bluuebunny/crossref_metadata_2025 huggingface dataset:
Differentiated care for youth across the HIV care cascade in Zimbabwe
Authors: Chikwari Chido Dziva , Kranzer Katharina , Simms Victoria , Patel Amani , Tembo Mandikudza , Mugurungi Owen , Sibanda Edwin , Mufare Onismo , Ndlovu Lilian , Muzangwa Joice , Vundla Rumbidzayi , Chibaya Abigail , Hayes Richard , Mackworth-Young Constance , Bernays Sarah , Mavodza Constancia , Hove Fadzanayi , Bandason Tsitsi , Dauya Ethel , Ferrand Rashida Abbas
Published: October 2023

Introduction

Youth living with HIV are at higher risk than adults of disengaging from HIV care. Differentiated models of care such as community antiretroviral therapy (ART) may improve treatment outcomes, including viral suppression.

Methods

This study was nested in a cluster-randomised controlled trial (CHIEDZA: Clinicaltrials.gov, Registration Number:NCT03719521) which was conducted in Harare, Bulawayo and Mashonaland East Provinces in Zimbabwe and aimed to investigate the impact of a youth-friendly community-based package of HIV services, integrated with sexual and reproductive health services for youth (16–24 years), on population-level HIV viral load (VL). HIV services included HIV testing, ART initiation and continuous care, VL testing, and adherence support. Coverage percentages across the HIV care cascade were analysed.

Results

Overall 377 youth were newly diagnosed with HIV at CHIEDZA, linkage to HIV care was confirmed for 265 (70.7%, 234 accessed care at CHIEDZA and 31 with other providers); 250 (94.3%) started ART. Among those starting ART at CHIEDZA attrition within 6 months of starting ART was 38% and viral suppression (<1000 copies/ml) among those who had a test at 6 months was 90%. In addition 1162 youth already diagnosed with HIV accessed CHIEDZA; 714 (61.4%) had a VL test, of those 565 (79.1%) were virally suppressed.

Conclusion

This study shows that provision of differentiated services for youth in the community is feasible. Linkage to care and retention during the initial months of ART was the main challenge as has been shown in other studies. Retention throughout the HIV-care journey for youth needs to become a priority programme goal to achieve the ambitious 95-95-95 UNAIDS targets.
Improving neglected tropical disease services and integration into primary healthcare in Southern Nations, Nationalities and People’s Region (SNNPR), Ethiopia: results from a mixed methods intervention evaluation
Authors: Donovan Laura , Habte Tedila , Batisso Esey , Getachew Dawit , Stratil Ann-Sophie , Tekalegne Agonafer , Seife Fikre , Mariam Damen , Baker Kevin
Published: October 2023

Background

Ethiopia is one of the countries with the highest burden of neglected tropical diseases (NTDs), with 16 of 20 recognised NTDs considered a public health problem, twelve of which have been identified as public health priorities by the Ethiopian Federal Ministry of Health. However, until recently NTDs have not received adequate attention at national and subnational levels in the country.

Methods

This study was conducted in Damot Gale district, Wolaita Zone in (Southern Nation Nationalities Peoples Region) SNNPR, Ethiopia and used a mixed methods approach to evaluate an intervention integrating four common NTDs (trachoma, lymphatic filariasis, schistosomiasis and podoconiosis) into Ethiopia’s primary healthcare system. The intervention consisted of adapted job aids, supportive supervision, and improved supplies of medical tools to improve diagnosis, management and reporting.

Results

found that the intervention was successful at improving the detection, management and reporting across the four common NTD’s included and had a high level of acceptance from health workers. The intervention demonstrated cost-effectiveness.

Conclusion

The findings highlight the need for further investment and consideration of integrating and scaling up NTD interventions at the primary healthcare level in Ethiopia, demonstrating that providing a package of interventions to support integration can be a cost-effective method.

Author Summary

Building on the findings of a previous small-scale operational study and formative phase, this study involved implementing an intervention to integrate the prevention, diagnosis, management and reporting of four common NTDs — trachoma, lymphatic filariasis, schistosomiasis and podoconiosis — into Ethiopia’s primary healthcare system. The intervention consisted of providing health workers with adapted job aids, supportive supervision and improved diagnostic and medical supplies to facilitate NTD diagnosis, management, and reporting. It was implemented for six months in one hospital, one health centre and five health posts in Damot Gale district, Ethiopia and the feasibility, acceptability and cost-effectiveness were evaluated. Results indicate that the capacity of all enrolled health facilities for detecting, managing, and recording target NTDs improved over time. The use of intervention materials by health workers also increased over time. The intervention tools proved to be highly acceptable to health workers who viewed them as helpful, relevant, and easy to use. The findings highlight that providing a package of interventions to support integration can be a cost-effective method and that the integration and scale of NTD interventions at the primary healthcare level in Ethiopia should be considered.
Nepeta catariaL. (catnip) can serve as a chassis for the engineering of secondary metabolic pathways
Authors: Geissler Marcus , Neubauer Christoph , Sheludko Yuriy V. , Brückner Adrian , Warzecha Heribert
Published: October 2023

Objective

Evaluation ofNepeta catariaas a host with specific endogenous metabolite background for transient expression and metabolic engineering of secondary biosynthetic sequences.

Results

The reporter geneGFP::licBM3 as well as three biosynthetic genes leading to the formation of the cannabinoid precursor olivetolic acid were adopted to the modular cloning standard GoldenBraid, transiently expressed in two chemotypes ofN. catariaand compared toNicotiana benthamiana. To estimate the expression efficiency in both hosts, quantification of the reporter activity was carried out with a sensitive and specific lichenase assay. WhileN. benthamianaexhibited lichenase activity of 676 ± 94 μmol g-1s-1(Gerasimenko et al. 2019),N. catariacultivar ‘1000’, and the cultivar ‘Citriodora’ showed an activity of 37 ± 8 μmol g-1s-1and 18 ± 4 μmol g-1s-1, respectively. Further, combinatorial expression of genes involved in cannabinoid biosynthetic pathwayacylactivating enzyme 1(aae1),olivetol synthase(ols) andolivetolic acid cyclase(oac) inN. catariacv. resulted presumably in thein vivoproduction of olivetolic acid glycosides.

Conclusion

Nepeta catariais amenable toAgrobacterium-mediated transient expression and could serve as a novel chassis for the engineering of secondary metabolic pathways and transient evaluation of heterologous genes.
Utilising an in silico model to predict outcomes in senescence-driven acute liver injury
Authors: Ashmore-Harris Candice , Antonopoulou Evangelia , Aird Rhona E. , Man Tak Yung , Finney Simon M. , Speel Annelijn M. , Lu Wei-Yu , Forbes Stuart J. , Gadd Victoria L. , Waters Sarah L.
Published: October 2023

Currently liver transplantation is the only treatment option for liver disease, but organ availability cannot meet demand and transplant recipients require lifelong immunosuppression. The identification of alternative treatments, e.g. cell therapies, able to tip resolution of injury from inflammation to regeneration requires an understanding of the host response to the degree of injury. We adopt a combinedin vivo-in silicoapproach and develop a mathematical model of acute liver disease able to predict the host response to injury. We utilise the Mdm2fl/flmouse model together with a single Cre induction through intravenous injection of the hepatotropic Adeno-associated Virus Serotype 8 Cre (AAV8.Cre) to model acute liver injury. We derive a complementary ordinary differential equation model to capture the dynamics of the key cell players in the injury response together with the extracellular matrix. We show that the mathematical model is able to predict the host response to moderate injury via qualitative comparison of the model predictions with the experimental data. We then use the model to predict the host response to mild and severe injury, and test these predictionsin vivo, obtaining good qualitative agreement.
Reduced S-acylation of SQSTM1/p62 in Huntington disease is associated with impaired autophagy
Authors: Abrar F. , Davies M.C. , Kumar A. , Dang A. , Nguyen Y.T.N. , Collins J. , Caron N. , Choudhary J.S. , Sanders S.S. , Collins M.O. , Hayden M.R. , Martin D.D.O.
Published: October 2023

Disruption of macroautophagy/autophagy has emerged as a common feature in many neurodegenerative diseases. Autophagy is a membrane-dependent pathway that requires many key regulators to quickly localize on and off membranes during induction promoting membrane fusion. Previously, our bioinformatic approaches have shown that autophagy and Huntington disease (HD) are enriched in S-acylated proteins. S-acylation involves the reversible addition of long chain fatty acids to promote membrane binding. Herein, we show that inhibition of S-acylation regulates the abundance of several key regulators of autophagy and leads to a partial block of autophagic flux. We show that the autophagy receptor SQSTM1/p62 (sequestosome 1) is S-acylated and directed to the lysosome. Importantly, we see that SQSTM1 S-acylation is significantly reduced in HD patient and mouse model brains, thus providing a novel mechanism for the generation of empty autophagosomes previously seen in HD models and patient cells.
Role of RANKL in Alveolar Epithelial Cell Regeneration: Potential Novel Contributor to Lung Tissue Repair
Authors: Habibie Habibie , Song Shanshan , Boorsma Carian E , Putri Kurnia S.S. , Reker-Smit Catharina , Vlasma Jelmer , Ruigrok Mitchel J.R. , Cool Robbert H , Wu Xinhui , Wang Yizhou , Quax Wim , Olinga Peter , Brandsma Corry-Anke , Timens Wim , Burgess Janette , Melgert Barbro N
Published: October 2023

Receptor activator for NF-κβ (RANK) ligand (RANKL) is found in lung tissue and elevated in lung diseases like chronic obstructive pulmonary disease (COPD), cystic fibrosis and silica-induced pulmonary fibrosis. RANKL is a well-known stimulator of bone tissue degradation, which may explain the association between these lung diseases and osteoporosis. However, RANKL is also reported to be involved in epithelial cell regeneration in breast and thymus. We hypothesized that RANKL, which is produced directly in lung tissue, is involved in the regeneration of lung epithelial cells. Therefore, we aimed to clarify the specific role of RANKL in this process.

Using an organoid model of lung epithelial development by co-culturing primary EpCAM+ lung epithelial cells with fibroblasts, we found higher numbers of alveolar organoids after soluble RANKL treatment compared to control. Importantly, this effect was similar in human RANKL-treated organoids derived from epithelial cells isolated from lung tissue of COPD patients. The effect of RANKL was abrogated upon addition of osteoprotegerin, the soluble inhibitor of RANKL. We also found that RANKL stimulated phosphorylation of Akt suggesting involvement of its receptor RANK in the signaling pathway. Moreover,in vivoRANKL administration resulted in more type II alveolar epithelial cells in lungs of mice with silica-induced pulmonary fibrosis.

In conclusion, we found that RANKL promotes type II alveolar epithelial cell regeneration and may therefore be a novel contributor to lung tissue repair.

New and Noteworthy

Our study provides compelling evidence demonstrating an as of yet unknown function of receptor activator for NF-κβ ligand (RANKL) in lung tissue regeneration. We found that RANKL plays a role in the regeneration of lung epithelial cells, particularly type II alveolar epithelial cells. This may also have clinical implications as promotion of alveolar epithelial cell regeneration may enhance lung tissue repair, an important target in patients with lung diseases like COPD and fibrosis.
An eco-physiological model of forest photosynthesis and transpiration under combined nitrogen and water limitation
Authors: Fransson Peter , Lim Hyungwoo , Zhao Peng , Tor-ngern Pantana , Peichl Matthias , Laudon Hjalmar , Henriksson Nils , Näsholm Torgny , Franklin Oskar
Published: October 2023

Although the separate effects of water and nitrogen (N) limitations on forest growth are well known, the question of how to predict their combined effects remains a challenge for modeling of climate change impacts on forests. Here, we address this challenge by developing a new eco-physiological model that accounts for plasticity in stomatal conductance and leaf N concentration. Based on an optimality principle, our model determines stomatal conductance and leaf N concentration by balancing carbon uptake maximization, hydraulic risk and cost of maintaining photosynthetic capacity. We demonstrate the accuracy of the model predictions by comparing them against gross primary production estimates from eddy covariance flux measurements and sap-flow scaled canopy transpiration in a long-term fertilized and an unfertilized Scots pine (Pinus sylvestrisL.) forest in northern Sweden. The model also explains the response to N fertilization as a consequence of (i) reduced carbon cost of N uptake and (ii) increased leaf area per hydraulic conductance. The results suggest that leaves optimally coordinate N concentration and stomatal conductance both on short (weekly) time scales in response to weather conditions and on longer time scales in response to soil water and N availabilities.
Histone H3 E50K mutation confers oncogenic activity and supports an EMT phenotype
Authors: Sad Kirti , Jones Celina Y , Fawwal Dorelle V , Hill Emily J , Skinner Katie , Adams Miranda , Lustenberger Severin , Lee Richard S , Lohano Sandhya V , Elayavalli Satvik R , Farhi Jonathan , Lemon Laramie D , Fasken Milo B , Hong Andrew L , Sloan Steven A , Corbett Anita H , Spangle Jennifer M
Published: October 2023

Sequencing of human patient tumors has identified recurrent missense mutations in genes encoding core histones. We report that mutations that convert histone H3 amino acid 50 from a glutamate to a lysine (H3E50K) support an oncogenic phenotype in human cells. Expression of H3E50K is sufficient to transform human cells as evidenced by a dramatic increase in cell migration and invasion, and a statistically significant increase in proliferation and clonogenicity. H3E50K also increases the invasive phenotype in the context of co-occurring BRAF mutations, which are present in patient tumors characterized by H3E50K. H3E50 lies on the globular domain surface in a region that contacts H4 within the nucleosome. We find that H3E50K perturbs proximal H3 post-translational modifications globally and dysregulates gene expression, activating the epithelial to mesenchymal transition. Functional studies usingS. cerevisiaereveal that, while yeast cells that express H3E50K as the sole copy of histone H3 show sensitivity to cellular stressors, including caffeine, H3E50K cells display some genetic interactions that are distinct from the characterized H3K36M oncohistone yeast model. Taken together, these data suggest that additional histone H3 mutations have the potential to be oncogenic drivers and function through distinct mechanisms that dysregulate gene expression.

Recurrent missense mutation that alter histone H3E50 were identified in patient tumors

H3E50K expression dysregulates global H3 post-translational modification, gene expression and may govern a transcriptional program associated with metastatic phenotypes

hht2-E50Kyeast cells exhibit growth defects in the presence of DNA damaging agents
Defining the mechanism of galectin-3-mediated TGF-β1 activation and its role in lung fibrosis
Authors: Calver Jessica F. , Parmar Nimesh R. , Harris Gemma , Lithgo Ryan M. , Stylianou Panayiota , Zetterberg Fredrik R. , Gooptu Bibek , Mackinnon Alison C. , Slack Robert J. , Carr Stephen B. , Scott David J. , Jenkins R. Gisli , John Alison E.
Published: October 2023

Integrin-mediated activation of the pro-fibrotic mediator transforming growth factor-β1 (TGF-β1), plays a critical role in idiopathic pulmonary fibrosis (IPF) pathogenesis. Galectin-3 is believed to contribute to the pathological wound healing seen in IPF individuals, although its mechanism of action is not precisely defined. We hypothesised that galectin-3 potentiates TGF-β1 activation and/or signaling in the lung to promote fibrogenesis. We show that galectin-3 induces TGF-β1 activation in human lung fibroblasts (HLFs) and specifically that extracellular galectin-3 promotes oleoyl-L-α-lysophosphatidic acid sodium salt (LPA)-induced integrin-mediated TGF-β1 activation. Surface plasmon resonance (SPR) analysis confirmed that galectin-3 binds to the αv integrins, αvβ1, αvβS and αvβ6 and also to the TGFβRII subunit in a glycosylation-dependent manner. This galectin-3 binding is heterogeneous and not a 1:1 binding stoichiometry. These binding interactions were blocked by small molecule inhibitors of galectin-3 which target the carbohydrate recognition domain. Binding of galectin-3 to the β1 integrin was validatedin vitroby co-immunoprecipitation (Co-IP) in HLFs. In addition, proximity ligation assay (PLA) data indicates that galectin-3 and the β1 integrin colocalize closely (40 nm) on the cell surface of HLFs, that colocalization is increased by TGF-β1 treatment and galectin-3 inhibitors prevented this colocalization. In the absence of TGF-β1 stimulation, such colocalization was detectable only in HLFs isolated from IPF patients suggesting that the proteins are inherently more closely associated in the disease state. Taken together, this data suggests that galectin-3 promotes TGF-β1 signaling and may induce fibrogenesis by interacting directly with components of the TGF-β1 signaling cascade.

Declaration of Interests

RGJ reports grants or contracts from AstraZeneca, Biogen, Galecto Biotech, GlaxoSmithKline, Nordic Biosciences, RedX, Plaint, consulting fees from Bristol Myers Squibb, Chiesi, Daewoong Veracyre, Resolution Therapeutics and Pliant, honoraria from Boehringer Ingelheim, Chiesi, Roche, PatientMPower, AstraZeneca, advisory roles with Boehringer Ingelheim, Galapagos and Vicore, non-financial support from NuMedii, and is a Trustee for Action for Pulmonary Fibrosis. AEJ reports grant funding from Galecto Biotech. BG reports CASE student project partnership with Galecto Biotech, honoraria from GlaxoSmithKline and Vertex and grants and fellowships from UKRI MRC and BBSRC, Alpha-1 Foundation, BLF/A+LUK, Wellcome Trust. RJS, ACM, FRZ, JFC are Galecto employees with shares/options in the company. NRP is a Roche employee. GH, RML, PS, SBC, DJS declare no competing interests.
Differential activation of mouse and human Panx1 channel variants
Authors: Cibelli Antonio , Dohare Preeti , Spray David C. , Scemes Eliana
Published: October 2023

Pannexins are ubiquitously expressed in human and mouse tissues. Pannexin 1 (Panx1), the most thoroughly characterized isoform of this family, forms plasmalemmal membrane channels permeable to relatively large molecules, such as ATP. Although human and mouse Panx1 amino acid sequences are conserved in the presently known regulatory sites involved in trafficking and modulation of the channel, differences are reported in the N- and C-termini of the protein, and the mechanisms of channel activation by different stimuli remain controversial. Here we used a neuroblastoma cell line to study the activation properties of endogenous mPanx1 and exogenously expressed hPanx1. Dye uptake and electrophysiological recordings revealed that in contrast to mouse Panx1, the human ortholog is insensitive to stimulation with high extracellular [K+] but responds similarly to activation of the purinergic P2X7 receptor. The two most frequent Panx1 polymorphisms found in the human population, Q5H (rs1138800) and E390D (rs74549886), exogenously expressed in Panx1-null N2a cells revealed that regarding P2X7 receptor mediated Panx1 activation, the Q5H mutant is a gain of function whereas the E390D mutant is a loss of function variant. Collectively, we demonstrate differences in the activation between human and mouse Panx1 orthologs and suggest that these differences may have translational implications for studies where Panx1 has been shown to have significant impact.
Bespoke single cell molecular and tissue-scale analysis reveals mechanisms underpinning development and disease in complex developing cell populations
Authors: Strauss Magdalena E , Ton Mai-Linh Nu , Mason Samantha , Bagri Jaana , Harland Luke TG , Imaz-Rosshandler Ivan , Wilson Nicola K , Nichols Jennifer , Tyser Richard CV , Göttgens Berthold , Marioni John C , Guibentif Carolina
Published: October 2023

Perturbation studies using gene knockouts have become a key tool for understanding the roles of regulatory genes in development and disease. Here we systematically characterise the knockout effects of the key developmental regulatorsTandMixl1in chimeric mouse embryos during gastrulation and organogenesis. We present a comprehensive and effective suite of statistical tools for systematic characterisation of effects at the level of differential abundance of cell types, lineage development, and gene dysregulation. Applying our computational approach to a novel chimera data set withMixl1knockout reveals a disruption in Epicardium development in the absence ofMixl1, characterized by lack of upregulation of the key transcription factorTbx18and the Wnt regulatorSfrp5, and by dysregulation of the recently identified juxta-cardiac field. Finally, we demonstrate the wider utility of our framework by applying it to published acute myeloid leukemia (AML) patient data, and show how different responses to therapy are reflected in changes in gene expression along the myeloid trajectory between healthy and AML patients.
Disrupted endosomal trafficking of the Vangl-Celsr polarity complex underlies congenital anomalies in trachea-esophageal morphogenesis
Authors: Edwards Nicole A. , Rankin Scott A. , Kashyap Adhish , Warren Alissa , Agricola Zachary N. , Kenny Alan P. , Kofron Matthew J. , Shen Yufeng , Chung Wendy K. , Zorn Aaron M.
Published: October 2023

Disruptions in foregut morphogenesis can result in life-threatening conditions where the trachea and esophagus fail to separate properly, such as esophageal atresia (EA) and tracheoesophageal fistulas (TEF). The developmental basis of these congenital anomalies is poorly understood, but recent genome sequencing reveals thatde novovariants in intracellular trafficking genes are enriched in EA/TEF patients. Here, we confirm that mutation of orthologous genes inXenopusdisrupts trachea-esophageal separation similar to EA/TEF patients. We show that the Rab11a recycling endosome pathway is required to localize Vangl-Celsr polarity complexes at the luminal cell surface where opposite sides of the foregut tube fuse. Partial loss of endosome trafficking or Vangl-Celsr complexes disrupts epithelial polarity and mutant cells accumulate at the fusion point, fail to downregulate Cadherin, and do not separate into distinct trachea and esophagus. These data provide insights into the mechanisms of congenital anomalies and general paradigms of tissue fusion during organogenesis.
Heterozygous expression of aKcnt1gain-of-function variant has differential effects on SST- and PV-expressing cortical GABAergic neurons
Authors: Shore Amy N. , Li Keyong , Safari Mona , Qunies Alshaima’a M. , Spitznagel Brittany D. , Weaver C. David , Emmitte Kyle A. , Frankel Wayne N. , Weston Matthew C.
Published: October 2023

More than twenty recurrent missense gain-of-function (GOF) mutations have been identified in the sodium-activated potassium (KNa) channel geneKCNT1in patients with severe developmental and epileptic encephalopathies (DEEs), most of which are resistant to current therapies. Defining the neuron types most vulnerable to KCNT1 GOF will advance our understanding of disease mechanisms and provide refined targets for precision therapy efforts. Here, we assessed the effects of heterozygous expression of aKcnt1GOF variant (Y777H) on KNacurrents and neuronal physiology among cortical glutamatergic and GABAergic neurons in mice, including those expressing vasoactive intestinal polypeptide (VIP), somatostatin (SST), and parvalbumin (PV), to identify and model the pathogenic mechanisms of autosomal dominantKCNT1GOF variants in DEEs. Although theKcnt1-Y777H variant had no effects on glutamatergic or VIP neuron function, it increased subthreshold KNacurrents in both SST and PV neurons but with opposite effects on neuronal output; SST neurons became hypoexcitable with a higher rheobase current and lower action potential (AP) firing frequency, whereas PV neurons became hyperexcitable with a lower rheobase current and higher AP firing frequency. Further neurophysiological and computational modeling experiments showed that the differential effects of the Y777H variant on SST and PV neurons are not likely due to inherent differences in these neuron types, but to an increased persistent sodium current in PV, but not SST, neurons. The Y777H variant also increased excitatory input onto, and chemical and electrical synaptic connectivity between, SST neurons. Together, these data suggest differential pathogenic mechanisms, both direct and compensatory, contribute to disease phenotypes, and provide a salient example of how a pathogenic ion channel variant can cause opposite functional effects in closely related neuron subtypes due to interactions with other ionic conductances.
Pseudo-linear Summation explains Neural Geometry of Multi-finger Movements in Human Premotor Cortex
Authors: Shah Nishal P. , Avansino Donald , Kamdar Foram , Nicolas Claire , Kapitonava Anastasia , Vargas-Irwin Carlos , Hochberg Leigh , Pandarinath Chethan , Shenoy Krishna , Willett Francis R , Henderson Jaimie
Published: October 2023

How does the motor cortex combine simple movements (such as single finger flexion/extension) into complex movements (such hand gestures or playing piano)? Motor cortical activity was recorded using intracortical multi-electrode arrays in two people with tetraplegia as they attempted single, pairwise and higher order finger movements. Neural activity for simultaneous movements was largely aligned with linear summation of corresponding single finger movement activities, with two violations. First, the neural activity was normalized, preventing a large magnitude with an increasing number of moving fingers. Second, the neural tuning direction of weakly represented fingers (e.g. middle) changed significantly as a result of the movement of other fingers. These deviations from linearity resulted in non-linear methods outperforming linear methods for neural decoding. Overall, simultaneous finger movements are thus represented by the combination of individual finger movements by pseudo-linear summation.
Microbiome-based risk prediction in incident heart failure: a community challenge
Authors: Erawijantari Pande Putu , Kartal Ece , Liñares-Blanco José , Laajala Teemu D. , Feldman Lily Elizabeth ,   The FINRISK Microbiome DREAM Challenge and ML4Microbiome Communities, Carmona-Saez Pedro , Shigdel Rajesh , Claesson Marcus Joakim , Bertelsen Randi Jacobsen , Gomez-Cabrero David , Minot Samuel , Albrecht Jacob , Chung Verena , Inouye Michael , Jousilahti Pekka , Schultz Jobst-Hendrik , Friederich Hans-Christoph , Knight Rob , Salomaa Veikko , Niiranen Teemu , Havulinna Aki S. , Saez-Rodriguez Julio , Levinson Rebecca T. , Lahti Leo
Published: October 2023

Heart failure (HF) is a major public health problem. Early identification of at-risk individuals could allow for interventions that reduce morbidity or mortality. The community-based FINRISK Microbiome DREAM challenge (synapse.org/finrisk) evaluated the use of machine learning approaches on shotgun metagenomics data obtained from fecal samples to predict incident HF risk over 15 years in a population cohort of 7231 Finnish adults (FINRISK 2002, n=559 incident HF cases). Challenge participants used synthetic data for model training and testing. Final models submitted by seven teams were evaluated in the real data. The two highest-scoring models were both based on Cox regression but used different feature selection approaches. We aggregated their predictions to create an ensemble model. Additionally, we refined the models after the DREAM challenge by eliminating phylum information. Models were also evaluated at intermediate timepoints and they predicted 10-year incident HF more accurately than models for 5- or 15-year incidence. We found that bacterial species, especially those linked to inflammation, are predictive of incident HF. This highlights the role of the gut microbiome as a potential driver of inflammation in HF pathophysiology. Our results provide insights into potential modeling strategies of microbiome data in prospective cohort studies. Overall, this study provides evidence that incorporating microbiome information into incident risk models can provide important biological insights into the pathogenesis of HF.
Effects of childhood and adult height on later life cardiovascular disease risk estimated through Mendelian randomization
Authors: Richardson Tom G , Urquijo Helena , Howe Laurence J , Hawkes Gareth , Frayling Timothy M , Davey Smith George
Published: October 2023

Background

Taller individuals are at elevated and protected risk of various cardiovascular disease endpoints. Whether this is due to a direct consequence of their height during childhood, a long-term effect of remaining tall throughout the lifecourse, or confounding by other factors, is unknown.

Methods

We sought to address this by harnessing human genetic data to separate the independent effects of childhood and adulthood height using an approach known as lifecourse Mendelian randomization (MR). We analysed 5 cardiovascular disease endpoints (coronary artery disease (CAD), stroke, peripheral arterial disease (PAD), atrial fibrillation (AF) and thoracic aortic aneurysm (TAA)) using findings from large-scale genome-wide consortia (n=184,305 to 1,030,836).

Results

Protective effects of taller childhood height on risk of later life CAD (OR=0.78 per change in height category, 95% CI=0.70 to 0.86, P=4×10−10) and stroke (OR=0.93, 95% CI=0.86 to 1.00, P=0.03) were found using a univariable model, although evidence of these effects attenuated in a multivariable setting upon accounting for adulthood height. In contrast, direct effects of taller childhood height on increased risk of later life AF (OR=1.61, 95% CI=1.42 to 1.79, P=5×10−7) and TAA (OR=1.55, 95% CI=1.16 to 1.95, P=0.03) were found even after accounting for adulthood height in the multivariable model.

Conclusions

The protective effect of childhood height on risk of CAD and stroke is largely attributed to the causal pathway involving adulthood height, w hich may therefore be explained by taller children typically becoming taller individuals in later life. Conversely, the independent effect of childhood height on increased risk of AF and TAA may point towards developmental mechanisms in early life which confer a lifelong risk on these disease outcomes.
BASIS: BioAnalysis SEDFIT Integrated Software for cGMP Analysis of SV-AUC Data
Authors: Yarawsky Alexander E. , Gough Erik S. , Zai-Rose Valeria , Figueroa Natalya , Cunningham Hazel M. , Burgner John W. , DeLion Michael T. , Paul Lake N.
Published: October 2023

Sedimentation velocity analytical ultracentrifugation (SV-AUC) has long been an important method for characterization of antibody therapeutics. Recently, SV-AUC has experienced a wave of new interest and usage from the gene and cell therapy industry, where SV-AUC has proven itself to be the “gold-standard” analytical approach for determining capsid loading ratios for adeno-associate virus (AAV) and other viral vectors. While other more common approaches have existed in the realm of cGMP-compliant techniques for years, SV-AUC has long been used strictly for characterization, but not for release testing. This manuscript describes the challenges faced in bringing SV-AUC to a cGMP environment and describes a new program, “BASIS”, which allows for 21 CFR Part 11-compliant data handling and data analysis using the well-known and frequently cited SEDFIT analysis software.
Effects of voltage on microstructure and properties of micro-arc oxidation ceramic coatings on AZ31B magnesium alloy under constant current–constant voltage operation mode
Authors: Shu Y.F. , Jiang B. , Wang C. , Song R.G.
Published: October 2023

Purpose

The purpose of this paper is to study the effects of voltage on microstructure and properties of micro-arc oxidation (MAO) ceramic coatings formed on AZ31B magnesium alloy under the constant current–constant voltage operation mode.

Design/methodology/approach

The wear and corrosion resistance of MAO coating on AZ31B magnesium alloy was studied by MAO in silicate electrolyte under constant current and constant voltage.

Findings

When the voltage is 360 V, the wear and corrosion resistance of AZ31B magnesium alloy is the best.

Originality/value

The wear and corrosion resistance of MAO coating on AZ31B magnesium alloy was studied by friction wear and electrochemical workstation.
An overview of legal and policy barriers to opioid analgesics access and opioid agonist therapy in Morocco
Authors: Tinasti Khalid , Outaleb Lahcen
Published: October 2023

Purpose

Through its 1922 Act on poisonous substances and more recent national normative guidance, Morocco attempts to address high prevalence of HIV among people who inject illegal opioids, and to lift legal and policy barriers to the availability of opioid-based essential controlled medicines. This paper aims to map the Moroccan opioid regulation environment, with a focus on responses to the legal and illegal markets.

Design/methodology/approach

The policy paper focuses on legal provisions for the control of opioids for pain relief and methadone for substitution therapies. It reviews existing reported data from official national, regional and international sources, studies and grey literature. It allows, by presenting the current state of affairs, to measure the limited pace of policy changes.

Findings

The authors provide a clear mapping of the laws and regulations restricting access to opioids in Morocco; the health impacts on populations; and an overall overview of institutional barriers to policy change despite more efforts such as the introduction of opioid agonist therapies.

Research limitations/implications

Due to limited available data and sources, the policy paper exploits the maximum of existing evidence from national and international sources to provide an overall review of opioid control policies in Morocco.

Originality/value

To the best of the authors’ knowledge, this policy paper is among the first to explore the legal environment of opioid use and control in Morocco, to highlight policy reforms, and to analyse the barriers to access to opioids.
Landing on Tata runway for a rapid takeoff: Air India beyond 2021
Authors: P. Rameshan
Published: October 2023

Learning outcomes

The case study highlights two strategic angles – that of the business unit (business strategy, profitability, market leadership. organizational culture, operational turnaround, industry structure and competitive dynamics) and the owner (returns, repositioning strategy and funding plan). By the end of this case study, students would be able to understand the changing competitive forces of a dynamic industry; analyse the circumstances leading to a change in the control of a firm from the state to the private sector; understand the logic of acquiring a perennially loss-making firm operating in a volatile environment without a unique strategy; identify a firm’s strategic and operational choices for financial turnaround, return to profitability and regaining market leadership; and learn about the actual strategic realities and choices confronting a troubled business organization in a difficult industry.

Case overview/synopsis

When the Tata Group took over Air India on 27 January 2022 from the state that had ownership for 68 years, Air India was under a long spell of poor performance, bleeding losses and unmanageable levels of debt. Unsatisfactory customer service, management issues and competition were the key reasons. Therefore, a crucial question facing the group’s Chairman N. Chandrasekaran was what workable strategy he could use to reposition Air India and make it profitable again so as to recover the $7.5bn of estimated investment involved in the acquisition and turnaround.

Complexity academic level

This case study is intended for undergraduate and graduate executive education levels in business administration and management and allied subjects, particularly for courses in strategic management, marketing, financial management, turnaround and transformation, mergers and acquisitions and organizational change.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CSS 11: Strategy.
Can an arms race promote stability? The inter-Korean qualitative arms race and US extended deterrence
Authors: Rim Hyun Ji
Published: October 2023

Purpose

This paper aims to provide a case study of complex conflict management within the arms race on the Korean Peninsula. Exploring the complex nexus of nuclear weapons, asymmetry and a qualitative arms race, the study explains how the arms race between Seoul and Pyongyang has promoted stability on the Korean Peninsula.

Design/methodology/approach

Presenting the limits of arguments that the US security guarantee is the factor that saved the two Koreas from going to war again, this paper explores the utility of the inter-Korean arms race as a stabilizer that promotes indirect negotiations. While presenting Korean anomalies, this paper analyzes the three stages of the inter-Korean arms race – especially its nuclear weapons, its asymmetry and the nature of arms races – and provides extant explanations on the causes and consequences of the qualitative arms race. These key elements drive the states’ strategic motives.

Findings

Using the case of the inter-Korean qualitative arms race and US extended nuclear deterrence on the Korean Peninsula, the study shows the complexities of conflict management today. This paper identifies three contributing factors – US nuclear weapons, asymmetry and the qualitative characteristic of the arms race – to explain the enduring stability on the peninsula despite the arms race’s intensification. The paper finds that although US nuclear-extended deterrence plays a critical role, it does not capture the full context of the ongoing, dynamic inter-Korean arms race; a prolonged arms race between the two Koreas has become a new regularity; the qualitative characteristic of the inter-Korean arms race, which is driven by technological advancement, contributes to stability in the arms race; and as the constant mismatch in priority technologies becomes more severe, the changes to the existing asymmetry could increase instability.

Originality/value

This paper offers a diverse perspective to the literature on conflict management and captures the complexities of 21st-century conflict management. Through a thorough examination of the inter-Korean arms race, it brings readers’ attention to the nested dynamics within the arms race and shows how an intensifying arms race can promote stability. Furthermore, the paper explains the implications for potential instability – fueled by the comprehensive mix of a dynamic qualitative arms race and the US extended nuclear deterrence – in the Indo-Pacific region.
Role of empowering leadership as a mediator between HPWPs and Gen Y employee engagement: evidence from Indian hotels
Authors: Singh Rakhi , Sihag Priyanka
Published: October 2023

Purpose

This study evaluated the bundled impact of high performance work practices (HPWPs) on Generation Y (Gen Y) employee engagement (EE) while considering empowering leadership (EL) as a mediator.

Design/methodology/approach

The data for the study are received from 404 Gen Y frontline service employees from three to five star Indian hotels and examined using structural equation modeling.

Findings

Gen Y employees' perception of HPWPs directly explains their engagement, and EL partially mediates the link between HPWPs and Gen Y EE.

Research limitations/implications

This study suggests managers to gain from implementing HPWPs and their impact on Gen Y engagement to boost their organizational performance.

Practical implications

This study suggests managers to gain from implementing HPWPs and their impact on Gen Y EE to boost their employee and hotel's performance.

Originality/value

The present research is one of the few attempts to study how HPWPs can engage the Gen Y cohort in the workplace, especially in developing countries (i.e. India).
Three-way interaction moderation model of legal origin in strengthening the role of firm characteristics in choice of sukuk type
Authors: Utami Datien Eriska
Published: October 2023

Purpose

This study aims to learn how a three-way interaction moderation model is used to analyse the role of country-specific characteristics, in the form of the implementation of Sharia law and legal origin in a particular country, in the choice of sukuk type.

Design/methodology/approach

The firm profitability and firm leverages of sukuk issuer are used as the firm characteristics that can influence the choice of sukuk type between Mudharaba sukuk, Ijara sukuk and Murabaha sukuk. The research sample of 545 global sukuk issuances, obtained from the IIFS database, includes the issuance of Mudharaba sukuk, Ijara sukuk and Murabaha sukuk from ten sukuk issuer countries all over the world.

Findings

The research results show that the probability of choosing Mudharaba and Ijara sukuk is found in issuers sukuk with a high firm leverage, while the probability of choosing Murabaha sukuk is found in issuers sukuk with a high firm profitability. A three-way interaction moderation model is used in this research to explain that sukuk issuers in countries that implement Sharia law and adopt a legal origin common law system will have a higher choice of Mudharabah and Ijarah sukuk types if the firm’s leverage is high. If the firms’ profitability is high, then the sukuk issuer prefers Murabaha sukuk.

Research limitations/implications

The use of firm’s characteristic variables is based solely on trade-off theory and pecking order theory. Also, limitations on the implementation of Sharia law in countries that do not provide opportunities for countries that apply a mixed law system.

Practical implications

The role of Sharia law and common law legal origin is proven, through a three-way interaction model, to strengthen the interaction of the firm leverage and choice of Mudharaba sukuk.

Social implications

Legal certainty for Islamic financial institutions is created in the context of ease of investing in sukuk. Flexibility in the structure is also one of the factors that encourage the development of market acceptance of sukuk. The right structure of the sukuk can be used for specific target markets.

Originality/value

There has been no study carried out on a three-way interaction moderation model used to analyse the role of country-specific characteristics. The role of Sharia law and common law legal origin is proven, through a three-way interaction model, to strengthen the interaction of the firm leverage and choice of Mudharaba sukuk.
Competition or cooperation? Exploring the impact of dominant modes on the competitive relationship in CLSC
Authors: Jian Jie , Yang Xingyu , Niu Shu , Su Jiafu
Published: October 2023

Purpose

The paper proposes a two-level closed-loop supply chain (CLSC) dynamic competitive model based on different competitive cooperation situations, and explores the impact of competitive cooperation methods on the pricing strategies, recycling and remanufacturing strategies and competitive model selection strategies of supply chain firms.

Design/methodology/approach

This paper establishes a CLSC game consisting of a manufacturer and two retailers. Firstly, five CLSC models are established in both horizontal and vertical dimensions, each of which competes with one another. Secondly, the recycling and remanufacturing pricing strategies are analyzed under different competition or cooperation models. Finally, the results are verified through numerical analysis.

Findings

The overall profitability of the CLSC is highest when the manufacturer–retailer partnership alliance is in place. The relationship between retailers and manufacturers is also found to be the best way to achieve overall optimization of the CLSC.

Originality/value

The paper investigates the relationship between the competitive partnership and the total profit of the CLSC, taking into account how to optimize the overall benefit, and focusing on how to optimize the individual interests of each participating enterprise. The results can provide basis and guidance for managers' pricing decision and competition cooperation.
Health-care leaders’ and professionals’ experiences and perceptions of compassionate leadership: A mixed-methods systematic review
Authors: Östergård Kevin , Kuha Suvi , Kanste Outi
Published: October 2023

Purpose

The purpose of this study is to identify and synthesise the best evidence on health-care leaders’ and professionals’ experiences and perceptions of compassionate leadership.

Design/methodology/approach

A mixed-methods systematic review was conducted in accordance with the Joanna Briggs Institute methodology for mixed-methods systematic reviews using a convergent integrated approach. A systematic search was done in January 2023 in PubMed, CINAHL, Scopus, Medic and MedNar databases. The results were reported based on Preferred Reporting Items for Systematic Reviews and Meta-analyses. The data was analysed using thematic analysis.

Findings

Ten studies were included in the review (five qualitative and five quantitative). The thematic analysis identified seven analytical themes as follows: treating professionals as individuals with an empathetic and understanding approach; building a culture for open and safe communication; being there for professionals; giving all-encompassing support; showing the way as a leader and as a strong professional; building circumstances for efficient work and better well-being; and growing into a compassionate leader.

Practical implications

Compassionate leadership can possibly address human resource-related challenges, such as health-care professionals’ burnout, turnover and the lack of patient safety. It should be taken into consideration by health-care leaders, their education and health-care organisations when developing their effectiveness.

Originality/value

This review synthesised the knowledge of compassionate leadership in health care and its benefits by providing seven core elements of health-care leaders’ and professionals’ experiences and perceptions of compassionate leadership.