bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypoglycaemia and the risk of dementia: a population-based cohort study using exposure density sampling
Authors: Alkabbani Wajd , Maxwell Colleen J , Marrie Ruth Ann , Tyas Suzanne L , Lega Iliana C , Gamble John-Michael
Published: September 2022

Background

Previous studies have shown hypoglycaemia to be associated with an increased risk of dementia; however, there are several design challenges to consider. The objective of this study is to assess the association between hypoglycaemia and dementia while addressing these challenges using a lag period, exposure density sampling (EDS) and inverse probability of treatment weighting (IPTW).

Methods

This was a population-based cohort using data (1996–2018) from British Columbia, Canada. From a cohort of incident type 2 diabetes patients aged 40–70 years, we created a dynamic sub-cohort of hypoglycaemia-exposed (≥1 episode requiring hospitalization or a physician visit) and unexposed individuals using EDS, in which four unexposed individuals per one exposed were randomly selected into risk sets based on diabetes duration and age. Follow-up was until dementia diagnosis, death, emigration or 31 December 2018. Those diagnosed with dementia within 2 years of follow-up were censored. We adjusted for confounding using IPTW and estimated the hazard ratio (HR, 95% CI) of dementia using weighted conditional cause-specific hazards risk models with death as a competing risk.

Results

Among 13 970 patients with incident type 2 diabetes, 2794 experienced hypoglycaemia. There were 329 dementia events over a median (interquartile range: IQR) follow-up of 5.03 (5.7) years. IPTW resulted in well-balanced groups with weighted incidence rates (95% CI) of 4.59 (3.52, 5.98)/1000 person-years among exposed and 3.33 (2.58, 3.88)/1000 person-years among unexposed participants. The risk of dementia was higher among those with hypoglycaemia (HR, 1.83; 95% CI 1.31, 2.57).

Conclusions

After addressing several methodological challenges, we showed that hypoglycaemia contributes to an increased risk of all-cause dementia among patients with type 2 diabetes.
Double-, single- and none-carbapenem-containing regimens for the treatment of carbapenem-resistant Enterobacterales (CRE) bloodstream infections: a retrospective cohort
Authors: Rigatto Maria Helena , Ramos Fabiano , Barros Andressa , Pedroso Silvia , Guasso Isabelli , Gonçalves Luciana , Bergo Pedro , Zavascki Alexandre P
Published: September 2022

Objectives

To investigate the effect of double-, single- and none-carbapenem-containing antimicrobial regimens in the treatment of patients with carbapenem-resistant Enterobacterales (CRE) bloodstream infections (BSIs).

Methods

We conducted a retrospective cohort study from 2013 to 2020 in two Brazilian hospitals. Patients ≥18 years old with CRE BSI were included and excluded if death or treatment duration for ≤48 h after BSI or non-Class A-producing carbapenemase isolates. We evaluated the impact of different carbapenem-containing regimens on 30 day mortality through a propensity score adjusted model and a Cox proportional hazards model.

Results

Two-hundred and seventy-nine patients were included for analyses: 47 (16.9%), 149 (53.4%) and 83 (29.8%) were treated with double-, single- and none-carbapenem-containing regimens, respectively. One-hundred and seventeen (41.9%) patients died in 30 days. Treatment with a single-carbapenem regimen was associated with a lower risk of death in 30 days compared with therapies containing no carbapenem [adjusted HR (aHR) 0.66, 95% CI 0.44–0.99, P = 0.048], when adjusted for Charlson score and ICU admission at baseline, while double-carbapenem regimens were not associated with a lower risk of death (aHR 0.78, 95% CI 0.46–1.32, P = 0.35). Propensity score adjusted model results went in the same direction.

Conclusions

Double-carbapenem- was not superior to single-carbapenem-containing regimens in patients with CRE BSIs. Single-carbapenem-containing schemes were associated with a lower mortality risk.
AACC Guidance Document on the Use of Point-of-Care Testing in Fertility and Reproduction
Authors: Nichols James H , Ali Mahesheema , Anetor John I , Chen Li Sheng , Chen Yu , Collins Sean , Das Saswati , Devaraj Sridevi , Fu Lei , Karon Brad S , Kary Heba , Nerenz Robert D , Rai Alex J , Shajani-Yi Zahra , Thakur Vinita , Wang Sihe , Yu Hoi Ying Elsie , Zamora Lindsey E
Published: September 2022

Background

The AACC Academy revised the reproductive testing section of the Laboratory Medicine Practice Guidelines: Evidence-Based Practice for Point-of-Care Testing (POCT) published in 2007.

Methods

A panel of Academy members with expertise in POCT and laboratory medicine was formed to develop guidance for the use of POCT in reproductive health, specifically ovulation, pregnancy, premature rupture of membranes (PROM), and high-risk deliveries. The committee was supplemented with clinicians having Emergency Medicine and Obstetrics/Gynecology training.

Results

Key recommendations include the following. First, urine luteinizing hormone (LH) tests are accurate and reliable predictors of ovulation. Studies have shown that the use of ovulation predicting kits may improve the likelihood of conception among healthy fertile women seeking pregnancy. Urinary LH point-of-care testing demonstrates a comparable performance among other ovulation monitoring methods for timing intrauterine insemination and confirming sufficient ovulation induction before oocyte retrieval during in vitro fertilization. Second, pregnancy POCT should be considered in clinical situations where rapid diagnosis of pregnancy is needed for treatment decisions, and laboratory analysis cannot meet the required turnaround time. Third, PROM testing using commercial kits alone is not recommended without clinical signs of rupture of membranes, such as leakage of amniotic fluid from the cervical opening. Finally, fetal scalp lactate is used more than fetal scalp pH for fetal acidosis due to higher success rate and low volume of sample required.

Conclusions

This revision of the AACC Academy POCT guidelines provides recommendations for best practice use of POCT in fertility and reproduction.
Dobbs and the future of health data privacy for patients and healthcare organizations
Authors: Clayton Ellen Wright , Embí Peter J , Malin Bradley A
Published: September 2022

The Supreme Court recently overturned settled case law that affirmed a pregnant individual’s Constitutional right to an abortion. While many states will commit to protect this right, a large number of others have enacted laws that limit or outright ban abortion within their borders. Additional efforts are underway to prevent pregnant individuals from seeking care outside their home state. These changes have significant implications for delivery of healthcare as well as for patient-provider confidentiality. In particular, these laws will influence how information is documented in and accessed via electronic health records and how personal health applications are utilized in the consumer domain. We discuss how these changes may lead to confusion and conflict regarding use of health information, both within and across state lines, why current health information security practices may need to be reconsidered, and what policy options may be possible to protect individuals’ health information.
Comparative Resistance to Insecticides in Populations of three Sympatric Species of Mosquitoes in the Coachella Valley of California
Authors: Apperson Charles S. , Georghiou George P.
Published: September 2022

Toxicelogical assays for resistance in sympatric populations of Culex tarsalis, Culex pipiens quinquefasciatus, and Culiseta inornata in the Coachella Valley of California revealed high level; of resistance in larvae and adults of C. tarsalis toward most organophosphorus insecticides tested but absence of resistance toward carbamates. C. p. quinquefasciatus and Cs. inornata were generally susceptible to the insecticides tested except DDT and dieldrin. Differences in the distribution of the 3 species in time and space were found to be important determinants cf resistance in the populations.
Methodological Considerations on COVID-19 Mortality in Cancer Patients: A Systematic Review and Meta-Analysis
Authors: Zewde Makda Getachew , Alpert Naomi , Taioli Emanuela
Published: September 2022

Background

Patients with cancer are at risk for severe COVID-19. Previous studies examining mortality in cancer patients with COVID-19 have produced inconclusive results. Several published meta-analyses have aimed to estimate this association; however, because of methodological limitations in study selection and data aggregation, these studies do not reliably estimate the independent association between cancer and COVID-19 mortality. We conducted this systematic review and meta-analysis to determine whether cancer is an independent risk factor for COVID-19 mortality.

Methods

A literature search was performed in PubMed to identify studies that compared COVID-19 mortality in adult patients with and without cancer. Selection criteria included polymerase chain reaction–confirmed COVID-19, multivariate adjustment and/or matching for mortality risk estimates, and inclusion of hospitalized noncancer controls. Adjusted odds ratios and/or hazard ratios for mortality based on cancer status were extracted. Odds ratio and hazard ratio estimates were pooled using a random effects model.

Results

The analysis included 42 studies comprising 129 840 patients: 8612 cancer patients and 121 228 noncancer patients. Of these studies, 18 showed a null difference in survival between cancer and noncancer patients with COVID-19, and 24 studies showed statistically significantly worse survival in cancer patients with COVID-19. Meta-analysis revealed an increased risk of mortality in patients with cancer compared with noncancer patients with COVID-19 (odds ratio = 1.93, 95% confidence interval = 1.55 to 2.41; hazard ratio = 1.54, 95% confidence interval = 1.29 to 1.84).

Conclusion

We conclude that cancer is an independent risk factor for mortality in unvaccinated patients admitted for or diagnosed with COVID-19 during hospitalization.
Administrative Errors and Race: Can Technology Mitigate Inequitable Administrative Outcomes?
Authors: Compton Mallory E , Young Matthew M , Bullock Justin B , Greer Robert
Published: September 2022

Scholars have long recognized the role of race and ethnicity in shaping the development and design of policy institutions in the United States, including social welfare policy. Beyond influencing the design of policy institutions, administrative discretion can disadvantage marginalized clientele in policy implementation. Building on previous work on street-level bureaucracy, administrative discretion, and administrative burden, we offer a theory of racialized administrative errors and we examine whether automation mitigates the adverse administrative outcomes experienced by clientele of color. We build on recent work examining the role of technological and administrative complexity in shaping the incidence of administrative errors, and test our theory of racialized administrative errors with claim-level administrative data from 53 US unemployment insurance programs, from 2002 to 2018. Using logistic regression, we find evidence of systematic differences by claimant race and ethnicity in the odds of a state workforce agency making an error when processing unemployment insurance claims. Our analysis suggests that non-white claimants are more likely to be affected by agency errors that result in underpayment of benefits than white claimants. We also find that automated state–client interactions reduce the likelihood of administrative errors for all groups compared to face-to-face interactions, including black and Hispanic clientele, but some disparities persist.
Solving small-scale clustering problems in approximate light-cone mocks
Authors: Smith Alex , Cole Shaun , Grove Cameron , Norberg Peder , Zarrouk Pauline
Published: September 2022

Realistic light-cone mocks are important in the clustering analyses of large galaxy surveys. For simulations where only the snapshots are available, it is common to create approximate light-cones by joining together the snapshots in spherical shells. We assess the two-point clustering measurements of central galaxies in approximate light-cones built from the Millennium-XXL simulation, which are constructed using different numbers of snapshots. The monopole and quadrupole of the real-space correlation function is strongly boosted on small scales below 1 h−1 Mpc, due to some galaxies being duplicated at the boundaries between snapshots in the light-cone. When more snapshots are used, the total number of duplicated galaxies is approximately constant, but they are pushed to smaller separations. The effect of this in redshift space is small, as long as the snapshots are cut into shells in real space. Randomly removing duplicated galaxies is able to reduce the excess clustering signal. Including satellite galaxies will reduce the impact of the duplicates, since many small-scale pairs come from satellites in the same halo. Galaxies that are missing from the light-cone at the boundaries can be added to the light-cone by having a small overlap between each shell. This effect will impact analyses that use very small-scale clustering measurements, and when using mocks to test the impact of fibre collisions.
Common envelope binary interaction simulations between a thermally pulsating AGB star and a low mass companion
Authors: González-Bolívar Miguel , De Marco Orsola , Lau Mike Y M , Hirai Ryosuke , Price Daniel J
Published: September 2022

At least one in five of all planetary nebulae are the product of a common envelope (CE) interaction, where the companion in-spirals into the envelope of an asymptotic giant branch (AGB) star ejecting the nebula and leaving behind a compact binary. In this work we carry out 3D smoothed particle hydrodynamics simulations of the CE interaction between a 1.7 M⊙ AGB star and a 0.6 M⊙ companion. We model the AGB structure using a 1D stellar model taken at the seventh thermal pulse. The interaction takes place when the giant is on the expanding phase of the seventh thermal pulse and has a radius of 250 R⊙. The post-CE orbital separations varies between 20 and 31 R⊙, with the inclusion of recombination energy resulting in wider separations. Based on the observed short in-spiral time-scales, we suggest that thermal pulses can trigger CEs, extending the ability of AGB stars to capture companions into CEs, that would lead to the prediction of a larger population of post-AGB, post-CE binaries. Simulations that include a tabulated equation of state unbind a great deal more gas, likely unbinding the entire envelope on short time-scales. The shape of the CE after the in-spiral is more spherical for AGB than red giant branch stars, and even more so if recombination energy is included. We expect that the planetary nebula formed from this CE will have different features compared to those formed from red giant branch stars.
Genome-wide analysis of DNaseI hypersensitivity unveils open chromatin associated with histone H3 modifications after areca nut with lime exposure
Authors: Swargiary Pooja , Boruah Nabamita , Singh Chongtham Sovachandra , Chatterjee Anupam
Published: September 2022

Research over the years revealed that precocious anaphase, securin overexpression, and genome instability in both target and nontarget cells are significantly associated with the increased risk of areca nut (AN) and lime-induced oral, esophageal, and gastric cancers. Further, hyperphosphorylation of Rb and histone H3 epigenetic modifications both globally and in the promoter region of the securin gene were demonstrated after AN + lime exposure. This study aims whether the extract of raw AN + lime relaxes chromatin structure which further facilitates the histone H3 epigenetic modifications during the initial phase of carcinogenesis. Three groups of mice (10 in each group) were used. The treated group consumed 1 mg/day/mice of AN extract with lime ad libitum in the drinking water for 60 days. The dose was increased by 1 mg every 60 days. Isolated nuclei were digested with DNaseI and 2 kb and below DNA was eluted from the agarose gel, purified and PCR amplified by using securin and GAPDH primers. Securin and E2F1 expression, pRb phosphorylation, and histone epigenetic modifications were analyzed by immunohistochemistry. The number of DNA fragments within 2 kb in size after DNaseI treatment was higher significantly in AN + lime exposed tissue samples than in the untreated one. The PCR result showed that the number of fragments bearing securin gene promoter and GAPDH gene was significantly higher in AN + lime exposed DNaseI-treated samples. Immunohistochemistry data revealed increased Rb hyperphosphorylation, upregulation of E2F1, and securin in the AN + lime-treated samples. Increased trimethylation of histone H3 lysine 4 and acetylation of H3 lysine 9 and 18 were observed globally in the treated samples. Therefore, the results of this study have led to the hypothesis that AN + lime exposure relaxes the chromatin, changes the epigenetic landscape, and deregulates the Rb–E2F1 circuit which might be involved in the upregulation of securin and some other proto-oncogenes that might play an important role in the initial phases of AN + lime mediated carcinogenesis.
A narrative review of the functional components of human breast milk and their potential to modulate the gut microbiome, the consideration of maternal and child characteristics, and confounders of breastfeeding, and their impact on risk of obesity later in life
Authors: Porro Margherita , Kundrotaite Elena , Mellor Duane D , Munialo Claire D
Published: September 2022

Nutritional exposure and, therefore, the metabolic environment during early human development can affect health later in life. This can go beyond the nutrients consumed; there is evidence that the development and modulation of the gut microbiome during early life can affect human growth, development, and health, and the gut microbiome is associated with the risk of obesity later in life. The primary aim of this review was to evaluate existing evidence, to identify the components of human breast milk, which may modulate the gut microbiome, and to assess the impact of the gut microbiome on the risk of becoming obese later in life. This review also considers maternal and child characteristics, and confounders of breastfeeding and how they impact on the infant gut microbiome. Current evidence supports a positive association between fecal, branched short-chain fatty acids and human milk oligosaccharide diversity and a gut microbiome associated with better metabolic health. A negative correlation was found between microbiome diversity and human milk oligosaccharide evenness, which was associated with a greater fat mass and percentage of fat. The components of human breast milk, including oligosaccharides, probiotics, milk fat globule membrane, and adiponectin, were hypothesized to positively influence infant growth and body weight by modulating the microbial diversity and composition of the gut. Maternal diet, timing and duration of breast feeding, and the mode of delivery were all shown to affect the human milk microbiota. However, more experimental studies with long follow-up are required to shed light on the governing mechanisms linking breast milk components with a diverse infant microbiome and healthier body weight later in life.
ETHYLENE RESPONSE FACTOR 34 promotes secondary cell wall thickening and strength of rice peduncles
Authors: Zhang Jiao , Liu Zengyu , Sakamoto Shingo , Mitsuda Nobutaka , Ren Anran , Persson Staffan , Zhang Dabing
Published: September 2022

Cellulose and lignin are critical cell wall components for plant morphogenesis and adaptation to environmental conditions. The cytoskeleton supports cell wall deposition, but much of the underpinning regulatory components remain unknown. Here, we show that an APETALA2/ETHYLENE RESPONSE FACTOR (ERF) family transcription factor, OsERF34, directly promotes the expression of the actin- and microtubule-binding protein Rice Morphology Determinant (RMD) in rice (Oryza sativa) peduncles. OsERF34 and RMD are highly expressed in sclerenchymatous peduncle cells that are fortified by thick secondary cell walls (SCWs) that provide mechanical peduncle strength. erf34 and rmd-1 mutants contained lower cellulose and lignin contents and thinner SCWs, while ERF34 over-expressing (OE) lines maintained high cellulose and lignin content with thicker SCWs. These characteristics impacted peduncle mechanical strength, that is, reduced strength in erf34 and rmd-1 and increased strength of ERF34 OE plants. Taken together, our results demonstrate that the OsERF34-RMD cascade positively regulates SCW synthesis and mechanical strength in rice peduncles, which is important for yield, and provide a potential guide for improved peduncle breeding efforts in rice.
Probing the mutational landscape of the SARS-CoV-2 spike protein via quantum mechanical modeling of crystallographic structures
Authors: Zaccaria Marco , Genovese Luigi , Dawson William , Cristiglio Viviana , Nakajima Takahito , Johnson Welkin , Farzan Michael , Momeni Babak
Published: September 2022

We employ a recently developed complexity-reduction quantum mechanical (QM-CR) approach, based on complexity reduction of density functional theory calculations, to characterize the interactions of the SARS-CoV-2 spike receptor binding domain (RBD) with ACE2 host receptors and antibodies. QM-CR operates via ab initio identification of individual amino acid residue’s contributions to chemical binding and leads to the identification of the impact of point mutations. Here, we especially focus on the E484K mutation of the viral spike protein. We find that spike residue 484 hinders the spike's binding to the human ACE2 receptor (hACE2). In contrast, the same residue is beneficial in binding to the bat receptor Rhinolophus macrotis ACE2 (macACE2). In agreement with empirical evidence, QM-CR shows that the E484K mutation allows the spike to evade categories of neutralizing antibodies like C121 and C144. The simulation also shows how the Delta variant spike binds more strongly to hACE2 compared to the original Wuhan strain, and predicts that a E484K mutation can further improve its binding. Broad agreement between the QM-CR predictions and experimental evidence supports the notion that ab initio modeling has now reached the maturity required to handle large intermolecular interactions central to biological processes.
The First 40 Years of Gastrojejunostomy
Authors: Pappas Theodore N.
Published: September 2022

In the early era of therapeutic laparotomy, surgeons developed operations where the extirpation of pathology only required simple ligation of blood supply, detachment of diseased organs or drainage of infection. In 1881, when sutured anastomosis was in its infancy, a surgeon at Billroth’s clinic in Vienna, Anton Wolfler, performed the first successful gastrojejunostomy to treat gastric outlet obstruction. The patient was a 38-year-old male who presented weak and emaciated with an obstructing stomach cancer. After Dr Wolfler’s sutured gastrojejunostomy, the patient recovered without complication and was able to eat by mouth. Over the next 40 years, surgeons around the world explored variations in the technique of this operation until it was used in common practice for the management of gastric outlet obstruction. During that same era, gastrojejunostomy severed as a testing ground for sutured anastomosis, which became the accepted method of enteric anastomosis. This article will review the early history of gastrojejunostomy, its origination and the European and American innovators who created modifications of this life-saving operation. The importance that gastrojejunostomy had in the evolution of sutured enteric anastomosis will be highlighted.
Faith Community Nurses Making a Difference for Older African Americans in a Pandemic
Authors: Bradley Linda
Published: September 2022

During and after COVID-19, African Americans experienced a disparate amount of social isolation and loneliness and subsequent increases in morbidity and mortality. Faith community nurses are equipped to assist community providers, health practitioners, and local officials in addressing gaps in older African Americans' financial, social, physical, and spiritual needs during social distancing.
External Validation of Cochlear Implant Screening Tools Demonstrates Modest Generalizability
Authors: Lee David S. , Herzog Jacques A. , Walia Amit , Firszt Jill B. , Zhan Kevin Y. , Durakovic Nedim , Wick Cameron C. , Buchman Craig A. , Shew Matthew A.
Published: September 2022

Objective

To assess the clinical application of five recently published cochlear implant (CI) candidacy evaluation (CICE) referral screening tools through external validation.

Study Design

Retrospective cohort study.

Setting

Tertiary otology/neurotology practice.

Patients

Adults who underwent CICE between December 2020 and September 2021.

Intervention(s)

CICE referral screening tools versus CI candidacy criteria.

Main Outcome Measure(s)

CICE screening tool performance, based on the ability to identify patients who met the CI candidacy criteria, was evaluated. CI candidacy criteria were defined as best-aided AzBio sentences at +10 signal-to-noise ratio and either 60% or less accuracy to reflect traditional criteria used in clinical settings or 40% or less accuracy (only patients 65 years or older) to reflect Medicare-eligible criteria.

Results

Screening criteria of proposed CICE referral tools vary widely across pure-tone average and word recognition scores. When screened by traditional criteria, the sensitivities and specificities of these referral tools varied from 40 to 77% and from 22 to 86%, respectively. When screened by Medicare-eligible criteria, sensitivities and specificities varied from 41 to 81% and from 24 to 91%, respectively. The screening tool proposed by Zwolan et al. (Otol Neurotol 2020;41(7):895–900) demonstrated the best overall performance for traditional (Youden's J, 0.37; sensitivity, 62%; specificity, 75%) and Medicare-eligible patients (Youden's J, 0.44; sensitivity, 66%; specificity, 78%). All screening tools performed worse on the validation cohort compared with their respective development cohorts.

Conclusions

Current tools for determining CICE referral have diverse screening criteria. These combinations of pure-tone average and word recognition score are modestly successful at identifying CI candidates.
Histologically Remarkable Eosinophilic Esophagitis Responsive to Dupilumab in a Gastrostomy Tube–Dependent Pediatric Patient on Amino Acid Formula
Authors: Castro Kenny , Arostegui Dalia , Schwarz Steven , Gandhi Sonia , Peshimam Juveria , Rabinowitz Simon , Pittman Meredith , Wallach Thomas
Published: September 2022

Eosinophilic esophagitis (EoE), an eosinophil predominant, TH2-mediated condition increasing in prevalence in pediatric and adult populations, is typically treated with dietary manipulations to avoid triggering antigens. However, identifying specific dietary causes remains a persistent challenge, and restrictive diets are burdensome. Total dietary modification using amino acid–based formula does not always produce symptomatic or histologic resolution, suggesting that exposure to ingested aeroallergens drives their disease. EoE patients demonstrate symptomatic exacerbation from July to September correlating with higher grass and ragweed pollen counts. We present a 7-year-old tracheostomy- and gastrostomy-dependent girl who was found on surveillance endoscopy to have profound eosinophilic infiltration throughout the esophagus with inflammatory changes including basal cell hyperplasia on histology. She responded partially to topical corticosteroid therapy with fluticasone and had complete resolution of esophageal eosinophilic infiltrate with subcutaneous dupilumab.
Multisite longitudinal efficacy trial of a disclosure intervention (TRACK) for HIV+ mothers: An update
Authors: Murphy Debra A. , Marelich William D. , Armistead Lisa , Schulte Marya T.
Published: September 2022

Background

The Teaching, Raising, And Communicating with Kids (TRACK) intervention full-scale longitudinal efficacy trial was published in 2021 and was based on a previously successful pilot intervention published in 2011. The TRACK intervention assists mothers living with HIV (MLH) with serostatus disclosure to their young children. In the publication reporting the full-scale trial, TRACK MLH were four times more likely to disclose their HIV serostatus than controls, with the rate increasing to six times more likely applying GEE logistic regression. Intervention MLH showed improvements in communication, social support, family routines, and disclosure self-efficacy; they also demonstrated decreased anxiety and better physical and mental health scores; and their children reported significantly more decline in worry than controls.

Methods

This preprint presents recent analyses showing increases in the reported HIV disclosure rates over and above those reported in the full-scale trial, due to additional follow-up datapoints received after the 2021 publication.

Results

For MLH in the intervention group, disclosure is 37.6% compared to 34.1% from the 2021 publication, and 12.1% in the control condition compared to 11%. Odds of disclosing if participants were in the intervention group are 4.39 (95% CI. = 2.0, 9.5) compared to 4.20 (95% CI. = 1.8, 9.3), with the intervention group 30% more likely to disclose compared to the 28% reported in 2021. Regarding site disclosure rates for the intervention group, the California disclosure rate is 43.6% compared to 35.9% previously reported; Georgia’s site rate remained unchanged.

Conclusions

These updates are now included in our final analysis dataset and show the intervention was more successful than previously reported.
UB-612 Multitope Vaccine Targeting SARS-CoV-2 Spike and Non-Spike Proteins Provides Broad and Durable Immune Responses
Authors: Wang Chang Yi , Peng Wen-Jiun , Kuo Be-Sheng , Liu Hope , Ho Yu-Hsin , Wang Min-Sheng , Yang Ya-Ting , Chang Po-Yen , Shen Yea-Huei , Hwang Kao-Pin
Published: September 2022

The SARS-CoV-2 non-Spike (S) structural protein targets of nucleocapsid (N), membrane (M) and envelope (E), critical in the host cell interferon response and memory T-cell immunity, have been grossly overlooked since the inception of COVID vaccine development. To pursue a universal (pan-sarbecovirus) vaccine against ever-emergent future mutants, we explored booster immunogenicity of UB-612, a multitope-vaccine that contains S1-RBD-sFc protein and sequence-conserved rationally designed promiscuous Th and CTL epitope peptides on the Sarbecovirus N, M and S2 proteins. To a subpopulation of infection-free participants (aged 18-85 years) involved in a two-dose Phase-2 trial, a UB-612 booster (third dose) was administered 6-8 months after the second dose. The immunogenicity was evaluated at 14 days post-booster with overall safety monitored until the end of study. The booster induced high viral-neutralizing antibodies against live Wuhan WT (VNT50, 1,711) and Delta (VNT50, 1,282); and against pseudovirus WT (pVNT50, 11,167) vs. Omicron BA.1/BA.2/BA.5 variants (pVNT50, 2,314/1,890/854), respectively. The lower primary neutralizing antibodies in the elderly were uplifted upon boosting to approximately the same high level in young adults. UB-612 also induced potent, durable Th1-oriented (IFN-γ+-) responses (peak/pre-boost/post-boost SFU/106 PBMCs, 374/261/444) along with robust presence of cytotoxic CD8+ T cells (peak/pre-boost/post-boost CD107a+-Granzyme B+, 3.6%/1.8%/1.8%). Booster vaccination is safe and well tolerated without SAEs. By recognition against epitopes on Spike (S1-RBD and S2) and non-Spike (N and M) structure proteins, UB-612 provides potent, broad and long-lasting B-cell and T-cell memory immunity and offers a potential as a universal vaccine to fend off Omicrons and new VoCs.

SIGNIFICANCE STATEMENT

The Omicron has swept the globe with a rapid succession of dominating sublineages from BA.1, BA.2, to the current BA.5 with increasing infectivity and antibody evasion. Concerningly, the non-Spike structure proteins that promote T-cell immunity are grossly overlooked in vaccine development. Looking beyond short-interval booster jabs and omicron-updated vaccines, a pragmatic approach to curbing ever-emergent new mutants would be “universal (pan-Sarbecovirus) vaccines” targeting conserved nonmutable epitopes on coronavirus. UB-612, a multitope-vaccine armed with Spike (S1-RBD and S2) and non-Spike targets (Nucleocapsid N and Membrane M), allows booster vaccination to elicit potent, broadly-recognizing, durable B- and T-cell memory immunity. Sequence-conserved epitope peptides were rationally-designed from S2, N and M proteins to synergistically enhance memory helper and cytotoxic T-cell immunity and B-cell immunity.
Soluble TREM2 mediates earliest amyloid-associated p-tau increases and cerebral glucose hypermetabolism in Alzheimer’s disease
Authors: Biel Davina , Suárez-Calvet Marc , Hager Paul , Rubinski Anna , Dewenter Anna , Steward Anna , Roemer Sebastian , Ewers Michael , Haass Christian , Brendel Matthias , Franzmeier Nicolai ,   for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: September 2022

Background

Microglial activation occurs early in Alzheimer’s disease (AD) and previous studies reported both detrimental and protective effects of microglia on AD progression. Therefore, it is critical to investigate at which AD stages microglial activation could be protective or detrimental to evaluate microglia as a treatment target. To address this, we used CSF sTREM2 (i.e. Triggering receptor expressed on myeloid cells 2) to investigate disease stage-dependent drivers of microglial activation and to determine downstream consequences on AD biomarker progression.

Methods

We included 402 cognitively normal and mild cognitively impaired patients with CSF sTREM2 assessments. To assess AD severity, we included measures of earliest beta-amyloid (i.e. Aβ) in CSF (i.e. Aβ1-42) and late-stage fibrillary Aβ pathology (i.e. amyloid-PET centiloid), as well as p-tau181and FDG-PET for assessing downstream changes in tau and cerebral glucose metabolism. To determine disease stage, we stratified participants according to earliest Aβ abnormalities (i.e. Aβ CSF+/PET−; early Aβ-accumulators, n=70) or fully developed fibrillary Aβ pathology (i.e. Aβ CSF+/PET+; late Aβ-accumulators, n=201) plus 131 healthy controls (i.e. Aβ CSF−/PET−).

Results

In early Aβ-accumulators, higher centiloid was associated with cross-sectional/longitudinal sTREM2 and p-tau increases, suggesting reactive microglial and p-tau increases in response to earliest Aβ fibrillization. Further, higher sTREM2 mediated the association between centiloid and cross-sectional/longitudinal p-tau increases and higher sTREM2 was associated with FDG-PET hypermetabolism in line with previous findings of increased glucose consumption of activated microglia. In late Aβ-accumulators, we found no association between centiloid and sTREM2 but a cross-sectional association between higher sTREM2, higher p-tau and glucose hypometabolism, suggesting that sTREM2 parallels tau and neurodegeneration rather than Aβ once fully developed Aβ pathology is present.

Conclusions

Our findings suggest that sTREM2-related microglial activation occurs in response to earliest Aβ fibrillization, manifests in inflammatory glucose hypermetabolism and may facilitate subsequent p-tau increases in earliest AD, while previous reports of protective sTREM2 effects may occur in later AD stages.
SOCIAL INEQUITIES IN A PSYCHOLOGICAL DOMAIN OF FOOD INSECURITY AMONG MOTHERS FROM SOUTHERN BRAZIL DURING THE COVID-19 PANDEMIC
Authors: Martins-Silva Thais , Carpena Marina Xavier , Blumenberg Cauane , Martins Rafaela Costa , Olazo Kamyla M. , Del-Ponte Bianca , Marmitt Luana P. , Meucci Rodrigo , Cesar Juraci A. , Trude Angela C. B. , de Mola Christian Loret
Published: September 2022

We aimed to investigate the social inequalities in the fear of not having enough food for the household, a psychological domain of food insecurity, during the COVID-19 pandemic among mothers from the 2019 Rio Grande birth cohort. In 2019 we invited all mothers who gave birth to a singleton liveborn in the municipality of Rio Grande (southern Brazil) to respond to a standardized questionnaire. In 2020, we followed these mothers twice. In wave I we located 1,077 of all eligible mothers and 1,033 in wave II (follow-up rate of 52.1% and 50.4%). We estimated the absolute and relative inequalities of food insecurity according to the number of people living in the household, maternal education, family income, and income change during the pandemic using the slope index of inequalities (SII) and the concentration index (CIX), respectively. 1,021 mothers reported having food insecurity, and the prevalence was 42.8% and 44.7% for waves I and II, respectively. In wave I we observed inequities in the distribution of food insecurity, being higher among mothers living with ≥3 people (SII:-17.3; 95%CI[-29.6;-5.0]), with a lower education (SII:-36.7; 95%CI[-47.0;-26.4]), lower income (SII-48.9; 95%CI[-58.0;-39.7]), and with an income that decreased during the pandemic (SII:-47.1; 95%CI[-57.3;-36.9]). These inequities widened from wave I to wave II. This study describes the impact of the COVID-19 pandemic on maternal and family food insecurity and the increased social disparities during the pandemic, especially among the most vulnerable populations.
Relationship of preoperative oral hypofunction with prognostic nutritional index in gastric cancer
Authors: Abe Atsushi , Nakayama Atsushi , Otsuka Yuya , Shibata Kanae , Matsui Yoshihito , Ito Yu , Hayashi Hiroki , Momokita Moeko , Taniguchi Shinichi
Published: September 2022

We recruited patients with perioperative gastric cancer and examined preoperative oral hypofunction and its relationship with prognostic nutritional index. This cross-sectional study analysed 95 patients who underwent oral function management. We assessed the following parameters: body mass index, stage of gastric cancer, C-reactive protein, total lymphocyte count, albumin, and prognostic nutritional index. The patients were divided into two groups: prognostic nutritional index <45 and prognostic nutritional index >45. Logistic regression analysis was used to assess the association between the measurements of oral function and the prognostic nutritional index.A univariate analysis of factors associated with decreased oral function and prognostic nutritional index showed significant differences in C-reactive protein, neutrophils and tongue pressure (p<0.01) between the two groups. However, oral hygiene, oral dryness, occlusal force, tongue-lip motor function, masticatory function, and swallowing function were not significantly different. Multivariate analysis showed that C-reactive protein (odds ratio: 0.12, 95% confidence interval: 0.30–0.45, p<0.01) and tongue pressure (odds ratio: 3.62, 95% confidence interval: 1.04–12.60, p<0.05) were independent risk factors for oral hypofunction. Oral function is decreased in perioperative patients with gastric cancer, and decreased tongue pressure is associated with decreased prognostic nutritional index.
Computed Tomography 3D Segmentation Based on Gray-Level Histograms
Authors: Guimeráns-Otero Carlos T. , Martín-Rodríguez Fernando , Isasi-de-Vicente Fernando , Fernández-Barciela Mónica
Published: September 2022

3D imaging technologies like CT (Computed Tomography) and MRI (Magnetic Resonance Imaging) have represented a great advance for diagnosis. These studies are composed of many 2D grayscale images that represent slices of patient’s body, normally orthogonal to body main axis (from head to feet, normally axis Z in Cartesian representation). These slices (normally called axial slices) are good for many diagnosis issues, but sometimes it is interesting to consider the whole study as a 3D volume. This paper is about segmenting 3D volumes obtained from medical studies (mainly CT). We base ourselves on studying the statistical distribution of gray levels so that we can segment different tissues and treating them as separate 3D objects. Note than in a CT image, gray level is basically proportional to tissue density and this technique should be good to distinguish hard tissues like bones or teeth from soft ones like muscles or skin.
Impact of hyperactive neuropsychiatric symptoms on brain morphology in mild cognitive impairment and Alzheimer’s disease
Authors: El Haffaf Lyna Mariam , Ronat Lucas , Cannizzaro Adriana , Hanganu Alexandru ,   for the ADNI
Published: September 2022

Background

The neuroanatomy of hyperactive neuropsychiatric symptoms (NPS) is poorly understood, and it is unclear whether these symptoms result from the same pathogenic processes responsible for cognitive decline or if they have an independent etiology to the neurodegeneration due to Alzheimer’s disease (AD).

Objective

We aim to investigate how the severity of hyperactive NPS (i.e., agitation, disinhibition, and irritability) can impact brain structures at different stages of cognitive decline.

Methods

Neuropsychiatric and 3T MRI data from 223 cognitively normal (CN) participants, 367 participants with mild cognitive impairment (MCI) and 175 participants with AD were extracted from the Alzheimer Disease Neuroimaging Initiative (ADNI) database. Statistical analyses based on the general linear model (GLM) were performed to define the effects of neuropsychiatric variables on brain structures in a two-by-two comparison (AD-MCI, CN-MCI and CN-AD). Linear regression analysis was also performed to investigate cortical changes as a function of NPS severity.

Results

In the AD group, the frontal dorsolateral is the most influenced region receiving an impact from more severe agitation, disinhibition and irritability. In AD, agitation and irritability influence some temporal inferior and parietal superior regions. Furthermore, severe disinhibition seems to have a stronger influence on CN participants compared to the other two groups, particularly in the occipital lingual, frontal middle rostral and frontal pars triangularis regions.

Conclusion

Our study shows that hyperactive NPS influence differently the brain morphology at different stages of cognitive performance. This might imply that their severity should be evaluated in relation to results of cognitive evaluations.
Optimizing the Implementation of Clinical Predictive Models to Minimize National Costs: A Sepsis Case Study
Authors: Rogers Parker , Boussina Aaron E. , Shashikumar Supreeth P. , Wardi Gabriel , Longhurst Christopher A. , Nemati Shamim
Published: September 2022

Objective

To optimize the parameters of a sepsis prediction model within distinct patient groups to minimize the excess cost of sepsis care and analyze the potential effect of factors contributing to end-user response to sepsis alerts on overall model utility.

Materials and Methods

We calculated the excess costs of sepsis by comparing patients with and without a secondary sepsis diagnosis but with the same primary diagnosis and baseline comorbidities. We optimized the parameters of a sepsis prediction algorithm across different diagnostic categories to minimize these excess costs. At the optima, we evaluated diagnostic odds ratios and analyzed the impact of compliance factors—like non-compliance, treatment efficacy, and tolerance for false alarms—on the net benefit of triggering sepsis alerts.

Results

Compliance factors significantly contributed to the net benefit of triggering a sepsis alert. However, a customized deployment policy can achieve a significantly higher diagnostic odds ratio and reduced costs of sepsis care. Implementing our optimization routine with powerful predictive models could result in $4.6 billion in excess cost savings for the Medicare program.

Discussion

Sepsis costs and incidence vary dramatically across diagnostic categories, warranting a customized approach for implementing predictive models. We designed a framework for customizing sepsis alert protocols within different diagnostic categories to minimize excess costs and analyzed model performance as a function of false alarm tolerance and compliance with model recommendations.

Conclusion

Customizing the implementation of clinical predictive models by accounting for various behavioral and economic factors may improve the practical benefit of predictive models.
Lived experiences of caregivers of persons with epilepsy attending an epilepsy clinic at a tertiary hospital, eastern Uganda: A phenomenological approach
Authors: Okiah Lindah , Olowo Samuel , Iramiot Stanely J. , Nekaka Rebecca , Ssenyonga Lydia VN.
Published: September 2022

Introduction

Epilepsy has been found to affect caregivers’ quality of life, life style, psychological health, social well-being and their working time. Caregivers in Uganda as in the rest of the world are important in assisting a person with epilepsy in complying with medical directions and can be actively involved in communicating with health care professionals. Little is known about the lived experiences of caregivers of persons afflicted with epilepsy in Uganda. The purpose of the study was to determine the lived experiences of caregivers of persons with epilepsy attending the epilepsy clinic at Mbale regional referral hospital, eastern Uganda.

Methods and materials

Forty participants were selected for the study through purposive sampling. Face to face in-depth interviews with unstructured interview guide were conducted to gather participants’ information. The investigator conceptualized the interview guide, reviewed by co-investigators, and revised and approved as the final data collection instrument after an extensive and comprehensive literature review. The interview guide comprised of two sections, the first section comprised of the questions that elicited the participants’ social demographic information. The second section comprised questions that explored caregivers experiences of persons afflicted with epilepsy. Notations were taken and a digital recorder was used purposely for audio-recordings. All interviews lasted for an hour and were audio-recorded with the participants’ consent. An inductive thematic analysis was employed and adopted to identify the patterns emerging from the texts.

Results

The caregivers majorly perceived epilepsy as a burden. Four main themes were revealed from the analysis and these are; psychological, social, economic, and physical burdens.

Conclusion

The caregivers majorly perceived epilepsy as a serious burden. This burden can be psychological, social, economic, and physical. Therefore, services and plans targeting patients with epilepsy need to consider the burden that caregivers encounter to comprehensively manage epilepsy and its resultant burden.