bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect ofBacillus coagulansUnique IS-2 in Inflammatory Bowel Disease (IBD): A Randomized Controlled Trial
Authors: Bamola V Deepak , Dubey Divya , Samanta Projoyita , Kedia Saurabh , Madempudi Ratna Sudha , Neelamraju Jayanthi , Ahuja Vineet , Chaudhry Rama
Published: July 2021

Probiotic intervention is an important approach for the treatment and health restoration in inflammatory bowel disease (IBD). A study was conducted to assess the effect ofBacillus coagulansUnique IS-2 in IBD patients. Recruited subjects were given either probioticB. coagulansUnique IS-2 or placebo for 4 weeks as per randomization. Survival of the given probiotic strain in GI, presence of beneficial gut bacteria, serum cytokines, serum serotonin and serum dopamine, symptoms of disease, physical, behavioral and psychological parameters of the subjects were evaluated before and after intervention. In this studyB. coagulansUnique IS-2 was well tolerated with no severe adverse events in IBD patients and demonstrated good survival in GI tract by significantly high detection in probiotic treated group (p <0.001). Significant enhancement in beneficialLactobacilliwas observed in probiotic treated group (p <0.01). Metagenomic analysis also showed an increase in the abundance of bacterial generaBacillus, Lactobacillus, Bifidobacterium, Faecalibacterium, Bacteroides, Megamonas, Lachnospira, Blautia, Alistipes and decrease inSutterella, Dialister, Roseburia and Megasphaerawas observed in the post intervention samples in the treatment group. Increased secretion of cytokine IL-10 and variable decrease in the secretion of IL-6, IL-1β, TNF-α, IL -17 and IL -23 was observed in in the probiotic treated group. Post intervention change in serum serotonin and serum dopamine was not significant in both the groups. A reduction in the severity of disease symptoms and improvement in the physical, behavioral and psychological parameter was observed in the probiotic treated group. The observed results demonstrated thatB. coagulansUnique IS-2 with SMT was effective in adult IBD patients. Study was registered with Clinical Trials Registry India (CTRI) - (registration no.-CTRI/2019/11/022087).
On dynamics of fractional incommensurate model of Covid-19 with nonlinear saturated incidence rate
Authors: hamou Abdelouahed Alla , Azroul Elhoussine , Hammouch Zakia , alaoui Abdelilah Lamrani
Published: July 2021

In December 2019, a new virus belonging to the coronavirus strain has been discovered in Wuhan, China, this virus has attracted world-wide attention and it spread rapidly in the world, reaching nearly 216 countries in the world in November 2020. In this chapter, we study the fractional incommensurate SIQR (susceptible, infections,quarantined and removed) COVID-19 model with nonlinear saturated incidence rate using Atangana–Baleanu fractional derivatives. The existence and uniqueness of the solutions for the fractional model is proved using fixed point theorem, the model are shown to have two equilibrium point (disease-free and an endemic equilibrium). Some numerical simulations using Euler method are also carried out to support our theoretical results. We estimated the value of the fractional orders and the parameters of the proposed model using the least squares method.. Further, the sensitivity analysis of the parameter is performed as a result, our incommensurate model gives a good approximation to real data of COVID-19.
Reprogramming of pro-tumor macrophages by hydroxychloroquine in an abdominally metastasized diffuse midline glioma
Authors: Ruiz-Moreno Cristian , Keramati Farid , Brazda Peter , Megchelenbrink Wout , Pas Brigit te , Boshuisen Kim , Besse Helena C. , Kester Lennart , Kranendonk Mariette E.G. , van der Lugt Jasper , van Vuurden Dannis , Stunnenberg Hendrik G.
Published: July 2021

Macrophage (Mϕ) repolarization from a pro-tumor, immunosuppressive phenotype towards an anti-tumor, pro-inflammatory state represents a promising therapeutic strategy in patients with cancer1. Successful reprogramming of Mϕ in a clinical setting has not been documented. Here, we traced the evolution at single-cell resolution of a diffuse midline glioma (DMG) with H3K27M mutation which metastasized in the abdomen after placing a ventriculoperitoneal (VP) shunt and exploited this information for therapeutic decision-making. The primary tumor showed a complex cellular and genomic landscape characterized by heterogeneous cancer cells and a tumor-supportive immune microenvironment. Upon metastasis, malignant cells populated the peritoneum and triggered a massive anti-inflammatory immune cell infiltration and expansion of myeloid-derived suppressor cells (MDSCs) in peripheral blood. Hydroxychloroquine adjuvant treatment started to overcome the immunosuppressive milieu, which resulted in a decrease in peritoneal cancer cells and pro-tumor innate immune cells. Importantly, an emergence of anti-tumor, pro-inflammatory macrophages and cytotoxic T-cells was observed, accompanied by the activation of monocytes in the blood. Our study advocates the employment of single-cell technologies to better understand and inspire therapeutic regimens in patients with cancer.
Structural changes to primary visual cortex in the congenital absence of cone input in achromatopsia
Authors: Molz Barbara , Herbik Anne , Baseler Heidi A. , de Best Pieter B. , Vernon Richard , Raz Noa , Gouws Andre , Ahmadi Khazar , Lowndes Rebecca , McLean Rebecca J. , Gottlob Irene , Kohl Susanne , Choritz Lars , Maguire John , Kanowski Martin , Käsmann-Kellner Barbara , Wieland Ilse , Banin Eyal , Levin Netta , Hoffmann Michael B. , Morland Antony B.
Published: July 2021

Autosomal recessive Achromatopsia (ACHM) is a rare inherited disorder associated with dysfunctional cone photoreceptors resulting in a congenital absence of cone input to visual cortex. This might lead to distinct changes in cortical architecture with a negative impact on the success of gene augmentation therapies. To investigate the status of the visual cortex in these patients, we performed a multi-centre study focusing on the cortical structure of regions that normally receive predominantly cone input. Using high-resolution T1-weighted MRI scans and surface-based morphometry, we compared cortical thickness, surface area and grey matter volume in foveal, parafoveal and paracentral representations of primary visual cortex in 15 individuals with ACHM and 42 normally sighted, healthy controls (HC). In ACHM, surface area was reduced in all tested representations, while thickening of the cortex was found highly localized to the most central representation. These results were comparable to more widespread changes in brain structure reported in congenitally blind individuals, suggesting similar developmental processes, i.e., irrespective of the underlying cause and extent of vision loss. Our findings indicate that there may be an optimum time window for gene therapy to counteract developmental cortical changes related to the absence of sensory input.

Highlights

We assessed cortical anatomy of a large cohort of patients with genetically confirmed cone photoreceptor dysfunction (achromatopsia) using surface-based morphometry.

We found widespread reduction in cortical surface area across foveal, parafoveal and paracentral proportions of primary visual cortex in participants with achromatopsia.

highly localized cortical thickening in participants with achromatopsia at the region of visual cortex that lacked inputs from the retinal region occupied solely by cones.

Further evidence that the visual cortex is unlikely to take on normal properties if vision were restored after the developmental plastic period.

Early intervention is preferable when considering vision restoration treatment in achromatopsia.
Characterization of SARS CoV-2 Antibodies in Breast Milk from 21 Women with Confirmed COVID-19 Infection
Authors: Bode Lars , Bertrand Kerri , Najera Julia A. , Furst Annalee , Honerkamp-Smith Gordon , Shandling Adam D. , Chambers Christina D. , Camerini David , Campo Joseph J.
Published: July 2021

One potential mechanism for protection from SARS-CoV-2 in infants and young children is through passive immunity via breast milk from a mother previously infected with the novel coronavirus. The primary objectives of this study were to establish the presence of SARS-CoV-2 specific IgA and IgG and to characterize the specific antigenic regions of SARS-CoV-2 proteins that were reactive with antibodies in breast milk from women with confirmed SARS-CoV-2 infection.

Between March 2020 and September 2020, 21 women with confirmed SARS-CoV-2 infection were enrolled into Mommy’s Milk at the University of California, San Diego. Women donated serial breast milk samples. Breast milk samples were used to probe a multi-coronavirus protein microarray containing full-length proteins and variable length overlapping fragments of SARS-CoV-2 spike (S), envelope (E), membrane (M), nucleocapsid (N), and open reading frame (ORF) proteins.

The breast milk samples contained IgA reactive with a variety of SARS-CoV-2 antigens. The most IgA-reactive SARS-CoV-2 proteins were N (42.9% of women responded to 1 ≥ N fragment) and S proteins (23.9% of women responded to ≥ 1 fragment of S1 or S2). Overall, individual COVID-19 cases had diverse and unique milk IgA profiles over the course of follow-up since onset of SARS-CoV-2 symptoms.
Deep learning-based identification of genetic variants: Application to Alzheimer’s disease classification
Authors: Jo Taeho , Nho Kwangsik , Bice Paula , Saykin Andrew J. ,   for the Alzheimer’s Neuroimaging Initiative
Published: July 2021

Deep learning is a promising tool that uses nonlinear transformations to extract features from high-dimensional data. Deep learning is challenging in genome–wide association studies (GWAS) with high-dimensional genomic data. Here we propose a novel three-step approach (SWAT-CNN) for identification of genetic variants using deep learning to identify phenotype-related single nucleotide polymorphisms (SNPs) that can be applied to develop accurate disease classification models. In the first step, we divided the whole genome into non-overlapping fragments of an optimal size and then ran Convolutional Neural Network (CNN) on each fragment to select phenotype-associated fragments. In the second step, using a Sliding Window Association Test (SWAT), we ran CNN on the selected fragments to calculate phenotype influence scores (PIS) and identify phenotype-associated SNPs based on PIS. In the third step, we ran CNN on all identified SNPs to develop a classification model. We tested our approach using GWAS data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) including (N=981; cognitively normal older adults (CN) =650 and AD=331). Our approach identified the well-known APOE region as the most significant genetic locus for AD. Our classification model achieved an area under the curve (AUC) of 0.82, which was compatible with traditional machine learning approaches, Random Forest, and XGBoost. SWAT-CNN, a novel deep learning-based genome-wide approach, identified AD-associated SNPs and a classification model for AD and may hold promise for a range of biomedical applications.
Impaired learning, memory, and extinction in posttraumatic stress disorder: translational meta-analysis of clinical and preclinical studies
Authors: Sep Milou S.C. , Geuze Elbert , Joëls Marian
Published: July 2021

Background

Current evidence-based treatments for post-traumatic stress disorder (PTSD) are efficacious in only part of PTSD patients. Therefore, novel neurobiologically-informed approaches are urgently needed. Clinical and translational neuroscience point to altered learning and memory processes as key in (models of) PTSD psychopathology. We extended this notion by clarifying at a meta-level i) the role of information valence, i.e. neutral versus emotional/fearful, and ii) comparability between clinical and preclinical phenotypes. We hypothesized that, cross-species, neutral versus emotional/fearful information processing is, respectively, impaired and enhanced in PTSD.

Methods

This preregistered meta-analysis involved a literature search on PTSD+Learning/Memory+Behavior, performed in PubMed. First, the effect of information valence was estimated with a random-effects meta-regression. Then sources of variation were explored with a random forest-based analysis.

Results

The analyses included 92 clinical (N=6732 humans) and 182 preclinical (N=6834 animals) studies. A general impairment of learning, memory and extinction processes was observed in PTSD patients, regardless of information valence. Impaired neutral learning/memory and fear extinction were also present in animal models of PTSD. Yet, PTSD enhanced fear/trauma memory in preclinical studies and impaired emotional memory in patients. Clinical data on fear/trauma memory was limited. Mnemonic phase and valence explained most variation in rodents but not humans.

Conclusions

Impaired neutral learning/memory and fear extinction show very stable cross-species PTSD phenotypes. These could be targeted for novel PTSD treatments, building on neurobiological animal studies. We argue that seemingly cross-species discrepancies in emotional/fearful memory deserve further study; until then animal models targeting this phenotype should be applied with care.
Comparative profiles of SARS-CoV-2 Spike-specific human milk antibodies elicited by mRNA- and adenovirus-based COVID-19 vaccines
Authors: Yang Xiaoqi , Fox Alisa , DeCarlo Claire , Norris Caroline , Griffin Samantha , Wedekind Sophie , Flanagan James M. , Shenker Natalie , Powell Rebecca L.
Published: July 2021

Numerous COVID-19 vaccines are authorized globally. To date, ∼71% of doses are comprised of the Pfizer/BioNTech vaccine, and ∼17% the Moderna/NIH vaccine, both of which are mRNA-based. The chimpanzee Ad-based Oxford/AstraZeneca (AZ) vaccine comprises ∼9%, while the Johnson & Johnson/Janssen (J&J) human adenovirus (Ad26) vaccine ranks 4th at ∼2% [1]. No COVID-19 vaccines are yet available for children 0-4. One method to protect this population may be passive immunization via antibodies (Abs) provided in the milk of a lactating vaccinated person. Our early work [2] and other reports [3-5] have demonstrated that unlike the post-SARS-CoV-2 infection milk Ab profile, which is rich in specific secretory (s)IgA, the vaccine response is highly IgG-dominant. In this report, we present a comparative assessment of the milk Ab response elicited by Pfizer, Moderna, J&J, and AZ vaccines. This analysis revealed 86% -100% of mRNA vaccine recipient milk exhibited Spike-specific IgG endpoint titers, which were 12 – 28-fold higher than those measured for Ad vaccine recipient milk. Ad-based vaccines elicited Spike-specific milk IgG in only 33%-38% of recipients. Specific IgA was measured in 52%-71% of mRNA vaccine recipient milk and 17%-23% of Ad vaccine recipient milk. J&J recipient milk exhibited significantly lower IgA than Moderna recipients, and AZ recipients exhibited significantly lower IgA titers than Moderna and Pfizer. <50% of milk of any group exhibited specific secretory Ab, with Moderna recipient IgA titers measuring significantly higher than AZ. Moderna appeared to most frequently elicit >2-fold increases in specific secretory Ab titer relative to pre-vaccine sample. These data indicate that current Ad-based COVID-19 vaccines poorly elicit Spike-specific Ab in milk compared to mRNA-based vaccines and that mRNA vaccines are preferred for immunizing the lactating population. This study highlights the need to design vaccines better aimed at eliciting an optimal milk Ab response.
Phase I single center trial of Ketogenic Diet for Adults with Traumatic Brain Injury
Authors: Arora Niraj , Litofsky N. Scott , Mojgan Golzy , Aneja Rachna , Staudenmyer Danielle , Qualls Kathyrn , Patil Sachin
Published: July 2021

Background

Traumatic Brain injury (TBI) is a major cause of mortality and morbidity in the United States. Ketogenic diet (KD) has been shown to have neuroprotective effects in acute brain injury, but limited data about its use in adult TBI patients is available. The objective of this study is to investigate the feasibility and safety of ketogenic diet (KD) for adult TBI patients in the Neuroscience Intensive Care Unit (NSICU).

Methods

TBI patients admitted to NSICU between June 2019 to March 2021 were enrolled in this single-center, open label, single-arm prospective intervention study. The primary feasibility outcome was achievement of ketosis (detection and maintenance of serum beta-hydroxybutyrate (BOB) levels above normal); secondary outcomes included laboratory and clinical adverse effects related to KD.

Results

10 adults with TBI with Abbreviated Injury Score (AIS)-Head of at least 3 and ventriculostomy tube inserted met inclusion/exclusion criteria and were considered for KD. Mean age was47 years, and all patients were male. Eight out of 10 patients achieved ketosis within mean 2.2 days. KD was initiated within 8-33 hours (average 23 hours) of hospital admission. No clinical adverse effects were noted, 2 patients developed hypertriglyceridemia and 1 patient developed hypoglycemia. Serum glucose showed a decreasing trend in most patients.

Conclusions

This pilot study shows that KD is feasible and safe in the management of TBI patients. A randomized controlled trial (RCT) is justified to further understand the optimal serum BOB levels, dose and duration of KD in TBI and its effect on the outcome.

ClinicalTrials.gov Identifier: NCT03982602, Registered 06/11/2019, https://clinicaltrials.gov/ct2/show/NCT03982602?term=brain+injury&cond=ketogenic+diet&draw=2&rank=3.
Gene Therapy Restores the Transcriptional Program of Hematopoietic Stem Cells in Fanconi Anemia
Authors: Lasaga Miren , Río Paula , Vilas-Zornoza Amaia , Planell Nuria , Navarro Susana , Alignani Diego , Fernández-Varas Beatriz , Zubicaray Josune , Pujol Roser M. , Nicoletti Eileen , Schwartz Jonathan D. , Sevilla Julián , Ainciburi Marina , Ullate-Agote Asier , Surrallés Jordi , Perona Rosario , Sastre Leandro , Prosper Felipe , Gomez-Cabrero David , Bueren Juan A.
Published: July 2021

Fanconi anemia (FA) is an inherited disease associated with marked hematopoietic stem and progenitor cell (HSPC) defects. Ongoing clinical trials have shown that lentiviral-mediated gene therapy can ameliorate bone marrow failure (BMF) in non-conditioned FA patients thanks to the proliferative advantage of corrected FA HSPCs. Here we investigated whether gene therapy can revert affected molecular pathways in diseased HSPCs, a question not previously addressed in any HSC gene therapy trial. Single-cell RNA sequencing was performed in chimeric populations of corrected and uncorrected HSPCs coexisting in BM of gene therapy treated FA patients. Our study demonstrates that gene therapy reverts the transcriptional signature of FA HSPCs, which then resembles the transcriptional program of healthy donor HSPCs. This includes a downregulated expression of TGF-β and p21, typically upregulated in FA HSPCs, and upregulation of DNA damage response and telomerase maintenance pathways. Our results show for the first time the potential of gene therapy to rescue defects in the HSPC transcriptional program from patients with inherited diseases, in this case in FA characterized by BMF and cancer predisposition.
Intentions to participate in cervical and colorectal cancer screening during the COVID-19 pandemic: a mixed-methods study
Authors: Wilson Rebecca , Quinn-Scoggins Harriet , Moriarty Yvonne , Hughes Jacqueline , Goddard Mark , Cannings-John Rebecca , Whitelock Victoria , Whitaker Katriina L , Grozeva Detelina , Townson Julia , Osborne Kirstie , Smits Stephanie , Robling Michael , Hepburn Julie , Moore Graham , Gjini Ardiana , Brain Kate , Waller Jo
Published: July 2021

Worldwide, cancer screening faced significant disruption in 2020 due to the COVID-19 pandemic. If this has led to changes in public attitudes towards screening and reduced intention to participate, there is a risk of long-term adverse impact on cancer outcomes. In this study, we examined previous participation and future intentions to take part in cervical and colorectal cancer (CRC) screening following the first national lockdown in the UK.

Overall, 7543 adults were recruited to a cross-sectional online survey in August-September 2020. Logistic regression analyses were used to identify correlates of strong screening intentions among 2,319 participants eligible for cervical screening and 2,502 eligible for home-based CRC screening. Qualitative interviews were conducted with a sub-sample of 30 participants. Verbatim transcripts were analysed thematically.

Of those eligible, 74% of survey participants intended to attend cervical screening and 84% intended to complete home-based CRC screening when next invited. Thirty percent and 19% of the cervical and CRC samples respectively said they were less likely to attend a cancer screening appointment now than before the pandemic. Previous non-participation was the strongest predictor of low intentions for cervical (aOR 26.31, 95% CI: 17.61-39.30) and CRC (aOR 67.68, 95% CI: 33.91-135.06) screening. Interview participants expressed concerns about visiting healthcare settings but were keen to participate when screening programmes resumed.

Intentions to participate in future screening were high and strongly associated with previous engagement in both programmes. As screening services recover, it will be important to monitor participation and to ensure people feel safe to attend.
BNT162b2 Vaccine Induces Divergent B cell responses to SARS-CoV-2 S1 and S2
Authors: Brewer R. Camille , Ramadoss Nitya S. , Lahey Lauren J. , Robinson William H. , Lanz Tobias V.
Published: July 2021

The first ever messenger RNA (mRNA) vaccines received emergency approvals in December 2020 and are highly protective against SARS-CoV-21–3. However, the contribution of each dose to the generation of antibodies against SARS-CoV-2 spike (S) protein and the degree of protection against novel variants, including delta, warrant further study. Here, we investigated the B cell response to the BNT162b2 vaccine by integrating repertoire analysis with single-cell transcriptomics of B cells from serial blood collections pre- and post-vaccination. The first vaccine dose elicits highly mutated IgA+ plasmablasts against the S protein subunit S2 at day 7, suggestive of recall of a memory B cell response generated by prior infections with heterologous coronaviruses. On day 21, we observed minimally-mutated IgG+ activated switched memory B cells targeting the receptor binding domain (RBD) of the S protein, likely representing a primary response derived from naïve B cells. The B cell response against RBD is specifically boosted by the second vaccine dose, and encodes antibodies that potently neutralize SARS-CoV-2 pseudovirus and partially neutralize novel variants, including delta. These results demonstrate that the first vaccine dose activates a non-neutralizing recall response predominantly targeting S2, while the second vaccine dose is vital to boosting neutralizing anti-S1 RBD B cell responses.
Change in age distribution of COVID-19 deaths with the introduction of COVID-19 vaccination
Authors: Pastorino Roberta , Pezzullo Angelo Maria , Villani Leonardo , Causio Francesco Andrea , Axfors Cathrine , Contopoulos-Ioannidis Despina G. , Boccia Stefania , Ioannidis John P.A.
Published: July 2021

Background

Most countries initially deployed COVID-19 vaccines preferentially in elderly populations. Population-level vaccine effectiveness may be heralded by an increase in the proportion of deaths among non-elderly populations that were less covered by vaccination programs.

Methods

We collected data from 40 countries on age-stratified COVID-19 deaths during the vaccination period (1/14/2021-5/31/2021) and two control periods (entire pre-vaccination period and excluding the first wave). We meta-analyzed the proportion of deaths in different age groups in vaccination versus control periods in countries with low vaccination rates; (2) countries with age-independent vaccination policies; and (3) countries with standard age-dependent vaccination policies.

Findings

Countries that prioritized vaccination among older people saw an increasing share of deaths among 0-69 year old people in the vaccination versus the two control periods (summary prevalence ratio 1·32 [95 CI% 1·24-1·41] and 1·35 [95 CI% 1·26-1·44)]. No such change was seen on average in countries with age-independent vaccination policies (1·05 [95 CI% 0·78-1·41 and 0·97 [95 CI% 0·95-1·00], respectively) and limited vaccination (0·93 [95 CI% 0·85-1·01] and 0·95 [95 CI% 0·87-1·03], respectively). Prevalence ratios were associated with the difference of vaccination rates in elderly versus non-elderly people. No significant changes occurred in the share of deaths in age 0-49 among all 0-69 deaths in the vaccination versus pre-vaccination periods.

Interpretation

The substantial shift in the age distribution of COVID-19 deaths in countries that rapidly implemented vaccination predominantly among elderly may herald the population level-effectiveness of COVID-19 vaccination and a favorable evolution of the pandemic towards endemicity with fewer elderly deaths.

Funding

This study received no specific funding.
Excess mortality in India from June 2020 to June 2021 during the COVID pandemic: death registration, health facility deaths, and survey data
Authors: Deshmukh Yashwant , Suraweera Wilson , Tumbe Chinmay , Bhowmick Aditi , Sharma Sankalp , Novosad Paul , Fu Sze Hang , Newcombe Leslie , Gelband Hellen , Brown Patrick , Jha Prabhat
Published: July 2021

Background

India’s official death totals from the COVID pandemic are widely regarded as under-reports.

Methods

We quantified all-cause excess mortality in India, comparing deaths during the peak of the first and second COVID waves (Jul-Dec 2020 and April-June 2021) with month wise deaths in 2015-19 from three sources: Civil Registration System (CRS) mortality reports from 15 states or cities with 37% of India’s population; deaths in 0.2 million health facilities; and a representative survey of 0.14 million adults about COVID deaths.

Results

During the first viral wave, the median excess mortality compared to CRS baseline was 22% and 41%, respectively, in included states and cities, rising to 46% and 85% during the second wave. In settings with 10 or more months of data across the two waves, the median excess mortality was 32% and 37% for states and cities, respectively. Deaths in health facilities showed a 27% excess mortality from July 2020-May 2021, reaching 120% during April-May 2021. The national survey found 3.5% of adults reported a COVID death in their household in April-June 2021, approximately doubling the 3.2% expected overall deaths. The national survey showed 29-32% excess deaths from June 1, 2020 to June 27, 2021, most of which were likely to be COVID. This translates to 3.1-3.4 million COVID deaths (including 2.5-2.8 million during April-June 2021). National extrapolations from health facility and CRS data suggest 2.7-3.3 million deaths during the year.

Conclusions

India’s COVID death rate may be about 7-8 times higher than the officially reported 290/million population.
Simple, accurate calculation of mechanical power in Pressure Controlled Ventilation (PCV)
Authors: Trinkle Christine A. , Broaddus Richard N. , Sturgill Jamie L. , Waters Christopher M. , Morris Peter E.
Published: July 2021

Power is a promising new metric to assess energy transfer from a ventilator to a patient, as it combines the effects of multiple different parameters into a single comprehensive value. For volume-controlled ventilation (VCV), excellent equations exist for calculating power from basic ventilator parameters, but for pressure-controlled ventilation (PCV), an accurate, easy-to-use equation has been elusive. Here, we present a new power equation and evaluate its accuracy compared to the three published PCV power equations. When applied to a sample of 50 patients on PCV with a non-zero rise time, we found that our equation estimated power within an average of 8.4% ± 5.9% (mean ± standard deviation) of the reference value. This new equation is accurate and simple to use, making it an attractive option to estimate power in PCV cases at the bedside.
Optimal vaccine allocation for COVID-19 in the Netherlands: a data-driven prioritization
Authors: Miura Fuminari , Leung Ka Yin , Klinkenberg Don , Ainslie Kylie E. C. , Wallinga Jacco
Published: July 2021

For the control of COVID-19, vaccination programmes provide a long-term solution. The amount of available vaccines is often limited, and thus it is crucial to determine the allocation strategy. While mathematical modelling approaches have been used to find an optimal distribution of vaccines, there is an excessively large number of possible schemes to be simulated.

Here, we propose an algorithm to find a near-optimal allocation scheme given an intervention objective such as minimization of new infections, hospitalizations, or deaths, where multiple vaccines are available. The proposed principle for allocating vaccines is to target subgroups with the largest reduction in the outcome of interest, such as new infections, due to vaccination that fully immunizes a single individual. We express the expected impact of vaccinating each subgroup in terms of the observed incidence of infection and force of infection. The proposed approach is firstly evaluated with a simulated epidemic and then applied to the epidemiological data on COVID-19 in the Netherlands.

Our results reveal how the optimal allocation depends on the objective of infection control. In the case of COVID-19, if we wish to minimize deaths, the optimal allocation strategy is not efficient for minimizing other outcomes, such as infections. In simulated epidemics, an allocation strategy optimized for an outcome outperforms other strategies such as the allocation from young to old, from old to young, and at random. Our simulations clarify that the current policy in the Netherlands (i.e., allocation from old to young) was concordant with the allocation scheme that minimizes deaths.

The proposed method provides an optimal allocation scheme, given routine surveillance data that reflect ongoing transmissions. The principle of allocation is useful for providing plausible simulation scenarios for complex models, which give a more robust basis to determine intervention strategies.

Author summary

Vaccination is the key to controlling the ongoing COVID-19 pandemic. In the early stages of an epidemic, there is shortage of vaccine stocks. Here, we propose an algorithm that computes an optimal vaccine distribution among groups for each intervention objective (e.g., minimizing new infections, hospitalizations, or deaths). Unlike existing approaches that use detailed information on at-risk contacts between and among groups, the proposed algorithm requires only routine surveillance data on the number of cases. This method is applicable even when multiple vaccines are available. Simulation results show that the allocation scheme optimized by our algorithm performed the best compared with other strategies such as allocating vaccines at random and in the order of age. Our results also reveal that an allocation scheme optimized for one specific objective is not necessarily efficient for another, indicating the importance of the decision-making at the early phase of distributions.
A newly identified group of P-like (PL) fimbriae from extra-intestinal pathogenic Escherichia coli (ExPEC) encode distinct adhesin subunits and mediate adherence to host cells
Authors: Habouria Hajer , Bessaiah Hicham , Buron Julie , Houle Sébastien , Dozois Charles M.
Published: July 2021

Fimbrial adhesins play a critical role for bacterial adherence and biofilm formation. Sequencing of avian pathogenic Escherichia coli (APEC) strain QT598 identified a fimbrial gene cluster belonging to the π group that we named PL (P-like) fimbriae, since genetic organization and sequence are similar to Pap and related fimbriae. Screening of genomic databases indicated that genes encoding PL fimbriae located on IncF plasmids are present in a diversity of E. coli isolates from poultry, human systemic infections, and other sources. As with P fimbriae, PL fimbriae exhibit sequence divergence in adhesin encoding genes, and strains could be divided into 5 classes based on differences in sequences of the PlfG adhesin protein. The plf genes from two predominant PlfG adhesin classes, PlfG-I and PlfG-II were cloned. PL fimbriae were visualized by electron microscopy, promoted biofilm formation, demonstrated distinct hemagglutination profiles and promoted adherence to human bladder and kidney epithelial cell lines. Hybrid fimbriae comprised of genes from plfQT598 wherein plfG was replaced by papG encoding adhesin genes were also shown to be functional and mediate adherence to epithelial cells, further indicating similarity and functional compatibility between these two types of fimbriae. Although deletion of plf genes did not significantly reduce colonization of the mouse urinary tract, plf gene expression was increased over 40-fold in the bladder compared to during in vitro culture. Overall, PL fimbriae represent a new group of fimbriae demonstrating both functional differences and similarities to P fimbriae and may contribute to adherence to cells and colonization of host tissues.

Importance

Fimbriae are important colonization factors in many bacterial species. The identification of a new type of fimbriae encoded on some IncF plasmids in E. coli was investigated. Genomic sequences demonstrated these fimbrial gene clusters have genetic diversity, particularly in the adhesin encoding PlfG gene. Functional studies demonstrated differences in hemagglutination specificity, although both types of Plf adhesin under study mediated adherence to human urinary epithelial cells. Such fimbriae may represent previously unrecognized adhesins that could contribute to host specificity and tissue tropism of some E. coli strains.
Workplace risk management for SARS-CoV-2: a three-step early in-tervention strategy for effective containment of infection chains with special regards to virus variants with increased infectivity
Authors: Paaßen Andreas , Anderle Laura , John Karsten , Wilbrand Sebastian
Published: July 2021

Background

Priority during the SARS-CoV2 pandemic is that employees need to be protected from infection risks and business activities need to be ensured. New virus variants with increased infection risks require an evolved risk strategy.

Material and methods

Several standard measures such as testing, isolation and quarantine are combined to a novel risk strategy. Epidemiological model calculations and scientific knowledge about the course of SARS-CoV2 infectivity are used to optimize this strategy. The procedure is implemented in an easy-to-use calculator based on Excel.

Layout in practice and results

Alternative combinations of measures and practical aspects are discussed. Example calculations are used to demonstrate the effect of the discussed measures.

Conclusion

That quarantine calculator derived from these principles enables even non-specialists to perform a differentiated risk analysis and to introduce optimized measures. Targeted testing routines and alternative measures ensure staff availability.
Increasing SARS-CoV-2 antibody prevalence in England at the start of the second wave: REACT-2 Round 4 cross-sectional study in 160,000 adults
Authors: Ward Helen , Atchison Christina , Whitaker Matt , Donnelly Christl A , Riley Steven , Ashby Deborah , Darzi Ara , Barclay Wendy S , Cooke Graham , Elliott Paul ,   for the REACT study team
Published: July 2021

Background

REACT-2 Study 5 is a population survey of the prevalence of SARS-CoV-2 antibodies in the community in England.

Methods

We contacted a random sample of the population by sending a letter to named individuals aged 18 or over from the NHS GP registrations list. We then sent respondents a lateral flow immunoassay (LFIA) kit for SARS-CoV-2 antibody self-testing and asked them to perform the test at home and complete a questionnaire, including reporting of their test result. Overall, 161,537 adults completed questionnaires and self-administered LFIA tests for IgG against SARS-CoV-2 between 27 October and 10 November 2020.

Results

The overall adjusted and weighted prevalence was 5.6% (95% CI 5.4-5.7). This was an increase from 4.4% (4.3-4.5) in round 3 (September), a relative increase of 26.9% (24.0-29.9).The largest increase by age was in the 18 to 24 year old age group, which increased (adjusted and weighted) from 6.7% (6.3-7.2) to 9.9% (9.3-10.4), and in students, (adjusted, unweighted) from 5.9% (4.8-7.1) to 12.1% (10.8-13.5). Prevalence increased most in Yorkshire and The Humber, from 3.4% (3.0-3.8) to 6.3% (5.9-6.8) and the North West from 4.5% (4.2-4.9) to 7.7% (7.2-8.1). In contrast, the prevalence in London was stable, at 9.5% (9.0-9.9) and 9.5% (9.1-10.0) in rounds 3 and 4 respectively. We found the highest prevalence in people of Bangladeshi 15.1% (10.9-20.5), Pakistani 13.9% (11.2-17.2) and African 13.5% (10.7-16.8) ethnicity, and lowest in those of white British ethnicity at 4.2% (4.0-4.3).

Interpretation

The second wave of infection in England is apparent in increasing antibody prevalence, particularly in younger people, students, and in the Northern Regions. By late October a large proportion of the population remained susceptible to SARS-CoV-2 infection in England based on naturally acquired immunity from the first and early second wave.
Blockade of Interleukin Seventeen (IL-17A) with Secukinumab in Hospitalized COVID-19 patients – the BISHOP study
Authors: Resende Gustavo Gomes , da Cruz Lage Ricardo , Lobê Samara Quadros , Medeiros Amanda Fonseca , Costa e Silva Alessandra Dias , Nogueira Sá Antônio Tolentino , Oliveira Argenil José de Assis , Sousa Denise , Guimarães Henrique Cerqueira , Gomes Isabella Coelho , Souza Renan Pedra , Aguiar Renato Santana , Tunala Roberto , Forestiero Francisco , Bueno Filho Julio Silvio Souza , Teixeira Mauro Martins
Published: July 2021

Background

Patients with severe COVID-19 seem to have a compromised antiviral response and hyperinflammation. Neutrophils are critical players in COVID-19 pathogenesis. IL-17A plays a major role in protection against extracellular pathogens and neutrophil attraction and activation. We hypothesized that secukinumab, an anti-IL17A monoclonal antibody, could mitigate the deleterious hyperinflammation in COVID-19.

Methods

BISHOP was an open-label, single-center, phase-II controlled trial. Fifty adults hospitalized Covid-19 patients, confirmed by a positive SARS-CoV-2 RT-PCR, were randomized 1:1 to receive 300mg of secukinumab subcutaneously at day-0 (group A) plus standard of care (SoC: antiviral drugs, antimicrobials, corticosteroids, and/or anticoagulants) or SoC alone (group B). A second dose of 300mg of secukinumab could be administered on day-7, according to staff judgment. The primary endpoint was ventilator-free days at day-28 (VFD-28). Secondary efficacy and safety outcomes were also explored.

Findings

An intention-to-treat analysis showed no difference in VFD-28: 23.7 (95%CI 19.6-27.8) in group A vs. 23.8 (19.9-27.6) in group B, p=0.62; There was also no difference in hospitalization time, intensive care unit demand, the incidence of circulatory shock, acute kidney injury, fungal or bacterial co-infections, and severe adverse events. Pulmonary thromboembolism was less frequent in group A (4.2% vs. 26.2% p=0.04). There was one death in each group. Viral clearance, defined by the viral load fold change (2-ΔΔCT) in upper airways, between day-0 and day-7, was also similar: 0.17 (0.05-0.56) in group A vs. 0.24 (0.10-0.57) in group B.

Interpretation

The efficacy of secukinumab in the treatment of Covid19 was not demonstrated. No difference between groups in adverse events and no unexpected events were observed.

Funding

Novartis Brazil supported this research providing expert input in the development of the project, drug supply, data management, and monitoring.
Optical manipulations reveal strong reciprocal inhibition but limited recurrent excitation within olfactory bulb glomeruli
Authors: Zak Joseph D. , Schoppa Nathan E.
Published: July 2021

The local circuitry within olfactory bulb glomeruli filters, transforms, and facilitates information transfer from olfactory sensory neurons to bulb output neurons. Two key elements of this circuit are glutamatergic tufted cells (TCs) and GABAergic periglomerular (PG) cells, both of which actively shape mitral cell activity and bulb output. A subtype of TCs, the external tufted cells (eTCs), can synaptically excite PG cells, but there are unresolved questions about other aspects of the glomerular connections, including the extent of connectivity between eTCs and the precise nature of reciprocal interactions between eTCs and PG cells. We combined patch-clamp recordings in OB slices and optophysiological tools to investigate local functional connections within glomeruli. When TCs were optically suppressed, we found a large decrease in excitatory post-synaptic currents (EPSCs) in “uniglomerular” PG cells that extend dendrites to one glomerulus, indicating that TC activation was required for most excitation of these PG cells. However, TC suppression had no effect on EPSCs in eTCs, arguing that TCs make few, if any, direct excitatory synaptic connections onto eTCs. The absence of synaptic connections between eTCs was also supported by recordings in eTC pairs. Lastly, we show using similar optical suppression methods that PG cells that express GAD65, mainly uniglomerular PG cells, provide strong inhibition onto eTCs. Our results indicate that the local network of TCs form potent reciprocal synaptic connections with GAD65-expressing uniglomerular PG cells but not other TCs. This configuration favors local inhibition over recurrent excitation within a glomerulus, limiting information transfer to downstream cortical regions.
Evolutionary tuning of a key helix drove androgen selectivity
Authors: Denise Okafor C. , Colucci Jennifer K. , Cato Michael L. , Khan Sabab H. , Cottrill Kirsten , Hercules David , Eick Geeta N. , Thornton Joseph W. , Ortlund Eric A.
Published: July 2021

The genetic and biophysical mechanisms by which new protein functions evolve are central concerns in evolutionary biology and molecular evolution. Despite much speculation, we know little about how protein function evolves. Here, we use ancestral proteins to trace the evolutionary history of ligand recognition in a sub-class of steroid receptors (SRs), an ancient family of ligand-regulated transcription factors that enable long-range cellular communication central to multicellular life. The most ancestral members of this family display promiscuous ligand binding due to their large ligand binding pockets, while more recently evolved SRs tend to have smaller cavities. Less obvious, however, are the forces driving the selectivity of highly similar ligands. A key example is the divergence between the progesterone and androgen receptors (PR, AR), which display a high degree of sequence similarity and yet display differential ligand preferences. This work uses the ancestral steroid receptor 2 (AncSR2), the common ancestor of all 3-ketosteroids and the ancestral androgen receptor 1 (AncAR1), the seminal androgen receptor, to explore the biophysical mechanisms that drove the evolution of androgen specificity. We determine that ligand specificity in androgen receptors is driven by changes in the conformational dynamics of the receptor as well as altered binding pocket interactions, with helix 10 (H10) playing a critical role in tuning ligand specificity.
Functional similarity, not phylogenetic relatedness, predicts the relative strength of competition
Authors: Mahon Michael B. , Jennings David E. , Civitello David J. , Lajeunesse Marc J. , Rohr Jason R.
Published: July 2021

Predicting the outcome and strength of species interactions is a central goal of community ecology. Researchers have proposed that outcomes of species interactions (competitive exclusion and coexistence) are a function of both phylogenetic relatedness and functional similarity. Studies relating phylogenetic distance to competition strength have shown conflicting results. Work investigating the role of phylogenetic relatedness and functional similarity in driving competitive outcomes has been limited in terms of the breadth of taxa and ecological contexts examined, which makes the generality of these studies unclear. Consequently, we gathered 1,748 pairwise competition effect sizes from 269 species and 424 unique species pairs with divergence times ranging from 1.14 to 1,275 million years and used meta-regression and model selection approaches to investigate the importance of phylogenetic relatedness and functional similarity to competition across ecological contexts. We revealed that functional similarity, but not phylogenetic relatedness, predicted the relative strength of interspecific competition (defined as the strength of interspecific competition relative to intraspecific competition). Further, we found that the presence of predators, certain habitats, increasing density of competitors, and decreasing spatial grain of experiments were all associated with more intense interspecific competition relative to intraspecific competition. Our results demonstrate that functional similarity, not phylogenetic relatedness, may explain patterns of competition-associated community assembly, highlighting the value of trait-based approaches in clarifying biotic assembly dynamics.
Dichloroacetate improves systemic energy balance and feeding behavior during sepsis
Authors: Oh Tae Seok , Zabalwi Manal , Jain Shalini , Long David , Stacpoole Peter W , McCall Charles E , Quinn Matthew A
Published: July 2021

Sepsis is a life-threatening organ dysfunction by dysregulated host response to an infection. The metabolic aberrations associated with sepsis underly an acute and organism wide hyper-inflammatory response and multiple organ dysfunction; however, crosstalk between systemic metabolomic alterations and metabolic reprograming at organ levels remains unknown. We analyzed substrate utilization by the respiratory exchange ratio, energy expenditure, metabolomic screening and transcriptional profiling in a cecal ligation and puncture (CLP) model, to show that sepsis increases circulating free fatty acids and acylcarnitines but decreases levels of amino acids and carbohydrates leading to a drastic shift in systemic fuel preference. Comparative analysis of previously published metabolomics from septic liver indicates a positive correlation with hepatic and plasma metabolites during sepsis. In particular, glycine deficiency was a common abnormality of both plasma and the liver during sepsis. Interrogation of the hepatic transcriptome in septic mice suggests that the septic liver may contribute to systemic glycine deficiency by downregulating genes involved in glycine synthesis. Interestingly, intraperitoneal injection of the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate (DCA) reverses sepsis-induced anorexia, energy imbalance, dyslipidemia, hypoglycemia, and glycine deficiency. Collectively, our data indicate that PDK inhibition rescues systemic energy imbalance and metabolic dysfunction in sepsis partly through restoration of hepatic fuel metabolism.