bluuebunny/crossref_metadata_2025 huggingface dataset:
Meta-transcriptomics reveals potential virus transfer between Aedes communis mosquitoes and their parasitic water mites
Authors: Ortiz-Baez Ayda Susana , Holmes Edward C , Charon Justine , Pettersson John H-O , Hesson Jenny C
Published: September 2022

Arthropods harbor a largely undocumented diversity of RNA viruses. Some arthropods, like mosquitoes, can transmit viruses to vertebrates but are themselves parasitized by other arthropod species, such as mites. Very little is known about the viruses of these ectoparasites and how they move through the host–parasite relationship. To address this, we determined the virome of both mosquitoes and the mites that feed on them. The mosquito Aedes communis is an abundant and widely distributed species in Sweden, in northern Europe. These dipterans are commonly parasitized by water mite larvae (Trombidiformes: Mideopsidae) that are hypothesized to impose negative selection pressures on the mosquito by reducing fitness. In turn, viruses are dual-host agents in the mosquito–mite interaction. We determined the RNA virus diversity of mite-free and mite-detached mosquitoes, as well as their parasitic mites, using meta-transcriptomic sequencing. Our results revealed an extensive RNA virus diversity in both mites and mosquitoes, including thirty-seven putative novel RNA viruses that cover a wide taxonomic range. Notably, a high proportion of viruses (20/37) were shared between mites and mosquitoes, while a limited number of viruses were present in a single host. Comparisons of virus composition and abundance suggest potential virus transfer between mosquitoes and mites during their symbiotic interaction. These findings shed light on virome diversity and ecology in the context of arthropod host–parasite–virus relationships.
Characterization of Foliar Fungal Endophyte Communities from White Pine Blister Rust Resistant and Susceptible Pinus flexilis in Natural Stands in the Southern Rocky Mountains
Authors: Ata Jessa P. , Schoettle Anna W. , Sitz Rachael A. , Caballero Jorge R. Ibarra , Holtz Christine T. , Abdo Zaid , Stewart Jane E.
Published: September 2022

Fungal endophytic communities in needles of field-grown Pinus flexilis previously inferred to carry major gene resistance (R) to white pine blister rust (WPBR) or to lack it (S) were surveyed to identify unique microbes that may be recruited by WPBR-resistant genotypes. Resistant and susceptible trees were sampled in each of 11 P. flexilis populations for a total of 50 trees sampled. Through next-generation sequencing, this study showed a diverse needle mycobiota in P. flexilis, of which many remain unknown, regardless of the presence or absence of the WPBR resistance gene, Cr4. Ascomycota dominated the mycobiota (88.9%) followed by Basidiomycota (4.4%) and Chytridiomycota (0.03%), and the remaining 6.7% were unclassified. Shared ( n = 105) and unique ( n = 48 in R and n = 49 in S) fungal taxa, including differentially abundant operational taxonomic units, were identified that could provide insights into core mycobiota and host genotype-specific fungal groups. Marginal variation of the fungal diversity and structure was observed between host genotypes, which indicates that neither Cr4 nor the physiological differences associated with the presence or absence of the gene affects mycobiota recruitment. Instead, other parameters, including host size (diameter at breast height) and site elevation, significantly influenced the variability of the composition and structure of the fungal endophytic community. Further investigations are needed to understand the relationship of unique or differentially abundant taxa with one genotype or the other, and to determine the role of the needle mycobiota in WPBR disease development in natural stands of P. flexilis.
Strain on the ICU resources and patient outcomes in the COVID-19 pandemic
Authors: Stattin Karl , Frithiof Robert , Hultström Michael , Lipcsey Miklos , Kawati Rafael
Published: September 2022

BACKGROUND

The Coronavirus 2019 (COVID-19) pandemic has led to an unprecedented strain on the ICU resources. It is not known how the ICU resources employed in treating COVID-19 patients are related to inpatient characteristics, use of organ support or mortality.

OBJECTIVES

To investigate how the use of ICU resources relate to use of organ support and mortality in COVID-19 patients.

DESIGN

A national register-based cohort study.

SETTING

All Swedish ICUs from March 2020 to November 2021.

PATIENTS

All patients admitted to Swedish ICUs with a primary diagnosis of COVID-19 reported to the national Swedish Intensive Care Register (SIR).

MAIN OUTCOME MEASURES

Organ support (mechanical ventilation, noninvasive ventilation, high-flow oxygen therapy, prone positioning, surgical and percutaneous tracheostomy, central venous catheterisation, continuous renal replacement therapy and intermittent haemodialysis), discharge at night, re-admission, transfer and ICU and 30-day mortality.

RESULTS

Seven thousand nine hundred and sixty-nine patients had a median age of 63 years, and 70% were men. Median daily census was 167% of habitual census, daily new admissions were 20% of habitual census and the median occupancy was 82%. Census and new admissions were associated with mechanical ventilation, OR 1.37 (95% CI 1.28 to 1.48) and OR 1.44 (95% CI 1.13 to 1.84), respectively, but negatively associated with noninvasive ventilation, OR 0.83 (95% CI 0.77 to 0.89) and OR 0.40 (95% CI 0.30 to 52) and high-flow oxygen therapy, OR 0.72 (95% CI 0.67 to 0.77) and OR 0.77 (95% CI 0.61 to 0.97). Occupancy above 90% of available beds was not associated with mechanical ventilation or noninvasive ventilation, but with high-flow oxygen therapy, OR 1.36 (95% CI 1.21 to 1.53). All measures of pressure on resources were associated with transfer to other hospitals, but none were associated with discharge at night, ICU mortality or 30-day mortality.

CONCLUSIONS

Pressure on ICU resources was associated with more invasive respiratory support, indicating that during these times, ICU resources were reserved for sicker patients.
YINDARA-4 Relieves Visceral Hypersensitivity in Irritable Bowel Syndrome Rats via Regulation of Gut Microbiota and Serotonin Levels
Authors: Ling Yaqin , Ding Ling , Tian Zhigang , Pei Lingpeng , Wu Enqi
Published: September 2022

Objective:

The present study aims to evaluate the in vivo efficacy of YINDARA-4 in improving the symptoms of IBS in a rat model and investigate the impact of YINDARA-4 on potential targets of IBS management, such as the serotonin level in intestinal tissues and the structure and composition of the gut microbiota.

Methods:

We developed an IBS rat model by combining stress from maternal separation, acetic acid administration, and restraint. We administered YINDARA-4 water extract to the IBS rat model for 10 consecutive days. The fecal water content, visceral sensitivity, gut microbiota, and serotonin levels in the colonic tissue were then analyzed and compared between the control group, IBS model group, and YINDARA-4 treated groups.

Results:

Treatment with YINDARA-4 reversed visceral hypersensitivity in a dose-dependent manner in the experimental rat model of IBS. The relief of visceral hypersensitivity upon treatment with YINDARA-4 involved regulation of the gut microbiota structure and composition, and normalization of elevated serotonin levels in the colon. The decrease in colonic serotonin levels with YINDARA-4 treatment might be associated with a reduction in the abundance of Helicobacter and enrichment of Butyricimonas.

Conclusion:

Treatment with YINDARA-4 was beneficial against visceral hypersensitivity in a rat model of IBS. The improved symptoms exhibited in IBS rats were associated with favorably altered gut microbiota and normalization of serotonin levels in the colon.
Metronomic Chemotherapy for Burkitt Lymphoma in a Patient With HIV: Case Report
Authors: Dwivedi Pankaj , Kapse Atul , Bangurwar Chaitali , Tamhane Ankita , Banavali Shripad
Published: September 2022

Burkitt lymphoma (BL) is an aggressive type of non-Hodgkin lymphoma (NHL). With high-dose combination chemotherapy, cure rates are excellent. Treatment for HIV-positive BL is similar to that for HIV-negative BL. Offering long-term intensive chemotherapy is difficult in resource-limited settings. Oral metronomic chemotherapy, though in vogue as a treatment modality, has limited evidence of its efficacy in HIV-positive BL. Here, we present the case of a child who was diagnosed with BL and HIV and administered metronomic chemotherapy, and also review the literature on the role of metronomic chemotherapy in non-Hodgkin lymphoma with and without HIV.
T-Cell-Replete Haploidentical Hematopoietic Stem Cell Transplantation for a Patient With Tcf3-Hlf-Positive Acute Lymphoblastic Leukemia Extramedullary Relapse After Unrelated Bone Marrow Transplantation
Authors: Takahashi Nobuhisa , Mochizuki Kazuhiro , Kobayashi Shogo , Ohara Yoshihiro , Kudo Shingo , Saito Yuya , Ikeda Kazuhiko , Ohto Hitoshi , Kikuta Atsushi , Sano Hideki
Published: September 2022

TCF3-HLF-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has an extremely poor prognosis. A 2-year-old boy with TCF3-HLF-positive BCP-ALL had an isolated extramedullary relapse in multiple bones after allogeneic hematopoietic stem cells transplantation (HSCT) from a human leukocyte antigen-matched unrelated donor. In this study, he received a T-cell-replete haploidentical HSCT (TCR-haplo-HSCT) from his father when in nonremission state, which resulted in a sustained complete remission for over 3 years. Immune therapies for patients with an extramedullary relapse of TCF3-HLF-positive BCP-ALL have been attempted; however, long-term efficacies of these therapies remain unknown. Our TCR-haplo-HSCT may be an effective therapeutic option for such patients.
Thrombotic Microangiopathy Due to Progressive Disseminated Histoplasmosis in a Child With Down Syndrome and Acute Lymphoblastic Leukemia
Authors: Cowfer Brittany A. , Hunley Tracy E. , Mason Emily F. , Dulek Daniel E. , Benedetti Daniel J.
Published: September 2022

Histoplasmosis, a common mycosis in the south-central United States, may be life threatening in immunocompromised patients. We describe a 4-year-old female with Down syndrome and acute lymphoblastic leukemia who developed hemolytic anemia, thrombocytopenia, and renal failure, consistent with thrombotic microangiopathy. Bone marrow biopsy revealed non-necrotizing granulomas with GMS staining demonstrating budding yeast. Serum Histoplasma antigen testing was positive, providing further evidence for the diagnosis of progressive disseminated histoplasmosis. Treatment with amphotericin B, plasma exchange, and ventilator, vasopressor, and renal replacement support led to a full recovery. Providers should have a low threshold for histoplasmosis testing in ill immunocompromised patients, who are at greater risk for infection-related morbidity.
The Doula Model in American Health Care in the 21st Century
Authors: Lentz Judy
Published: September 2022

The doula model has been used in American health care for the past 50 years. The model dates back to biblical times—a woman who serves—the model that has passed the test of time. American women sought to improve the birthing experience in the mid-70s, and the doula model used in England was incorporated into American obstetrical care to respond to this need.

With the turn of the 21st century, providing greater comfort to the dying became the focus. The birth doula model became the template. During the next 2 decades, other types of doulas—comfort doulas, delirium doulas, hospice doulas, end-of-life doulas, death doulas, and palliative care doulas—evolved. This model has provided companionship, comfort, support, advocacy, and education for many individuals and loved ones who are experiencing serious illnesses.

Doulas have access to educational training and certification; however, standardization of registration, education, and/or certification has been sporadic and inconsistent. Many doulas are volunteers, and yet, many others are paid for their services. The variations in service, type, reimbursement, and roles make this model less attractive, and yet, the values of cost-effectiveness, care satisfaction, and guidance through the difficult medical experience justify further consideration in future research.
Therapeutic Targeting of FGFR Signaling in Head and Neck Cancer
Authors: Wang Zechen , Anderson Karen S.
Published: September 2022

Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most prevalent cancer worldwide, with an annual incidence of 600,000 new cases. Despite advances in surgery, chemotherapy, and radiotherapy, the overall survival for HNSCC patients has not been significantly improved over the past several decades. Fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) genomic alterations are frequently detected in HNSCC, including amplification, activating mutation, and chromosomal rearrangement. Among them, FGFR1 amplification, FGF amplifications, and FGFR3 mutations are the most prevalent. In addition, FGF/FGFR expression has also been observed in most HNSCCs. However, the prognostic value of FGF/FGFR aberrations remains unclear, especially for gene amplification and overexpression. Nonetheless, FGF/FGFR has been a promising target for HNSCC treatment, and recent preclinical studies demonstrate the potential of the combination treatment regimens involving FGFR inhibitors on HNSCC. Therefore, there are a number of FGFR inhibitors currently in clinical trials for the treatment of head and neck cancers.
Suicidality Among People Living With HIV From 2010 to 2021: A Systematic Review and a Meta-regression
Authors: Tsai Yi-Tseng , Padmalatha Sriyani , Ku Han-Chang , Wu Yi-Lin , Yu Tsung , Chen Mu-Hong , Ko Nai-Ying
Published: September 2022

Objective

The association between human immunodeficiency virus (HIV)/AIDS and suicidality is not well understood, partly because of variability in results. This meta-analysis aimed to investigate the predictive value of HIV/acquired immune deficiency syndrome for incident suicidality.

Methods

A literature review was conducted of articles published between January 1, 2010, and October 31, 2021. The following databases were searched: Embase, MEDLINE, CINAHL, Web of Science, and Scopus. The search terms included human immunodeficiency virus (HIV), suicidal behavior, auto mutilation, and self-injurious behavior. Observational studies were screened following a registered protocol, and eligible ones were meta-analyzed and followed by meta-regression.

Results

A total of 43 studies were included in this systematic review, and a meta-regression included 170,234 participants. The pooled prevalence estimates of suicidal ideation, attempted suicide, and deaths by suicide were 22.3%, 9.6%, and 1.7%, respectively. The following significant risk factors for suicide ideation were found: substance use, depression, low quality of life, low social support, without HIV status disclosure, living alone, low level of memory problems, family history of suicide, and stage III of HIV. Risk factors for suicide attempts were depression and family history of suicide. An elevated risk for suicide-related death was found for people living with HIV (PLHIV) who had a psychiatric disorder and in studies conducted in hospital-based settings (versus national database studies or HIV clinic settings).

Conclusions

The risk of suicidality is high among PLHIV within all six World Health Organization regions during the modern antiretroviral therapy era. Assessment of socioeconomic and psychological factors is recommended for further management to prevent suicide among PLHIV. The present findings are useful for design of intervention protocols and development of clinical practice guidelines intended to manage the well-being of PLHIV worldwide.
Anterior Insula Activation during Cardiac Interoception Relates to Depressive Symptom Severity in HIV-positive and HIV-negative Post-Menopausal Women
Authors: McIntosh Roger C. , Lobo Judith D. , Reed Michael , Britton Jennifer C.
Published: September 2022

Objective

Determine whether subclinical symptoms of depression in post-menopausal women are associated with blood oxygen level-dependent (BOLD) activity within the anterior insula during cardiac interoceptive awareness (IA) and whether this association differs for persons living with the Human Immunodeficiency Virus (PWH).

Method

wenty-three postmenopausal (mean age = 56.5, SD = 4.8) and 27 HIV-negative women (mean age = 56.4, SD = 8.0), underwent functional magnetic resonance imaging while performing a heartbeat detection task. BOLD activation within the bilateral anterior insula based on the contrast of a heartbeat detection condition with and without a distracting tone were entered along with age, HIV status, and psychological stress into two multivariate regression models with self-reported depressive symptom severity as the outcome.

Results

Depressive symptoms did not vary by HIV status nor was there a main effect or interaction for PWH on insula BOLD activation. Depressive symptoms were positively associated with psychological stress for the left (β = 0.310, t(49) = 2.352, p = .023) and right brain models (β = 0.296, t(49) = 2.265, p = .028) as well as the magnitude of BOLD activation in the left insula (β = 0.290, t(49) = 2.218, p = .032) and right insula (β = 0.318, t(49) = 2.453, p = .018), respectively. Exploratory analyses revealed greater magnitude of BOLD activation attributed to exteroceptive noise (tone) was also correlated with self-reported distrust and preoccupation with interoceptive sensations.

Conclusion

Results support an active interference model for IA wherein greater BOLD signal in the anterior insula in the presence of distracting exteroceptive stimuli may reflect greater prediction error, a feature of depression.
miR-199a-5p regulates the proliferation and apoptosis of degenerative nucleus pulposus cells through the CDKN1B/NF-κB axis
Authors: Li Xiangxin
Published: September 2022

Intervertebral disc degeneration is a multi-factorial pathological disease. miR-199a-5p is exceedingly implicated in regulating degenerative nucleus pulposus cell (DNPC). We explored the roles of miR-199a-5p in DNPCs. Cell morphology and Collagen II positive expression were observed. Cell proliferation, apoptosis, and Bax and Bcl-2 levels were assessed. miR-199a-5p inhibitor, pcDNA3.1-CDKN1B or si-CDKN1B were transfected into DNPCs. miR-199a-5p and CDKN1B expressions were detected. The binding relationship between miR-199a-5p and CDKN1B was verified. DNPCs with silenced miR-199a-5p and CDKN1B were treated with PDTC. The NF-κB pathway-related protein levels were detected. DNPCs showed decreased proliferation and promoted apoptosis. miR-199a-5p was highly expressed in DNPCs. miR-199a-5p knockdown increased DNPC proliferation and inhibited apoptosis. CDKN1B was repressed in DNPCs. miR-199a-5p targeted CDKN1B. CDKN1B knockdown partially abrogated the effects of miR-199a-5p inhibition on DNPC proliferation and apoptosis. In DNPCs, p65 was translocated to the nucleus, IκB protein phosphorylation level were increased and the NF-κB pathway was activated. miR-199a-5p knockdown or CDKN1B overexpression repressed the NF-κB pathway activation, NF-κB pathway inhibitor promoted DNPC proliferation and inhibited apoptosis. Briefly, miR-199a-5p was up-regulated in DNPCs. We discovered for the first time that miR-199a-5p silencing repressed the NF-κB pathway by promoting CDKN1B transcription, thus promoting DNPC proliferation and inhibiting apoptosis.
Disparities in the Effects of Acuity Circle–based Liver Allocation on Waitlist and Transplant Practice Between Centers
Authors: Nagai Shunji , Ivanics Tommy , Kitajima Toshihiro , Shimada Shingo , Shamaa Tayseer M. , Collins Kelly , Rizzari Michael , Yoshida Atsushi , Moonka Dilip , Abouljoud Marwan
Published: September 2022

Background.

Liver allocation in the United States was updated on February 4, 2020, by introducing the acuity circle (AC)–based model. This study evaluated the early effects of the AC-based allocation on waitlist outcomes.

Methods.

Adult liver transplant (LT) candidates listed between January 1, 2019, and September 30, 2021, were assessed. Two periods were defined according to listing date (pre- and post-AC), and 90-d waitlist outcomes were compared. Median transplant Model for End-stage Liver Disease (MELD) score of each transplant center was calculated, with centers categorized as low- (<25 percentile), mid- (25–75 percentile), and high-MELD (>75 percentile) centers.

Results.

A total of 12 421 and 17 078 LT candidates in the pre- and post-AC eras were identified. Overall, the post-AC era was associated with higher cause-specific 90-d hazards of transplant (csHR, 1.32; 95% confidence interval [CI], 1.27-1.38; P < 0.001) and waitlist mortality (cause-specific hazard ratio [csHR], 1.20; 95% CI, 1.09-1.32; P < 0.001). The latter effect was primarily driven by high-MELD centers. Low-MELD centers had a higher proportion of donations after circulatory death (DCDs) used. Compared with low-MELD centers, mid-MELD and high-MELD centers had significantly lower cause-specific hazards of DCD-LT in both eras (mid-MELD: csHR, 0.47; 95% CI, 0.38-0.59 in pre-AC and csHR, 0.56; 95% CI, 0.46-0.67 in post-AC and high-MELD: csHR, 0.11; 95% CI, 0.07-0.17 in pre-AC and csHR, 0.14; 95% CI, 0.10-0.20 in post-AC; all P < 0.001). Using a structural Bayesian time-series model, the AC policy was associated with an increase in the actual monthly DCD-LTs in low-, mid-, and high-MELD centers (actual/predicted: low-MELD: 19/16; mid-MELD: 21/14; high-MELD: 4/3), whereas the increase in monthly donation after brain death–LTs were only present in mid- and high-MELD centers.

Conclusions.

Although AC-based allocation may improve waitlist outcomes, regional variation exists in the drivers of such outcomes between centers.
Emerging patterns of fluoroquinolone resistance in Campylobacter jejuni in the UK [1998–2018]
Authors: Veltcheva Dessislava , Colles Frances M. , Varga Margaret , Maiden Martin C. J. , Bonsall Michael B.
Published: September 2022

Campylobacter jejuni

(C.jejuni) is the most common causative agent of bacterial food poisoning worldwide and is known to be genetically highly diverse.

C. jejuni

is increasingly resistant to fluoroquinolone antibiotics, but very few studies have investigated variant-specific patterns of resistance across time. Here we use statistical modelling and clustering techniques to investigate patterns of fluoroquinolone resistance amongst 10,359 UK isolates from human disease sampled over 20 years. We observed six distinct patterns of fluoroquinolone sensitivity/resistance in

C. jejuni

across time, grouping by clonal complex (CC). Some CCs were fully resistant, some shifted from susceptible to resistant following a sigmoidal shape, and some remained susceptible over time. Our findings indicate that the fluoroquinolone resistance patterns of

C. jejuni

are complicated and cannot be analysed as a single species but divided into variant dynamics so that the factors driving resistance can be thoroughly investigated.
Astrocytes amplify neurovascular coupling to sustained activation of neocortex in awake mice
Authors: Institoris Adam , Vandal Milène , Peringod Govind , Catalano Christy , Tran Cam Ha , Yu Xinzhu , Visser Frank , Breiteneder Cheryl , Molina Leonardo , Khakh Baljit S. , Nguyen Minh Dang , Thompson Roger J. , Gordon Grant R.
Published: September 2022

Brain requires increased local cerebral blood flow (CBF) for as long as necessary during neuronal activation to match O2and glucose supply with demand – termed functional hyperemia. Ca2+elevation in astrocytes can drive arteriole dilation to increase CBF, yet affirmative evidence for the necessity of astrocytes in functional hyperemiain vivois lacking. In awake and active mice, we discovered that functional hyperemia is bimodal with a distinct early and late component whereby arteriole dilation progresses as sensory stimulation is sustained. Clamping astrocyte Ca2+signalingin vivoby expressing a high-affinity plasma membrane Ca2+ATPase (CalEx) reduces sustained but not brief sensory-evoked arteriole dilation. Reciprocally, elevating astrocyte free Ca2+using chemogenetics selectively augments sustained but not brief hyperemia. Neither locomotion, arousal, nor changes in neuronal signaling account for the selective effect of astrocyte Ca2+on the late phase of the CBF response. Antagonizing NMDA-receptors or epoxyeicosatrienoic acid production reduces only the late component of functional hyperemia, leaving brief increases in CBF to sensory stimulation intact. We propose that a fundamental role of astrocyte Ca2+is to amplify functional hyperemia when neuronal activation is prolonged.
Structure-function coupling reveals seizure onset connectivity patterns
Authors: Maher Christina , D’Souza Arkiev , Barnett Michael , Kavehei Omid , Wang Chenyu , Nikpour Armin
Published: September 2022

The implications of combining structural and functional connectivity to quantify the most active brain regions in seizure onset remain unclear. We obtained structural connectomes from diffusion MRI (dMRI) and functional connectomes from electroencephalography (EEG) to assess whether high structure-function coupling corresponded with the seizure onset region. We mapped individual electrodes to their nearest cortical region to allow for a one-to-one comparison between the structural and functional connectomes. A seizure laterality score and expected onset zone were defined. The patients with well-lateralised seizures revealed high structure-function coupling consistent with the seizure onset zone. However, a lower seizure lateralisation score translated to reduced alignment between the high structure-function coupling regions and the seizure onset zone. This feasibility study tested a new model for incorporating dMRI in clinical practice. We illustrate that dMRI, in combination with EEG, can improve the identification of the seizure onset zone. Our model may be valuable in enhancing ultra-long-term monitoring by indicating optimal, individualised electrode placement.
Excess death estimates from multiverse analysis in 2009-2021
Authors: Levitt Michael , Zonta Francesco , Ioannidis John P.A.
Published: September 2022

Excess death estimates have great value in public health, but they can be sensitive to analytical choices. Here we propose a multiverse analysis approach that considers all possible different time periods for defining the reference baseline and a range of 1 to 4 years for the projected time period for which excess deaths are calculated. We used data from the Human Mortality Database on 33 countries with detailed age-stratified death information on an annual basis during the period 2009-2021. The use of different time periods for reference baseline led to large variability in the absolute magnitude of the exact excess death estimates. However, the relative ranking of different countries compared to others for specific years remained largely unaltered. The relative ranking of different years for the specific country was also largely independent of baseline. Averaging across all possible analyses, distinct time patterns were discerned across different countries. Countries had declines between 2009 and 2019, but the steepness of the decline varied markedly. There were also large differences across countries on whether the COVID-19 pandemic years 2020-2021 resulted in an increase of excess deaths and by how much. Consideration of longer projected time windows resulted in substantial shrinking of the excess deaths in many, but not all countries. Multiverse analysis of excess deaths over long periods of interest can offer a more unbiased approach to understand comparative mortality trends across different countries, the range of uncertainty around estimates, and the nature of observed mortality peaks.
Land use influences human mental and respiratory health in a conservation priority area in southeastern Brazil
Authors: Ferreira Matteus Carvalho , Massara Rodrigo Lima , de Ávila Chaves Marcelo , Fernandes Mota Bruno Eduardo , Guimarães Rodrigues Flávio Henrique
Published: September 2022

Human activities generate negative environmental impacts that can compromise ecological processes and ecosystem services and thus, influence human health. We assessed how natural and altered areas affect human respiratory and mental health in one of the largest mining provinces in the world, the Quadrilátero Ferrífero (QF), in southeastern Brazil. We used a model selection approach to evaluate socioeconomic and environmental factors that would influence hospitalization rates for mental and behavioral disorders, as well as for respiratory diseases in 22 municipalities in QF. Municipalities with higher rates of urbanization had higher rates of hospitalizations for mental and behavioral disorders. Conversely, the adult population (15-59 years old) of both gender and the elderly female population (60 years old or more) presented lower rates of hospitalization for respiratory diseases in municipalities with a higher rate of urbanization, suggesting a greater ease of access to prophylactic measures of the population located in these municipalities compared to those with a lower rate of urbanization. Municipalities with larger urban forest areas had lower rates of hospitalization for respiratory diseases in the young (0-14 years) female population, while municipalities with larger mining areas had higher rates. The elderly male population (60 years or older) also had higher rates of hospitalization for respiratory diseases in municipalities with larger mining areas. Our findings show important ecosystem services provided by urban forests and highlight impacts on health, in different segments of the population, due to anthropogenic changes in the landscape.

Highlights

We present a multiscale method to determine factors that influence human health.

Demographic groups are differently influenced by socio-environmental variables.

Urbanization rate is associated with worse mental health of human population.

Forest in urban areas is associated with better respiratory health for children.

Mining is associated with worse respiratory health for children and elderly.

Graphical Abstract
NetAllergen, a random forest model integrating MHC-II presentation propensity for improved allergenicity prediction
Authors: Li Yuchen , Sackett Peter Wad , Nielsen Morten , Barra Carolina
Published: September 2022

Allergy is a pathological immune reaction towards innocuous protein antigens. Although only a narrow fraction of plant or animal proteins induce allergy, atopic disorders affect millions of children and adults and cost billions in healthcare systems worldwide. In-silico predictors can aid in the development of more innocuous food sources. Previous allergenicity predictors used sequence similarity, common structural domains, and amino acid physicochemical features. However, these predictors strongly rely on sequence similarity to known allergens and fail to predict protein allergenicity accurately when similarity diminishes. In addition, ‘allergen’ is a broad terminology that may include different compounds, hindering the classification task. To overcome these limitations, we collected allergens from AllergenOnline, a curated database of IgE-inducing allergens, carefully removed allergen redundancy with a novel protein partitioning pipeline, and developed a new allergen prediction method, introducing MHC presentation propensity as a novel feature. NetAllergen outperformed a sequence similarity-based BLAST baseline approach, and previous allergenicity predictor AlgPred 2 when similarity to known allergens is limited. NetAllergen is available as a web service (services.healthtech.dtu.dk/service.php?NetAllergen-1.0) and can predict allergenicity from a protein sequence.
Differential representation of natural and manmade images in the human ventral visual stream
Authors: Gopnarayan Mrugsen Nagsen , Rathore Deeksha R. , Bauer Fabio S. , Hillard Jasper , Chawla Prerita
Published: September 2022

Abstract

The human visual cortex processes visual stimuli hierarchically. Early visual areas (V1, V2) of the ventral visual stream feed crude visual features (like orientation and edges) into later visual areas (V4, lateral occipital (Lat Occ), inferior temporal (IT)) that then encode complex visual features (like object form). Previous studies have reported a difference in fMRI responses between natural and urban landscapes in certain parts of the brain. Here we asked if this distinction in the representation of complex natural and man-made visual stimuli extends to the ventral visual stream and if state-of-the-art convolutional neural networks (CNN) provide a map to this categorical distinction. To assess this, we used an open source fMRI data set of V1-4 and LatOcc BOLD responses to 1750 passively viewed natural and man-made grayscale images. The same images were fed into the pre-trained CORnet-S, a CNN designed to model hierarchical human visual processing layer-wise. To identify differences in representations within and between the human visual cortex and the CNN, we computed representational dissimilarity matrices. The BOLD response to the manmade and natural images shows correlation differences for the two categories, which increase across V4 and LatOcc. Such differences were also observed in the model CORnet-S for the layers V4 and IT. Our results suggest that the human visual cortex processes natural and manmade images differently starting from V4 and that this representational difference is modeled in CORnet-S. In both, categorical representation is progressively established in the later processing stages. This might indicate that the brain has perhaps developed two-distinct systems for their representations which can be directed through evolution. Further analysis may elucidate the contributory role of evolution towards this paradigm.
High dimensional co-expression networks enable discovery of transcriptomic drivers in complex biological systems
Authors: Morabito Samuel , Reese Fairlie , Rahimzadeh Negin , Miyoshi Emily , Swarup Vivek
Published: September 2022

Biological systems are immensely complex, organized into a multi-scale hierarchy of functional units based on tightly-regulated interactions between distinct molecules, cells, organs, and organisms. While experimental methods enable transcriptome-wide measurements across millions of cells, the most ubiquitous bioinformatic tools do not support systems-level analysis. Here we present hdWGCNA, a comprehensive framework for analyzing co-expression networks in high dimensional transcriptomics data such as single-cell and spatial RNA-seq. hdWGCNA provides built-in functions for network inference, gene module identification, functional gene enrichment analysis, statistical tests for network reproducibility, and data visualization. In addition to conventional single-cell RNA-seq, hdWGCNA is capable of performing isoform-level network analysis using long-read single-cell data. We showcase hdWGCNA using publicly available single-cell datasets from Autism spectrum disorder and Alzheimer’s disease brain samples, identifying disease-relevant co-expression network modules in specific cell populations. hdWGCNA is directly compatible with Seurat, a widely-used R package for single-cell and spatial transcriptomics analysis, and we demonstrate the scalability of hdWGCNA by analyzing a dataset containing nearly one million cells.
Neuronal pentraxin Nptx2 regulates complement activity in the brain
Authors: Zhou Jiechao , Wade Sarah D. , Graykowski David , Xiao Mei-Fang , Zhao Binhui , Giannini Lucia AA , Hanson Jesse E. , van Swieten John C , Sheng Morgan , Worley Paul F. , Dejanovic Borislav
Published: September 2022

Complement overactivation mediates microglial synapse elimination in neurological diseases like Alzheimer’s disease and frontotemporal dementia (FTD), but how complement activity is regulated in the brain remains largely unknown. We identified that the secreted neuronal pentraxin Nptx2 binds complement C1q and thereby regulates its activity in the brain. Nptx2-deficient mice show increased complement activity and C1q-dependent microglial synapse engulfment and loss of excitatory synapses. In a neuroinflammation culture model and in aged TauP301S mice, AAV-mediated neuronal overexpression of Nptx2 was sufficient to restrain complement activity and ameliorate microglia-mediated synapse loss. Analysis of human CSF samples from a genetic FTD cohort revealed significantly reduced levels of Nptx2 and Nptx2-C1q protein complexes in symptomatic patients, which correlated with elevated C1q and activated C3. Together, these results show that Nptx2 regulates complement activity and microglial synapse elimination in the healthy and diseased brain and that diminished Nptx2 levels might exacerbate complement-mediated neurodegeneration in FTD patients.
Cytosolic condensates enriched in polyserine repeats are preferred sites of tau fiber propagation
Authors: Lester Evan , Alstyne Meaghan Van , McCann Kathleen L. , Reddy Spoorthy , Cheng Li Yi , Kuo Jeff , Pratt James , Parker Roy
Published: September 2022

Tau aggregates are a hallmark of multiple neurodegenerative diseases and can contain RNAs and RNA binding proteins, including SRRM2 and PNN. How these resident nuclear proteins mislocalize and their influence on the prion-like propagation of tau fibers remains unknown. We demonstrate that polyserine repeats in SRRM2 and PNN are necessary and sufficient for recruitment to tau aggregates. Moreover, we demonstrate tau fibers preferentially grow in association with endogenous cytoplasmic assemblies – mitotic interchromatin granules and cytoplasmic speckles – which contain SRRM2 and PNN. Polyserine undergoes self-assemblyin vitroand in cells, where polyserine-assemblies are sites of tau fiber propagation. Modulating the levels of polyserine containing proteins results in a corresponding change in tau aggregation. These findings define a specific protein motif, and cellular condensates, that promote tau fiber propagation. As cytoplasmic speckles form in iPSC neurons under inflammatory or hyperosmolar stress, they may promote tau fiber propagation in various neurodegenerative diseases.
Consideration of within-patient diversity highlights transmission pathways and antimicrobial resistance gene variability in vancomycin resistantEnterococcus faecium
Authors: McHugh Martin P , Pettigrew Kerry A , Taori Surabhi , Evans Thomas J , Leanord Alistair , Gillespie Stephen H , Templeton Kate E , Holden Matthew TG
Published: September 2022

Synopsis

Background

Whole genome sequencing (WGS) is increasingly applied to healthcare-associated vancomycin-resistantEnterococcus faecium(VREfm) outbreaks. Within-patient diversity could complicate transmission resolution if single colonies are sequenced from identified cases.

Objectives

Determine the impact of within-patient diversity on transmission resolution of VREfm

Methods

Fourteen colonies were collected from VREfm positive rectal screens, single colonies were collected from clinical samples, and Illumina WGS performed. Two isolates were selected for Oxford Nanopore sequencing and hybrid genome assembly to generate lineage-specific reference genomes. Mapping to closely related references was used to identify genetic variations and closely related genomes. A transmission network was inferred for the entire genome set using Phyloscanner.

Results

In total, 229 isolates from 11 patients were sequenced. Carriage of 2-3 sequence types was detected in 27% of patients. Presence of antimicrobial resistance genes and plasmids was variable within genomes from the same patient and sequence type. We identified two dominant sequence types (ST80 and ST1424), with two putative transmission clusters of two patients within ST80, and a single cluster of six patients within ST1424. We found transmission resolution was impaired using fewer than 14 colonies.

Conclusions

Patients can carry multiple sequence types of VREfm, and even within related lineages the presence of mobile genetic elements and antimicrobial resistance genes can vary. VREfm within-patient diversity should be considered to ensure accurate resolution of transmission networks.
The variability of nociplastic and central pain definition in literature: a scoping review
Authors: Margelli Michele , Enrico Bonas , Giovanni Obinu , Gianluca De Marco , Andrea Baroni , Carlo Sartorio
Published: September 2022

Background

Currently, the concept of pain is widely discussed in the scientific community, particularly chronic musculoskeletal pain.

One important classification concerns the mechanisms of pain generation, according to which pain is divided into nociceptive pain, neuropathic pain, nociplastic pain (NP), and central sensitization (CS).

Often the terms nociplastic pain and central sensitization are used incorrectly, as synonyms, or improperly; this can make data transmission complicated.

The aim of this review will be to provide a clearer overview of the concept of pain in the scientific literature, describe the variability on the use of the terms nociplastic pain and central sensitization, and describe the mechanisms in relation to musculoskeletal pain syndromes.

Inclusion Criteria

Every study describing the mechanisms of nociplastic pain or central sensitization in a population of adults (> 18 years old), with acute or chronic musculoskeletal pain, in one or more anatomic regions. This scoping review will consider studies conducted in any context. Articles in English or Italian will be considered.

Methods

The proposed scoping review will be conducted in accordance with the Joanna Briggs Institute methodology (JBI) for scoping reviews.

The search will be carried out on 5 databases: MEDLINE, Cochrane Central, Scopus, Embase, and PEDro.

Selection and data extraction will be conducted by two blind independent researchers and inconsistencies will be resolved by a third reviewer.

The results will be presented in a schematic, tabular and descriptive format that will line up with the objectives and scope of the review.

Conclusions

This will be the first scoping review to provide a comprehensive overview of the topic. The results will add meaningful information for clinicians. Furthermore, any knowledge gaps of the topic will be identified. The results of this research will be published in a peer-reviewed journal and will be presented at relevant (inter)national scientific events.
The BAF complex inhibitor pyrimethamine reverses HIV-1 latency in people with HIV-1 on antiretroviral therapy
Authors: Prins H.A.B. , Crespo R. , Lungu C. , Rao S. , Li L. , Overmars R.J. , Papageorgiou G. , Mueller Y.M. , Hossain T. , Kan T.W. , Rijnders B.J.A. , Bax H.I. , van Gorp E.C.M. , Nouwen J.L. , de Vries-Sluijs T.E.M.S. , Schurink C.A.M. , de Mendonça Melo M. , van Nood E. , Colbers A. , Burger D. , Palstra R-J. , van Kampen J.J.A. , van de Vijver D.A.M.C. , Mesplède T. , Katsikis P.D. , Gruters R.A. , Koch B.C.P. , Verbon A. , Mahmoudi T. , Rokx C.
Published: September 2022

A major barrier towards HIV-1 cure is the presence of a replication-competent latent reservoir that, upon treatment cessation, can spark viral rebound leading to disease progression. Pharmacological reactivation of the latent HIV-1 reservoir with Latency reversing agents (LRAs) is a first step toward triggering reservoir decay. Inhibitors of the BAF-complex, a key repressor of HIV-1 transcription were identified to act as LRAs, and enhanced the effect of other LRAs such as histone deacetylase inhibitors ex-vivo. We repurposed the licensed drug pyrimethamine as a BAF-inhibitor to investigate its in vivo impact on the HIV-1 reservoir of people living with HIV-1 (PLWH). Twenty eight PLWH on suppressive antiviral therapy were randomized in a 1:1:1:1 ratio to receive pyrimethamine; high dose valproic acid; both valproic acid and pyrimethamine; or no intervention for 14 days. The primary endpoint was change in HIV-1 reactivation measured as cell associated (CA)HIV-1 RNA at treatment initiation and at the end of treatment. We observed a rapid, modest and significant increase in CAHIV-1 RNA in CD4+T-cells in response to pyrimethamine exposure, which persisted throughout the 14 day treatment, concomitant with induction of BAF target genes as biomarkers of pyrimethamine activity as well as detected plasma pyrimethamine levels. Valproic acid treatment alone did not lead to increase in CAHIV-1 RNA, nor did valproic acid augment the latency reversal effect of pyrimethamine. Despite demonstrated latency reversal, pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir as determined by a tat/rev limiting dilution assay. Serious adverse events were not observed, although physician-directed treatment adjustments occurred, particularly when combining valproic acid with pyrimethamine. These data underline the need for pharmacovigilance in combinatorial clinical strategies and demonstrate that the BAF inhibitor pyrimethamine reverses HIV-1 latency in vivo in PLWH, substantiating its potential in advancement in clinical studies to target the proviral reservoir. Clinicaltrials.gov:NCT03525730

One sentence summary

This clinical trial shows that the BAF inhibitor pyrimethamine reverses HIV-1 latency in vivo which supports repurposing this drug for cure studies.
Post-COVID-19 syndrome: retinal microcirculation as a potential marker for chronic fatigue
Authors: Schlick Sarah , Lucio Marianna , Bartsch Alexander , Skornia Adam , Hoffmanns Jakob , Szewczykowski Charlotte , Schröder Thora , Raith Franziska , Rogge Lennart , Heltmann Felix , Moritz Michael , Beitlich Lorenz , Schottenhamml Julia , Herrmann Martin , Harrer Thomas , Ganslmayer Marion , Kruse Friedrich E. , Lämmer Robert , Mardin Christian , Hohberger Bettina
Published: September 2022

Post-COVID-19 syndrome (PCS) summarizes persisting sequelae after infection with the severe-acute-respiratory-syndrome-Coronavirus-2 (SARS-CoV-2). PCS can affect patients of all covid-19 disease severities. As previous studies revealed impaired blood flow as a provoking factor for triggering PCS, it was the aim of the present study to investigate a potential association of self-reported chronic fatigue and retinal microcirculation in patients with PCS, potentially indicating an objective biomarker.

A prospective study was performed, including 201 subjects: 173 patients with PCS and 28 controls. Retinal microcirculation was visualized by OCT-Angiography (OCT-A) and quantified by the Erlangen-Angio-Tool as macula and peripapillary vessel density (VD). Chronic Fatigue (CF) was assessed with the variables ‘Bell score’, age and gender. The VD in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) were analyzed considering the repetitions (12 times). Taking in account of such repetitions a mixed model was performed to detect possible differences in the least square means between different groups of analysis.

An age effect on VD was observed between patients and controls (p<0.0001). Gender analysis yielded that women with PCS showed lower VD levels in SVP compared to male patients (p=0.0015). The PCS patients showed significantly lower VD of ICP as compared to the controls (p=0.0001, [CI: 0.32; 1]). Moreover, considering PCS patients, the mixed model reveals a significant difference between chronic fatigue (CF) and without CF in VD of SVP (p=0.0033, [CI: -4.5; -0.92]). The model included age, gender and the variable ‘Bell score’, representing a subjective marker for CF. Consequently, the retinal microcirculation might be an objective biomarker in subjective-reported chronic fatigue of patients with PCS.