bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of precisely meeting estimated daily energy and lysine requirements for gestating sows over three consecutive pregnancies on sow reproductive and lactation performance
Authors: Stewart Victoria , Buis R Quincy , Christensen Brenda , Hansen Lauren L , de Lange Cornelis F M , Mandell Ira B , Huber Lee-Anne
Published: December 2021

The objective of the current study was to determine the effects of precisely meeting estimated daily energy and Lys requirements for gestating sows over three consecutive pregnancies on sow reproductive and lactation performance. A total of 105 sows (initial reproductive cycle 1.4 ± 0.5) were randomly assigned to a precision (PF; n = 50) or control (CON; n = 55) feeding program between days 2 and 9 of gestation and housed in group-pens equipped with electronic sow feeders capable of blending two diets. The PF sows received unique daily blends of two isocaloric diets (2518 kcal/kg NE; 0.80% and 0.20% standardized ileal digestible [SID] Lys, respectively), whereas CON sows received a static blend throughout gestation to achieve 0.56% SID Lys. After weaning, sows were re-bred and entered the same feeding program as in the previous pregnancy for two subsequent pregnancy cycles (PF: n = 36; CON: n = 37; average reproductive cycle: 2.4 ± 0.5; PF: n = 25; CON: n = 24; average reproductive cycle: 3.5 ± 0.5). Sows on the PF program received 97%, 105%, and 118% (average over three pregnancy cycles) of dietary energy and 67%, 79%, and 106% of SID Lys intakes compared to CON between days 5 and 37, 38 and 72, and 73 and 108 of gestation, respectively. Estimated N (26.1%) retention did not differ between gestation feeding programs in any pregnancy, but excess N excretion was less (1617 vs. 1750 ± 54 g/sow; P < 0.01) for PF vs. CON sows. Regardless of pregnancy cycle, sows that received the PF program had greater ADG between days 38 and 72 (614 vs. 518 ± 63 g/d; P < 0.05) and between days 73 and 108 (719 vs. 618 ± 94 g/d; P = 0.063) of gestation, and greater loin depth gain between days 63 and 110 of gestation (0.7 vs. −1.1 ± 1.6 mm; P < 0.05), but BW (235.1 kg) and backfat (17.8 mm) and loin (70.5 mm) depths on day 110 of gestation did not differ. The number of piglets born alive, stillborn, and mummified, and litter birth weight (16.5 kg) did not differ in any pregnancy cycle, nor did piglet ADG during lactation (250 g/d) and piglet BW (6.7 kg) at weaning. Sows that received the PF program during gestation had lower ADFI during lactation (5.7 vs. 6.2 ± 0.2 kg; P < 0.01). Therefore, using feeding programs that precisely match estimated daily energy and Lys requirements for gestating sows provides the opportunity to reduce N losses to the environment and reduce lactation feed usage, without negatively affecting sow reproductive and lactation performance.
A review of the role of non-invasive ventilation in critical care responses to COVID-19 in low- and middle-income countries: lessons learnt from Baghdad
Authors: Thomas Richard , Abdulateef Mustafa M , Godard Aurelie
Published: December 2021

In 2021, the burden of the coronavirus disease 2019 (COVID-19) pandemic became especially severe in low- and middle-income countries (LMICs). With high numbers of patients requiring advanced respiratory support and invasive mechanical ventilation (IMV), many ICUs were overwhelmed. This problem is particularly pronounced in LMICs, where the availability of intensive care beds may be limited. Non-invasive ventilation (NIV) has been increasingly used in COVID-19, as both a bridge to intubation as well as a definitive treatment. Use of NIV may be a feasible management strategy in settings where performing IMV is not possible on a large scale due to resource constraints. During 2020–2021, Médecins Sans Frontière helped manage a COVID-19 ICU in Baghdad, Iraq. The predominant mode of treatment was NIV. Due to a shortage of intensive care ventilators, NIV was delivered in the majority of cases by home continuous positive airway pressure machines. In total, 709 patients were admitted to the ICU during the study period with an overall mortality of 61.1%. In addition to the ventilation strategy, patients must be treated holistically, with a comprehensive package of critical care. We aim to highlight the role of NIV in this setting and summarise our experiences to assist future critical care projects during the pandemic.
Mohs Micrographic Surgery Versus Wide Local Excision in the Treatment of Merkel Cell Carcinoma: A Systematic Review
Authors: Carrasquillo Osward Y. , Cancel-Artau Karina J. , Ramos-Rodriguez Alvaro J. , Cruzval-O’Reilly Estefania , Merritt Bradley G.
Published: December 2021

BACKGROUND

Merkel cell carcinoma (MCC) is an aggressive neoplasm with high rates of recurrences. Current guidelines recommend wide local excision (WLE) with 1 to 2 cm margins. However, Mohs micrographic surgery (MMS) offers a potential advantage over WLE because of its ability of sparing healthy tissue and assessing 100% of margins.

OBJECTIVE

To systematically evaluate the surgical modalities for the treatment of MCC.

MATERIALS AND METHODS

Eligible articles were identified using MEDLINE, Scopus, EMBASE, and Cochrane Library. All available studies investigating surgical treatment of MCC with WLE or MMS were considered.

RESULTS

Forty studies met the inclusion criteria. Thirty-one studies described patients treated with WLE, 3 with MMS, and 6 with either WLE or MMS. Subgroup analysis of Stage I MCC showed recurrence rates similar in both surgical modalities with local recurrence rate of 6.8% for WLE versus 8.5% for MMS (p = .64) and a regional recurrence rate of 15.2% for WLE versus 15.3% for MMS (p = .99).

CONCLUSION

Overall WLE cases were at a higher stage at presentation. Subgroup analysis showed that MMS is not inferior to WLE excision for the treatment of Stage I MCC and is a reasonable option for anatomic locations where tissue sparing is important.
Updates on targeting human epidermal growth factor receptor 2-positive breast cancer: what's to know in 2021
Authors: McAndrew Nicholas P.
Published: December 2021

Purpose of review

To highlight recent practice changing clinical trials, focusing on those leading to new drug approvals, in human epidermal growth factor receptor 2-positive (HER2+) breast cancer.

Recent findings

The improved disease-free survival of adjuvant trastuzumab emtansine (T-DM1) over trastuzumab in patients with residual disease has made neoadjuvant sequencing of therapy standard for most patients with early stage disease. In patients with metastatic HER2+ breast cancer, trastuzumab deruxtecan has recently shown dramatically improved efficacy over T-DM1. Tucatinib is an oral tyrosine kinase inhibitor with best in class blood-brain barrier penetration. Margetuximab, a novel HER2-targeted chimeric monoclonal antibody with an engineered Fc receptor designed to activate local immune response, was recently approved in heavily pretreated patients based on modest but significant improvement in progression-free survival.

Patients with HER2+ breast cancer have a variety of therapeutic options in the early stage and metastatic setting. Optimal sequencing of therapy will depend on patient-specific factors such as site of tumor progression and underlying comorbidities. De-escalation of the first-line metastatic regimen may be considered in select patients with hormone positive/HER2+ breast cancer, by using endocrine therapy instead of chemotherapy in combination with HER2-targeted therapy, which may improve side effects without sacrificing efficacy.
The Role of Supermicrosurgery and Arborization Capture in Improving Free-styled Propeller Flap Survival
Authors: Khajuria Ankur , Koshima Isao , Kannan Ruben Y.
Published: December 2021

Background:

Propeller flaps have a higher-than-normal incidence of partial flap necrosis. Although venous supercharging has been shown to reduce this risk, its application is limited outside the scope of lower limb propeller flaps. In this article, we look at the ability of arborization capture and supermicrosurgery to allow propeller flaps to capture adjacent perforasomes and significantly improve flap survival.

Methods:

In a retrospective case series across two institutions, the outcomes of two groups of patients who had propeller flaps were compared. Group A patients were those who had conventional free-styled propeller flaps (n = 25), whereas Group B (n = 19) patients had propeller flaps algorithmically selected for either (1) arborization capture or (2) venous supercharging, or both. Two-way ANOVA analysis was performed to evaluate inter-group differences.

Results:

Conventional propeller flaps had a 64% complete survival rate (32% partial necrosis rate and a 4% total necrosis rate) compared with a 94% complete survival rate in modified propeller flaps. Of the 12 cases of arborization capture (perforator complex diameters of 1–2 mm), only one flap sustained partial flap loss, whereas all seven supercharged propeller flaps (selected for perforator diameter <1 mm, with venous supercharging, in addition to arborization capture) survived completely.

Conclusions:

The arborization technique should be the mainstay technique for all propeller flaps with perforator complex diameters of less than 2 mm while supercharging further enhances its survival, particularly in perforator complex diameters of less than 1 mm.
Eosinophilia in Migrant Children
Authors: Bustamante Jorge , García López-Hortelano Milagros , Barcia Cristina , Díaz Almirón Mariana , Subirats Mercedes , Montero Vega Dolores , Mellado María José , Sainz Talía
Published: December 2021

Background:

The diagnostic approach to eosinophilia is complex, given the numerous reported etiologies. Intestinal parasites (especially helminths) are a concern in children from high-burden settings. We describe the diagnostic approach and clinical management of eosinophilia in a cohort of migrant children.

Methods:

We conducted a retrospective observational study that included children diagnosed with eosinophilia at a reference center for pediatric tropical diseases from 2014 to 2018. All patients were screened according to a unified protocol, including direct microbiologic and serologic tests.

Results:

A total of 163 children presented with eosinophilia during the study period [median age, 7.7 years (4.1–12.2); 57.1% boys], mostly from Asia (27.6%) and South America (22.1%). Most were internationally adopted children (43.6%) or migrants (26.4%). Only 34.4% of the children were symptomatic, and the main etiology for eosinophilia was helminths (56.4%). After a sequential diagnostic approach, no etiology was found for 40.5% of the patients. The independent risk factors for an unexplained etiology were younger age (≤2 years: odds ratio, 3.6; 95% CI, 1.3–10.2; P = 0.015), absence of symptoms (odds ratio, 4.8; 95% CI, 1.8–12.5; P = 0.001) and mild eosinophilia (<1000/µL: odds ratio, 4.2; 95% CI, 4.5–11.7; P = 0.005). Only 6 children were treated empirically. In those children with an identified cause and in those treated empirically, the eosinophilia resolved in 52% in a median of 7 months (5–9).

Conclusions:

Helminths are the main cause of eosinophilia in migrant children and need to be hunted, especially in older children with eosinophil counts >1000 eosinophils/µL.
Early Cochlear Implantation Allows Deaf Children to Control Voice Pitch and Loudness independently
Authors: Yamazaki Hiroshi , Suehiro Atsushi , Ueda Yuko , Kondo Kanako , Ishida Ai , Yamamoto Norio , Takagi Akira , Omori Koichi
Published: December 2021

Objective:

Congenitally deaf children with a cochlear implant (CI) improve their speech production intelligibility, but their prosody, including stress and intonation produced by voice pitch and loudness changes, often differs from normal hearing people, which affects their fluent oral communication. This study is aimed to clarify abnormal characteristics of voice pitch and loudness control in CI recipients using a newly developed visually guided pitch change task.

Methods:

We included 13 normal hearing volunteers (NH group) and 17 congenitally deaf CI users who showed good speech intelligibility. The 17 CI users were divided into Early-CI and Late-CI groups, based on their age at implantation of 2.5 years. Using the visually guided pitch change task and acoustic voice analysis of sustained vowels, we assessed their vocal skills to maintain constant pitch and loudness and intentionally change the voice pitch independent from loudness. At the time of examination, the mean age was 24.1, 12.7, and 18.9 years in the NH, Early-CI, and Late-CI groups.

Results:

During constant vowel production, Early-CI and Late-CI groups showed more significant fluctuations in pitch and loudness than the NH group. However, when focusing on intentionally changing only the pitch of the voice, the Early-CI group was significantly better than the Late-CI group and comparable to the NH group in terms of their ability to change vocal pitch independently from loudness.

Conclusion:

Among congenitally deaf patients, age at implantation was associated with the development of voice skills to control voice pitch and loudness separately, which may influence their fluent prosody production.
Dietary factors and brain health
Authors: Lefèvre-Arbogast Sophie , Thomas Aline , Samieri Cécilia
Published: December 2021

Purpose of review

Nutrition is a complex exposure (i.e., the food exposome) that influences brain function and health through multiple pathways. We review recent epidemiological studies that have improved the characterization of the food exposome and brain health in humans and have revealed promising nutrition-based strategies to prevent cognitive aging.

Recent findings

A selection of epidemiological research from the past 18 months of both observational and clinical studies is presented, with a focus on novel findings, including novel nutrient and diet patterns, diet-related approaches to rescue brain energetics defects in aging, and biomarker-based studies to decipher specific neurobiological pathways of nutrition and brain health.

Although healthy diets such as the Mediterranean diet promote brain health throughout life, specific diets, such as the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay diet, or specific nutrients (LC n-3 polyunsaturated fatty acids, carotenoids, vitamin D, B vitamins, polyphenols) alone or in combination, may prevent cognitive aging. Diet management approaches to rescue brain energetics defects such as the Modified Mediterranean-ketogenic diet may be promising to prevent neurodegenerative diseases. Expanding research also suggests that promotion of a healthy gut microbiome through prebiotic foods may preserve the diet–gut–brain axis with aging. Future studies should explore more individualized preventive approaches through a ’precision nutrition’ framework.
Understanding Pre-Exposure Prophylaxis Adherence in Young Women in Kenya
Authors: Haberer Jessica E. , Mugo Nelly , Bukusi Elizabeth Ann , Ngure Kenneth , Kiptinness Catherine , Oware Kevin , Garrison Lindsey E. , Musinguzi Nicholas , Pyra Maria , Valenzuela Susie , Thomas Katherine K. , Anderson Peter L. , Thirumurthy Harsha , Baeten Jared M.
Published: December 2021

Objective:

To present detailed analyses of long-term pre-exposure prophylaxis (PrEP) use and associated behaviors and perceptions among young Kenyan women.

Design:

Prospective, observational cohort.

Methods:

The Monitoring PrEP among Young Adult women Study involved 18 to 24-year-old women at high HIV risk initiating PrEP in Kisumu and Thika, Kenya. Visits for PrEP counseling and dispensing, HIV testing, and socio-behavioral data collection occurred at Month 1 and quarterly for 2 years. PrEP adherence was measured with pharmacy refill and real-time electronic monitoring, plus tenofovir diphosphate levels in 15% of participants. HIV risk behavior and perception were assessed by self-report in weekly short message service surveys from Months 6–24. Predictors of adherence were assessed with multivariable logistic regression analysis.

Results:

Three hundred forty-eight women (median age 21, VOICE risk score 7) were followed for 617 person-years. Pharmacy refills steadily declined from 100% (Month 0–1) to 54% (Months 22–24). Average electronically monitored adherence similarly declined from 65% (Month 0–1) to 15% (Months 22–24). Electronically monitored adherence had moderately high concordance with tenofovir diphosphate levels (67%). High average adherence (5+ doses/week) was seen at 385/1898 (20%) participant-visits and associated with low baseline VOICE risk score, >1 current sexual partner, ≤1-hour travel time to clinic, and the Kisumu site. short message service-reported behavior and risk perception were not associated with adherence. Four women acquired HIV (incidence 0.7/100 person-years).

Conclusions:

PrEP adherence was modest and declined over time. HIV risk was inconsistently associated with adherence; clinic access and site-level factors were also relevant. Relatively low HIV incidence suggests participants may have achieved protection through multiple strategies.
Brief Report: Efficacy and Safety of Oral Islatravir Once Daily in Combination With Doravirine Through 96 Weeks for Treatment-Naive Adults With HIV-1 Infection Receiving Initial Treatment With Islatravir, Doravirine, and Lamivudine
Authors: Molina Jean-Michel , Yazdanpanah Yazdan , Afani Saud Alejandro , Bettacchi Christopher , Chahin Anania Carolina , Klopfer Stephanie O. , Grandhi Anjana , Eves Karen , Hepler Deborah , Robertson Michael N. , Hwang Carey , Hanna George J. , Correll Todd
Published: December 2021

Background:

Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for treatment and prevention of HIV-1. We present efficacy and safety data for islatravir and doravirine (DOR) through 96 weeks of the phase 2b trial (NCT03272347).

Methods:

In this randomized, double-blind, dose-ranging trial, participants initially received islatravir (0.25, 0.75, or 2.25 mg) with doravirine (100 mg) and lamivudine (3TC, 300 mg) or a fixed-dose combination of doravirine, 3TC, and tenofovir disoproxil fumarate (DOR/3TC/TDF) daily. Beginning at week 24, participants receiving islatravir stopped 3TC if HIV-1 RNA from the prior visit was <50 copies per milliliter and continued taking the assigned islatravir dose (still blinded) with doravirine. All islatravir groups transitioned to open-label use of 0.75 mg between weeks 60 and 84. Efficacy end points at week 96 included the proportion of participants maintaining HIV-1 RNA of <50 copies per milliliter (FDA Snapshot). Safety was assessed by adverse event (AE) reporting.

Results:

One hundred twenty-one treatment-naive participants received the study drugs and were included in the analyses. Through week 96, HIV-1 RNA<50 copies per milliliter was maintained in 86.2% (25/29), 90.0% (27/30), and 67.7% (21/31) of participants in the 0.25-, 0.75-, and 2.25-mg islatravir groups, respectively, 81.1% (73/90) of the combined islatravir group, and 80.6% (25/31) of the DOR/3TC/TDF group. One participant in the 2.25-mg islatravir group had Protocol-Defined Virologic Failure after week 48. Drug-related AE rates were higher for DOR/3TC/TDF participants (22.6%) compared with islatravir (combined 7.8%). Two participants (2.2%) receiving islatravir with doravirine and one (3.2%) receiving DOR/3TC/TDF discontinued because of an AE.

Conclusions:

Treatment regimens containing islatravir and doravirine maintained viral suppression through week 96 and were well tolerated regardless of dose.
Impact of Integrase Strand Transfer Inhibitor Use During Pregnancy on Viral Suppression at Delivery and Infant Outcomes: A Statewide Retrospective Cohort Study
Authors: Latham A. Hayden , Nissim Oriel A. , Spitznagel Marjorie C. , Kirk Stephanie E. , Tarleton Jessica L. , Lazenby Gweneth B.
Published: December 2021

Background:

We sought to determine whether pregnant women with HIV prescribed integrase strand transfer inhibitor (INSTI) were more likely to have viral suppression at delivery and any increased risk of adverse infant outcomes.

Methods:

This was a retrospective, statewide cohort study of women with HIV and their HIV-exposed infants who delivered in South Carolina from 2008 to 2019. Women's antenatal AVRs were classified as INSTI or non-INSTI. We compared the percentage of women with undetectable HIV RNA viral load (<40 copies/mL) at delivery between groups. We compared the percentage of HIV-exposed singleton infants who were born preterm delivery, low birth weight, and small for gestational age and had confirmed perinatal HIV infection. Categorical outcomes were compared using the χ2 test or Fischer exact test.

Results:

A total of 832 infants, including 11 sets of twins, were exposed to maternal HIV. Detailed antiretroviral regimens were available for analysis in a third of mother–infant pairs (n = 315). Half of the infants were exposed to INSTI (159) and half to non-INSTI antiretrovirals (156). Most women had an undetectable viral load at delivery (80% INSTI and 73% non-INSTI, P= 0.11). The percentage of singleton infants with adverse outcomes was similar between INSTI and non-INSTI groups: preterm delivery (21% and 16%, P = 0.3), low birth weight (19% and 21%, P = 0.7), small for gestational age (11% vs 9%, P = 0.5), and perinatal HIV infection (2.5% and 1.3%, P = 0.7).

Conclusions:

We observed that viral suppression before delivery was similar between pregnant women prescribed INSTI and non-INSTI antiretroviral therapy. The percentage of infants with adverse outcomes was similar when exposed to INSTI and non-INSTI antiretroviral therapy.
Minimal cross-over between mutations associated with Omicron variant of SARS-CoV-2 and CD8+ T cell epitopes identified in COVID-19 convalescent individuals
Authors: Redd Andrew D , Nardin Alessandra , Kared Hassen , Bloch Evan M , Abel Brian , Pekosz Andrew , Laeyendecker Oliver , Fehlings Michael , Quinn Thomas C , Tobian Aaron AR
Published: December 2021

There is a growing concern that ongoing evolution of SARS-CoV-2 could lead to variants of concern (VOC) that are capable of avoiding some or all of the multi-faceted immune response generated by both prior infection or vaccination, with the recently described B.1.1.529 (Omicron) VOC being of particular interest. Peripheral blood mononuclear cell samples from PCR-confirmed, recovered COVID-19 convalescent patients (n=30) infected with SARS-CoV-2 in the United States collected in April and May 2020 who possessed at least one or more of six different HLA haplotypes were selected for examination of their anti-SARS-CoV-2 CD8+ T-cell responses using a multiplexed peptide-MHC tetramer staining approach. This analysis examined if the previously identified viral epitopes targeted by CD8+ T-cells in these individuals (n=52 distinct epitopes) are mutated in the newly described Omicron VOC (n=50 mutations). Within this population, only one low-prevalence epitope from the Spike protein restricted to two HLA alleles and found in 2/30 (7%) individuals contained a single amino acid change associated with the Omicron VOC. These data suggest that virtually all individuals with existing anti-SARS-CoV-2 CD8+ T-cell responses should recognize the Omicron VOC, and that SARS-CoV-2 has not evolved extensive T-cell escape mutations at this time.

Importance

The newly identified Omicron variant of concern contains more mutations than any of the previous variants described to date. In addition, many of the mutations associated with the Omicron variant are found in areas that are likely bound by neutralizing antibodies, suggesting that the first line of immunological defense against COVID-19 may be compromised. However, both natural infection and vaccination develop T-cell based responses, in addition to antibodies. This study examined if the parts of the virus, or epitopes, targeted by the CD8+ T-cell response in thirty individuals who recovered from COVID-19 in 2020 were mutated in the Omicron variant. Only one of 52 epitopes identified in this population contained an amino acid that was mutated in Omicron. These data suggest that the T-cell immune response in previously infected, and most likely vaccinated individuals, should still be effective against Omicron.
Warming During Embryogenesis Induces a Lasting Transcriptomic Signature in Fishes
Authors: Ripley Daniel M. , Garner Terence , Hook Samantha A. , Veríssimo Ana , Grunow Bianka , Moritz Timo , Clayton Peter , Shiels Holly A. , Stevens Adam
Published: December 2021

Exposure to elevated temperatures during embryogenesis can influence the plasticity of tissues in later-life. Despite these long-term changes in plasticity, few differentially expressed genes are ever identified, suggesting that the developmental programming of later-life plasticity may occur through the modulation of other aspects of the transcriptomic architecture, such as gene network function. Here, we use network modelling approaches to demonstrate that warm temperatures during embryonic development (developmental warming) have consistent effects in later-life on the organisation of transcriptomic networks across four diverse species of fishes:Scyliorhinus canicula, Danio rerio, Dicentrarchus labrax, andGasterosteus aculeatus. The transcriptomes of developmentally warmed fishes are characterised by an increased entropy of their pairwise gene interaction networks, implying a less structured, more ‘random’ set of gene interactions. We also show that, in zebrafish subject to developmental warming, the entropy of an individual gene within a network is associated with that gene’s probability of expression change during temperature acclimation in later-life. However, this association is absent in animals reared under ‘control’ conditions. Thus, the thermal environment experienced during embryogenesis can alter transcriptomic organisation in later-life, and these changes may influence an individual’s responsiveness to future temperature challenges.
Arginine-Vasopressin Expressing Neurons in the Murine Suprachiasmatic Nucleus Exhibit a Circadian Rhythm in Network Coherence In Vivo
Authors: Stowie Adam , Qiao Zhimei , Do Carmo Buonfiglio Daniella , Beckner Delaney M. , Ehlen J. Christopher , Benveniste Morris , Davidson Alec J.
Published: December 2021

The Suprachiasmatic Nucleus (SCN) is composed of functionally distinct sub-populations of GABAergic neurons which form a neural network responsible for synchronizing most physiological and behavioral circadian rhythms in mammals. To date, little is known regarding which aspects of SCN rhythmicity are generated by individual SCN neurons, and which aspects result from neuronal interaction within a network. Here, we utilize in vivo miniaturized microscopy to measure fluorescent GCaMP-reported calcium dynamics in AVP-expressing neurons in the intact SCN of awake, behaving mice. We report that SCN AVP neurons exhibit periodic, slow calcium waves which we demonstrate, using in vivo electrical recordings, likely reflect burst-firing. Further, we observe substantial heterogeneity of function in that AVP neurons exhibit unstable rhythms, and relatively weak rhythmicity at the population level. Network analysis reveals that correlated cellular behavior, or coherence, among neuron pairs also exhibited stochastic rhythms with about 33% of pairs rhythmic at any time. Unlike single-cell variables, coherence exhibited a strong rhythm at the population level with time of maximal coherence among AVP neuronal pairs at CT/ZT 6 and 9, coinciding with the timing of maximal neuronal activity for the SCN as a whole. These results demonstrate robust circadian variation in the coordination between stochastically rhythmic neurons and that interactions between AVP neurons in the SCN may be more influential than single-cell activity in the regulation of circadian rhythms. Furthermore, they demonstrate that cells in this circuit, like those in many other circuits imaged in vivo, exhibit profound heterogenicity of function over time and space.

Significance Statement

This work is the first to employ two novel in vivo recording techniques, miniaturized calcium microscopy and optogentically-targeted single unit activity recording, to examine the rhythmic behavior of AVP expressing neurons both at the individual neuronal and network level. These results suggest that while AVP neurons are important for organismal rhythmicity, individual cellular rhythms are unstable and diverse. However, we observed correlated activity among these neurons which appears more reliably rhythmic, suggesting that emergent network properties of the SCN may be more relevant for organismal rhythmicity than individual neuronal characteristics.
Complementary role of mathematical modeling in preclinical glioblastoma: differentiating poor drug delivery from drug insensitivity
Authors: Urcuyo Javier C. , Massey Susan Christine , Hawkins-Daarud Andrea , Marin Bianca-Maria , Burgenske Danielle M. , Sarkaria Jann N. , Swanson Kristin R.
Published: December 2021

Glioblastoma is the most malignant primary brain tumor with significant heterogeneity and a limited number of effective therapeutic options. Many investigational targeted therapies have failed in clinical trials, but it remains unclear if this results from insensitivity to therapy or poor drug delivery across the blood-brain barrier. Using well-established EGFR-amplified patient-derived xenograft (PDX) cell lines, we investigated this question using an EGFR-directed therapy. With only bioluminescence imaging, we used a mathematical model to quantify the heterogeneous treatment response across the three PDX lines (GBM6, GBM12, GBM39). Our model estimated the primary cause of intracranial treatment response for each of the lines, and these findings were validated with parallel experimental efforts. This mathematical modeling approach can be used as a useful complementary tool that can be widely applied to many more PDX lines. This has the potential to further inform experimental efforts and reduce the cost and time necessary to make experimental conclusions.

Author summary

Glioblastoma is a deadly brain cancer that is difficult to treat. New therapies often fail to surpass the current standard of care during clinical trials. This can be attributed to both the vast heterogeneity of the disease and the blood-brain barrier, which may or may not be disrupted in various regions of tumors. Thus, while some cancer cells may develop insensitivity in the presence of a drug due to heterogeneity, other tumor areas are simply not exposed to the drug. Being able to understand to what extent each of these is driving clinical trial results in individuals may be key to advancing novel therapies. To address this challenge, we used mathematical modeling to study the differences between three patient-derived tumors in mice. With our unique approach, we identified the reason for treatment failure in each patient tumor. These results were validated through rigorous and time-consuming experiments, but our mathematical modeling approach allows for a cheaper, quicker, and widely applicable way to come to similar conclusions.
Orally administered epeleuton inhibits SARS-CoV-2 viral load, replication and pathology in the Syrian Hamster model
Authors: Climax John , Hamza Moayed , Lafferty Adam , Guilfoyle Kate , van Amerongen Geert , Stadler Konrad , Wohlsein Peter , Baumgärtner Wolfgang , Weissbach Markus , Coughlan David
Published: December 2021

Early treatment of patients with confirmed COVID-19 presenting mild symptoms can reduce the number that progress to more severe disease and require hospitalization. Considering the potential for the development of drug resistance to existing therapies and the emergence of new SARS-CoV-2 variants, there is a need for an expanded armamentarium of treatment options for COVID-19. Epeleuton is a novel orally administered second-generation n-3 fatty acid with potential direct antiviral and immunomodulatory actions, and a favourable clinical safety profile. In this study we show that epeleuton inhibits SARS-CoV-2 infectious viral load, replication and disease pathology in the lungs and upper airways in the Syrian hamster model of SARS-CoV-2 infection. These data support the potential utility of epeleuton in the early treatment and prevention of SARS-CoV-2 infection. Clinical trials are needed to evaluate the efficacy of epeleuton as an outpatient treatment and prevention of COVID-19.
The Presence of the Temporal Horn Exacerbates the Vulnerability of Hippocampus during Head Impacts
Authors: Zhou Zhou , Li Xiaogai , Domel August G , Dennis Emily L , Georgiadis Marios , Liu Yuzhe , Raymond Samuel J. , Grant Gerald , Kleiven Svein , Camarillo David , Zeineh Michael
Published: December 2021

Hippocampal injury is common in traumatic brain injury (TBI) patients, but the underlying pathogenesis remains elusive. In this study, we hypothesize that the presence of the adjacent fluid-containing temporal horn exacerbates the biomechanical vulnerability of the hippocampus. Two finite element models of the human head were used to investigate this hypothesis, one with and one without the temporal horn, and both including a detailed hippocampal subfield delineation. A fluid-structure interaction coupling approach was used to simulate the brain-ventricle interface, in which the intraventricular cerebrospinal fluid was represented by an arbitrary Lagrangian-Eulerian multi-material formation to account for its fluid behavior. By comparing the response of these two models under identical loadings, the model that included the temporal horn predicted increased magnitudes of strain and strain rate in the hippocampus with respect to its counterpart without the temporal horn. This specifically affected cornu ammonis (CA) 1 (CA1), CA2/3, hippocampal tail, subiculum, and the adjacent amygdala and ventral diencephalon. These computational results suggest that the presence of the temporal horn exacerbate the vulnerability of the hippocampus, highlighting the mechanobiological dependency of the hippocampus on the temporal horn.
Staffing levels and hospital mortality in England: a national panel study using routinely collected data
Authors: Rubbo Bruna , Saville Christina , Dall’Ora Chiara , Turner Lesley , Jones Jeremy , Ball Jane , Culliford David , Griffiths Peter
Published: December 2021

Background

Most studies investigating the association between hospital staff levels and mortality have focused on single professional groups, in particular nursing. However, single staff group studies might overestimate effects or neglect important contributions to patient safety from other staff groups. We aimed to examine the association between multiple clinical staff levels and case-mix adjusted patient mortality in English hospitals.

Methods and Findings

This retrospective observational study used routinely available data from all 138 National Health Service hospital trusts that provided general acute adult services in England between 2015 and 2019. Standardised mortality rates were derived from the Summary Hospital level Mortality Indicator dataset. Estimates for the effect of clinical staffing from the single staff models were generally higher than estimates from models with multiple staff groups. Using a multilevel negative binomial random effects model, hospitals with higher levels of medical and allied healthcare professional (AHP) staff had significantly lower mortality rates (1.04, 95%CI 1.02 to 1.06, and 1.04, 95%CI 1.02 to 1.06, respectively), while those with higher support staff had higher mortality rates (0.85, 95%CI 0.79 to 0.91 for nurse support, and 1.00, 95%CI 0.99 to 1.00 for AHP support), after adjusting for multiple staff groups and hospital characteristics. Estimates of staffing levels on mortality were higher in magnitude between- than within-hospitals, which were not statistically significant in a within-between random effects model.

Conclusions

We showed the importance of considering multiple staff groups simultaneously when examining the association between hospital mortality and clinical staffing levels. Despite not being included in previous workforce studies, AHP and AHP support levels have a significant impact on hospital mortality. As the main variation was seen between-as opposed to within-hospitals, structural recruitment and retention difficulties coupled with financial constraints could contribute to the effect of staffing levels on hospital mortality.
Safety and Immunogenicity of SARS-CoV-2 S-2P Protein Vaccine MVC-COV1901 in People Living with HIV
Authors: Cheng Shu-Hsing , Lien Chia En , Hsieh Szu-Min , Cheng Chien-Yu , Liu Wang-Da , Lo Ching-Lung , Ko Wen-Chien , Chen Yen-Hsu , Huang Ching-Tai , Chang Hsiao-Ting , Hwang Shinn-Jang , Wang Ning-Chi , Liu Ming-Che , Lee Yu-Lin , Tai I-Chen , Garcia Estrada Josue Antonio , Lin Tzou-Yien , Lee Wen-Sen
Published: December 2021

Objectives

To provide data on the immune response to COVID-19 vaccines in people living with HIV (PWH), MVC-COV1901, a recombinant protein vaccine containing S-2P protein adjuvanted with CpG 1018 and aluminium hydroxide, was assessed.

Methods

A total of 57 PWH of ≥ 20 years of age who are on stable antiretroviral therapy and with CD4+ T cell ≥ 350 cells/mm3 and HIV viral load < 103 copies/ml were compared with 882 HIV-negative participants. Participants received 2 doses of MVC-COV1901 28 days apart. Safety and the immunogenicity were evaluated.

Results

No vaccine-related serious adverse events (SAEs) were recorded. Seroconversion rates (SCRs) of 100% and 99.8% were achieved in people living with HIV (PWH) and comparators, respectively, 28 days after second dose. The geometric mean titers (GMTs) (95% confidence interval [CI]) against wild type SARS-CoV-2 virus were 136.62 IU/mL (WHO Standardized International Unit) (95% CI 114.3-163.3) and 440.41 IU/mL (95% CI 421.3-460.4), for PWH and control groups, respectively, after adjusting for sex, age, BMI category, and comorbidity, and the adjusted GMT ratio of comparator/PWH was 3.22 (95% CI 2.6-4.1). A higher CD4/CD8 ratio was associated with a higher GMT (R=0.27, p=0.039).

Conclusions

MVC-COV1901 has shown robust safety but weaker immunogenicity responses in PWH. As a result, a third dose or booster doses of MVC-COV1901 may be appropriate for PWH.
The spread of SARS-CoV-2 variant Omicron with the doubling time of 2.0–3.3 days can be explained by immune evasion
Authors: Grabowski Frederic , Kochańczyk Marek , Lipniacki Tomasz
Published: December 2021

Omicron, the novel highly mutated SARS-CoV-2 Variant of Concern (VOC, Pango lineage B.1.1.529), was first collected in early November 2021 in South Africa. By the end of November 2021, it had spread and approached fixation in South Africa, and had been detected on all continents. We analyzed the exponential growth of Omicron over the four-week periods in two most populated South Africa’s provinces, Gauteng and KwaZulu-Natal, arriving at the doubling time estimates of respectively 3.3 days [95% CI: 3.2–3.4 days] and 2.7 days [95% CI: 2.3–3.3 days]. Similar or even shorter doubling times were observed in other locations: Australia (3.0 days), New York State (2.5 days), UK (2.4 days), and Denmark (2.0 days). Log– linear regression suggests that the spread began in Gauteng around October 11, 2021, however, due to presumable stochasticity in the initial spread, this estimate can be inaccurate. Phylogenetics-based analysis indicates that the Omicron strain started to diverge in between October 6 and October 29, 2021. We estimated that the weekly growth of the ratio of Omicron to Delta is in the range 7.2–10.2, considerably higher than the growth of the ratio of Delta to Alpha (estimated to be in in the range 2.5–4.2), and Alpha to pre-existing strains (estimated to be in the range of 1.8–2.7). High relative growth does not necessarily imply higher Omicron infectivity. A two-strain SEIR model suggests that the growth advantage of Omicron may stem from immune evasion, which permits this VOC to infect both the recovered and the fully vaccinated individuals. As we demonstrated within the model, immune evasion is more concerning than increased transmissibility, because it can facilitate larger epidemic outbreaks.
Vaccinating Children Against COVID-19 is Essential Prior to the Removal of Non-Pharmaceutical Interventions
Authors: Rosenstrom Erik , Mele Jessica , Ivy Julie , Mayorga Maria , Patel Mehul , Lich Kristen Hassmiller , Delamater Paul , Smith Raymond , Swann Julie L.
Published: December 2021

Objectives(s)

To evaluate the joint impact of childhood vaccination rates and masking policies, in schools and workplaces, on community transmission and severe outcomes due to COVID-19.

Study design

We utilized a stochastic, agent-based simulation of North Carolina, to evaluate the impact of 24 health policy decisions on overall incidence of disease, COVID-19 related hospitalization, and mortality from July 1, 2021-July 1, 2023.

Results

Universal mask removal in schools in January 2022 could lead to a 38.1-47%, 27.6-36.2%, and 15.9-19.7% increase in cumulative infections for ages 5-9, 10-19, and the total population, respectively, depending on the rate of vaccination of children relative to the adult population. Additionally, without increased vaccination uptake in the adult population, a 25% increase in child vaccination uptake from 50% to 75% uptake and from 75% to 100% uptake relative to the adult population, leads to a 22% and 18% or 28% and 33% decrease in peak hospitalizations in 2022 across scenarios when masks are removed either January 1st or March 8th 2022, respectively. Increasing vaccination uptake for the entire eligible population can reduce peak hospitalizations in 2022 by an average of 89% and 92% across all masking scenarios compared to the scenarios where no children are vaccinated.

Conclusion(s)

High vaccination uptake among both children and adults is necessary to mitigate the increase in infections from mask removal in schools and workplaces.
Harnessing gene-gene interactions via an RNA-Sequencing network analysis framework improves precision medicine prediction in rheumatoid arthritis
Authors: Sciacca Elisabetta , Surace Anna E. A. , Alaimo Salvatore , Pulvirenti Alfredo , Rivellese Felice , Goldmann Katriona , Ferro Alfredo , Latora Vito , Pitzalis Costantino , Lewis Myles J.
Published: December 2021

The study of gene-gene interactions in RNA-Sequencing (RNA-Seq) data has traditionally been hard owing the large number of genes detectable by Next-Generation Sequencing (NGS). However, differential gene-gene pairs can inform our understanding of biological processes and yield improved prediction models. Here, we utilised four well curated pathway repositories obtaining 10,537 experimentally evaluated gene-gene interactions. We then extracted specific gene-gene interaction networks in synovial RNA-Seq to characterise histologically-defined pathotypes in early rheumatoid arthritis patients. Specific gene-gene networks were also leveraged to predict response to methotrexate-based disease-modifying anti-rheumatic drug (DMARD) therapy in the Pathobiology of Early Arthritis Cohort (PEAC). We statistically evaluated the differential interactions identified within each network using robust linear regression models, and the ability to predict response was evaluated by receiver operating characteristic (ROC) curve analysis.

The analysis comparing different histological pathotypes showed a coherent molecular signature matching the histological changes and highlighting novel pathotype-specific gene interactions and mechanisms. Analysis of responders vs non-responders revealed higher expression of apoptosis regulating gene-gene interactions in patients with good response to conventional synthetic DMARD. Detailed analysis of interactions between pairs of network-linked genes identified the SOCS2/STAT2 ratio as predictive of treatment success, improving ROC area under curve (AUC) from 0.62 to 0.78. In conclusions, we demonstrate a novel, powerful method which harnesses gene interaction networks for leveraging biologically relevant gene-gene interactions leading to improved models for predicting treatment response.
Ancient DNA from a 2,700-year-old goitered gazelle (Gazella subgutturosa) confirms gazelle hunting in Iron Age Central Asia
Authors: Rodrigues Soares André Elias , Boroffka Nikolaus , Schröder Oskar , Sverchkov Leonid , Benecke Norbert , Günther Torsten
Published: December 2021

Central Asia has been an important region connecting the different parts of Eurasia throughout history and prehistory, with large states developing in this region during the Iron Age. Archaeogenomics is a powerful addition to the zooarchaeological toolkit for understanding the relation of these societies to animals. Here, we present the genetic identification of a goitered gazelle specimen (Gazella subgutturosa) at the site Gazimulla-Tepa, in modern-day Uzbekistan, confirming hunting of the species in the region during the Iron Age. The sample was directly radiocarbon dated to 2724-2439 calBP. A phylogenetic analysis of the mitochondrial genome places the individual into the modern variation of G. subgutturosa. Our data does represent both the first ancient DNA and the first nuclear DNA sequences of this species. The lack of genomic resources available for this gazelle and related species prevented us from performing a more in-depth analysis of the nuclear sequences generated. Therefore, we are making our sequence data available to the research community to facilitate other research of this nowadays threatened species which has been subject to human hunting for several millennia across its entire range on the Asian continent.
The UV RESISTANCE LOCUS 8-Mediated UV-B Response Is Required Alongside CRYPTOCHROME1 For Plant Survival Under Sunlight In The Field
Authors: Stockenhuber Reinhold , Akiyama Reiko , Tissot Nicolas , Yamazaki Misako , Wyler Michele , Arongaus Adriana B. , Podolec Roman , Sato Yasuhiro , Milosavljevic Stefan , Widmer Alex , Ulm Roman , Shimizu Kentaro K.
Published: December 2021

As sessile organisms, plants are subjected to fluctuating sunlight including potentially detrimental ultraviolet-B radiation (UV-B). In Arabidopsis thaliana, experiments under controlled conditions have shown that UV RESISTANCE LOCUS 8 (UVR8) controls photomorphogenic responses for acclimation and tolerance to UV-B; however, its long-term impacts on plant performance remain poorly understood in naturally fluctuating environments. Here we quantified the survival and reproduction of different Arabidopsis mutant genotypes in diverse field and laboratory conditions. We found that uvr8 mutants produced more fruits than wild type in growth chambers with artificial low UV-B conditions but not in natural field conditions. Importantly, independent double mutants of UVR8 and the blue-light photoreceptor gene CRYPTOCHROME 1 (CRY1) in two genetic backgrounds showed a drastic reduction in fitness in the field. UV-B attenuation experiments in field conditions and supplemental UV-B in growth chambers demonstrated that UV-B caused the conditional cry1 uvr8 lethality phenotype. RNA sequencing in different conditions revealed a large number of genes with statistical interaction of UVR8 and CRY1 mutations in the presence of UV-B in the field. Among them, Gene Ontology analysis identified enrichment of categories related to UV-B response, oxidative stress, photoprotection and DNA damage repair. Our study demonstrates the functional importance of the UVR8-mediated response across life stages in natura, which is partially redundant with CRY1, and provides an integral picture of gene expression associated with plant environmental responses under diverse environmental conditions.