Nevin Manimala

Genome Biol Evol. 2022 Aug 10:evac129. doi: 10.1093/gbe/evac129. Online ahead of print.

ABSTRACT

Over the last decade, molecular systematics has undergone a change of paradigm as high-throughput sequencing (HTS) now makes it possible to reconstruct evolutionary relationships using genome-scale datasets. The advent of ‘big data’ molecular phylogenetics provided a battery of new tools for biologists, but simultaneously brought new methodological challenges. The increase in analytical complexity comes at the price of highly specific training in computational biology and molecular phylogenetics, resulting very often in a polarized accumulation of knowledge (technical on one side, and biological on the other). Interpreting the robustness of genome-scale phylogenetic studies is not straightforward, particularly as new methodological developments have consistently shown that the general belief of ‘more genes, more robustness’ often does not apply, and because there is a range of systematic errors that plague phylogenomic investigations. This is particularly problematic because phylogenomic studies are highly heterogeneous in their methodology, and best practices are often not clearly defined. The main aim of this article is to present what I consider as the ten most important points to take into consideration when planning a well-thought-out phylogenomic study and while evaluating the quality of published papers. The goal is to provide a practical step-by-step guide that can be easily followed by non-experts and phylogenomic novices in order to assess the technical robustness of phylogenomic studies or improve the experimental design of a project.

PMID:35946263 | DOI:10.1093/gbe/evac129

Indian J Dent Res. 2022 Jan-Mar;33(1):94-99. doi: 10.4103/ijdr.ijdr_45_22.

ABSTRACT

BACKGROUND: Many studies explained the importance of remineralisation of early carious lesions with various remineralising agents. In the present study, we incorporated the remineralising agents in a dentifrice, applied that in artificial enamel caries and evaluated their remineralising potential and compared the efficacy among the three.

AIM: To evaluate and compare the remineralisation potential of a dentifrice containing bioactive glass, casein phosphopeptide-amorphous calcium phosphate and novel laboratory synthesised strontiumdoped nanohydroxyapatite paste in artificial enamel caries.

METHODS AND MATERIALS: 120 enamel specimens were divided into 4 groups of 30 specimens each, based on the type of dentifrice applied: GI – conventional toothpaste (control group), GII – calcium sodium phosphosilicate (Novamin), GIII – casein phosphopeptide-amorphous calcium phosphate (GC tooth mousse) and GIV- Novel strontiumdoped nanohydroxyapatite paste (SrnHAp paste). Specimens in all the groups were subjected to demineralisation, and calcium/phosphorous ratio was analysed followed by remineralisation and the mean calcium-phosphorus ratio was assessed using a scanning electron microscope and energy dispersing X-ray analysis.

STATISTICAL ANALYSIS: Data were analysed using IBM SPSS Statistics for Windows Software, version 22 (IBM Corp., Armonk, NY, USA). Descriptive statistics were used to calculate the mean and standard deviation. Kruskal-Wallis, ANOVA and Mann-Whitney tests were used. The level of significance was set at 5%.

RESULTS AND CONCLUSION: All except the control group showed a net increase in calcium and phosphorous values after application of the respective remineralising agents in respective groups. Inter-group comparison revealed that Group IV – SrnHAp paste yields higher net calcium and phosphorous values than other groups. Hence, novel SrnHAp can be considered as the material of choice in remineralising early enamel carious lesions.

PMID:35946253 | DOI:10.4103/ijdr.ijdr_45_22

Indian J Dent Res. 2022 Jan-Mar;33(1):85-89. doi: 10.4103/ijdr.ijdr_770_21.

ABSTRACT

CONTEXT (BACKGROUND): Resin composites are the most widely used material for restoring cervical defects. However, the high failure rate of these restorations is still a concern.

AIMS: The aim of this in vitro study was to evaluate, using microtomography (μCT), the interfacial gap and voids formation in Class V cavities in premolars restored with materials with lower polymerization shrinkage combined with different restorative techniques.

SETTINGS AND DESIGN: Cervical defects were created in 30 intact premolar and were randomly distributed to be restored by one of the following techniques (n = 6): Composite resin with two increments (CR), organic modified polymer (ORMOCER) with single (OR1) or two increments (OR2, or low viscosity bulk-fill composite resin with single (BF1) or two increments (BF2).

METHODS AND MATERIAL: Each tooth was scanned before filling to determine the volume of interest (VOI) to be applied in the second μCT after restoration and to control the cavity volume among the groups. In the μCT after filling, the volume of interfacial gaps and voids was calculated for each group.

STATISTICAL ANALYSIS: The groups were compared using one-way and Tukey HSD post hoc test (α = 0.05).

RESULTS: It was possible to identify higher gap formation in the OR1 group and higher void formation in CR group (P < 0.05). OR2 group showed better results than the group with one increment. BF2 showed the best filling capacity.

CONCLUSIONS: It was possible to conclude that the material and the number of increments directly influenced the internal adaptation and voids formation of Class V restorations.

PMID:35946251 | DOI:10.4103/ijdr.ijdr_770_21

BMC Pharmacol Toxicol. 2022 Aug 9;23(1):61. doi: 10.1186/s40360-022-00600-7.

ABSTRACT

BACKGROUND: Adipose-derived mesenchymal stem cells (ADMSCs) are a promising source of material source for medical regeneration of cartilage. Growth factors, including transforming growth factor-β (TGFβ) subfamily members and bone morphogenetic proteins (BMPs), play important roles in inducing and promoting chondrogenic differentiation of MSCs. However, these exogenous growth factors have some drawbacks related to their cost, biological half-life, and safety for clinical application. Several studies have reported that statins, the competitive inhibitors of 3-hydroxy-2-methylglutaryl coenzyme A (HMG-CoA) reductase, induce the expression of BMP2 in multiple cell types as the pleotropic effects. The objective of this study was to investigate the effects of fluvastatin during chondrogenic differentiation of human ADMSCs (hADMSCs).

METHODS: The effects of fluvastatin were analyzed during chondrogenic differentiation of hADMSCs in the pellet culture without exogenous growth factors by qRT-PCR and histology. For functional studies, Noggin, an antagonist of BMPs, mevalonic acid (MVA) and geranylgeranyl pyrophosphate (GGPP), metabolites of the mevalonate pathway, ROCK inhibitor (Y27632), or RAC1 inhibitor (NSC23766) were applied to cells during chondrogenic differentiation. Furthermore, RhoA activity was measured by RhoA pulldown assay during chondrogenic differentiation with or without fluvastatin. Statistically significant differences between groups were determined by Student’s t-test or the Tukey-Kramer test.

RESULTS: Fluvastatin-treated cells expressed higher levels of BMP2, SOX9, ACAN, and COL2A1 than control cells, and accumulated higher levels of glycosaminoglycans (GAGs). Noggin significantly inhibited the fluvastatin-mediated upregulation of ACAN and COL2A1. Both MVA and GGPP suppressed the effects of fluvastatin on the expressions of BMP2, SOX9, ACAN, and COL2A1. Furthermore, fluvastatin suppressed the RhoA activity, and inhibition of RhoA-ROCK signaling by Y27632 increased the expressions of BMP2, SOX9, ACAN, and COL2A1, as well as fluvastatin.

CONCLUSIONS: Our results suggest that fluvastatin promotes chondrogenic differentiation of hADMSCs by inducing endogenous BMP2, and that one of the mechanisms underlying the effects is inhibition of RhoA-ROCK signaling via suppression of GGPP. Fluvastatin is a safe and low-cost compound that holds promise for use in transplantation of hADMSCs for cartilage regeneration.

PMID:35945639 | DOI:10.1186/s40360-022-00600-7

Arch Public Health. 2022 Aug 9;80(1):186. doi: 10.1186/s13690-022-00946-8.

ABSTRACT

INTRODUCTION: Globally, Sierra Leone has some of the worst maternal and child health indicators. The situation is worsened by a dearth of evidence about the level of continuum of care, an evidence-based intervention aimed at reducing maternal and perinatal morbidity and mortality. Hence this study aimed to assess the level of and factors associated with continuum of maternal and newborn care in Sierra Leone.

METHOD: This study analyzed secondary data from the 2019 Sierra Leone Demographic Health Survey. Analysis was restricted to women who had a live birth in the 5 years preceding the survey (n = 7326). Complete continuum of care was considered when a woman reported having had at least eight antenatal care contacts, skilled birth attendance and mother and baby had at least one postnatal check-up. Bi-variable and multivariable logistic regression were performed using the statistical package for the social sciences software version 25.

RESULTS: Only 17.9% (95% CI: 17.4-19.1) of the women utilized complete continuum of care for maternal and newborn health services in Sierra Leone. About 22% (95% CI: 21.3-23.1) utilized 8 or more antenatal care contacts, 88% (95% CI: 87.9-89.4) had skilled birth attendance while 90.7% (95% CI: 90.2-91.5) and 90.4% (95% CI: 89.9-91.2) of mothers and neonates utilized postnatal care respectively. Having started antenatal care within the first trimester (aOR 1.71, 95% CI: 1.46-2.00), being resident in the Southern region (aOR 1.85, 95% CI: 1.23-2.80), belonging to richer wealth quintile (aOR 1.76, 95% CI: 1.27-2.44), using internet (aOR 1.49, 95% CI: 1.12-1.98) and having no big problems seeking permission to access healthcare (aOR 1.34, 95% CI: 1.06-1.69) were significantly associated with utilization of continuum of care.

CONCLUSION: The overall completion of continuum of maternal care is low, with ANC being the lowest utilized component of continuum of care. These findings call for urgent attention for maternal health stakeholders to develop and implement tailored interventions prioritizing women empowerment, access to affordable internet services, timely initiation of ANC contacts, women in developed regions such as the Western and those from poor households.

PMID:35945622 | DOI:10.1186/s13690-022-00946-8

Trials. 2022 Aug 9;23(1):645. doi: 10.1186/s13063-022-06536-x.

ABSTRACT

INTRODUCTION: Alliance for Clinical Trials in Oncology (Alliance) coordinated trials utilize Medidata Rave® (Rave) as the primary clinical data capture system. A growing number of innovative and complex cancer care delivery research (CCDR) trials are being conducted within the Alliance with the aims of studying and improving cancer-related care. Because these trials encompass patients, providers, practices, and their interactions, a defining characteristic of CCDR trials is multilevel data collection in pragmatic settings. Consequently, CCDR trials necessitated innovative strategies for database development, centralized data management, and data monitoring in the presence of these real-world multilevel relationships. Having real trial experience in working with community and academic centers, and having recently implemented five CCDR trials in Rave, we are committed to sharing our strategies and lessons learned in implementing such pragmatic trials in oncology.

METHODS: Five Alliance CCDR trials are used to describe our approach to analyzing the database development needs and the novel strategies applied to overcome the unanticipated challenges we encountered. The strategies applied are organized into 3 categories: multilevel (clinic, clinic stakeholder, patient) enrollment, multilevel quantitative and qualitative data capture, including nontraditional data capture mechanisms being applied, and multilevel data monitoring.

RESULTS: A notable lesson learned in each category was (1) to seek long-term solutions when developing the functionality to push patient and non-patient enrollments to their respective Rave study database that affords flexibility if new participant types are later added; (2) to be open to different data collection modalities, particularly if such modalities remove barriers to participation, recognizing that additional resources are needed to develop the infrastructure to exchange data between that modality and Rave; and (3) to facilitate multilevel data monitoring, orient site coordinators to the their trial’s multiple study databases, each corresponding to a level in the hierarchy, and remind them to establish the link between patient and non-patient participants in the site-facing NCI web-based enrollment system.

CONCLUSION: Although the challenges due to multilevel data collection in pragmatic settings were surmountable, our shared experience can inform and foster collaborations to collectively build on our past successes and improve on our past failures to address the gaps.

PMID:35945621 | DOI:10.1186/s13063-022-06536-x

Orphanet J Rare Dis. 2022 Aug 9;17(1):310. doi: 10.1186/s13023-022-02453-z.

ABSTRACT

BACKGROUND: Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder, frequently resulting in acute or subacute severe bilateral central vision loss. Vitamin B12 deficiency is also a known cause of optic neuropathy through mitochondrial dysfunction. Here we evaluated the prevalence and clinical significance of vitamin B12 deficiency in a large cohort of LHON patients and asymptomatic mutation carriers from a tertiary referral center.

METHODS: From the Munich LHON prospective cohort study, participants included all LHON patients and asymptomatic LHON mutation carriers, who were recruited between February 2014 and March 2020 and consented to participate. Neurological, general, and ophthalmological examinations were regularly performed, as were laboratory tests. Vitamin B12 deficiency was diagnosed if serum vitamin B12 was below 201 pg/mL, or if 201-339 pg/mL plus low serum holotranscobalamin or elevated serum methylmalonic acid or elevated total plasma homocysteine.

RESULTS: We analyzed 244 subjects, including 147 symptomatic LHON patients (74% males) and 97 asymptomatic mutation carriers (31% males). Median age at study baseline was 34 years (range 5-82 years). The prevalence of vitamin B12 deficiency was higher for LHON mutation carriers than for the general population in all age categories. This was statistically significant for the LHON mutation carriers under 65 years (21% vs. 5-7%, p = 0.002). While vitamin B12 deficiency prevalence was not statistically different between LHON patients and asymptomatic mutation carriers, its clinical correlates, e.g., macrocytosis and polyneuropathy, were more frequent in the subgroup of LHON patients. Excessive alcohol consumption was a significant predictor of vitamin B12 deficiency (p < 0.05).

CONCLUSIONS: The high prevalence of vitamin B12 deficiency in LHON mutation carriers, both asymptomatic mutation carriers and LHON patients, highlights the need for regular vitamin B12 screening in this population, in order to ensure early treatment, aiming for better outcomes. Our study is not conclusive regarding vitamin B12 deficiency as determinant for disease conversion in LHON, and further research is warranted to disentangle the role of vitamin B12 in the pathophysiology and prognosis of LHON.

PMID:35945620 | DOI:10.1186/s13023-022-02453-z

BMC Med. 2022 Aug 10;20(1):254. doi: 10.1186/s12916-022-02445-7.

ABSTRACT

Adaptive designs are a class of methods for improving efficiency and patient benefit of clinical trials. Although their use has increased in recent years, research suggests they are not used in many situations where they have potential to bring benefit. One barrier to their more widespread use is a lack of understanding about how the choice to use an adaptive design, rather than a traditional design, affects resources (staff and non-staff) required to set-up, conduct and report a trial. The Costing Adaptive Trials project investigated this issue using quantitative and qualitative research amongst UK Clinical Trials Units. Here, we present guidance that is informed by our research, on considering the appropriate resourcing of adaptive trials. We outline a five-step process to estimate the resources required and provide an accompanying costing tool. The process involves understanding the tasks required to undertake a trial, and how the adaptive design affects them. We identify barriers in the publicly funded landscape and provide recommendations to trial funders that would address them. Although our guidance and recommendations are most relevant to UK non-commercial trials, many aspects are relevant more widely.

PMID:35945610 | DOI:10.1186/s12916-022-02445-7

Genome Med. 2022 Aug 9;14(1):85. doi: 10.1186/s13073-022-01094-y.

ABSTRACT

BACKGROUND: Rare diseases collectively affect up to 10% of the population, but often lack effective treatment, and typically little is known about their pathophysiology. Major challenges include suboptimal phenotype mapping and limited statistical power. Population biobanks, such as the UK Biobank, recruit many individuals who can be affected by rare diseases; however, investigation into their utility for rare disease research remains limited. We hypothesized the UK Biobank can be used as a unique population assay for rare diseases in the general population.

METHODS: We constructed a consensus mapping between ICD-10 codes and ORPHA codes for rare diseases, then identified individuals with each rare condition in the UK Biobank, and investigated their age at recruitment, sex bias, and comorbidity distributions. Using exome sequencing data from 167,246 individuals of European ancestry, we performed genetic association controlling for case/control imbalance (SAIGE) to identify potential rare pathogenic variants for each disease.

RESULTS: Using our mapping approach, we identified and characterized 420 rare diseases affecting 23,575 individuals in the UK Biobank. Significant genetic associations included JAK2 V617F for immune thrombocytopenic purpura (p = 1.24 × 10^-13) and a novel CALR loss of function variant for essential thrombocythemia (p = 1.59 × 10^-13). We constructed an interactive resource highlighting demographic information ( http://www-personal.umich.edu/~mattpat/rareDiseases.html ) and demonstrate transferability by applying our mapping to a medical claims database.

CONCLUSIONS: Enhanced disease mapping and increased power from population biobanks can elucidate the demographics and genetic associations for rare diseases.

PMID:35945607 | DOI:10.1186/s13073-022-01094-y

Respir Res. 2022 Aug 9;23(1):202. doi: 10.1186/s12931-022-02126-2.

ABSTRACT

BACKGROUND: The efficacy and safety of complement inhibition in COVID-19 patients is unclear.

METHODS: A multicenter randomized controlled, open-label trial. Hospitalized COVID-19 patients with signs of systemic inflammation and hypoxemia (PaO₂/FiO₂ below 350 mmHg) were randomized (2:1 ratio) to receive standard of care with or without the C5 inhibitor zilucoplan daily for 14 days, under antibiotic prophylaxis. The primary outcome was improvement in oxygenation at day 6 and 15.

RESULTS: 81 patients were randomly assigned to zilucoplan (n = 55) or the control group (n = 26). 78 patients were included in the safety and primary analysis. Most were men (87%) and the median age was 63 years. The mean improvement in PaO₂/FiO₂ from baseline to day 6 was 56.4 mmHg in the zilucoplan group and 20.6 mmHg in the control group (mean difference + 35.8; 95% confidence interval (CI) – 9.4 to 80.9; p = 0.12), an effect also observed at day 15. Day 28 mortality was 9% in the zilucoplan and 21% in the control group (odds ratio 0.4; 95% CI 0.1 to 1.5). At long-term follow up, the distance walked in a 6-min test was 539.7 m in zilucoplan and 490.6 m in the control group (p = 0.18). Zilucoplan lowered serum C5b-9 (p < 0.001) and interleukin-8 (p = 0.03) concentration compared with control. No relevant safety differences between the zilucoplan and control group were identified.

CONCLUSION: Administration of zilucoplan to COVID-19 patients in this proof-of-concept randomized trial was well tolerated under antibiotic prophylaxis. While not reaching statistical significance, indicators of respiratory function (PaO₂/FiO₂) and clinical outcome (mortality and 6-min walk test) suggest that C5 inhibition might be beneficial, although this requires further research in larger randomized studies.

PMID:35945604 | DOI:10.1186/s12931-022-02126-2