PNA C-C<SUP>+</SUP> i-motif: superior stability of PNA TC<SUB>8</SUB> tetraplexes compared to DNA TC<SUB>8</SUB> tetraplexes at low pH

Study of self-assembly of PNA TC8 monitored by UV thermal transition at 295 nm indicates formation of a C-C+ tetraplex (i-motif) in acidic pH, with higher stability than the analogous dTC8

(α,α-dimethyl)glycyl (dmg) PNAs: Achiral PNA analogs that form stronger hybrids with cDNA relative to isosequential RNA

The design and facile synthesis of sterically constrained new analogs of PNA having gem-dimethyl substitutions on glycine (dmg-PNA-T) is presented. The PNA oligomers [aminoethyl dimethylglycyl (aedmg) and aminopropyl dimethylglycyl (apdmg)] synthesized from the monomers 6 and 12) effected remarkable stabilization of homothyminePNA2:homoadenine DNA/RNA triplexes and mixed base sequence duplexes with target cDNA or RNA. They show a higher binding to DNA relative to that with isosequential RNA. This may be a structural consequence of the sterically rigid gem-dimethyl group, imposing a pre-organized conformation favorable for complex formation with cDNA. The results complement our previous work that had demonstrated that cyclohexanyl-PNAs favor binding with cRNA compared with cDNA and imply that the biophysical and structural properties of PNAs can be directed by introduction of the right rigidity in PNA backbone devoid of chirality. This approach of tweaking selectivity in binding of PNA constructs by installing gem-dimethyl substitution in PNA backbone can be extended to further fine-tuning by similar substitution in the aminoethyl segment as well either individually or in conjunction with present substitution

Sequential entrapment of PNA and DNA in lipid bilayers stacks

Sequential immobilization of single stranded DNA and complementary PNA molecules in thermally evaporated fatty amine films is demonstrated and evidence for their in-situ hybridization is presented

Highly efficient chemo- and enantioselective enzymatic resolution of (±)-methyl O-acetylmandelates

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Cultural adaptation of Alzheimer’s disease assessment scale–cognitive subscale for use in India and validation of the Tamil version for South Indian population

Objective: Currently no standardized tools are available in the Indian languages to assess changes in cognition. Our objectives are to culturally adapt the Alzheimer’s disease Assessment Scale–Cognitive Subscale (ADAS-Cog) for use in India and to validate the Tamil version in an urban Tamil-speaking older adult population. / Methods: Two panels of key stakeholders and a series of qualitative interviews informed the cultural and linguistic adaptation of the ADAS-Cog-Tamil. Issues related to levels of literacy were considered during the adaptation. Validation of the ADAS-Cog-Tamil was completed with 107 participants − 54 cases with a confirmed diagnosis of mild-moderate dementia, and 53 age, gender and education matched controls. Concurrent validity was examined with the Vellore Screening Instrument for Dementia (VSID) in Tamil. Internal consistency using Cronbach’s alpha, sensitivity and specificity data using the Area under the Receiver Operating Characteristics (AUROC) curve values were computed. Inter-rater reliability was established in a subsample. / Results: The ADAS-Cog-Tamil shows good internal consistency (α = 0.91), inter-rater reliability and concurrent validity (with VSID-Patient version: r = –0.84 and with VSID-Caregiver version: r = –0.79). A cut-off score of 13, has a specificity of 89% and sensitivity of 90% for the diagnosis of dementia. / Conclusion: ADAS-Cog-Tamil, derived from a rigorous, replicable linguistic and cultural adaptation process involving service users and experts, shows good psychometric properties despite the limitations of the study. It shows potential for use in clinical settings with urban Tamil speaking populations. The English version of the tool derived from the cultural adaptation process could be used for further linguistic adaptation across South Asia

Build your own closed loop: Graph-based proof of concept in closed loop for autonomous networks

Next Generation Networks (NGNs) are expected to handle heterogeneous technologies, services, verticals and devices of increasing complexity. It is essential to fathom an innovative approach to automatically and efficiently manage NGNs to deliver an adequate end-to-end Quality of Experience (QoE) while reducing operational expenses. An Autonomous Network (AN) using a closed loop can self-monitor, self-evaluate and self-heal, making it a potential solution for managing the NGN dynamically. This study describes the major results of building a closed-loop Proof of Concept (PoC) for various AN use cases organized by the International Telecommunication Union Focus Group on Autonomous Networks (ITU FG-AN). The scope of this PoC includes the representation of closed-loop use cases in a graph format, the development of evolution/exploration mechanisms to create new closed loops based on the graph representations, and the implementation of a reference orchestrator to demonstrate the parsing and validation of the closed loops. The main conclusions and future directions are summarized here, including observations and limitations of the PoC

Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial

Background. Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM. Methods. TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL). Results. Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P < .01). Conclusions. In a pediatric TBM trial, functional outcomes were excellent overall. The trend toward higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial. Clinical Trials Registration. NCT02958709

Identifying the research, advocacy, policy and implementation needs for the prevention and management of respiratory syncytial virus lower respiratory tract infection in low- and middle-income countries

Introduction: The high burden of respiratory syncytial virus (RSV) infection in young children disproportionately occurs in low- and middle-income countries (LMICs). The PROUD (Preventing RespiratOry syncytial virUs in unDerdeveloped countries) Taskforce of 24 RSV worldwide experts assessed key needs for RSV prevention in LMICs, including vaccine and newer preventive measures. Methods: A global, survey-based study was undertaken in 2021. An online questionnaire was developed following three meetings of the Taskforce panellists wherein factors related to RSV infection, its prevention and management were identified using iterative questioning. Each factor was scored, by non-panellists interested in RSV, on a scale of zero (very-low-relevance) to 100 (very-high-relevance) within two scenarios: (1) Current and (2) Future expectations for RSV management. Results: Ninety questionnaires were completed: 70 by respondents (71.4% physicians; 27.1% researchers/scientists) from 16 LMICs and 20 from nine high-income (HI) countries (90.0% physicians; 5.0% researchers/scientists), as a reference group. Within LMICs, RSV awareness was perceived to be low, and management was not prioritised. Of the 100 factors scored, those related to improved diagnosis particularly access to affordable point-of-care diagnostics, disease burden data generation, clinical and general education, prompt access to new interventions, and engagement with policymakers/payers were identified of paramount importance. There was a strong need for clinical education and local data generation in the lowest economies, whereas upper-middle income countries were more closely aligned with HI countries in terms of current RSV service provision. Conclusion: Seven key actions for improving RSV prevention and management in LMICs are proposed

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)