only 25 citations met eligibility criteria. The pwTFA's fall risk assessment and fall detection are usually carried out by using different measurement tests.

Conclusions

Two classes of biomechanical markers for fall risk assessment have the potential to be incorporated in self-contained transfemoral powered prostheses equipped with sensory network and suitable computational capabilities. The first consists of kinematic/kinetic variables of some prosthesis components (e.g., foot acceleration, force loading the pylon, knee angle) to detect either an abrupt lack of balance or a fall-related occurrence as a consequence of knee buckling, slipping, or tripping. The second involves implementing automatic procedures to allow pwTFA to routinely carry out clinical tests, such as the timed up and go test and/or the Four Square Step Test to monitor the decline of sensory motor capabilities, likely documenting an increased fall risk.

Clinical Relevance

The next generation of powered prostheses could both monitor decline on neuromuscular capabilities and gather early signs of an acute lack of balance based on a suitable network of sensors on board. This approach is expected to prevent the fall risk in pwTFA.
Hip and Knee Replacement Patients' Experiences With an Orthopaedic Patient Navigator
Authors: Teng Larissa J. , Goldsmith Laurie J. , Sawhney Monakshi , Jussaume Linda
Published: September 2021

Hip and knee replacement surgery is common, yet more than 10% of patients who undergo total hip replacement (THR) and total knee replacement (TKR) report postsurgery dissatisfaction. Recommendations for improving patient experience after total joint replacement surgery include increasing support to patients, including having a patient navigator available to patients before and after surgery. This article reports on THR and TKR patients' experiences of using an orthopaedic patient navigator. We employed qualitative description to understand THR and TKR patients' experiences of interacting with an orthopaedic patient navigator in a community teaching hospital. Telephone interviews were conducted with 15 purposefully selected total joint replacement patients (TKR: n = 11; THR: n = 4) who had at least one contact with the navigator. Interview transcripts were analyzed using thematic analysis. Patients described receiving physical support services, emotional support services, informational support services, and care coordination services from the patient navigator. All interactions with the patient navigator were positive. Knowing the patient navigator was available for any future concerns also provided indirect benefits of reassurance, comfort, and security. Patients described these direct and indirect benefits as potentially having long-lasting and resilient positive effects. An orthopaedic patient navigator can have a positive impact on patients' THR and TKR experience and fill gaps in support identified in earlier studies. Addressing patients' complex and varied care needs is well suited to a clinical nurse specialist in the role. Investing in an orthopaedic patient navigator provides reassurance to patients that their needs are a priority and will be addressed in a timely manner.
Quantifying the Pipeline of Ethnically Underrepresented in Medicine Physicians in Academic Plastic Surgery Leadership
Authors: Hall Jennifer A. , Chen Wendy , Bhayana Kovid , Lee Phoebe , Moroni Elizabeth A. , Butler Paris D. , Delacruz Carolyn
Published: September 2021

Background

The lack of underrepresented in medicine (UIM) physicians in academic plastic surgery is emerging as a critical issue. Lack of diversity has a negative effect on patient care and on the culture of our health care system. This study reports the current status of ethnically UIM physicians in the plastic surgery pipeline, starting from the medical student level and progressing to national leadership positions.

Methods

The Electronic Residency Applications Service, National Resident Matching Program, Association of American Medical Colleges, and professional Web sites for journals and national societies were accessed for racial demographic information from 2008 to 2019.

Results

Over the past decade, there has been no change or a slight decrease in representation of Blacks among plastic surgery residency applicants, trainees, and academic faculty, at half or less than expected, compared with US Census data. The first point of drop-off occurs at the resident (3.8% of integrated and 5.6% of independent residents) to faculty level (<2.8%). Two percent of program directors and department heads/division chiefs are Black. The next point of drop-off occurs at the national level: there has never been a Black president of American Society of Plastic Surgeons or Plastic Surgery Foundation, and there are no Black editors-in-chiefs of major plastic surgery journals.

Following LatinX American surgeons down the pipeline over the past decade, there has been no change or a decrease in representation among plastic surgery residency applicants, resident physicians, and academic faculty, at one-third or less than expected, compared with US Census data. The first point of drop-off occurs at the faculty (4.8%) to local leadership level (0% of program directors and department heads/division chiefs) where there is no representation of LatinX. Once this drop-off occurs, there is no recovery at the national leadership level.

Conclusions

In order for our profession to reflect our nation's demographics, academic plastic surgery is in need of a paradigm shift now. Attrition of UIM physicians in plastic surgery begins at medical school graduation and persists through surgical training, faculty appointments, and attainment of leadership positions. Creative and innovative commitment to diversity and inclusion is necessary.
The Impact of Fellowship Training in Academic Plastic Surgery
Authors: Egro Francesco M. , Smith Brandon T. , Murphy Carolyn P. , Stavros Alexander G. , Nguyen Vu T.
Published: September 2021

Background

The competitive nature of an academic plastic surgery career has contributed to an increase in sub-specialization. The aim of this study is to assess the benefits of subspecialty fellowship training to pursue a career in academic plastic surgery.

Methods

A cross-sectional study was conducted of all current academic plastic surgeons (APSs) participating in Accreditation Council for Graduate Medical Education–certified residency programs. Online faculty website listings were used to collect their demographics, training and practice characteristics, academic rank and leadership positions, and research productivity.

Results

A total of 927 APSs met the inclusion criteria, of which 70.2% had undergone fellowship training, with an overall significant increase in fellowship-trained surgeons within the last 10 years (odds ratio [OR], 1.66; P = 0.0005). Hand training was the most common fellowship (35.6%), followed by craniofacial (32.0%) and microsurgery (28.1%). Fellowship training was more prevalent among younger (48.7 vs 53.5 years, P < 0.0001), White (67.8%), and non-White (77.4%, P = 0.0058) APSs who had received either integrated (67.1%) or independent (81.8%, P < 0.0001) plastic surgery training and are currently working in a department (OR, 1.44; P = 0.028). Fellowship training was shown to influence academic rank (associate professor: OR, 1.68 [P = 0.0073]; full professor: OR, 0.58 [P = 0.0008]), leadership position (fellowship director OR, 10.09; P < 0.0001) and research productivity (publications: 26 vs 16.5; P = 0.0009). In addition, fellowship attainment did not correlate with the size of the employing academic program, population of the city of practice, or being a residency director or chair.

Conclusion

The majority of APSs have undergone fellowship training, and there is very strong evidence supporting its impact in current entry and advancement in academic plastic surgery.
A larval aggregation pheromone as foraging cue for insectivorous birds
Authors: Díaz-Siefer Pablo , Tapia-Gatica Jaime , Martínez-Harms Jaime , Bergmann Jan , Celis-Diez Juan L.
Published: September 2021

Although birds have traditionally been considered anosmic, increasing evidence indicates that olfaction plays an important role in the foraging behaviours of insectivorous birds. Recent studies have shown that birds can exploit herbivore-induced plant volatiles and sexual pheromones of adult insects to locate their prey. Many insectivorous birds prey on immature insects, providing relevant ecosystem services as pest regulators in natural and agricultural ecosystems. We asked whether birds could rely on chemical cues emitted by the immature stages of insects to prey on them. To address this question, we performed field experiments to evaluate if insectivorous birds can detect the aggregation pheromone produced by the larvae of the carpenter worm,Chilecomadia valdiviana. Groups of five artificial larvae were placed in branches of 72 adult trees in a remnant fragment of a sclerophyllous forest in central Chile. Each grouping of larvae contained a rubber septum loaded with either larval pheromone as treatment or solvent alone as control. We found that the number of larvae damaged by bird pecks was significantly higher in groups with dispensers containing the larval extract than in control groups. Our results show that birds can rely on immature insect-derived chemical cues used for larvae aggregation to prey on them.
Imprinting on time-structured acoustic stimuli in ducklings
Authors: Monteiro Tiago , Hart Tom , Kacelnik Alex
Published: September 2021

Filial imprinting is a dedicated learning process that lacks explicit reinforcement. The phenomenon itself is narrowly heritably canalized, but its content, the representation of the parental object, reflects the circumstances of the newborn. Imprinting has recently been shown to be even more subtle and complex than previously envisaged, since ducklings and chicks are now known to select and represent for later generalization abstract conceptual properties of the objects they perceive as neonates, including movement pattern, heterogeneity and inter-component relationships of same or different. Here, we investigate day-old Mallard (
Anas platyrhynchos
) ducklings’ bias towards imprinting on acoustic stimuli made from mallards’ vocalizations as opposed to white noise, whether they imprint on the temporal structure of brief acoustic stimuli of either kind, and whether they generalize timing information across the two sounds. Our data are consistent with a strong innate preference for natural sounds, but do not reliably establish sensitivity to temporal relations. This fits with the view that imprinting includes the establishment of representations of both primary percepts and selective abstract properties of their early perceptual input, meshing together genetically transmitted prior pre-dispositions with active selection and processing of the perceptual input.
Natural variation at the
Drosophila melanogaster Or22
odorant receptor locus is associated with changes in olfactory behaviour
Authors: Shaw Katherine H. , Dent Craig I. , Johnson Travis K. , Anderson Alisha , de Bruyne Marien , Warr Coral G.
Published: September 2021

In insects, many critical olfactory behaviours are mediated by the large odorant receptor (
Or
) gene family, which determines the response properties of different classes of olfactory receptor neurons (ORNs). While ORN responses are generally conserved within and between
Drosophila
species, variant alleles of the
D. melanogaster Or22
locus have previously been shown to alter the response profile of an ORN class called ab3A. These alleles show potential clinal variation, suggesting that selection is acting at this locus. Here, we investigated if the changes seen in ab3A responses lead to changes in olfactory-related behaviours. We show that variation at the
Or22
locus and in the ab3A neurons are not fully compensated for by other ORNs and lead to overall changes in antennal odorant detection. We further show that this correlates with differences in odorant preference behaviour and with differences in oviposition site preference, with flies that have the chimaeric short allele strongly preferring to oviposit on banana. These findings indicate that variation at the
Or22
locus leads to changes in olfactory-driven behaviours, and add support to the idea that the ab3A neurons are of especial importance to the ecology of
Drosophila
flies.
The kinetic of SARS-CoV-2 antibody (Ab) decline determines the threshold for Ab persistence up to one year
Authors: Garner-Spitzer Erika , Wagner Angelika , Kundi Michael , Stockinger Hannes , Repic Anna , Schoetta Anna-Margarita , Gudipati Venugopal , Huppa Johannes B. , Kunert Renate , Mayrhofer Patrick , Kreil Thomas R. , Farcet Maria R. , Hoeltl Eva , Wiedermann Ursula
Published: September 2021

Twelve subjects with positive SARS-CoV-2 neutralization test (NT) titers (>1:10) identified in a seroprevalence study with 1655 working adults were followed up for one year. Here we report that 7 of these 12 individuals (58%) still had NT titers ≥1:50, S1-specific IgG concentrations ≥50 BAU/ml and ≥26% ACE2 receptor binding inhibition, measured with surrogate virus NT one year after mild COVID infection. Furthermore, NT_50 titers >1:10 and S1-specific IgG levels >60 BAU/ml present at three months post-infection persisted at detectable levels for 1 year and correlated with circulating S1-specific memory B-cells. Vaccine-induced SARS-CoV2 immune responses decline at similar rates as those after infection; thus the describes threshold of 60 BAU/ml at three months post infection might also be relevant for assessment of Ab persistence after vaccination.
Estimation of country-specific tuberculosis antibiograms using genomic data
Authors: Dixit Avika , Freschi Luca , Vargas Roger , Groeschel Matthias I. , Tahseen Sabira , Alam SM Masud , Kamal SM Mostofa , Skrahina Alena , Basilio Ramon P. , Lim Dodge R. , Ismail Nazir A , Farhat Maha R.
Published: September 2021

Background

Global tuberculosis (TB) drug resistance (DR) surveillance is largely focused on the drug rifampicin. We leveraged public and surveillance M. tuberculosis (Mtb) whole genome sequencing (WGS) data, to generate more comprehensive country-level resistance prevalence estimates (antibiograms) using in silico resistance prediction.

Methods

We curated and quality-controlled Mtb WGS data. We used a validated random forest model to predict phenotypic resistance to twelve drugs and bias-corrected for model performance, outbreak sampling, and resistance oversampling. We validated our estimates using a national DR survey conducted in South Africa.

Results

Mtb isolates from 29 countries (n=19,149) met sequence quality criteria. Marginal genotypic resistance estimates overlapped with the South African DR survey for all drugs except isoniazid and second-line injectables that were underestimated (n=3,134); among multi-drug resistant (MDR) TB, estimates overlapped for pyrazinamide and the fluoroquinolones. Globally, mono-resistance to isoniazid was estimated at 10.9% (95% CI: 10.2-11.7%, n = 14,012. Mono-levofloxacin resistance rates were highest in South Asia (Pakistan 3.4% [0.1-11%], n=111 and India 2.8% [0.08-9.4%], n=114). Rates of resistance discordance between isoniazid and ethionamide were high with 74.4% (IQR: 64.5-79.7%) of isoniazid resistant isolates predicted to be ethionamide susceptible. The global susceptibility rate to pyrazinamide and levofloxacin among MDR was 15.1% (95% CI: 10.2-19.9%, n=3,964).

Conclusions

This is the first attempt at global Mtb antibiogram estimation. DR prevalence in Mtb can be reliably estimated using public WGS and phenotypic resistance prediction for key antibiotics. Our results raise concerns about the empiric use of short-course fluoroquinolone regimens for drug susceptible TB in South Asia and suggest that ethionamide is an under-utilized drug in MDR treatment.
Dissecting the Epigenomic Differences between Smoking and Nicotine Dependence in a Veteran Cohort
Authors: Nagamatsu Sheila Tiemi , Pietrzak Robert H , Xu Ke , Krystal John H , Gelernter Joel , Montalvo-Ortiz Janitza Liz
Published: September 2021

Background

Smoking is a serious public health issue linked to more than 8 million deaths per year worldwide. It also may lead to nicotine dependence (ND). Smoking can induce long-lasting epigenetic changes. Although epigenetic alterations related to tobacco smoke have been largely studied, few works have investigated ND and its interaction with smoking status (SS).

Objective

We investigated the peripheral epigenomic profile of SS and ND in a U.S. male veteran cohort.

Methods

DNA from saliva was collected from 1,135 European American (EA) male U.S. military veterans. DNAm was assessed using the Illumina Infinium Human MethylationEPIC BeadChip array. SS was evaluated as: current smokers (n=137; 12.1%) and non-current smokers (never and former smokers; n=998; 87.9%). ND was assessed using the Fagerström Test for Nicotine Dependence (FTND). EWAS and co-methylation analyses were conducted for SS and ND.

Results

A total of 450 and 22 genome-wide significant differentially methylated sites (DMS) were associated with SS and ND, respectively (fifteen overlapped sites). We identified 97 DMS (43 genes) in SS-EWAS previously reported in the literature, including AHRR, and F2RL3 genes (p-value range: 1.95×10−83 to 4.5×10−33). ND novel DMS mapped to NEUROG1, ANPEP, and SLC29A1. Co-methylation analysis identified 386 modules (11 SS-related and 19 ND-related). SS-related modules showed enrichment for alcoholism, chemokine signaling pathway, and neurogenesis; while ND-related modules were enriched for cellular adhesion, and nicotine addiction.

Conclusions

This study confirms previous findings and identifies novel and -potentially specific - epigenetic signatures for SS and ND in a sample of EA male veterans.
Geographic partitioning of dengue virus transmission risk in Florida
Authors: Stephenson Caroline J. , Coatsworth Heather , Waits Christy M. , Nazario-Maldonado Nicole M. , Mathias Derrick K. , Dinglasan Rhoel R. , Lednicky John A.
Published: September 2021

Dengue viruses (DENVs) cause the greatest public health burden globally among the arthropod-borne viruses. DENV transmission risk has also expanded from tropical to subtropical regions due to the increasing range of its principal mosquito vector, Aedes aegypti. Focal out-breaks of dengue fever (dengue) in the state of Florida (FL) in the USA have increased since 2009. However, little is known about the competence of Ae. aegypti populations across different regions of FL to transmit DENVs. To understand the effects of DENV genotype and serotype variations on vector susceptibility and transmission potential in FL, we orally infected a colony of Ae. aegypti (Orlando/ORL) with laboratory and wild type DENV-1 through -4. Wild type DENVs were more infectious to and transmissible by ORL mosquitoes. We used these same DENVs to examine natural Ae. aegypti populations to determine whether spatial distributions correlated with differential vector competence. Vector competence across all DENV serotypes was greater for mosquitoes from areas with the highest dengue incidence in south FL compared to north FL. Vector competence for wild type DENVs was significantly higher, revealing that transmission risk is influenced by virus/vector combinations. These data support a targeted mosquito-plus-pathogen screening approach to more accurately estimate DENV transmission risk.
Children Living with Disabilities Are Absent From Severe Malnutrition Guidelines
Authors: Engl Magdalena , Binns Paul , Trehan Indi , Lelijveld Natasha , Angood Chloe , McGrath Marie , Groce Nora , Kerac Marko
Published: September 2021

Purpose

Children living with disabilities (CLWD) are at high risk of malnutrition but have long been marginalised in malnutrition treatment programmes and research. The 2013 World Health Organization (WHO) guidelines for Severe Acute Malnutrition (SAM) mention disability but do not contain specific details for treatment or support. This study assesses inclusion of CLWD in national and international SAM guidelines.

Methods

National and international SAM guidelines were sourced online and via direct enquiries. Eight scoping key informant interviews were conducted with experts involved in guideline development to help understand possible barriers to formalising malnutrition guidance for CLWD.

Results

71 malnutrition guidelines were reviewed (63 national, 8 international). Only 4% (3/71) had a specific section for CLWD, while the remaining lacked guidance on consistently including CLWD in programmes or practice. Only one guideline mentioned strategies to include CLWD during a nutritional emergency. Most (99%,70/71) did not link to other disability-specific guidelines. Of the guidelines that included CLWD, most only discussed disability in general terms despite the fact that different interventions are often needed for children with different conditions. Interviews pointed towards barriers related to medical complexity, resource constraints, epidemiology (e.g., unrecognised burden), lack of evidence, and difficulty of integration into existing guidelines.

Conclusion

Children living with disability are not recognised in most SAM guidelines. Where they are, recommendations are very limited. Better evidence is urgently needed to identify and manage CLWD in malnutrition programmes. More inclusion in the 2022 update of the WHO malnutrition guidelines could support this vulnerable group.
Antibody responses against SARS-CoV-2 variants induced by four different SARS-CoV-2 vaccines
Authors: van Gils Marit J. , Ayesha Lavell A. H. , van der Straten Karlijn , Appelman Brent , Bontjer Ilja , Poniman Meliawati , Burger Judith A. , Oomen Melissa , Bouhuijs Joey H. , van Vught Lonneke A. , Slim Marleen A. , Schinkel Michiel , Wynberg Elke , van Willigen Hugo D.G. , Grobben Marloes , Tejjani Khadija , van Rijswijk Jacqueline , Snitselaar Jonne L. , Caniels Tom G. ,   Amsterdam UMC COVID-19 S3/HCW study group, Vlaar Alexander P. J. , Prins Maria , de Jong Menno D. , de Bree Godelieve J. , Sikkens Jonne J. , Bomers Marije K. , Sanders Rogier W.
Published: September 2021

Background

Emerging and future SARS-CoV-2 variants may jeopardize the effectiveness of vaccination campaigns. Therefore, it is important to know how the different vaccines perform against diverse SARS-CoV-2 variants.

Methods

In a prospective cohort of 165 SARS-CoV-2 naive health care workers, vaccinated with either one of four vaccines (BNT162b2, mRNA-1273, AZD1222 or Ad26.COV2.S), we performed a head-to-head comparison of the ability of sera to recognize and neutralize SARS-CoV-2 variants of concern (VOCs; Alpha, Beta, Gamma, Delta and Omicron). Repeated serum sampling was performed 5 times during a year (from January 2021 till January 2022), including before and after booster vaccination with BNT162b2.

Findings

Four weeks after completing the initial vaccination series, SARS-CoV-2 wild-type neutralizing antibody titers were highest in recipients of BNT162b2 and mRNA-1273 (geometric mean titers (GMT) of 197 [95% CI 149-260] and 313 [95% CI 218-448], respectively), and substantially lower in those vaccinated with the adenovirus vector-based vaccines AZD1222 and Ad26.COV2.S (GMT of 26 [95% CI 18-37] and 14 [95% CI 8-25] IU/ml, respectively). These findings were robust for adjustment to age and sex. VOCs neutralization was reduced in all vaccine groups, with the largest (9- to 80-fold) reduction in neutralization observed against the Omicron variant. The booster BNT162b2 vaccination increased neutralizing antibody titers for all groups with substantial improvement against the VOCs including the Omicron variant. Study limitations include the lack of cellular immunity data.

Conclusions

Overall, this study shows that the mRNA vaccines appear superior to adenovirus vector-based vaccines in inducing neutralizing antibodies against VOCs four weeks after initial vaccination and after booster vaccination.
The activities of LRRK2 and GCase are positively correlated in clinical biospecimens and experimental models of Parkinson’s disease
Authors: Kedariti Maria , Frattini Emanuele , Baden Pascale , Cogo Susanna , Civiero Laura , Ziviani Elena , Aureli Massimo , Kaganovich Alice , Cookson Mark R , Stefanis Leonidas , Surface Matthew , Deleidi Michela , Di Fonzo Alessio , Alcalay Roy N. , Rideout Hardy , Greggio Elisa , Plotegher Nicoletta
Published: September 2021

LRRK2 is a kinase involved in different cellular functions, including autophagy, endolysosomal pathways and vesicle trafficking. Mutations inLRRK2cause autosomal dominant forms of Parkinson’s disease (PD). Heterozygous mutations inGBA1, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), are the most common genetic risk factors for PD. Moreover, GCase function is altered in idiopathic PD and in other genetic forms of the disease. Recent work suggests that LRRK2 kinase activity can regulate GCase function. However, both a positive and a negative correlation have been described. To gain insights into the impact of LRRK2 on GCase, we investigated GCase levels and activity inLRRK2G2019S knockin mice, in clinical biospecimens from PD patients carrying this mutation and in patient-derived cellular models. In these models we found a positive correlation between the activities of LRRK2 and GCase, which was further confirmed in cell lines with genetic and pharmacological manipulation of LRRK2 kinase activity. Overall, our study indicates that LRRK2 kinase activity affects both the levels and the catalytic activity of GCase.
Generative Adversarial Networks (GAN) for the simulation of central-place foraging trajectories
Authors: Roy Amédée , Bertrand Sophie Lanco , Fablet Ronan
Published: September 2021

Abstract

Miniature electronic device such as GPS have enabled ecologists to document relatively large amount of animal trajectories. Modeling such trajectories may attempt (1) to explain mechanisms underlying observed behaviors and (2) to elucidate ecological processes at the population scale by simulating multiple trajectories. Existing approaches to animal movement modeling mainly addressed the first objective and they are yet soon limited when used for simulation. Individual-based models based on ad-hoc formulation and empirical parametrization lack of generability, while state-space models and stochastic differential equations models, based on rigorous statistical inference, consist in 1st order Markovian models calibrated at the local scale which can lead to overly simplistic description of trajectories.

We introduce a ‘state-of-the-art’ tool from artificial intelligence - Generative Adversarial Networks (GAN) - for the simulation of animal trajectories. GAN consist in a pair of deep neural networks that aim at capturing the data distribution of some experimental dataset, and that enable the generation of new instances of data that share statistical similarity. In this study, we aim on one hand to identify relevant deep networks architecture for simulating central-place foraging trajectories and on the second hand to evaluate GAN benefits over classical methods such as state-switching Hidden Markov Models (HMM).

We demonstrate the outstanding ability of GAN to simulate ‘realistic’ seabirds foraging trajectories. In particular, we show that deep convolutional networks are more efficient than LSTM networks and that GAN-derived synthetic trajectories reproduce better the Fourier spectral density of observed trajectories than those simulated using HMM. Therefore, unlike HMM, GAN capture the variability of large-scale descriptive statistics such as foraging trips distance, duration and tortuosity.

GAN offer a relevant alternative to existing approaches to modeling animal movement since it is calibrated to reproduce multiple scales at the same time, thus freeing ecologists from the assumption of first-order markovianity. GAN also provide an ultra-flexible and robust framework that could further take environmental conditions, social interactions or even bio-energetics model into account and tackle a wide range of key challenges in movement ecology.
Response of Endozoicomonas montiporae to heat stress and coral host lysates
Authors: Chan Ya-fan , Chen Chia-Yu , Lu Chih-Ying , Tu Yung-Chi , Tandon Kshitij , Shikina Shinya , Tang Sen-Lin
Published: September 2021

Endozoicomonas, a core bacterial group in corals, may also be a coral symbiont. Endozoicomonas communities often decrease rapidly in corals under heat stress. However, how the bacteria respond to changes in temperature and coral host during heat stress is unknown. Here, we employed the cultivable, dominant species E. montiporae as a working organism to explore how Endozoicomonas responds to heat stress. We designed two experiments to clarify the extent to which E. montiporae is influenced by temperature and coral host. We detected differentially expressed protein (DEP) profiles in this bacterium at 31°C and 33°C compared to 25°C by tandem mass tags-based quantitative proteome analysis. Fifty DEPs, including many heat shock proteins, were detected when the temperature changed. The expression of antioxidant defense proteins and key pyruvate synthase proteins decreased, suggesting that E. montiporae were in a physiology of stress at 33°C. Furthermore, some proteins were differentially expressed because of the heat-stress-treated coral lysate specifically, suggesting that not only heat but also heat-induced host factors can affect the protein expression of the bacterium. This study provides an in-depth analysis of how the molecular mechanisms of Endozoicomonas are affected by heat stress and coral host.
Protein-protein interaction-Gaussian accelerated molecular dynamics (PPI-GaMD): Characterization of protein binding thermodynamics and kinetics
Authors: Wang Jinan , Miao Yinglong
Published: September 2021

Protein-protein interactions (PPIs) play key roles in many fundamental biological processes such as cellular signaling and immune responses. However, it has proven challenging to simulate repetitive protein association and dissociation in order to calculate binding free energies and kinetics of PPIs, due to long biological timescales and complex protein dynamics. To address this challenge, we have developed a new computational approach to all-atom simulations of PPIs based on a robust Gaussian accelerated molecular dynamics (GaMD) technique. The method, termed “PPI-GaMD”, selectively boosts interaction potential energy between protein partners to facilitate their slow dissociation. Meanwhile, another boost potential is applied to the remaining potential energy of the entire system to effectively model the protein’s flexibility and rebinding. PPI-GaMD has been demonstrated on a model system of the ribonuclease barnase interactions with its inhibitor barstar. Six independent 2 μs PPI-GaMD simulations have captured repetitive barstar dissociation and rebinding events, which enable calculations of the protein binding thermodynamics and kinetics simultaneously. The calculated binding free energies and kinetic rate constants agree well with the experimental data. Furthermore, PPI-GaMD simulations have provided mechanistic insights into barstar binding to barnase, which involve long-range electrostatic interactions and multiple binding pathways, being consistent with previous experimental and computational findings of this model system. In summary, PPI-GaMD provides a highly efficient and easy-to-use approach for binding free energy and kinetics calculations of PPIs.
Deep Learning Enables Design of Multifunctional Synthetic Human Gut Microbiome Dynamics
Authors: Baranwal Mayank , Clark Ryan L. , Thompson Jaron , Sun Zeyu , Hero Alfred O. , Venturelli Ophelia
Published: September 2021

Predicting the dynamics and functions of microbiomes constructed from the bottom-up is a key challenge in exploiting them to our benefit. Current ordinary differential equation-based models fail to capture complex behaviors that fall outside of a predetermined ecological theory and do not scale well with increasing community complexity and in considering multiple functions. We develop and apply a long short-term memory (LSTM) framework to advance our understanding of community assembly and health-relevant metabolite production using a synthetic human gut community. A mainstay of deep learning, the LSTM learns a high dimensional data-driven non-linear dynamical system model used to design communities with desired metabolite profiles. We show that the LSTM model can outperform the widely used generalized Lotka-Volterra model. We build methods decipher microbe-microbe and microbe-metabolite interactions from an otherwise black-box model. These methods highlight that Actinobacteria, Firmicutes and Proteobacteria are significant drivers of metabolite production whereas Bacteroides shape community dynamics. We use the LSTM model to navigate a large multidimensional functional landscape to identify communities with unique health-relevant metabolite profiles and temporal behaviors. In sum, the accuracy of the LSTM model can be exploited for experimental planning and to guide the design of synthetic microbiomes with target dynamic functions.