bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Genetic Loci and Sex Differences Associated with Amyloid Burden Using the AD‐BXD Mouse Population
Authors: Charland Kevin , Kaur Harpreet , Hadad Niran , Ouellette Andrew R , O'Connell Kristen MS , Kaczorowski Catherine C.
Published: December 2022

Background

In light of the rising prevalence of both diet‐induced obesity and Alzheimer’s Disease (AD) in the developed world, the influence of a high‐fat diet (HFD) on AD progression was investigated. Beta‐amyloid 1‐42 (Aβ42), in particular, was examined as little is known about the extent to which an individual’s genetics, sex, and diet determine the onset and progression of this classic AD neuropathology.

Method

AD‐BXD mice were generated by crossing female 5XFAD mice to male members of the BXD reference panel (Neuner, et al. 2019). Cortical Aβ42 levels were quantified (ELISA) from four hundred and twenty‐two mice (235 female, 187 male) across 52 AD‐BXD strains fed either a 6kcal% extruded control diet (n = 227) or 45kcal% HFD (n = 195) at 10 weeks of age until 3, 6, or 14 months old.

Result

While a 45kcal% HFD did not alter cortical Aβ42 levels in 5XFAD mice relative to control diet, there was a main effect of genetic background (strain) and sex. Specifically, wide variation in cortical Aβ42 was observed across the AD‐BXD mouse population that was highly heritable (h2≈0.9), and females displayed greater Aβ42 levels than males. Quantitative trait locus (QTL) mapping revealed significant genetic loci associated with increased amyloid burden with aging, indicating sequence differences on chromosomes (Chr) 19 and X that may underlie the observed sex differences when age was included as covariates. Furthermore, we identified several missense mutations within our Chr 19 QTL that could explain differences in Aβ42 phenotype, and expression QTL analysis is underway to identify putative regulatory variants of cortical amyloid burden.

Conclusion

We found that genetic factors, strain and sex, are key determinants of cortical amyloid burden – but not diet (environmental factor) suggesting involvement of other regulators/pathways in eliciting cognitive decline in AD‐BXD mouse population (Dunn et. al., AAIC 2021) Resolving genetic modifiers of amyloid burden located on Chr 19 and X may reveal novel targets for anti‐amyloid therapeutics and provide a possible mechanistic explanation for why females (XX) are at a higher risk for developing AD than males (XY).
Tau‐RNA complexes contribute to the pathogenesis and progression in Alzheimer’s disease and related tauopathies
Authors: Lessard Christian B , Koren John , Abisambra Jose F. F
Published: December 2022

Background

Recent in vitro and in vivo data show that Tau‐RNA complexes contribute to neuronal dysfunction. However, whether these complexes appear in human tauopathy brains, and whether they are inherently toxic remains unknown. Clarifying the dynamics of tau‐RNA interactions and its relevance in disease would reveal critical and urgently needed information to determine novel therapeutic targets.

Method

Human Alzheimer’s and age‐matched non‐demented control brains were subjected to enhanced cross‐linking immunoprecipitation (eCLIP) sequencing. Amount of RNA was quantified and sequenced in each group. Cell culture experiments were used to validate eCLIP data.

Result

Tau associated robustly with RNA, many of which have not been previously reported. Early and late‐stage AD tau‐RNA complexes shifted from coding to non‐coding sequences. The consensus sequences that associated with tau contain numerous splice sites and start codons. RNA‐stabilizing species associated with tau in AD brains. Tau overexpression impaired RNA processing, transport, and translation in vitro.

Conclusion

Tau‐RNA interactions, that have not been previously reported, were identified for the first time in human AD brains, and they reveal novel sequences that could be associated with disease.
Neuronal calcium dysregulation in mice at an early stage of tauopathy and its alleviation by a tau antibody
Authors: Ji Changyi , Lin Yan , Sigurdsson Einar M.
Published: December 2022

Background

Tau immunotherapies are promising approaches to treat Alzheimer’s disease and other tauopathies. How tau antibodies restore neuronal function remains unknown. Neuronal activity can be monitored by two‐photon calcium imaging in awake and behaving animals. Using this method, we observed altered neuronal calcium activity in the motor cortex of 12‐month‐old JNPL3 tauopathy mice during quiet wakefulness or forced running (Wu Q et al, Neurobiol. Dis. 2021). We also demonstrated that a mouse monoclonal antibody, targeting phosphorylated tau‐Ser396/Ser404, significantly restored the abnormal calcium activity and decreased pathological tau levels in these mice. Analysis of possible neuronal functional deficits and tau antibody efficacy in younger tauopathy mice warrants further investigation.

Methods

Somatic calcium activity in the motor cortex of 6‐month‐old JNPL3 mice were assessed by two‐photon microscopy when animals were either resting or running on a treadmill. At this age, JNPL3 mice are in their early stage of tauopathy. The frequency, amplitude and total activity of calcium transients were analyzed and compared between wild‐type and JNPL3 mice. After the first imaging session, two doses (100 µg each) of a tau antibody were administered intravenously to JNPL3 mice four days apart. The somatic calcium activity was assessed again in these animals four days later, and compared to their neuronal calcium activity profile before tau antibody treatment.

Results

We found abnormal cortical calcium activity in resting and running JNPL3 mice at 6 months of age. Brain levels of pathological tau correlated with the degree of calcium dysfunction. Acute treatment with a tau antibody attenuated these changes, whereas littermate JNPL3 mice treated with control IgG showed no improvements.

Conclusion

These findings revealed neuronal calcium dysregulation in JNPL3 mice at an early stage of tauopathy that was partially corrected by an acute tau antibody treatment, analogous to our prior findings at a later stage of tauopathy. Together, these results indicate that neuronal dysfunction correlates with tau pathology at various stages of tauopathy, which can be consistently alleviated by a tau antibody treatment. This type of functional evaluation in vivo is a valuable way to study tau pathogenesis, and assess therapeutic efficacy at different stages of tauopathy.
Advancing the Science of Recruitment and Retention in Alzheimer’s disease Clinical Studies among Spanish‐speaking immigrant Latino/Hispanic communities
Authors: Diaz‐Santos Mirella , Eliseo Stephanie G Ovalle , Ryan Gery W. , Talamantes Efrain , Bookheimer Susan Y. , Moreno Gerado
Published: December 2022

Background

While Latinos/Hispanics living with Alzheimer’s are projected to grow 832% by the year 2060, they make up approximately 7.5% of research participants across 32 federally funded Alzheimer’s Disease Research Centers. Our previous work presented at AAIC 2020 highlighted how the Human Connectome Project’s study design automatically excluded 94% of potential Latino/Hispanic community members in Southern California due to language. As a result, the individuals recruited and retained were mostly bilingual white Latinos/Hispanics with higher education and occupational attainment and high levels of research literacy, resembling the well‐known WEIRD sample (e.g., White, Educated, Industrialized, Rich, and Democratic). In the current study, we sought to understand the role of Latino/Hispanic community stakeholders in involving community members more representative of Southern California (Spanish‐Speaking, low income, immigrants, Afro‐Latinx, Indigenous Natives).

Method

During the COVID‐19 pandemic, we recruited 11 community stakeholders from Southern California to complete a 1‐hour semi‐structured interview via an HIPPA compliant zoom platform. All participants were involved in Latino healthy aging and Alzheimer’s Disease organizations. We conducted a preliminary reflexive thematic analysis from the interviews.

Result

The overarching theme surrounded the exclusion of Latinx/Hispanic community stakeholders from leadership conversations about Alzheimer’s disease clinical research priorities. The systematic exclusion of community stakeholders from leadership tables lead to non‐inclusive community engagement and research practices. They were solely used for outreach (“find me your people”), as well as for the translation of recruitment materials, and/or for the sole administration of poorly translated and non‐culturally adapted outcome measures. These practices lead to the exclusion of Spanish‐speaking, immigrant communities through language and cultural isolation, triggering negative cognitive schemas and negative beliefs from previous traumatic experiences of exclusionary practices in the United States.

Conclusion

Our findings highlight how the Alzheimer’s disease clinical research enterprise continues to propagate multi‐level systematic exclusionary practices, accounting for the lack of equitable representation of high‐risk Latinx/Hispanic communities in research. To advance the science of recruitment and retention, and brain health equity, we need to systematically employ transformative community engagement and inclusive science models where Latinx/Hispanic community stakeholders are essential in decision‐making research process with equal‐power and shared governance.
Amyloid beta deposition in the lumbosacral spinal circuit impairs both the short‐term and long‐term neuroplasticity of locomotion.
Authors: Huang Ruyi
Published: December 2022

Background

Locomotion deficits have emerged as a novel predictor of the pathological progression of the Alzheimer’s disease (AD). In this study, we hypothesize that spinal cord is impacted by the protein pathogenic in the AD.

Method

To rule out the impact of the supraspinal structures, we transected spinal cord completely at thoracic level 10 to cut off all connections between the lumbosacral spinal cord and all the rostral parts of the central nervous system (CNS). The short‐term plasticity of the lumbosacral locomotor circuit was evaluated by an instrumental learning model, paw withdrawal paradigm (PaWL) and the long‐term plasticity was investigated by weekly bipedal treadmill stepping paradigm, which lasted for seven weeks.

Result

Both 4mon and 13mon J20 mice showed significant decreases in the PaWL compared to their WT littermates (p = 0.0075). The spontaneous bipedal locomotion recovery was also blocked in spinal J20 mice when compared to WT littermates (p = 0.0031). These impairments of lumbar circuit plasticity were reversed by the administration of a gamma‐secretase inhibitor (Benzodiazepine‐type LY‐411575) in the spinal J20 mice, suggesting the generation of amyloid beta in local spinal cord circuit contribute to the locomotor deficits.

Conclusion

The soluble beta amyloid expression levels in the lumbar spinal cord impair both the the long‐term and short‐term neuroplasticity of locomotion.
Sleep medication use and falls risk among African Americans with dementia
Authors: Anderson Loretta R. , Wennberg Alexandra MV
Published: December 2022

Background

Sleep disturbances and falls are frequent in older adults and risk increases with increasing age (M. Ohayon, 2002; World Health Organization, 2007), especially for those people living with dementia (PLWD). While existing research sheds light on the difference between high‐ and low‐ frequency sleep medication use in people with and without dementia (L. Anderson, 2021), little evidence exists in the nature of racial differences. This study seeks to determine the differential effect of high versus low frequency sleep medication use in non‐Hispanic Blacks with dementia.

Method

We used data from the 2011 National Health and Aging Trends Study (n = 8,245) to create logistic regression models examining the association high‐ versus low‐ frequency sleep medication use with falls in community‐dwelling non‐Hispanic Blacks living with dementia. High‐frequency sleep medication use was defined as 5 or more nights per week, while low‐frequency sleep medication use was defined as 4 or fewer nights per week.

Result

In our fully adjusted model, non‐Hispanic Blacks living with dementia (n = 121) who were high‐frequency sleep medication users were much more likely to fall compared to non‐Hispanic Blacks living with dementia who were low‐frequency sleep medication users (OR = 7.59, 95% CI: 2.86, 20.13). Fully adjusted model controlled for sociodemographic characteristics, anxiety, depression, arthritis, diabetes, and hypertension.

Conclusion

After controlling for potential confounders, non‐Hispanic Blacks living with dementia and having high‐frequency sleep medication usage are over 7 times more likely to fall compared with non‐Hispanic Blacks with dementia who have low‐frequency sleep medication usage. Reducing sleep medication use in this population may help reduce the risk of falls and fall‐related outcomes.
Spreading of Tau and other corrupted proteins through the gut‐brain axis
Authors: Martin‐Peña Alfonso , Lopez‐Scarim Joshua , Tansey Malu Gamez
Published: December 2022

Background

Alzheimer’s disease (AD) is the most common form of dementia. However, although the clinical and pathological aspect of the disease are thoroughly characterized, the pathophysiological mechanism underlying the progressive neurodegenerative process is not well understood. In consequence, there is no cure and a disease‐modifying treatment is lacking. It is therefore imperative to identify the earliest signs of disease pathology to pave the way to identify the triggering molecular factors of the disease and the mechanisms underlying molecular spreading of toxic assemblies. Our search for these key clues in the periphery is founded on the fact that peripheral dysfunction, particularly in the gastrointestinal (GI) system, can arise decades before the onset of the classic symptoms in neurodegenerative disorders. In fact, the risk of AD increases significantly in patients with inflammatory bowel disease (IBD) when compared with the non‐IBD population. Furthermore, Tau accumulates in Crohn’s Disease guts and in sigmoid colon of AD and FTD patients. Therefore, we are investigating the physiological and molecular mechanisms that support Tau spreading in the prodromal stages and, particularly, along the gut‐brain axis.

Method

To test whether corrupted proteins expressed in the gut will spread to the brain, we employed the Gal4/UAS system and expressed wild type human Tau in selected populations of gut epithelium cells. We then monitor behavior on aging flies expressing Tau in the gut epithelium using Drosophila activity monitors (DAM) and analyzed their circadian patterns of activity along with several sleep parameters.

Result

We observed that flies selectively expressing full length (2N4R) human Tau in enteroendocrine cells of the gut exhibited a significant impairment in their daily activity pattern that specifically affected their behavior during the light phase (day) but not during the dark period (night). Interestingly, these flies also showed an increased sleepiness during the day without affecting their nocturnal sleep pattern. The onset of these behavioral changes appears to occur as early as 10 days after eclosion.

Conclusion

Our results support the presence of spreading mechanisms for Tau from gut epithelial cells to the brain; hence, affecting the neuronal physiology that sustain daily activity patterns.
SORL1‐retromer regulates endosomal recycling and helps explain Alzheimer’s regional vulnerability
Authors: Small Scott A.
Published: December 2022

The importance of the endosomal recycling pathway for cellular health was recognized ever since its reverse trafficking itinerary, clathrin‐dependent endocytosis, was described. Vital for synaptic function, a recent study found that neurons are endowed with a distinct unit dedicated to the recycling pathway. Akin to how endocytosis is regulated by a functional unit formed by the clathrin coat interacting with low‐density lipoprotein‐related receptors (LDLRs), recent studies will be reviewed suggesting that endosomal recycling in neurons is regulated by a functional unit comprised of a neuronal‐enriched retromer coat that interacts with the sortilin‐related receptor SORL1. Genetic studies suggest that rare truncating mutations in SORL1, inducing SORL1 haploinsuffiency, acts a causal event in triggering Alzheimer’s disease (AD). In agreement with this interpretation, recent studies will be reviewed showing that SORL1 haploinsufficiency can trigger AD’s cardinal pathologies, including showing in mice that it leads to selective atrophy in the trans‐entorhinal cortex. These studies suggest that SORL1‐retromer recycling is a causal pathway in AD that when disrupted can trigger AD’s molecular, cellular, and anatomical pathologies. When interpreted together with a collection of other studies this recent insight suggests why the trans‐entohrinal cortex is so dependent on SORL1‐retromer recycling, why the trans‐entorhinal cortex is differentially vulnerable even to ‘sporadic’ AD, and why AD anatomically ‘spreads’ over time.
Single cell biology to analyse cellular heterogeneity in the response to amyloid plaques in Alzheimer’s Disease
Authors: De Strooper Bart
Published: December 2022

Microglial activation and neuroinflammation are crucial in the pathogenesis of Alzheimer’s disease. However, studies in mouse models and human postmortem samples have yielded divergent results regarding transcriptional programs in microglia elicited by exposure to amyloid‐b pathology. Here, we investigate 127,000 single cell expression profiles of human microglia isolated freshly from a xenotransplantation model for AD. Human microglia adopt a different, more complex spectrum of cell states than mouse microglia. Besides a disease associated (DAM) profile, human microglia show a pronounced HLA‐response related to antigen presentation in response to amyloid‐b plaques, which is absent in mouse. Furthermore, oligomeric amyloid‐β present in this model induces a distinctive pro‐inflammatory CRM response characterized by the expression of cytokines and chemokines, also not seen in mice. TREM2 and APOE polymorphisms modulate the response of microglia to amyloid‐b plaques, much less to oligomeric Aβ. In conclusion, human microglia mount a multipronged ARM response to amyloid pathology in Alzheimer’s disease. This implies that therapeutic strategies targeting microglia need to analyse carefully the effect on these different cell states some of which seem protective.
Lifestyle impacts on insulin transport at the blood‐brain barrier in mice
Authors: Rhea Elizabeth
Published: December 2022

Background

The blood‐brain barrier (BBB) is a regulatory interface, controlling the blood‐to‐brain transport of many substances, resulting in nutrient delivery to the central nervous system (CNS) and communication between the periphery and CNS. There are structural and functional changes within the BBB in Alzheimer’s disease, which may contribute to the detrimental effects occurring within the CNS. CNS insulin resistance is one of many detrimental features of Alzheimer’s disease. As the BBB is responsible for the delivery of insulin to the CNS, alterations in insulin BBB transport could be a cause of CNS insulin resistance. Indeed, various lifestyle factors are known to impact insulin BBB pharmacokinetics, including diet and exercise, which have also been shown to impact Alzheimer’s disease progression.

Methods

Utilizing sensitive radiotracer methods of substrate transport at the BBB in young male and female mice, we investigated the impact of exposure to a voluntary running wheel and what role CNS insulin resistance has on insulin BBB pharmacokinetics.

Results

Acute exercise increased insulin BBB transport and CNS insulin resistance decreased insulin brain uptake.

Conclusion

CNS insulin resistance decreases insulin BBB transport in mice, particularly in females. We found a lifestyle intervention, such as exercise, is able to enhance insulin BBB transport, which may be able to attenuate CNS insulin resistance. Future work is necessary to determine if exercise can reverse the insulin BBB transport deficiencies observed due to CNS insulin resistance.
Shell‐type supernova remnants and very high energy cosmic rays
Authors: Sinitsyna Vera G. , Sinitsyna Vera Y.
Published: December 2022

The investigation of very high energy (VHE) γ‐ray sources by any methods, including mirror Cherenkov telescopes, touches on the problem of the cosmic‐ray origin and, accordingly, the role of the Galaxy in their generation. The SHALON observations have yielded the results on Galactic supernova remnants (SNR) of different ages. Among them are: the shell‐type SNRs Tycho's SNR, Cas A, IC 443, γCygni SNR, G166.0+4.3. For each of SNRs, the observation results are presented with spectral energy distribution by SHALON in comparison with other experiment data and images by SHALON in together with data from X‐ray by Chandra and radio‐data by CGPS. The experimental data presented here have confirmed the prediction of the theory about the hadronic generation mechanism of VHE 800 GeV–100 TeV γ‐rays in Tycho's SNR, Cas A and IC 443, and also the collected experimental data help to make clear the origin of TeV γ‐ray emission in the older SNRs like γCygni SNR and G166.0+4.3.
Two novel variations p.(Ser1275Thr) and p.(Ser1275Arg) in FLT4 causing prenatal hereditary lymphedema type 1
Authors: Lajmi Yosra , Loeuillet Laurence , Petrilli Giulia , Egloff Charles , Nectoux Juliette , Molac Clémence , Roux Nathalie , Pannier Emmanuelle , Achaiaa Amale , Arkoub Zaina Ait , Chuon Sophie , Coussement Aurélie , Dupont Jean Michel , Malan Valérie , Spaggiari Emmanuel , Razavi Ferechte , Amiel Jeanne , Bessières Bettina , Grotto Sarah , Attié‐Bitach Tania
Published: December 2022

Background

Hereditary lymphedema 1 is a rare congenital condition, characterized by the development of chronic swelling in body parts. It is highly variable in expression and age of onset with different presentations: from feet edema to hydrops fetalis. This affection is genetically heterogeneous with autosomal dominant inheritance and incomplete penetrance due to a mutation in the FLT4 gene in most cases.

Cases

In our study, we report on two fetuses harboring congenital lymphedema with FLT4 variation and review the prenatal confirmed ones of the literatures. Our cases were selected within fetuses explored by exome sequencing in a diagnosis setting. Prenatal ultrasonography showed hydrops fetalis in one case and an increased nuchal translucency with hydrothorax in the other. Comparative genomic hybridization array on amniocentesis was normal in both cases. Exome sequencing identified a variation p.(Ser1275Thr) and p.(Ser1275Arg) in fetus 1 and fetus 2 in the FLT4 gene, respectively. A de novo mutation at the same codon was reported in prenatal literature suggesting possible genotype phenotype correlation.

Conclusion

Cystic hygroma/hydrops fetalis are possible manifestations of several disorders. This study illustrates how the integration of exome sequencing in prenatal clinical practice can facilitate the diagnosis and genetic counseling of heterogeneous developmental affections.
Design, Synthesis, Insecticidal Activities and Molecular Docking of Sulfonamide Derivatives Containing Propargyloxy or Pyridine Groups
Authors: Zhu Jian‐Jun , Guo Tao , Zhang Zi‐Wei , Qian Hao , Tian Peng , Yu Ke‐Yin , Wu Wen‐Jun , Zhang Ji‐Wen
Published: December 2022

The discovery of new highly active molecules from natural products is a common method to create new pesticides. Celangulin V targeting Mythimna separate (M. separate) midgut V‐ATPase  H subunit, has received considerable attention for its excellent insecticidal activity and unique mechanism of action. Therefore, combined with our preliminary work, thirty‐seven sulfonamide derivatives bearing propargyloxy or pyridine groups were systematically synthesized to search for insecticidal candidate compounds with low cost and high efficiency on the  H subunit of V‐ATPase. Bioactive results showed that compounds A2‐A4 and A6‐A7 exhibited a better bioactivity with median effective concentration (LC50) values (2.78, 3.11, 3.34, 3.54 and 2.48 mg/mL, respectively) against third‐instar larvae of M. separate than Celangulin V (LC50=18.1 mg/mL). Additionally, molecular docking experiments indicated that these molecules may act on the H subunit of V‐ATPase. Based on the above results, these compounds provide new ideas for the discovery of insecticides.
Benedikt syndrome in a 74‐year‐old hypertensive woman: A case report
Authors: Adhikari Abhishek , Bhattarai Ayush Mohan , Pandit Ayushma , Rokaya Pooja , Khadka Manoj , Shahi Manoj , Baiju Swastika , Poudel Raju
Published: December 2022

Benedikt syndrome is a rare neurological disorder of the midbrain. Herein, we present a case of Benedikt syndrome, who presented with left‐sided body weakness, right oculomotor nerve palsy, cerebellar ataxia, and Holmes tremor in the left upper limb following midbrain infarction. She was treated with aspirin, clopidogrel, and amiodarone.
Influence of High Hydrostatic Pressure and Pulsed Electric Field Treatment on Moisture Absorption of Wheat Grains
Authors: Shorstkii Ivan , Mounassar Emad Hussein Ali , Bindrich Ute , Heinz Volker , Aganovic Kemal
Published: December 2022

The effect of high pressure (0.1–600 MPa) and pulsed electric field (E = 3 and 6 kV cm−1) pretreatments on the moisture absorption properties of non‐hulled wheat grains were investigated. Microwave sensor was used as a non‐invasive technique for determination of the moisture content. The results demonstrated that high pressure soaking (>100 MPa) of wheat grains significantly increased the water uptake. High pressure soaking (600 MPa) decreased the water uptake due to the starch gelatinization and as a result appearance of structural changes. Compared to control samples, PEF‐pretreated samples showed a sharp increase of water absorption at the initial process with a further reduction of equilibrium water content. Peleg's water absorption model was adapted to the measured data of non‐hulled wheat grains. Results showed a good prediction of Peleg's equation in all experiments, which gave the possibility for estimation of initial water absorption rate and equilibrium moisture content.
The Facets of Diversity: The EFMC Perspective**
Authors: Borsari Chiara , Matagne Brieuc , Goncharenko Kristina , Moreira Rui , Auberson Yves P.
Published: December 2022

Diversity in science refers to cultivating talent, while promoting full inclusion across the community. In medicinal chemistry and chemical biology, it enhances creativity and encourages contributions from multiple perspectives, leading to better decision making and broader scientific impact. The European Federation for Medicinal chemistry and Chemical biology (EFMC) embraces and promotes diversity, to ensure representation of all talents, and enable equality of opportunity through fairness and transparency. EFMC has historically paid continuous attention to diversity in terms of culture, geography and equilibrium between academia and industry, with over the last few years a focus on increasing gender balance, aiming at a fair representation of the scientific community and equal opportunities independently of gender. EFMC promotes cultural diversity as it reinforces openness and mutual respect. All scientific organizations of a scope compatible with its remit are welcome within EFMC, where their members benefit from a welcoming, psychologically safe, and stimulating environment. Herein, we describe the state of diversity within the EFMC, how the situation has evolved over the years and where diversity should be further encouraged.
Clinical impact of minimal residual disease and genetic subtypes on the prognosis of childhood acute lymphoblastic leukemia
Authors: Yu Chih‐Hsiang , Jou Shiann‐Tarng , Su Ying‐Hui , Coustan‐Smith Elane , Wu Gang , Cheng Chao‐Neng , Lu Meng‐Yao , Lin Kai‐Hsin , Wu Kang‐Hsi , Chen Shu‐Huey , Huang Fang‐Liang , Chang Hsiu‐Hao , Wang Jinn‐Li , Yen Hsiu‐Ju , Li Meng‐Ju , Chou Shu‐Wei , Ho Wan‐Ling , Liu Yen‐Lin , Chang Chia‐Ching , Lin Ze‐Shiang , Lin Chien‐Yu , Chen Hsuan‐Yu , Ni Yu‐Ling , Lin Dong‐Tsamn , Lin Shu‐Wha , Yang Jun J. , Ni Yen‐Hsuan , Pui Ching‐Hon , Yu Sung‐Liang , Yang Yung‐Li
Published: December 2022

Background

This study analyzed data from two consecutive protocols for children newly diagnosed with acute lymphoblastic leukemia (ALL) to determine the clinical impact of minimal/measurable residual disease (MRD) and recently identified tumor genetic subtypes.

Methods

Genetic subtypes were determined by sequential approaches including DNA indexing, reverse transcriptase–polymerase chain reaction, multiplex ligation‐dependent probe amplification, and RNA‐sequencing. MRD was assessed by flow cytometry. The Taiwan Pediatric Oncology Group TPOG‐ALL‐2013 study enrolled patients who received MRD‐directed therapy.

Results

The 5‐year event‐free survival (EFS) and overall survival rates in the 2013 cohort were 77.8% and 86.9% compared to those of the 2002 cohort, which were 62.4% and 76.5%. Among patients treated with MRD‐guided therapy, those with ETV6‐RUNX1 fusion and high hyperdiploidy had the highest 5‐year EFS (91.4% and 89.6%, respectively). The addition of dasatinib improved outcomes in patients with BCR‐ABL1 ALL. Recently identified subtypes like DUX4‐rearranged, ZNF384‐rearranged, MEF2D‐rearranged, and PAX5alt subtypes were frequently positive for MRD after remission induction, and these patients consequently received intensified chemotherapy. Treatment intensification according to the MRD improved the outcomes of patients presenting DUX4 rearrangements. In high‐risk or very‐high‐risk subtypes, the TPOG‐ALL‐2013 regimen did not confer significant improvements compared to TPOG‐ALL‐2002, and the outcomes of BCR‐ABL1‐like, MEF2D‐rearranged, and KMT2A‐rearranged ALL subtypes (in addition to those of T‐cell ALL) were not sufficiently good. Novel agents or approaches are needed to improve the outcomes for these patients.

Conclusions

The TPOG‐ALL‐2013 study yielded outcomes superior to those of patients treated in the preceding TPOG‐ALL‐2002 study. This study provides important data to inform the design of future clinical trials in Taiwan.

Plain language summary

MRD‐directed therapy improved the outcomes for pediatric ALL, especially standard‐risk patients.

Genomic analyses and MRD might be used together for risk‐directed therapy of childhood ALL.

Our work provides important data to inform the design of future clinical trials in Taiwan
Surgical outcomes and factors associated with postoperative complications of colorectal cancer in a Colombian Caribbean population: Results from a regional referral hospital
Authors: Dagobeth Edgar Ernesto Vergara , Rojas Gian Alberto Núñez , Valdelamar Juan Carlos Hoyos , Lozada‐Martínez Ivan David , Causado Amileth Suarez , Narvaez‐Rojas Alexis Rafael
Published: December 2022

Introduction

Colorectal cancer is the most common malignant neoplasm of the gastrointestinal tract. Its incidence and mortality vary markedly at a global level. Assessing the epidemiological behavior of this condition allows reevaluating diagnostic, therapeutic and prognostic options, based on new findings. In Colombia, few studies have correlated variables associated with surgical and oncological outcomes in this type of cancer. Then, the aim of this study was to evaluate the surgical outcomes and factors associated with postoperative complications of colorectal cancer in a Colombian Caribbean Population.

Methods

Retrospective cross‐sectional study, including patients with a histopathological diagnosis of colorectal cancer who underwent open or laparoscopic surgery, during a period of two years (2018–2020), from a regional referral hospital. Clinical history variables were collected. Frequencies and prevalence ratios were calculated.

Results

A total of 84 patients were finally included. Adenocarcinoma of non‐special type with advanced clinical stages was the most prevalent (72.6%). Rectal neoplasia (45.2%) was the most frequent anatomical subsite, followed by proximal colon (p = 0.026). The anatomical subsite of the neoplasm, intraoperative complication (PR 1.38; 95% CI, 1.21–1.59, p = 0.001) and intensive care stay (PR 1.062; 95% CI, 1.01–1.12, p = 0.048) were associated with postoperative outcome.

Conclusions

The anatomical subsite of the neoplasm location, the presence of intraoperative complications and the stay in intensive care may be associated with the surgical and oncological outcome of individuals with colon cancer from the Colombian Caribbean region.
Identification and cloning of early senescence leaf mutant esl13 in rice (Oryza sativa L.)
Authors: Zhang Yingying , Chen Xinlong , Du Dan , Ma Lu , He Guanghua
Published: December 2022

Senescence in plants is a complex and highly regulated process. However, the early senescence of leaf directly affects crop yield and quality. Identifying early senescence mutants and understanding its mechanism are critical to crop genetic improvement. In this study, we isolated an early senescence mutant esl13 (early senescence leaf 13) by ethyl methane sulfonate mutagenesis of Xinong 1B. Under paddy field conditions, the leaves of esl13 are normal green at the tillering stage, yellow at the booting stage, and gradually extended to the base of the leaves, and the senescence was most severe at the mature stage. At the booting stage, the leaves of mutant showed significantly lower photosynthetic pigment content, weaker chloroplast autofluorescence, and a highly significant reduction in net photosynthetic rate, resulting in shorter plants heights, shorter spike length, and lower seed yield at the mature stage. Similarly, the activity of antioxidant enzymes catalase, superoxide dismutase, and peroxidase decreased continuously, and malondialdehyde and superoxide anion (O2−) accumulated in the mutant esl13. Genetic analysis showed that the leaf senescence phenotype of esl13 is controlled by a single recessive nuclear gene, which was fine mapped between two molecular markers insertion‐deletion 4‐4 and SNP220 on chromosome 4. Gene sequencing showed that the 1230th base starting from ATG of the candidate gene LOC_Os04g48530 changed from T to A, causing the encoded amino acid change. Genetic complementation experiments confirmed the gene LOC_Os04g48530 controlled the mutant phe notype. This research provides new clues for further elucidating the regulation mechanism of rice senescence.
Prep your campus for the opportunity to offer Pell Grants to incarcerated students
Authors: Sutton Halley
Published: December 2022

Earlier this year, the U.S. Department of Education announced that it would reinstate Pell Grant eligibility for incarcerated students, starting with the 2023–2024 academic year, reversing a 1994 decision that barred incarcerated people from accessing Pell funds. That decision came with the passage of the Free Application for Federal Student Aid Simplification Act and will go into effect July 1, 2023. Findings by the Prison Policy Institute found that restoring Pell Grant access could make approximately 463,000 people eligible for free college courses.
Ethnobotanical notes and pharmacological overview of traditional plant: Adhatoda vasica
Authors: Biharee Avadh , Bhartiya Sudha , Dubey Dheeraj , Yadav Raju P. , Sharma Arun , Pathak Sachchidanand , Chaudhary Anu , Yadav Arpita
Published: December 2022

Background

Adhatoda vasica (Nees.) of the Acanthaceae family has excellent medicinal properties. It is a crucial ingredient in a number of formulations that have been used for decades in India to treat a wide range of health‐related difficulties, including fever, jaundice, headaches, colds, cough, whooping cough, asthma, dyspnea, phthisis, chronic bronchitis, and diarrhea. In our country (India) and other countries, the A. vasica plant has great medicinal importance. In the Ayurveda system of treatment, this plant is frequently employed.

Aim

The aim of this comprehensive study is to provide updated information on the phytochemical and pharmacological activity of A. vasica.

Objectives

The stated objectives are to collect systematic data on the botanical description, phytochemistry, pharmacology, and toxicity of A. vasica, as well as detailed information on the many formulations that have conventionally been available on the Indian market.

Method

The relevant information was obtained from a variety of peer‐reviewed journals. Google Scholar, PubMed, ScienceDirect, and SciFinder were used to retrieve the journals.

Result

A. vasica is a rich source of therapeutic agents that may have the potential to treat a variety of illnesses, while a detailed investigation of pharmacological activity is needed to confirm the contributing mechanism.

Conclusion

A. vasica is an important medicinal shrub, abundantly found across India, and a rich source of several alkaloids, terpenoids, carbohydrates, and terpenoids that may be used therapeutically in the medical system for treating a range of illnesses. It is a key ingredient in several Ayurvedic and Unani preparations available on the Indian market that are being used to treat a variety of illnesses.
Limited bedding nesting paradigm alters maternal behavior and pup's early developmental milestones but did not induce anxiety‐ or depressive‐like behavior in two different inbred mice
Authors: Pardo Grace V. E. , Alfaro Saca Eros Emanuel , Becerra Flores Christell Tatiana , Delgado Casós Walter Fares , Pacheco‐Otalora Luis F.
Published: December 2022

Animal models are crucial to understanding the mechanisms underlying the deleterious consequences of early‐life stress. Here, we aimed to examine the effect of the limited bedding nesting (LBN) paradigm on early life development milestones and anxiety‐ and/or depression‐like behavior in adolescent and adult mice from two inbred mice of both sexes. C57BL/6NCrl and BALB/c litters were exposed to the LBN paradigm postnatal day (PND) 2–9. Maternal behavior recording occurred on PND 3–9, and pups were weighed daily and examined to verify the eye‐opening on PND 10–22. The male and female offspring underwent evaluation in the open field test, elevated plus‐maze, and the forced swimming test during adolescence (PND 45–49) and adulthood (PND 75–79). We found that LBN impaired the maternal behavior patterns of both strain dams, mainly on C57BL/6NCrl strain. Also, LBN delayed the pup's eye‐opening time and reduced body weight gain, impacting C57BL/6NCrl pups more. We also found that LBN decreased anxiety‐related indices in adolescent and adult male but not female mice of both strains. Furthermore, LBN decreased depression‐related indices only adolescent female and male BALB/c and female but not male C57BL/6NCrl mice. These findings reinforce the evidence that the LBN paradigm impairs the maternal behavior pattern and pup's early developmental milestones but does not induce anxiety‐ or depressive‐like behavior outcomes during later life.
Age‐specific sensitivity analysis of stable, stochastic and transient growth for stage‐classified populations
Authors: Giaimo Stefano , Traulsen Arne
Published: December 2022

Sensitivity analysis in ecology and evolution is a valuable guide to rank demographic parameters depending on their relevance to population growth. Here, we propose a method to make the sensitivity analysis of population growth for matrix models solely classified by stage more fine‐grained by considering the effect of age‐specific parameters. The method applies to stable population growth, the stochastic growth rate, and transient growth. The method yields expressions for the sensitivity of stable population growth to age‐specific survival and fecundity from which general properties are derived about the pattern of age‐specific selective forces molding senescence in stage‐classified populations.
GHBS‐13 as an enhanced EAN‐13 barcode module for monitoring processed consumable products in Ghana
Authors: Siaw‐Yeboah Felix , Adebayo Felix Adekoya , Appiahene Peter , Weyori Benjamin Asubam
Published: December 2022

When it comes to tracking goods from manufacturers to consumers, barcodes are useful instruments for monitoring and certifying their legitimacy. Because of its capacity to self‐validate all generated codes, the EAN‐13 is the most extensively used barcode for processed consumable products. Further investigations into the construction of the EAN‐13 barcode revealed that several additional components were required to make the EAN‐13 more credible for consumer use. Country code, production code, product code, and check digit make up the present EAN‐13 format. Meanwhile, the type of product and the number of times it has been manufactured are key components that must be included in the EAN‐13 barcode structure for barcode analysts to interpret. The study presented the GHBS‐13, an upgraded barcode structure that captured the two new components, namely, the product type and production count. The paper proposed a universal method called Tabiri Check Digit as a mathematical means of easily computing the check digit of the two barcodes. The formula was validated using EAN‐13 and GHBS‐13 barcodes, and the results were correct. The study also established a central point platform for customers to use to validate processed consumable products they buy in Ghana.
Care beyond Covid
Authors: Gary Mercer
Published: December 2022

Care has become a popular topic of conversation in the context of Covid‐19. But what will it take for the value of care to be realized when the use of “care” in corporate slogans inspires cynicism or when conflicting appeals to care dilute the concept's meaning? In this brief essay, Hastings Center postdoctoral fellow Mercer Gary suggests that building helpfully on the current interest in care as an ethical value and a form of work requires strengthening the conditions that make care possible. Two projects on which Gary is collaborating at The Hastings Center concern supporting older adults in aging in place, with one demonstrating the necessity of stable housing and the other highlighting how the labor of informal care providers is often assumed, but not provided for, in aging‐in‐place initiatives.
Complex Decisions
Authors: Haupt Laura
Published: December 2022

Essays and articles in the November‐December 2022 issue of the Hastings Center Report explore the complexities of medical decision‐making. A case‐study essay, for example, argues that the dismaying decision to perform resuscitation efforts on a patient who had obviously been dead for some time can be understood in the context of the harmful practice of defensive medicine. A narrative essay concerns whether an adolescent with locked‐in syndrome should be asked her wishes about life‐sustaining interventions, and the articles illuminate the ethical value of the parental role in pediatric decision‐making, an array of ways in which patient decision‐making is interdependent, and the limitations of measures designed to evaluate the quality of a patient's decision and decision‐making process.
Critical success factors for school‐based integrated health care models: Learnings from an Australian example
Authors: Burman Charlotte , Mendoza Diaz Antonio , Leslie Andrew , Goldthorp Kristie , Jubb Brendan , Simms Aunty Ruth , Eapen Valsamma
Published: December 2022

Issues Addressed

Integrated school‐based health services have the potential to address the unmet health needs of children experiencing disadvantage, yet these models remain poorly evaluated. The current article examines an integrated social and health care hub located on the grounds of a regional Australian public primary school, the Our Mia Mia Wellbeing Hub, to identify critical success factors for this service and others like it.

Methods

Semi‐structured qualitative interviews were conducted with N = 55 multi‐sector stakeholders comprising parents, students, school staff, social and health care providers, and local Aboriginal community members. Interview transcripts were analysed according to a grounded theory approach.

Results

Six themes emerged from the analysis, reflecting important success factors for the model: service accessibility; service coordination; integration of education and health systems; trust; community partnerships; and perceptions of health.

Conclusions

Findings highlighted Our Mia Mia as a promising model of care, yet also revealed important challenges for the service as it responds to the varied priorities of the stakeholders it serves.

So What?

Through capturing the perspectives of a large number of stakeholders, the current study provides valuable insight into key challenges and success factors for Our Mia Mia; these learnings can guide the development of other emerging school‐based health services and integrated care hubs.
Predictive factors of vaccination status, knowledge, attitudes, and practice towards prevention of hepatitis B infection among Bangladeshi people: A cross‐sectional study
Authors: Hosen Ismail , Moonajilin Mst. Sabrina , Hussain Nur
Published: December 2022

Background and Aims

Infection with the hepatitis B virus is a serious public health problem that is growing all over the world. Therefore, in this context, there is no exception to public participation in disease burden reduction. Consequently, for the first time in Bangladesh, the current study aims to assess the level of vaccination status, knowledge, attitude, and practice of hepatitis B infection among general people.

Methods

A cross‐sectional study was carried out between December 15, 2021, and January 17, 2022, including sociodemographic information as well as questions about vaccination status and knowledge, attitude, and practice related to hepatitis B. Data were analyzed using descriptive (frequency) and inferential statistics (Mann–Whitney U, Kruskal–Wallis H, χ2, binary logistic regression, and spearman's rho correlation coefficient).

Results

Results indicated that about one‐third (37.9%) of the 807 participants had received hepatitis B vaccine, with an overall mean score of 11.506 ± 5.403 for knowledge, 5.435 ± 1.038 and 4.252 ± 1.776 for attitude and practice, respectively. Risk factors related to vaccination were age, religion, educational qualification, occupation, residence area, marital status, comorbidity, and family member suffering from hepatitis B. Higher level of knowledge was significantly found among the young people aged between 10 and 29; had higher secondary or tertiary education (median = 13); were employed (median = 13.5, interquartile range [IQR] = 8); living in divisional city (median = 13, IQR = 7); were single (media = 13, IQR = 7); and whose family members were suffering from hepatitis B. Besides, poor practice was observed among those aged between 50 and higher (p = 0.004), had no formal education [p < 0.001), a retired or housewife (p < 0.001), divorced or widowed (p < 0.001), absence of comorbidity (p = 0.02), and whose family members were not infected with hepatitis B (p < 0.001).

Conclusions

The results exposed that vaccination rates and preventative behavior are unsatisfactory, which will hinder efforts to eradicate hepatitis B worldwide by the year 2030.