bluuebunny/crossref_metadata_2025 huggingface dataset:
The CALCIPHYX study: a randomized, double-blind, placebo-controlled, Phase 3 clinical trial of SNF472 for the treatment of calciphylaxis
Authors: Sinha Smeeta , Gould Lisa J , Nigwekar Sagar U , Serena Thomas E , Brandenburg Vincent , Moe Sharon M , Aronoff George , Chatoth Dinesh K , Hymes Jeffrey L , Miller Stephan , Padgett Claire , Carroll Kevin J , Perelló Joan , Gold Alex , Chertow Glenn M
Published: July 2021

Background

Calcific uraemic arteriolopathy (CUA; calciphylaxis) is a rare disease seen predominantly in patients receiving dialysis. Calciphylaxis is characterized by poorly healing or non-healing wounds, and is associated with mortality, substantial morbidity related to infection and typically severe pain. In an open-label Phase 2 clinical trial, SNF472, a selective inhibitor of vascular calcification, was well-tolerated and associated with improvement in wound healing, reduction of wound-related pain and improvement in wound-related quality of life (QoL). Those results informed the design of the CALCIPHYX trial, an ongoing, randomized, placebo-controlled, Phase 3 trial of SNF472 for treatment of calciphylaxis.

Methods

In CALCIPHYX, 66 patients receiving haemodialysis who have an ulcerated calciphylaxis lesion will be randomized 1:1 to double-blind SNF472 (7 mg/kg intravenously) or placebo three times weekly for 12 weeks (Part 1), then receive open-label SNF472 for 12 weeks (Part 2). All patients will receive stable background care, which may include pain medications and sodium thiosulphate, in accordance with the clinical practices of each site. A statistically significant difference between the SNF472 and placebo groups for improvement of either primary endpoint at Week 12 will demonstrate efficacy of SNF472: change in Bates-Jensen Wound Assessment Tool-CUA (a quantitative wound assessment tool for evaluating calciphylaxis lesions) or change in pain visual analogue scale score. Additional endpoints will address wound-related QoL, qualitative changes in wounds, wound size, analgesic use and safety.

Conclusions

This randomized, placebo-controlled Phase 3 clinical trial will examine the efficacy and safety of SNF472 in patients who have ulcerated calciphylaxis lesions. Patient recruitment is ongoing.
Central and peripheral sympathetic activation in heart failure
Authors: Grassi Guido , Mancia Giuseppe , Esler Murray
Published: July 2021

The sympathetic nervous system overdrive occurring in heart failure has been reported for more than half a century. Refinements in the methodological approaches to assess human sympathetic neural function have allowed during recent years to better define various aspects related to the neuroadrenergic alteration. These include (i) the different participation of the individual regional sympathetic cardiovascular districts at the process, (ii) the role of the central nervous system in determining the neuroadrenergic overdrive, (iii) the involvement of baroreflex, cardiopulmonary reflex, and chemoreflex mechanisms in the phenomenon, which is also closely linked to inflammation and the immune reaction, (iv) the relationships with the severity of the disease, its ischaemic or idiopathic nature and the preserved or reduced left ventricular ejection fraction, and (v) the adverse functional and structural impact of the sympathetic activation on cardiovascular organs, such as the brain, the heart, and the kidneys. Information have been also gained on the active role exerted by the sympathetic activation on the disease outcome and its potential relevance as a target of the therapeutic interventions based on non-pharmacological, pharmacological, and invasive approaches, including the renal denervation, the splanchnic sympathetic nerve ablation, and the carotid baroreflex stimulation. The still undefined aspects of the neurogenic alterations and the unmet goals of the therapeutic approach having the sympathetic activation as a target of the intervention will be finally mentioned.
Intimal aortic atherosclerosis in cardiac surgery: surgical strategies to prevent embolic stroke
Authors: Knol Wiebe G , Budde Ricardo P J , Mahtab Edris A F , Bekkers Jos A , Bogers Ad J J C
Published: July 2021

OBJECTIVES

Although the incidence of perioperative stroke after cardiac surgery gradually decreased over the last decades, there is much variation between centres. This review aimed to create a concise overview of the evidence on possible surgical strategies to prevent embolic stroke in patients with intimal aortic atherosclerosis.

METHODS

The PubMed and EMBASE databases were searched for studies on surgical management of aortic atherosclerosis and the association with perioperative stroke in cardiac surgery, including specific searches on the most common types of surgery. Articles were screened with emphasis on studies comparing multiple strategies and studies reporting on the patients’ severity of aortic atherosclerosis. The main findings were summarized in a figure, with a grade of the corresponding level of evidence.

RESULTS

Regarding embolic stroke risk, aortic atherosclerosis of the tunica intima is most relevant. Although several strategies in general cardiac surgery seem to be beneficial in severe disease, none have conclusively been proven most effective. Off-pump surgery in coronary artery bypass grafting should be preferred with severe atherosclerosis, if the required expertise is present. Although transcatheter aortic valve replacement is used as an alternative to surgery in patients with a porcelain aorta, the risk profile concerning intimal atherosclerosis remains poorly defined.

CONCLUSIONS

A tailored approach that uses the discussed alternative strategies in carefully selected patients is best suited to reduce the risk of perioperative stroke without compromising other outcomes. More research is needed, especially on the perioperative stroke risk in patients with moderate aortic atherosclerosis.
Grading in Hungarian Primary Schools: Mechanisms of Ethnic Discrimination against Roma Students
Authors: Kisfalusi Dorottya , Janky Béla , Takács Károly
Published: July 2021

The present study aims to shed light on the mechanisms of ethnic discrimination in teacher assessments in Hungarian primary schools. For this purpose, we use data collected among Roma minority and non-Roma majority students. First, we identify a considerable ethnic difference in non-blind school grades, which is beyond the ethnic difference in blind standardized test scores. Then, we derive and empirically test predictions from different theories of discrimination that might explain the ethnic difference in grades. We find that stereotype-based theories of discrimination do not explain why minority students receive lower grades than majority students. We do not exclude the possibility that taste-based discrimination exists among teachers against Roma students. A considerable part of ethnic discrimination, however, is explained by teachers’ indirectly discriminatory grading practices: Roma students’ school behaviour is evaluated more negatively by teachers than that of non-Roma students and school behaviour seems to be taken into account in grading without legitimate justification. This practice does not only disadvantage Roma students, but boys and low status students as well.
Serratia marcescens SCH909 as reservoir and source of genetic elements related to wide dissemination of antimicrobial resistance mechanisms
Authors: Gambino Anahí S , Déraspe Maxime , Álvarez Verónica E , Quiroga María Paula , Corbeil Jacques , Roy Paul H , Centrón Daniela
Published: July 2021

Serratia marcescens SCH909 is a multidrug resistant strain isolated in 1988 harboring three class 1 integrons. We wondered if these integrons were retained over time and if there were other antimicrobial resistant determinants contributing to its multidrug resistant profile. Genomic analysis showed a fourth multidrug resistance integron, a Tn7 transposon with dfrA1-sat2-ybeA-ybfA-ybfB-ybgA gene cassettes in the variable region. Insertion sequences were involved in the genesis of novel composite transposons in the L4 subtype plasmid pSCH909, such as Tn6824 carrying an arsenic regulon and two head to head class 1 integrons surrounded by two complete IS1. Remarkably, a novel chromosomal genomic island, SmaR, was identified, closely related to Multiple Antimicrobial Resistance Regions (MARR), usually found in AbaR0-type and AbGRI2-0 from global clones of Acinetobacter baumannii, and in M-type plasmids circulating in Enterobacteriaceae. Maintenance studies showed that the three class 1 integrons were maintained over 1 month without antimicrobial pressure. Since S. marcescens is considered a relevant nosocomial pathogen that can have a wide range of niches – human, plant, animal, soil and inanimate surfaces, our findings support the ability of this species to capture, maintain and spread a broad variety of antimicrobial resistance elements.
Behavior ofSalmonellaEnteritidis andShigella flexneriduring induction and recovery of the viable but nonculturable state
Authors: Oliveira Mayara Messias , de Almeida Felipe Alves , Baglinière François , de Oliveira Leandro Licursi , Vanetti Maria Cristina Dantas
Published: July 2021

Bacteria may enter into a viable but nonculturable (VBNC) state as a response to stresses, such as those found in food processing. Cells in the VBNC state lose the ability to grow in a conventional culture medium but man recover culturability. The viability, culturability and intracellular reactive oxygen species (ROS) of Salmonella Enteritidis and Shigella flexneri were evaluated under stress conditions to induce a VBNC state. Cells were maintained under nutritional, osmotic and cold stresses (long-term induction) in Butterfield's phosphate solution plus 1.2 M of NaCl at 4°C and under nutritional and oxidative stresses (short-term induction) in 10 mM of H2O2. Culture media, recovery agents, sterilization methods of media and incubation temperature, were combined and applied to recover the culturability of the VBNC cells. Salmonella entered in the VBNC state after 135 days under long-term induction, while Shigella maintained culturability after 240 days. Under short-term induction, Salmonella and Shigella lose culturability after 135 and 240 min, respectively. Flow cytometric analysis revealed viable cells and intracellular ROS in both species in VBNC. It was not possible to recover the culturability of VBNC cells using the 42 combinations of different factors.
Mitochondrial pyruvate carrier regulates the lignocellulosic decomposition rate through metabolism in Ganoderma lucidum
Authors: Xu Wenzhao , Fan Junpei , Wang Yihong , Wang Yunxiao , Zhu Jing , Ren Ang , Yu Hanshou , Shi Liang , Zhao Mingwen
Published: July 2021

The activity of mitochondrial pyruvate carrier (MPC) can be modulated to regulate intracellular metabolism under different culture conditions. In Ganoderma lucidum, the role of MPC in regulating carbon sources remains unknown. By knocking down MPC genes (MPC1 and MPC2), this research found that the loss of MPC increased the growth rate of G. lucidum by ~30% in a medium with wood chips as a carbon source. Then cellulase and laccase activities were tested. Endoglucanase and laccase activity increased by ~50% and ~35%, respectively, in MPC knockdown mutants compared with that in the wild type strain. Finally, the expression levels of genes related to glycolysis were assayed, and the transcription levels of these enzymes were found to be increased by ~250% compared with the wild type strain. In conclusion, the regulation of intracellular metabolism by MPC provides a new way to improve the use of nondominant carbon sources such as lignocellulose.
Metabolites of the oral microbiome: important mediators of multikingdom interactions
Authors: Barbour Abdelahhad , Elebyary Omnia , Fine Noah , Oveisi Morvarid , Glogauer Michael
Published: July 2021

The oral cavity hosts over 700 different microbial species that produce a rich reservoir of bioactive metabolites critical to oral health maintenance. Over the last two decades, new insights into the oral microbiome and its importance in health and disease have emerged mainly due to the discovery of new oral microbial species using next-generation sequencing. This advancement has revolutionized the documentation of unique microbial profiles associated with different niches and health/disease states within the oral cavity and the relation of the oral bacteria to systemic diseases. However, less work has been done to identify and characterize the unique oral microbial metabolites that play critical roles in maintaining equilibrium between the various oral microbial species and their human hosts. This article discusses the most significant microbial metabolites produced by these diverse communities of oral bacteria that can either foster health or contribute to disease. Finally, we shed light on how advances in genomics and genome mining can provide a high-throughput platform for discovering novel bioactive metabolites derived from the human oral microbiome to tackle emerging infectious and systemic diseases.
Association of Vascular Risk Scores and Cognitive Performance in a Diverse Cohort: The Multi-Ethnic Study of Atherosclerosis
Authors: Schaich Christopher L , Yeboah Joseph , Espeland Mark A , Baker Laura D , Ding Jingzhong , Hayden Kathleen M , Sachs Bonnie C , Craft Suzanne , Rapp Stephen R , Luchsinger José A , Fitzpatrick Annette L , Heckbert Susan R , Post Wendy S , Burke Gregory L , Allen Norrina B , Hughes Timothy M
Published: July 2021

Background

Vascular risk scores are associated with incident dementia. Information regarding their association with cognitive performance and decline in racially/ethnically diverse cohorts is lacking.

Method

In 4 392 Multi-Ethnic Study of Atherosclerosis participants (aged 60.1 ± 9.4 years; 53% women; 41% White, 11% Chinese American, 26% African American, 21% Hispanic), we compared associations of Exam 1 (2000–2002) Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham Stroke Risk Profile (FSRP), and atherosclerotic cardiovascular disease pooled cohort equation (ASCVD-PCE) risk scores with Exam 5 (2010–2012) Cognitive Abilities Screening Instrument (CASI), Digit Symbol Coding (DSC), and Digit Span (DS) cognitive test performance using multivariable linear regression, and examined racial/ethnic interactions. In 1 838 participants with repeat CASI data at Exam 6 (2016–2018), we related risk scores to odds of a 1-SD decline in CASI performance using multivariable logistic regression.

Results

SD increments in each risk score were associated with worse cognitive performance. CAIDE had stronger associations with CASI performance than the FSRP and ASCVD-PCE, but associations of ASCVD-PCE with the DSC and DS were similar to CAIDE (difference in β [95% CI] = −0.57 [−1.48, 0.34] and −0.21 [−0.43, 0.01], respectively). Race/ethnicity modified associations. For example, associations between CAIDE and CASI were greater in African Americans and Hispanics than in Whites (difference in β = 0.69 [0.02, 1.36] and 1.67 [0.95, 2.39], respectively). Risk scores were comparably associated with decline in CASI performance.

Conclusions

Antecedent vascular risk scores are associated with cognitive performance and decline in the 4 most common U.S. racial/ethnic groups, but associations differ among risk scores and by race/ethnicity.
Is Reliance on the Affect Heuristic Associated With Age?
Authors: Nolte Julia , Löckenhoff Corinna E
Published: July 2021

Objectives

With age, decision makers rely more on heuristic and affect-based processing. However, age differences have not been quantified with respect to the affect heuristic, which derives judgments based on positive and negative feelings toward stimuli and concepts. This study examined whether reliance on the affect heuristic is associated with age, whether these patterns vary by task type, and which covariates account for age effects.

Method

In a preregistered study, an adult life-span sample (N = 195, 21–90 years, Mage = 52.95, 50% female, 71% non-Hispanic White) completed a battery of cognitive, personality, and socioemotional covariates as well as 3 established affect heuristic tasks: (a) a risk–benefit task, (b) a dread–inference task, and (c) an affect–impact task. Reliance on affect was indexed through (a) a negative relationship between perceived food risks and benefits, (b) a positive relationship between feelings of dread and statistical inferences about mortality risks, and (c) a positive relationship between affective responses and impact judgments when evaluating catastrophes.

Results

For all 3 tasks, usage of the affect heuristic was documented at the group and the individual levels. Contrary to hypotheses, age was not associated with affect heuristic use for any of the tasks. Affect heuristic indices did not correlate across tasks and showed no consistent associations with the covariates.

Discussion

Results suggest that the use of affect-based heuristics is context- or stimulus-dependent rather than a stable, age-associated trait. Further research is needed to validate the present results across additional domains, tasks, and stimulus types.
Culturally based coping with COVID-19 pandemic: using constructive roles of the spiritual systems with appropriate function
Authors: Omidvari Sepideh
Published: July 2021

Considering the global number of confirmed COVID-19 cases and deaths, it is not strange that COVID-19 disease is a reminiscent of concepts such as death and affliction with a serious disease. Furthermore, it might remind people of issues such as the reason(s) for occurrence of deplorable events in the universe, the meaning of life, individuals’ duties toward themselves and others, the relationship between the nature and human beings, and individuals’ relationship with a higher being (in case there is a belief in a higher being), i.e. the subjects spirituality deals with. The constructive or destructive role of each of religious and non-religious spiritual systems at the time of crises are observed more clearly than ever. The present paper addresses roles which spiritual systems might play in facing the COVID-19 disease crisis, considering different areas of spiritual well-being and the possibility that spiritual systems might be affected by perceived challenges during a pandemic. Because of the problems interfering with overcoming COVID-19 pandemic and the risk of next waves of its epidemics and pandemics, it is necessary for health policy-makers to use all available capacities and capabilities to counteract the disease, including using both internal motivations (such as spiritual beliefs which prohibit hurting oneself and others and which emphasize performing social responsibilities) and external ones (e.g. regulations) to cope with it. It makes sense for public health officials in different countries to use more actively the potential of those spiritual systems that support COVID-19 public health recommendations, as a culturally based intervention and policy.
Balanced harvest as a potential management strategy for tropical small-scale fisheries
Authors: Pelage Latifa , Bertrand Arnaud , Ferreira Beatrice Padovani , Lucena-Frédou Flávia , Justino Anne K S , Frédou Thierry
Published: July 2021

Tropical small-scale fisheries (SSFs) are characterised by their multidimensionality (fleets, gears, habitats, and species). As many targeted species move between habitats throughout their life cycle, managing coexisting fleets exploiting the same resource is challenging. However, the SSFs operating over multiple habitats target a variety of species and sizes and could benefit from a management strategy such as balanced harvest (BH)—harvesting all species and sizes in proportion to their production rate. To test this hypothesis, we characterised the fishing pattern (distribution of overall fishing pressure on species and sizes) of northeast Brazil SSFs targeting migratory species along an estuarine-shelf break gradient. Specifically, we described the relative captures by gear type and developed a conceptual model to understand fishers’ strategies. All ontogenetic classes of the twelve selected species were caught along the estuary-shelf break gradient, achieving a fishing pattern in line with BH. Young individuals and low trophic level species predominated in most gears. In that context, size limitations would not be sufficient to prevent overfishing and could prejudice the fleets that target small sizes. An ecosystem-based approach like BH, aiming to regulate the overall fishing pressure and consistent with the existing fishing pattern, should instead be promoted.
Making Sense of Patient-Derived iPSCs, Transdifferentiated Neurons, Olfactory Neuronal Cells, and Cerebral Organoids as Models for Psychiatric Disorders
Authors: Unterholzner Jakob , Millischer Vincent , Wotawa Christoph , Sawa Akira , Lanzenberger Rupert
Published: July 2021

The improvement of experimental models for disorders requires a constant approximation towards the dysregulated tissue. In psychiatry, where an impairment of neuronal structure and function is assumed to play a major role in disease mechanisms and symptom development, this approximation is an ongoing process implicating various fields. These include genetic, animal, and post-mortem studies. To test hypotheses generated through these studies, in vitro models using non-neuronal cells such as fibroblasts and lymphocytes have been developed. For brain network disorders, cells with neuronal signatures would, however, represent a more adequate tissue. Considering the limited accessibility of brain tissue, research has thus turned towards neurons generated from induced pluripotent stem cells as well as directly induced neurons, cerebral organoids, and olfactory neuroepithelium. Regarding the increasing importance and amount of research using these neuronal cells, this review aims to provide an overview of all these models to make sense of the current literature. The development of each model system and its use as a model for the various psychiatric disorder categories will be laid out. Also, advantages and limitations of each model will be discussed, including a reflection on implications and future perspectives.
The perceptions of informal carers of older people with dementia about the role of their pharmacists
Authors: El-Saifi Najwan N F , Moyle Wendy , Jones Cindy J , Tuffaha Haitham W A
Published: July 2021

Objectives

As medication experts, pharmacists can play a significant role in helping people living with dementia and their informal carers make the best use of medications. However, little is known about this population’s needs and expectations of their pharmacists. The objective of this study was to report informal carers’ perceptions about the role of their pharmacists.

Methods

In a previous study, informal carers were interviewed to explore factors influencing medication adherence in older people living with dementia. The interview transcripts from the previous study were analysed thematically using an inductive approach to explore carers’ perceptions about the role of community pharmacists in helping carers and people living with dementia use medications as prescribed.

Key findings

The interviews of 20 informal carers were analysed. Carers were primarily females (85%), married (60%), completed university (60%) and unemployed (70%). The majority of care recipients had comorbidities (75%), and the number of medications ranged from 1 to 20. Three significant roles emerged: (1) provision of medication information, (2) advising on medication organisation and (3) conducting medication reviews.

Conclusions

Informal carers face several challenges in administering the medications to older people living with dementia. Pharmacists are expected to play a more active role in helping people living with dementia, and their carers make safe and effective use of medications.
Factors Predicting Blood Culture Positivity in Children With Enteric Fever
Authors: Srinivasan Manikandan , Sindhu Kulandaipalayam Natarajan , Ramanujam Karthikeyan , Ramasamy Ranjith Kumar , Subramaniam Sathyapriya , Ganesan Santhosh Kumar , Vajja Swathi , David Anita Shirley , Lankala Pramitha , Rose Winsley , Moses Prabhakar D , Grassly Nicholas C , Kang Gagandeep , John Jacob
Published: July 2021

Background

Blood culture, despite low sensitivity, is the gold standard for enteric fever diagnosis. Understanding predictors of blood culture positivity may help design strategies to optimize enteric fever diagnosis.

Methods

A cohort of 6760 children aged 0.5–15 years was followed for 3 years for enteric fever with blood cultures in an automated system, for fevers >3 days. Factors affecting test positivity in fevers and participant-level predictors for culture refusals were analyzed using regression models.

Results

Overall, 6097 suspected typhoid/paratyphoid fever (STF) episodes were reported, of which 5703 (93.5%) STFs had sampling for blood cultures, with 394 (6.5%) refusals. Salmonella enterica serovar Typhi/Paratyphi positivity was culture-confirmed in 3.8% (218/5703) of STF episodes. Older children (odds ratio [OR], 1.96 [95% CI, 1.39–2.77]), larger blood volume inoculated (OR, 2.82 [95% CI, 1.71–4.66]), higher temperatures during fever (OR, 3.77 [95% CI, 2.89–4.91]), and fevers diagnosed as suspected typhoid or acute undifferentiated fever (OR, 6.06 [95% CI, 3.11–11.78]) had a higher probability of culture positivity. Antibiotics before culture did not decrease culture positivity. Blood culture refusals were higher for children from wealthier households or with milder illness.

Conclusions

Performing blood cultures in older children with fever, especially those fevers with toxic presentation and increasing blood volume for inoculation are strategies to improve enteric fever detection in surveillance settings.
Conceptualizing equidistant diplomacy in international relations: the case of Singapore
Authors: Teo Ang Guan , Koga Kei
Published: July 2021

How can we systematically conceptualize equidistant diplomacy? This article argues that while ‘equidistant diplomacy’ has its own tactical utility to signal and shape a state’s image of political neutrality to the target states, it is not indicative of the state strategy. This is because state strategy is generally determined by material capabilities and is categorized as balancing, bandwagoning, and hedging. Rather, equidistant diplomacy is perception managementmerely an independent diplomatic tactic aimed at signaling a neutral image through three main tools: paralleling, downplaying, and broadcasting. This diplomatic tactic is most likely to be part of ‘hedging’ behavior. However, states can similarly employ equidistant diplomacy for balancing or bandwagoning if they desire to project a neutral image and their target states do not force them to alter this tactic with diplomatic or material sanctions. With this conceptual framework, Singapore’s diplomatic behavior vis-a-vis the United States and China from the 1990s will be examined.
Do cross-polity contacts change policy preferences? Using the attitudes of Taiwanese student delegations visiting Mainland China towards unification–independence as an example
Authors: Wang Chia-Chou
Published: July 2021

Does the experience of visiting Mainland China change the attitude of Taiwanese youth towards the unification–independence issue? What are the factors influencing such a change, if any? In this article, a panel study was conducted of 538 Taiwanese youths visiting Mainland China. Four hypotheses were proposed based on social contact theory and rational choice theory and then validated using a regression model. After visiting Mainland China, 17.57% and 15.89% of the Taiwanese students shifted to support for unification and independence respectively, whereas 66.54% indicated no changes in their stance. They increasingly favored unification with an improved impression of Mainland China, reduced hostility, increased willingness to integrate into China, and a decline in their evaluation of Taiwan’s democracy. These findings corroborated the effects of true acquaintances, casual contacts, and the maximization of self-interest advocated by theories of social contact and rational choice.
Prevalence of gp160 polymorphisms known to be related to decreased susceptibility to temsavir in different subtypes of HIV-1 in the Los Alamos National Laboratory HIV Sequence Database
Authors: Gartland Margaret , Arnoult Eric , Foley Brian T , Lataillade Max , Ackerman Peter , Llamoso Cyril , Krystal Mark
Published: July 2021

Background

Fostemsavir, a prodrug of the gp120-directed attachment inhibitor temsavir, is indicated for use in heavily treatment-experienced individuals with MDR HIV-1. Reduced susceptibility to temsavir in the clinic maps to discrete changes at amino acid positions in gp160: S375, M426, M434 and M475.

Objectives

To query the Los Alamos National Laboratory (LANL) HIV Sequence Database for the prevalence of polymorphisms at gp160 positions of interest.

Methods

Full-length gp160 sequences (N = 7560) were queried for amino acid polymorphisms relative to the subtype B consensus at positions of interest; frequencies were reported for all sequences and among subtypes/circulating recombinant forms (CRFs) with ≥10 isolates in the database.

Results

Among 239 subtypes in the database, the 5 most prevalent were B (n = 2651, 35.1%), C (n = 1626, 21.5%), CRF01_AE (n = 674, 8.9%), A1 (n = 273, 3.6%) and CRF02_AG (n = 199, 2.6%). Among all 7560 sequences, the most prevalent amino acids at positions of interest (S375, 73.5%; M426, 82.1%; M434, 88.2%; M475, 89.9%) were the same as the subtype B consensus. Specific polymorphisms with the potential to decrease temsavir susceptibility (S375H/I/M/N/T/Y, M426L/P, M434I/K and M475I) were found in <10% of isolates of subtypes D, G, A6, BC, F1, CRF07_BC, CRF08_BC, 02A, CRF06_cpx, F2, 02G and 02B. S375H and M475I were predominant among CRF01_AE (S375H, 99.3%; M475I, 76.3%; consistent with previously reported low temsavir susceptibility of this CRF) and 01B (S375H, 71.7%; M475I, 49.5%).

Conclusions

Analysis of the LANL HIV Sequence Database found a low prevalence of gp160 amino acid polymorphisms with the potential to reduce temsavir susceptibility overall and among most of the common subtypes.
Bias and fairness assessment of a natural language processing opioid misuse classifier: detection and mitigation of electronic health record data disadvantages across racial subgroups
Authors: Thompson Hale M , Sharma Brihat , Bhalla Sameer , Boley Randy , McCluskey Connor , Dligach Dmitriy , Churpek Matthew M , Karnik Niranjan S , Afshar Majid
Published: July 2021

Objectives

To assess fairness and bias of a previously validated machine learning opioid misuse classifier.

Materials & Methods

Two experiments were conducted with the classifier’s original (n = 1000) and external validation (n = 53 974) datasets from 2 health systems. Bias was assessed via testing for differences in type II error rates across racial/ethnic subgroups (Black, Hispanic/Latinx, White, Other) using bootstrapped 95% confidence intervals. A local surrogate model was estimated to interpret the classifier’s predictions by race and averaged globally from the datasets. Subgroup analyses and post-hoc recalibrations were conducted to attempt to mitigate biased metrics.

Results

We identified bias in the false negative rate (FNR = 0.32) of the Black subgroup compared to the FNR (0.17) of the White subgroup. Top features included “heroin” and “substance abuse” across subgroups. Post-hoc recalibrations eliminated bias in FNR with minimal changes in other subgroup error metrics. The Black FNR subgroup had higher risk scores for readmission and mortality than the White FNR subgroup, and a higher mortality risk score than the Black true positive subgroup (P < .05).

Discussion

The Black FNR subgroup had the greatest severity of disease and risk for poor outcomes. Similar features were present between subgroups for predicting opioid misuse, but inequities were present. Post-hoc mitigation techniques mitigated bias in type II error rate without creating substantial type I error rates. From model design through deployment, bias and data disadvantages should be systematically addressed.

Conclusion

Standardized, transparent bias assessments are needed to improve trustworthiness in clinical machine learning models.
Risk Assessment-Based Enhanced Analytical Quality-by-Design Approach to Eco-Friendly and Economical Multicomponent Spectrophotometric Methods for Simultaneous Estimation of Montelukast Sodium and Bilastine
Authors: Prajapati Pintu , Tamboli Jayesh , Surati Parth , Mishra Ashish
Published: July 2021

Background

Concomitant montelukast and bilastine are used as additive therapy for seasonal allergic rhinoconjuctivitis and mild to moderate asthma. According to a literature review, no UV-visible spectrophotometric method has been reported yet for simultaneous estimation of montelukast sodium and bilastine in their combined pharmaceutical dosage forms.

Objective

Five different multicomponent spectrophotometric methods were therefore developed and validated for simultaneous estimation of montelukast sodium and bilastine using a risk assessment-based enhanced analytical quality-by-design approach.

Method

The identification and assessment of method risk parameters were carried out using the risk priority number ranking and filtering method according to the International Conference on Harmonization (ICH) Q9 guideline. The wavelength for detection and solvents such as 0.1 N NaOH and 0.1 N HCl were found to be critical method parameters for the development of the target methods. The developed methods were validated as per the ICH Q2(R1) guideline.

Results

The developed and validated methods were applied for assay of combined pharmaceutical dosage forms of montelukast sodium and bilastine and results were found to be in good agreement with their label claims.

Conclusions

The developed methods did not include the usage of any organic solvent and are a good alternative to the costly chromatography method. Hence, the methods are eco-friendly and economical for the simultaneous estimation of bilastine and montelukast sodium.

Highlights

Five multicomponent spectrophotometric methods were developed for simultaneous estimation of montelukast sodium and bilastine using a risk-based analytical quality-by-design approach. An assay of combined tablet dosage forms of montelukast sodium and bilastine was then carried out using the developed methods.
Long-Term Pulmonary Sequelae After Inhalation Injury: A Retrospective Case–Control Study
Authors: Wier Julian , Hulsebos Ian , Spera Leigh , Yenikomshian Haig , Gillenwater Justin
Published: July 2021

Inhalation injury (INHI) has strong associations with increased rates of in-patient mortality and pneumonia. This study’s aim is to review long-term pulmonary outcomes in INHI patients. We present a retrospective cohort of burn patients admitted to an ABA-certified burn unit. Burn patients with or without medically confirmed INHI who were admitted were studied. The control groups were ventilated patients (V) and nonventilated patients (NV). Primary study outcomes were rates of postdischarge pulmonary sequelae, including ineffective airway clearance, infections, shortness of breath, and malignancy. Secondary outcomes included rates of postdischarge surgeries and readmission, postdischarge nonpulmonary sequelae, and postdischarge days to pulmonary/nonpulmonary sequelae. The study population included 33 INHI, 45 V, and 50 NV patients. There were no significant differences in age (P = .98), sex (P = .68), % TBSA (P = .18), pulmonary comorbidity (P = .5), or smoking status (P = .92). Outpatient pulmonary sequelae were significantly higher for both INHI and V groups as compared to NV (21% and 17% vs 4%, P = .023, .043). The number of days from discharge to pulmonary sequelae was significantly shorter in the INHI group vs the V group (162 ± 139 vs 513 ± 314 days, P = .024). All other measures were not significant when comparing INHI to V or NV (P > .05). Both INHI and V groups resulted in higher rates of outpatient pulmonary sequelae independent of inpatient course as compared to NV. While outpatient pulmonary sequelae were not significantly different between INHI and V, the INHI patients presented with complaints earlier.
Spectral-ratio tomography for seismic attenuation estimation
Authors: Jin Ziqi , Shi Ying , Ma Qiqi , Tian Deguang , Meng Qi'an , Wang Weihong
Published: July 2021

When measuring surface seismic data, an accurate attenuation estimation method is necessary to compensate for the energy loss and phase distortion of seismic waves, and is also beneficial for further quantitative amplitude analyses and reservoir parameter predictions. For conventional Q-estimation methods (such as the log spectral-ratio (LSR) method and attenuated traveltime tomography), accuracy may be affected by the differences between the overburden ray paths of two selected reflections (we call it the overburden effect). In this study, we design a more accurate Q-tomography method to estimate Q-values (both in the overburden and target layer simultaneously) without overburden assumptions. We address the overburden effect by using an inversion method, which allows us to separate attenuation effects from the overburden through the traveltime differences in the tomography grid cells. We test the method on synthetic data and prove its feasibility and effectiveness by applying it to field data.
Paired Tumor-Normal Sequencing Provides Insights Into the TP53-Related Cancer Spectrum in Patients With Li-Fraumeni Syndrome
Authors: Ceyhan-Birsoy Ozge , Selenica Pier , Chui M Herman , Jayakumaran Gowtham , Ptashkin Ryan , Misyura Maksym , Aypar Umut , Jairam Sowmya , Yang Ciyu , Li Yirong , Mehta Nikita , Kemel Yelena , Salo-Mullen Erin , Maio Anna , Sheehan Margaret , Zehir Ahmet , Carlo Maria , Latham Alicia , Stadler Zsofia , Robson Mark , Offit Kenneth , Ladanyi Marc , Walsh Michael , Reis-Filho Jorge S , Mandelker Diana
Published: July 2021

Background

Genetic testing for Li-Fraumeni syndrome (LFS) is performed by using blood specimens from patients selected based on phenotype-dependent guidelines. This approach is problematic for understanding the LFS clinical spectrum because patients with nonclassical presentations are missed, clonal hematopoiesis–related somatic blood alterations cannot be distinguished from germline variants, and unrelated tumors cannot be differentiated from those driven by germline TP53 defects.

Methods

To provide insights into the LFS-related cancer spectrum, we analyzed paired tumor-blood DNA sequencing results in 17 922 patients with cancer and distinguished clonal hematopoiesis–related, mosaic, and germline TP53 variants. Loss of heterozygosity and TP53 mutational status were assessed in tumors, followed by immunohistochemistry for p53 expression on a subset to identify those lacking biallelic TP53 inactivation.

Results

Pathogenic/likely pathogenic TP53 variants were identified in 50 patients, 12 (24.0%) of which were clonal hematopoiesis related and 4 (8.0%) of which were mosaic. Twelve (35.3%) of 34 patients with germline TP53 variants did not meet LFS testing criteria. Loss of heterozygosity of germline TP53 variant was observed in 96.0% (95% confidence interval [CI] = 79.7% to 99.9%) of core LFS spectrum–type tumors vs 45.5% (95% CI = 16.8% to 76.6%) of other tumors and 91.3% (95% CI = 72.0% to 98.9%) of tumors from patients who met LFS testing criteria vs 61.5% (95% CI = 31.6% to 86.1%) of tumors from patients who did not. Tumors retaining the wild-type TP53 allele exhibited wild-type p53 expression.

Conclusions

Our results indicate that some TP53 variants identified in blood-only sequencing are not germline and a substantial proportion of patients with LFS are missed based on current testing guidelines. Additionally, a subset of tumors from patients with LFS do not have biallelic TP53 inactivation and may represent cancers unrelated to their germline TP53 defect.
Local Adaptation of Bitter Taste and Ecological Speciation in a Wild Mammal
Authors: Jiao Hengwu , Wang Qian , Wang Bing-Jun , Li Kexin , Lövy Matěj , Nevo Eviatar , Li Qiyang , Su Wenchuan , Jiang Peihua , Zhao Huabin
Published: July 2021

Sensory systems are attractive evolutionary models to address how organisms adapt to local environments that can cause ecological speciation. However, tests of these evolutionary models have focused on visual, auditory, and olfactory senses. Here, we show local adaptation of bitter taste receptor genes in two neighboring populations of a wild mammal—the blind mole rat Spalax galili—that show ecological speciation in divergent soil environments. We found that basalt-type bitter receptors showed higher response intensity and sensitivity compared with chalk-type ones using both genetic and cell-based functional analyses. Such functional changes could help animals adapted to basalt soil select plants with less bitterness from diverse local foods, whereas a weaker reception to bitter taste may allow consumption of a greater range of plants for animals inhabiting chalk soil with a scarcity of food supply. Our study shows divergent selection on food resources through local adaptation of bitter receptors, and suggests that taste plays an important yet underappreciated role in speciation.
Photorhabdus antibacterial Rhs polymorphic toxin inhibits translation through ADP-ribosylation of 23S ribosomal RNA
Authors: Jurėnas Dukas , Payelleville Amaury , Roghanian Mohammad , Turnbull Kathryn J , Givaudan Alain , Brillard Julien , Hauryliuk Vasili , Cascales Eric
Published: July 2021

Bacteria have evolved sophisticated mechanisms to deliver potent toxins into bacterial competitors or into eukaryotic cells in order to destroy rivals and gain access to a specific niche or to hijack essential metabolic or signaling pathways in the host. Delivered effectors carry various activities such as nucleases, phospholipases, peptidoglycan hydrolases, enzymes that deplete the pools of NADH or ATP, compromise the cell division machinery, or the host cell cytoskeleton. Effectors categorized in the family of polymorphic toxins have a modular structure, in which the toxin domain is fused to additional elements acting as cargo to adapt the effector to a specific secretion machinery. Here we show that Photorhabdus laumondii, an entomopathogen species, delivers a polymorphic antibacterial toxin via a type VI secretion system. This toxin inhibits protein synthesis in a NAD+-dependent manner. Using a biotinylated derivative of NAD, we demonstrate that translation is inhibited through ADP-ribosylation of the ribosomal 23S RNA. Mapping of the modification further showed that the adduct locates on helix 44 of the thiostrepton loop located in the GTPase-associated center and decreases the GTPase activity of the EF-G elongation factor.
Effects of veverimer on serum bicarbonate and physical function in diabetic patients with chronic kidney disease and metabolic acidosis: subgroup analysis from a randomized, controlled trial
Authors: Mathur Vandana S , Li Elizabeth , Wesson Donald E
Published: July 2021

Background

Metabolic acidosis is a complication of chronic kidney disease (CKD) that increases risk of CKD progression, and causes bone demineralization and muscle protein catabolism. Patients with diabetes are prone to metabolic acidosis and functional limitations that decrease quality of life. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis. This post hoc subgroup analysis evaluated effects of veverimer on metabolic acidosis and physical function among patients with diabetes.

Methods

This was a Phase 3, multicenter, randomized, blinded, placebo-controlled trial in 196 patients with CKD (estimated glomerular filtration rate 20–40 mL/min/1.73 m2) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo.

Results

At Week 52, veverimer-treated patients with diabetes (n = 70), had a significantly greater increase in mean serum bicarbonate than the placebo group (n = 57) (4.4 versus 2.9 mmol/L, P < 0.05). Patient-reported limitations of physical function on the Kidney Disease and Quality of Life-Physical Function Domain (e.g. walking several blocks and climbing a flight of stairs) improved significantly in the veverimer versus placebo group (+12.5 versus +0.3, respectively, P < 0.001) as did objective physical performance on the repeated chair stand test (P < 0.0001).

Conclusions

Few interventions for patients with diabetes and CKD have successfully improved quality of life or physical functioning. Our study demonstrated that veverimer effectively treated metabolic acidosis in patients with diabetes and CKD, and significantly improved how these patients felt and functioned.
The sequenced genomes of nonflowering land plants reveal the innovative evolutionary history of peptide signaling
Authors: Furumizu Chihiro , Krabberød Anders K. , Hammerstad Marta , Alling Renate M. , Wildhagen Mari , Sawa Shinichiro , Aalen Reidunn B.
Published: July 2021

An understanding of land plant evolution is a prerequisite for in-depth knowledge of plant biology. Here we extract and explore information hidden in the increasing number of sequenced plant genomes, from bryophytes to angiosperms, to elucidate a specific biological question—how peptide signaling evolved. To conquer land and cope with changing environmental conditions, plants have gone through transformations that must have required innovations in cell-to-cell communication. We discuss peptides mediating endogenous and exogenous changes by interaction with receptors activating intracellular molecular signaling. Signaling peptides were discovered in angiosperms and operate in tissues and organs such as flowers, seeds, vasculature, and 3D meristems that are not universally conserved across land plants. Nevertheless, orthologs of angiosperm peptides and receptors have been identified in nonangiosperms. These discoveries provoke questions regarding coevolution of ligands and their receptors, and whether de novo interactions in peptide signaling pathways may have contributed to generate novel traits in land plants. The answers to such questions will have profound implications for the understanding of the evolution of cell-to-cell communication and the wealth of diversified terrestrial plants. Under this perspective, we have generated, analyzed, and reviewed phylogenetic, genomic, structural, and functional data to elucidate the evolution of peptide signaling.