Dissipation and recovery in collagen fibrils under cyclic loading: A molecular dynamics study.

The hysteretic behavior exhibited by collagen fibrils, when subjected to cyclic loading, is known to result in both dissipation as well as accumulation of residual strain. On subsequent relaxation, partial recovery has also been reported. Cross-links have been considered to play a key role in overall mechanical properties. Here, we modify an existing coarse-grained molecular dynamics model for collagen fibril with initially cross-linked collagen molecules, which is known to reproduce the response to uniaxial strain, by incorporating reformation of cross-links to allow for possible recovery of the fibril. Using molecular dynamics simulations, we show that our model successfully replicates the key features observed in experimental data, including the movement of hysteresis loops, the time evolution of residual strains and energy dissipation, as well as the recovery observed during relaxation. We also show that the characteristic cycle number, describing the approach toward steady state, has a value similar to that in experiments. We also emphasize the vital role of the degree of cross-linking on the key features of the macroscopic response to cyclic loading.

Examining the linkages between maternity services and postpartum modern contraceptive adoption among young women in India: Insights from the 2015-16 and 2019-21 National Family Health Survey.

BACKGROUND: The adoption of maternity services and postpartum modern contraception are the two most crucial components that help in reducing maternal and infant mortality; still, India is consistently struggling with it. This paper, therefore, aimed to examine the linkages between use of maternity services and postpartum modern contraceptive adoption. DATA AND METHODS: The required reproductive calendar data were extracted from the 2015-16 and 2019-21 National Family Health Survey (NFHS) datasets. The assessment was made based on a sample of currently married women aged 15-24 years who had given most recent childbirth in five years preceding the survey. For the analysis, a time-to-event approach was applied using the Kaplan-Meier survival statistic, Log-Rank Chi-square test and Cox-Proportional Hazard (Cox-PH) models. RESULTS: The results revealed that the proportion of postpartum modern contraceptive uptake among young users increased by 9%, from 33% in 2015-16 to 42% in 2019-21. The Cox-PH models revealed that, in both NFHS waves, the associations between various components of maternity services and postpartum modern contraceptive uptake were strongly significant, even after controlling for selected socio-economic and demographic correlates. CONCLUSIONS: The findings of this study reinforced urgent need for implementing integrated maternal-child health and family planning programmes and for boosting effective family planning counselling by health professionals to promote and motivate young women with a desire to early adoption of modern contraception in subsequent months after a recent childbirth.

Role of composition in fracture behavior of two-phase solids.

In a two-phase solid, we examine the growth of a preexisting macroscopic crack based on simulations of a random spring network model. We find that the enhancement in toughness, as well as strength, is strongly dependent on the ratio of elastic moduli as well as on the relative proportion of the phases. We find that the mechanism that leads to enhancement in toughness is not the same as that for enhancement in strength; however, the overall enhancement is similar in mode I and mixed-mode loading. Based on the crack paths, and the spread of the fracture process zone, we identify the type of fracture to transition from nucleation type, for close to single-phase compositions, whether hard or soft, to avalanche type for more mixed compositions. We also show that the associated avalanche distributions exhibit power-law statistics with different exponents for each phase. The significance of variations in the avalanche exponents with the relative proportion of phases and possible connections to the fracture types are discussed in detail.

Kinetic model description of dissipation and recovery in collagen fibrils under cyclic loading.

Collagen fibrils, when subjected to cyclic loading, are known to exhibit hysteretic behavior with energy dissipation that is partially recovered on relaxation. In this paper, we develop a kinetic model for a collagen fibril incorporating presence of hidden loops and stochastic fragmentation as well as reformation of sacrificial bonds. We show that the model reproduces well the characteristic features of reported experimental data on cyclic response of collagen fibrils, such as moving hysteresis loops, time evolution of residual strains and energy dissipation, recovery on relaxation, etc. We show that the approach to the steady state is controlled by a characteristic cycle number for both residual strain as well as energy dissipation and is in good agreement with reported existing experimental data.

Multiplatform molecular analyses refine classification of gliomas arising in patients with neurofibromatosis type 1.

Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or high-grade, and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 inactivation and epigenetic classification of these tumors remain limited. Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas. The first harbored biallelic NF1 inactivation only, occurred primarily during childhood, followed a more indolent clinical course, and had a unique epigenetic signature for which we propose the terminology "pilocytic astrocytoma, arising in the setting of NF1". The second subgroup harbored additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, occurred primarily during adulthood, followed a more aggressive clinical course, and was epigenetically diverse, with most tumors aligning with either high-grade astrocytoma with piloid features or various subclasses of IDH-wildtype glioblastoma. Several patients were treated with small molecule MEK inhibitors that resulted in stable disease or tumor regression when used as a single agent, but only in the context of those tumors with NF1 inactivation lacking additional oncogenic alterations. Together, these findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.

Intensive Multimodality Therapy for Extraocular Retinoblastoma: A Children's Oncology Group Trial (ARET0321).

PURPOSE: Metastatic retinoblastoma has a poor prognosis when treated with conventional chemotherapy and radiation therapy (RT). Intensified therapy may improve the outcome. METHODS: A prospective, international trial enrolled patients with extraocular retinoblastoma. Patients with stage II or III (locoregional) retinoblastoma received four cycles of chemotherapy, followed by involved field RT (45 Gy). Patients with stage IVa or IVb (metastatic or trilateral) retinoblastoma also received four cycles of chemotherapy and those with ≥ partial response then received one cycle of high-dose carboplatin, thiotepa, and etoposide with autologous hematopoietic stem-cell support. Patients with stage IVa or IVb with residual tumor postchemotherapy received RT. The proportion of patients who achieved event-free survival would be reported and compared with historical controls separately for each of the three groups of patients. RESULTS: Fifty-seven eligible patients were included in the analyses. Event-free survival at 1 year was 88.1% (90% CI, 66.6 to 96.2) for stage II-III, 82.6% (90% CI, 61.0 to 92.9) for stage IVa, and 28.3% (90% CI, 12.7 to 46.2) for stage IVb/trilateral. Toxicity was significant as expected and included two therapy-related deaths. CONCLUSION: Intensive multimodality therapy is highly effective for patients with regional extraocular retinoblastoma and stage IVa metastatic retinoblastoma. Although the study met its aim for stage IVb, more effective therapy is still required for patients with CNS involvement (ClinicalTrials.gov identifier: NCT00554788).

Nutritional status and concomitant factors of stunting among pre-school children in Malda, India: A micro-level study using a multilevel approach.

BACKGROUND: Malnutrition was the main cause of death among children below 5 years in every state of India in 2017. Despite several flagship programmes and schemes implemented by the Government of India, the latest edition of the Global Nutrition Report 2018 addressed that India tops in the number of stunted children, which is a matter of concern. Thus, a micro-level study was designed to know the level of nutritional status and to study this by various disaggregate levels, as well as to examine the risk factors of stunting among pre-school children aged 36-59 months in Malda. METHOD: A primary cross-sectional quantitative survey was conducted using structured questionnaires following a multi-stage, stratified simple random sampling procedure in 2018. A sum of 731 mothers with at least one eligible child aged 36-59 months were the study participants. Anthropometric measures of children were collected following the WHO child growth standard. Children were classified as stunted, wasted, and underweight if their HAZ, WHZ, and WAZ scores, respectively, were less than -2SD. The random intercept multilevel logistic regression model has been employed to estimate the effects of possible risk factors on childhood stunting. RESULTS: The prevalence of stunting in the study area is 40% among children aged 36-59 months, which is a very high prevalence as per the WHO's cut-off values (≥40%) for public health significance. Results of the multilevel analysis revealed that preceding birth interval, low birth weight, duration of breastfeeding, mother's age at birth, mother's education, and occupation are the associated risk factors of stunting. Among them, low birth weight (OR 2.22, 95% CI: 1.44-3.41) and bidi worker as mothers' occupation (OR 1.92, 95% CI: 1.18-3.12) are the most influencing factors of stunting. Further, about 14 and 86% variation in stunting lie at community and child/household level, respectively. CONCLUSION: Special attention needs to be placed on the modifiable risk factors of childhood stunting. Policy interventions should direct community health workers to encourage women as well as their male partners to increase birth interval using various family planning practices, provide extra care for low birth weight baby, that can help to reduce childhood stunting.

Role of spatial patterns in fracture of disordered multiphase materials.

Multiphase materials, such as composite materials, exhibit multiple competing failure mechanisms during the growth of a macroscopic defect. For the simulation of the overall fracture process in such materials, we develop a two-phase spring network model that accounts for the architecture between the different components as well as the respective disorders in their failure characteristics. In the specific case of a plain weave architecture, we show that any offset between the layers reduces the delocalization of the stresses at the crack tip and thereby substantially lowers the strength and fracture toughness of the overall laminate. The avalanche statistics of the broken springs do not show a distinguishable dependence on the offsets between layers. The power-law exponents are found to be much smaller than that of disordered spring network models in the absence of a crack. A discussion is developed on the possibility of the avalanche statistics being those near breakdown.

Women's autonomy and utilization of maternal healthcare in India: Evidence from a recent national survey.

OBJECTIVE: The present study aims to examine the association between women's decision-making autonomy and utilization of maternal healthcare services among the currently married women in India. METHODS: A total of 32,698 currently married women aged 15-49 years who had at least one live birth in the past five years preceding the survey and had information regarding autonomy collected by the National Family Health Survey 2015-16 were used for analysis. Bivariate and multivariate logistic regression models were employed for the analyses of this study. RESULTS: Utilization of maternal healthcare services was higher among the women having a high level of decision-making autonomy compared to those who had a low autonomy in the household. The regression results indicate that women's autonomy was significantly associated with increased odds of maternal healthcare services in India. Women with high autonomy had 37% and 33% greater likelihood of receiving ANC (AOR: 1.37, 95% CI: 1.25-1.50) and PNC care (AOR: 1.33, 95% CI: 1.24-1.42) respectively compared to women having low autonomy. However, no significant association was observed between women's autonomy and institutional delivery in the adjusted analysis. CONCLUSION: This study recommends the need for comprehensive strategies involving improvement of women's autonomy along with expansion of education, awareness generation regarding the importance of maternity care, and enhancing public health infrastructure to ensure higher utilization of maternal healthcare services that would eventually reduce maternal mortality.

Next-Generation Sequencing of Retinoblastoma Identifies Pathogenic Alterations beyond RB1 Inactivation That Correlate with Aggressive Histopathologic Features.

PURPOSE: To determine the usefulness of a comprehensive, targeted-capture next-generation sequencing (NGS) assay for the clinical management of children undergoing enucleation for retinoblastoma. DESIGN: Cohort study. PARTICIPANTS: Thirty-two children with retinoblastoma. METHODS: We performed targeted NGS using the UCSF500 Cancer Panel (University of California, San Francisco, San Francisco, CA) on formalin-fixed, paraffin-embedded tumor tissue along with constitutional DNA isolated from peripheral blood, buccal swab, or uninvolved optic nerve. Peripheral blood samples were also sent to a commercial laboratory for germline RB1 mutation testing. MAIN OUTCOME MEASURES: Presence or absence of germline RB1 mutation or deletion, tumor genetic profile, and association of genetic alterations with clinicopathologic features. RESULTS: Germline mutation or deletion of the RB1 gene was identified in all children with bilateral retinoblastoma (n = 12), and these NGS results were 100% concordant with commercial germline RB1 mutation analysis. In tumor tissue tested with NGS, biallelic inactivation of RB1 was identified in 28 tumors and focal MYCN amplification was identified in 4 tumors (2 with wild-type RB1 and 2 with biallelic RB1 inactivation). Additional likely pathogenic alterations beyond RB1 were identified in 13 tumors (41%), several of which have not been reported previously in retinoblastoma. These included focal amplifications of MDM4 and RAF1, as well as damaging mutations involving BCOR, ARID1A, MGA, FAT1, and ATRX. The presence of additional likely pathogenetic mutations beyond RB1 inactivation was associated with aggressive histopathologic features, including higher histologic grade and anaplasia, and also with both unilateral and sporadic disease. CONCLUSIONS: Comprehensive NGS analysis reliably detects relevant mutations, amplifications, and chromosomal copy number changes in retinoblastoma. The presence of genetic alterations beyond RB1 inactivation correlates with aggressive histopathologic features.

Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial.

BACKGROUND: Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients. METHODS: The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3-21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAFV600E [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101. FINDINGS: Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported. INTERPRETATION: Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1. FUNDING: National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.

The University of California, San Francisco Documentation System for Retinoblastoma: Preparing to Improve Staging Methods for This Disease.

BACKGROUND/AIMS: Current retinoblastoma staging systems do not adequately describe the disease, especially in eyes with multiple tumors. The aims of this study were to develop methods for documenting individual tumors and to score disease burden over time. METHODS: A coding system was devised to describe each tumor according to affected eye, meridian, anteroposterior location, activity, growth pattern, type of seed, and treatment. A scoring system for quantifying disease burden was developed, taking account of tumor number, size, spread, and secondary effects on the eye. RESULTS: Our coding system allowed contemporaneous tumor documentation, producing datasets that enabled generation of fundus diagrams, Kaplan-Meier curves, and tables summarizing disease progression in individual tumors and eyes. Our data showed disparities between ocular and tumor documentation, e.g., indicating earlier tumor development in the left eye but younger age at presentation if disease was worse in the right eye. Actuarial rates of local treatment failure were lower when individual tumors were analyzed than when data were reported in terms of whole eyes. CONCLUSION: Our methods for documenting individual retinoblastomas have facilitated the review of patients' progress in our routine practice and may provide data that could be used to refine retinoblastoma classifications in the future.

The genetic landscape of gliomas arising after therapeutic radiation.

Radiotherapy improves survival for common childhood cancers such as medulloblastoma, leukemia, and germ cell tumors. Unfortunately, long-term survivors suffer sequelae that can include secondary neoplasia. Gliomas are common secondary neoplasms after cranial or craniospinal radiation, most often manifesting as high-grade astrocytomas with poor clinical outcomes. Here, we performed genetic profiling on a cohort of 12 gliomas arising after therapeutic radiation to determine their molecular pathogenesis and assess for differences in genomic signature compared to their spontaneous counterparts. We identified a high frequency of TP53 mutations, CDK4 amplification or CDKN2A homozygous deletion, and amplifications or rearrangements involving receptor tyrosine kinase and Ras-Raf-MAP kinase pathway genes including PDGFRA, MET, BRAF, and RRAS2. Notably, all tumors lacked alterations in IDH1, IDH2, H3F3A, HIST1H3B, HIST1H3C, TERT (including promoter region), and PTEN, which genetically define the major subtypes of diffuse gliomas in children and adults. All gliomas in this cohort had very low somatic mutation burden (less than three somatic single nucleotide variants or small indels per Mb). The ten high-grade gliomas demonstrated markedly aneuploid genomes, with significantly increased quantity of intrachromosomal copy number breakpoints and focal amplifications/homozygous deletions compared to spontaneous high-grade gliomas, likely as a result of DNA double-strand breaks induced by gamma radiation. Together, these findings demonstrate a distinct molecular pathogenesis of secondary gliomas arising after radiation therapy and identify a genomic signature that may aid in differentiating these tumors from their spontaneous counterparts.

The genetic landscape of anaplastic pleomorphic xanthoastrocytoma.

Pleomorphic xanthoastrocytoma (PXA) is an astrocytic neoplasm that is typically well circumscribed and can have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO grade III), however, is associated with a more aggressive biologic behavior and worse prognosis. The factors that drive anaplastic progression are largely unknown. We performed comprehensive genomic profiling on a set of 23 PXAs from 19 patients, including 15 with anaplastic PXA. Four patients had tumor tissue from multiple recurrences, including two with anaplastic progression. We find that PXAs are genetically defined by the combination of CDKN2A biallelic inactivation and RAF alterations that were present in all 19 cases, most commonly as CDKN2A homozygous deletion and BRAF p.V600E mutation but also occasionally BRAF or RAF1 fusions or other rearrangements. The third most commonly altered gene in anaplastic PXA was TERT, with 47% (7/15) harboring TERT alterations, either gene amplification (n = 2) or promoter hotspot mutation (n = 5). In tumor pairs analyzed before and after anaplastic progression, two had increased copy number alterations and one had TERT promoter mutation at recurrence. Less commonly altered genes included TP53, BCOR, BCORL1, ARID1A, ATRX, PTEN, and BCL6. All PXA in this cohort were IDH and histone H3 wildtype, and did not contain alterations in EGFR. Genetic profiling performed on six regions from the same tumor identified intratumoral genomic heterogeneity, likely reflecting clonal evolution during tumor progression. Overall, anaplastic PXA is characterized by the combination of CDKN2A biallelic inactivation and oncogenic RAF kinase signaling as well as a relatively small number of additional genetic alterations, with the most common being TERT amplification or promoter mutation. These data define a distinct molecular profile for PXA and suggest additional genetic alterations, including TERT, may be associated with anaplastic progression.

Reirradiation and PD-1 inhibition with nivolumab for the treatment of recurrent diffuse intrinsic pontine glioma: a single-institution experience.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a rare, aggressive brain tumor with no known cure. Reirradiation (reRT) at recurrence can prolong survival. The impact of irradiation may be heightened when combined with PD-1 inhibition. We describe our experience using reRT, with or without PD-1 inhibition, in a cohort of patients with recurrent DIPG. METHODS: We performed a retrospective cohort analysis of children who received reRT with or without concomitant PD-1 inhibition for recurrent DIPG at a single institution between 2005 and 2016. We compared progression-free (PFS) and overall survival (OS) between those who received reRT alone or in combination with PD-1 inhibition. We then compared reRT to a cohort of patients who did not receive reRT. RESULTS: Thirty-one patients were included (8-reRT with nivolumab; 4-reRT alone; 19-no reRT). Patients who received reRT had prolonged OS compared to no reRT (22.9 months-reRT with nivolumab; 20.4 months-reRT alone; 8.3 months-no reRT; p < 0.0001). Patients who received reRT with nivolumab vs. reRT only had slightly prolonged OS from diagnosis and from reRT (22.9 vs. 20.4 months for time from diagnosis; 6.8 vs. 6.0 months for time from reRT). All patients receiving reRT with or without nivolumab tolerated the therapy without acute or late toxicity. CONCLUSIONS: Our experience demonstrates the tolerability of reRT with concurrent PD-1 inhibition for recurrent DIPG and suggests that combination therapy may offer survival benefit. Future prospective studies are needed to confirm the benefits of this combination therapy.

The genetic landscape of ganglioglioma.

Ganglioglioma is the most common epilepsy-associated neoplasm that accounts for approximately 2% of all primary brain tumors. While a subset of gangliogliomas are known to harbor the activating p.V600E mutation in the BRAF oncogene, the genetic alterations responsible for the remainder are largely unknown, as is the spectrum of any additional cooperating gene mutations or copy number alterations. We performed targeted next-generation sequencing that provides comprehensive assessment of mutations, gene fusions, and copy number alterations on a cohort of 40 gangliogliomas. Thirty-six harbored mutations predicted to activate the MAP kinase signaling pathway, including 18 with BRAF p.V600E mutation, 5 with variant BRAF mutation (including 4 cases with novel in-frame insertions at p.R506 in the ß3-αC loop of the kinase domain), 4 with BRAF fusion, 2 with KRAS mutation, 1 with RAF1 fusion, 1 with biallelic NF1 mutation, and 5 with FGFR1/2 alterations. Three gangliogliomas with BRAF p.V600E mutation had concurrent CDKN2A homozygous deletion and one additionally harbored a subclonal mutation in PTEN. Otherwise, no additional pathogenic mutations, fusions, amplifications, or deletions were identified in any of the other tumors. Amongst the 4 gangliogliomas without canonical MAP kinase pathway alterations identified, one epilepsy-associated tumor in the temporal lobe of a young child was found to harbor a novel ABL2-GAB2 gene fusion. The underlying genetic alterations did not show significant association with patient age or disease progression/recurrence in this cohort. Together, this study highlights that ganglioglioma is characterized by genetic alterations that activate the MAP kinase pathway, with only a small subset of cases that harbor additional pathogenic alterations such as CDKN2A deletion.

Role of porosity and matrix behavior on compressive fracture of Haversian bone using random spring network model.

Haversian remodeling is known to result in improved resistance to compressive fracture in healthy cortical bone. Here, we examine the individual roles of the mean porosity, structure of the network of pores and remodeled bone matrix properties in the fracture behavior of Haversian bone. The detailed structure of porosity network is obtained both pre- and post-testing of dry cubical bone samples using micro-Computed Tomography. Based on the periodicity in the features of porosity along tangential direction, we develop a two dimensional porosity-based random spring network model for Haversian bone. The model is shown to capture well the macroscopic response and reproduce the avalanche statistics similar to recently reported experiments on porcine bone. The predictions suggest that at the millimeter scale, the remodeled bone matrix of Haversian bone is less stiff but tougher than that of plexiform/primary bone.