Differences in Childhood Growth Parameters Between Patients With Somatic and Heritable Retinoblastoma.

Purpose: Little is known regarding differences in childhood growth between somatic and heritable retinoblastoma (Rb) populations. We aimed to compare childhood growth parameters between somatic and heritable Rb cohorts at birth and at time of diagnosis with Rb. Methods: A multinational, longitudinal cohort study was conducted with patients from 11 centers in 10 countries who presented with treatment naïve Rb from January to December 2019. Variables of interest included age, sex, and size characteristics at birth and at time of presentation, as well as germline mutation status. After Bonferroni correction, results were statistically significant if the P value was less than 0.005. Results: We enrolled 696 patients, with 253 analyzed after exclusion criteria applied. Between somatic (n = 39) and heritable (n = 214) Rb cohorts, with males and females analyzed separately, there was no significant difference in birth weight percentile, weight percentile at time of diagnosis, length percentile at time of diagnosis, weight-for-length percentile at time of diagnosis, or change of weight percentile from birth to time of diagnosis. Patients with heritable Rb had a smaller mean weight percentile at birth and smaller mean weight and length percentiles at time of diagnosis with Rb, although this difference was not statistically significant. All cohorts experienced a slight negative change of weight percentile from birth to time of diagnosis. No cohort mean percentiles met criteria for failure to thrive, defined as less than the 5th percentile. Conclusions: Children with Rb seem to have normal birth and childhood growth patterns. There is no definitive evidence that somatic or heritable Rb has a biological or environmental impact on childhood growth parameters.

An in silico approach to evaluate the bindings of natural flavonoids and RNA-DNA hybrids.

Flavonoids, low molecular weight polyphenolic compounds, are important natural products that belong to plant secondary metabolites. They have diverse biomedical applications such as antioxidative, anti-inflammatory, enzyme inhibitory, antimutagenic, anticarcinogenic, aromatase inhibitory effects, etc. Some of the flavonoids have been exported for bindings with certain DNA and tRNA structures both experimentally and computationally. RNA-DNA hybrid (RDH) falls into an important category of noncanonical nucleic acid structures that have many important biological functions. We have investigated the interaction of RDH structures with some of the dietary flavonoids with the aid of computational methods such as docking and molecular dynamics simulation. The presence of the - OH group on the ligand and the availability of a proper binding pocket in the macromolecule are the two main factors driving the binding preference. Thus, this computationally guided report explains the binding of the flavonoids with RDH structures to assist the researchers in designing noncanonical nucleic acid-targeted drug molecules.Communicated by Ramaswamy H. Sarma.

New Xanthone Derivatives as Potent G-Quadruplex Binders for Developing Anti-Cancer Therapeutics.

Xanthone is an important scaffold for various medicinally relevant compounds. However, it has received scant attention in the design of agents that are cytotoxic to cancer cells via targeting the stabilization of G-quadruplex (G4) nucleic acids. Specific G4 DNA recognition against double-stranded (ds) DNA is receiving epoch-making interest for the development of G4-mediated anticancer agents. Toward this goal, we have synthesized xanthone-based derivatives with various functionalized side-arm substituents that exhibited significant selectivity for G4 DNA as compared to dsDNA. The specific interaction has been demonstrated by performing various biophysical experiments. Based on the computational study as well as the competitive ligand binding assay, it is inferred that the potent compounds exhibit an end-stacking mode of binding with G4 DNA. Additionally, compound-induced conformational changes in the flanking nucleotides form the binding pocket for effective interaction. Selective action of the compounds on cancer cells suggests their effectiveness as potent anti-cancer agents. This study promotes the importance of structure-based screening approaches to get molecular insights for new scaffolds toward desired specific recognition of non-canonical G4 DNA structures.

Diffuse large cell lymphoma of the lacrimal sac may mimic as acute dacryocystitis.

A 36-year-old male patient presented with a firm swelling in the left lacrimal sac region with a history of recurrent episodes of acute dacryocystitis, which partly resolved with systemic antibiotics. Computed tomography showed diffuse soft tissue mass without bony erosion in the same area. Incisional biopsy confirmed diffuse large cell lymphoma of non-Hodgkin's type by histopathology and immunohistochemistry. Oncologists did not detect systemic involvement, and the patient received six cycles of cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone (CHOP). Epiphora was resolved, and no recurrence of the lesion was seen with subsequent dacryocystorhinostomy with intubation and was in good health for up to 3 years of follow-up. Although primary lacrimal sac lymphoma is a rare entity, high suspicion, and prompt action in atypical cases can save lives from aggressive diffuse large cell lymphoma.

Risk factors associated with abandonment of care in retinoblastoma: analysis of 692 patients from 10 countries.

BACKGROUND: Rates of care abandonment for retinoblastoma (RB) demonstrate significant geographical variation; however, other variables that place a patient at risk of abandoning care remain unclear. This study aims to identify the risk factors for care abandonment across a multinational set of patients. METHODS: A prospective, observational study of 692 patients from 11 RB centres in 10 countries was conducted from 1 January 2019 to 31 December 2019. Multivariate logistic regression was used to identify risk factors associated with higher rates of care abandonment. RESULTS: Logistic regression showed a higher risk of abandoning care based on country (high-risk countries include Bangladesh (OR=18.1), Pakistan (OR=45.5) and Peru (OR=9.23), p<0.001), female sex (OR=2.39, p=0.013) and advanced clinical stage (OR=4.22, p<0.001). Enucleation as primary treatment was not associated with a higher risk of care abandonment (OR=0.59, p=0.206). CONCLUSION: Country, advanced disease and female sex were all associated with higher rates of abandonment. In this analysis, enucleation as the primary treatment was not associated with abandonment. Further research investigating cultural barriers can enable the building of targeted retention strategies unique to each country.

The role of maternal age & birth order on the development of unilateral and bilateral retinoblastoma: a multicentre study.

BACKGROUND/OBJECTIVES: Retinoblastoma is a common childhood intraocular malignancy, the bilateral form of which most commonly results from a de novo germline pathogenic variant in the RB1 gene. Both advanced maternal age and decreasing birth order are known to increase the risk of de novo germline pathogenic variants, while the influence of national wealth is understudied. This cohort study aimed to retrospectively observe whether these factors influence the ratio of bilateral retinoblastoma cases compared to unilateral retinoblastoma, thereby inferring an influence on the development of de novo germline pathogenic variants in RB1. SUBJECTS/METHODS: Data from 688 patients from 11 centres in 10 countries were analysed using a series of statistical methods. RESULTS: No associations were found between advanced maternal age, birth order or GDP per capita and the ratio of bilateral to unilateral retinoblastoma cases (p values = 0.534, 0.201, 0.067, respectively), indicating that these factors do not contribute to the development of a de novo pathogenic variant. CONCLUSIONS: Despite a lack of a definitive control group and genetic testing, this study demonstrates that advanced maternal age, birth order or GDP per capita do not influence the risk of developing a bilateral retinoblastoma.

Design and Synthesis of Xanthone Analogues Conjugated with Aza-aromatic Substituents as Promising G-Quadruplex Stabilizing Ligands and their Selective Cancer Cell Cytotoxic Action.

We have examined the stabilization of higher-order noncanonical G-quadruplex (G4) DNA structures formed by the G-rich sequences in the promoter region of oncogenes such as c-MYC, c-KIT, VEGF and BCl2 by newly synthesized, novel nitrogen-containing aromatics conjugated to xanthone moiety. Compounds with N-heterocyclic substituents such as pyridine (XNiso), benzimidazole (XBIm), quinoxaline (XQX) and fluorophore dansyl (XDan) showed greater effectiveness in stabilizing the G4 DNA as well as selective cytotoxicity for cancer cells (mainly A549) over normal cells both in terms of UV-Vis spectral titrations and cytotoxicity assay. Both fluorescence spectral titrimetric measurements and circular dichroism (CD) melting experiments further substantiated the G4 stabilization phenomenon by these small-molecular ligands. In addition, these compounds could induce the formation of parallel G4 structures in the absence of any added salt condition in Tris⋅HCl buffer at 25 °C. In a polymerase stop assay, the formation of stable G4 structures in the promoter of oncogenes and halting of DNA synthesis in the presence of the above-mentioned compounds was demonstrated by using oncogene promoter as the DNA synthesis template. Apoptosis-mediated cell death of the cancer cells was proved by Annexin V-PI dual staining assay and cell-cycle arrest occurred in the S phase of the cell cycles. The plausible mode of binding involves the stacking of the xanthone core on the G4 DNA plane with the possibility of interaction with the 5'-overhang as indicated by molecular dynamics simulation studies.

The complete mitochondrial genome study and phylogenetic analysis of Asiatic Water Snake (Fowlea piscator) using 'Next-Generation Sequencing' technology.

The first complete mitochondrial genome sequencing of Asiatic Water snake or Checkered Keelback or Fowlea piscator (=Xenochrophis piscator) was carried out using Next-Generation Sequencing technology. The complete mitochondrial genome of Asiatic Water snake is 16,999bp long with a base composition of 33% A, 28% T, 12% G and 27% C, with a GC content of 39%. Like the typical snake mitochondrial genome, F. piscator also shows relatively similar mitogenome arrangement comprising 37 genes including 13 protein-coding genes, 22 tRNA genes, two rRNA genes and two non-coding regions or a duplicated control region (D-Loop) along with an origin of replication. Nine genes including eight tRNAs and NAD6 were encoded on the Light or L-strand. Phylogenetic analyses using the complete mitochondrial genome of F. piscator demonstrate a close relationship with the family Colubridae and sub family Natricinae.

Deciphering the Binding Insights of Novel Disubstituted Anthraquinone Derivatives with G-Quadruplex DNA to Exhibit Selective Cancer Cell Cytotoxicity.

Anthraquinone-based compounds are well-known as duplex DNA as well as G-quadruplex DNA binders. Implications of various anthraquinone derivatives for specific recognition of G-quadruplex DNA over duplex DNA is a 'challenging' research work that requires adequate experience with molecular design. To address this important issue, we designed and synthesized ten new 2,6-disubstituted anthraquinone-based derivatives with different functionalized piperazinyl side-chains. Among these, particular compounds with certain distant groups have shown selective and significant binding affinities toward the c-MYC and c-KIT G-quadruplex DNA over the duplex DNA, as noticed from various biophysical experiments. The structural difference of quadruplex and duplex DNA was utilized to probe these derivatives for the end-stacking mode of binding with G-quadruplex DNA. The ability of the ligands to halt DNA synthesis by stabilizing G-quadruplex structures is one of the crucial points to further apply them for quadruplex-mediated anti-cancer therapeutics. Interestingly, these ligands trigger apoptosis to exhibit selective cytotoxicity toward cancer cells over normal cells. This was further evidenced by ligand-induced cell cycle arrest as well as cellular apoptotic morphological changes. These blood-compatible ligands provided detailed structure-activity relationship approaches for the molecular design of anthraquinone-based G-quadruplex binders.

Chemical Information and Computational Modeling of Targeting Hybrid Nucleic Acid Structures of PIM1 Sequences by Synthetic Pyrrole-Imidazole Carboxamide Drugs.

DNA can adopt various distinct structural motifs, such as quadruplex, duplex, i-motifs, etc. which have multifarious applications in biomedical therapeutics. Quadruplex-duplex hybrids (QDHs) consist of the juxtaposed quadruplex and duplex motifs and are thermally stable and biologically relevant. Selective binding toward these secondary structures plays an important role in the evaluation of the structure-specific ligands. Herein, several small molecules containing anthraquinone conjugated oligopyrrole, oligoimidazole, and pyrrole-imidazole derivatives have been screened for the binding of the quadruplex-duplex nucleic acid hybrids formed in PIM1 sequences through docking and molecular dynamics (MD) simulation studies. The binding interaction of the anthraquinone polypyrrole ligands has also been checked by performing different biophysical experiments. PIM1, being a coactivator of the MYC oncogene, can be targeted by these small molecules to control MYC expression which is overexpressed in the majority of human cancer cells. Accordingly, these cancer cell-specific and blood-compatible anthraquinone conjugated oligopyrrole ligands can be employed for anticancer therapeutic applications. Thus, the structure-activity relationship (SAR) of the screened ligands manifested prudent structural information for designing PIM1 QDHs targeting small molecules.

Pegylated interferon-alpha-2a for the treatment of ocular surface squamous neoplasia.

Ocular surface squamous neoplasia (OSSN) is the most common nonpigmented ocular surface neoplasm. Interferon-alpha (IFNα)-2b has been proved to be an effective immunotherapeutic agent to treat OSSN. We have used intralesional and topical (36 µg/ml) pegylated (peg) IFNα-2a to treat a recurrent surgically failed case of OSSN instead of IFNα-2b. In this case report, we have shared our initial experience with the novel use of peg-IFNα-2a to treat OSSN. According to our brief clinical experience, peg-IFNα-2a is nontoxic to ocular surface and has a promising role to treat OSSN.

The Effects of Breastfeeding on Retinoblastoma Development: Results from an International Multicenter Retinoblastoma Survey.

The protective effects of breastfeeding on various childhood malignancies have been established but an association has not yet been determined for retinoblastoma (RB). We aimed to further investigate the role of breastfeeding in the severity of nonhereditary RB development, assessing relationship to (1) age at diagnosis, (2) ocular prognosis, measured by International Intraocular RB Classification (IIRC) or Intraocular Classification of RB (ICRB) group and success of eye salvage, and (3) extraocular involvement. Analyses were performed on a global dataset subgroup of 344 RB patients whose legal guardian(s) consented to answer a neonatal questionnaire. Patients with undetermined or mixed feeding history, family history of RB, or sporadic bilateral RB were excluded. There was no statistically significant difference between breastfed and formula-fed groups in (1) age at diagnosis (p = 0.20), (2) ocular prognosis measures of IIRC/ICRB group (p = 0.62) and success of eye salvage (p = 0.16), or (3) extraocular involvement shown by International Retinoblastoma Staging System (IRSS) at presentation (p = 0.74), lymph node involvement (p = 0.20), and distant metastases (p = 0.37). This study suggests that breastfeeding neither impacts the sporadic development nor is associated with a decrease in the severity of nonhereditary RB as measured by age at diagnosis, stage of disease, ocular prognosis, and extraocular spread. A further exploration into the impact of diet on children who develop RB is warranted.

Minimally invasive harvesting fascia lata (FL) in ophthalmic plastic surgery.

PURPOSE: To describe a minimally invasive technique of harvesting fascia lata, and also to analyze the clinical uses and the outcome of fascia lata in Ophthalmic Plastic and Reconstructive surgery. METHODS: This interventional study was done in three tertiary care eye hospitals in Bangladesh from July 2014 to June 2020. We obtained autologous fascia lata for the correction of congenital ptosis with poor levator function (⩽4 mm), covering the ciliary staphyloma, repair of the extruded implant following anophthalmic socket surgery, and was also used to wrap the orbital implant after enucleation. Preserved FL was used only for children before 6 years of age for the treatment of congenital ptosis. RESULTS: Out of 60 subjects, 38 (63.3%) were male and 22 (36.7%) were female. Autogenous fascia lata was used for frontalis brow suspension (FBS) in 25 (41.67%) patients of congenital ptosis with poor levator function, as patch graft in ciliary staphyloma (11 cases, 18.3%), to wrap orbital implant following enucleation in intraocular malignancies (nine cases, 15%), to repair of implant extrusion following evisceration (five cases, 8.3%), and as fascial sling to correct recurrent paralytic ectropion (one case, 1.67%). Allogeneic or preserved fascia lata was used to correct congenital ptosis in patients less than 6 years of age (nine cases, 15%). Mean follow-up time was 5.32 months. CONCLUSION: Fascia lata (autogenous and allogeneic preserved) has varied uses in ophthalmic plastic surgery. Harvesting fascia lata (FL) using with minimally invasive method was successful with the least scar on the thigh to correct congenital ptosis, ciliary staphyloma, repair of extruded implant, and in wrapping implant after enucleation to get better cosmesis and motility.

Theoretical Insight into the Library Screening Approach for Binding of Intermolecular G-Quadruplex RNA and Small Molecules through Docking and Molecular Dynamics Simulation Studies.

The interactions of intermolecular G-quadruplex RNA and small molecules have been investigated by computational studies. Various anthraquinone, bisbenzimidazole, and carbazole-benzimidazole based ligands have shown a distinct preference to G-quadruplex structures as opposed to the corresponding duplex forms of DNA that were docked with telomeric G-quadruplex RNA. The comparative binding study of such ligands with G-quadruplex (G4) RNA showed higher binding affinities toward carbazole-benzimidazole ligands than those of the anthraquinone and bisbenzimidazole based ligands. A molecular dynamics simulation study was used to examine quadruplex-ligand interactions. Analysis of the binding free energy indicated the formation of the thermodynamically favorable RNA-ligand complex. The formation of several H-bonding interactions and the change of the solvent accessible surface area (SASA) also support the effective binding of the carbazole-benzimidazole ligands with G4 RNA structures. Thus, the library screening approach has assisted in getting a structure-activity relationship for the selected small molecules toward the G-quadruplex RNA binding, which can be applied in the targeting of G-quadruplex RNA medicated anticancer therapeutics.

Lag Time between Onset of First Symptom and Treatment of Retinoblastoma: An International Collaborative Study of 692 Patients from 10 Countries.

BACKGROUND: The relationship between lag time and outcomes in retinoblastoma (RB) is unclear. In this study, we aimed to study the effect of lag time between onset of symptoms and diagnosis of retinoblastoma (RB) in countries based on their national-income and analyse its effect on the outcomes. METHODS: We performed a prospective study of 692 patients from 11 RB centres in 10 countries from 1 January 2019 to 31 December 2019. RESULTS: The following factors were significantly different among different countries based on national-income level: age at diagnosis of RB (p = 0.001), distance from home to nearest primary healthcare centre (p = 0.03) and mean lag time between detection of first symptom to visit to RB treatment centre (p = 0.0007). After adjusting for country income, increased lag time between onset of symptoms and diagnosis of RB was associated with higher chances of an advanced tumour at presentation (p < 0.001), higher chances of high-risk histopathology features (p = 0.003), regional lymph node metastasis (p < 0.001), systemic metastasis (p < 0.001) and death (p < 0.001). CONCLUSIONS: There is a significant difference in the lag time between onset of signs and symptoms and referral to an RB treatment centre among countries based on national income resulting in significant differences in the presenting features and clinical outcomes.

Successful integration of HIV pre-exposure prophylaxis into a community-based HIV prevention program for female sex workers in Kolkata, India.

We assessed the impact of pre-exposure prophylaxis (PrEP) in the context of a community-based HIV program among female sex workers (FSWs) in Kolkata, India. This was an open-label, uncontrolled demonstration trial. HIV seronegative FSWs over 18 years were eligible. Participants were administered daily tenofovir/emtricitabine (TDF-FTC) with follow-up visits at months 1, 3, 6, 9, 12, and 15. Drug adherence was monitored by self-report, and a random subset of participants underwent plasma TDF testing. 843 women were screened and 678 enrolled and started on PrEP. Seventy-nine women (11%) did not complete all scheduled visits: four women died of reasons unrelated to PrEP and 75 withdrew, for a 15-month retention rate of 89%. Self-reported daily adherence was over 70%. Among those tested for TDF, the percentage of women whose level reached ≥40 ng/mL was 65% by their final visit. There were no HIV seroconversions, and no evidence of significant changes in sexual behavior. This study demonstrated the feasibility and effectiveness of PrEP for FSWs in Kolkata, with very high levels of adherence to PrEP and no HIV seroconversions. The integration of PrEP into an existing community-based HIV prevention program ensured community support and facilitated adherence.

Primary Conjunctival Pigmented Basal Cell Carcinoma with Increased Numbers of Intra-Tumour Melanocytes, Mimicking Melanoma: A Case Report and Review of the Literature.

A 60-year-old, South-Asian male patient presented with a dark brown lesion on his left conjunctiva surface near the limbus for 2 years. Examination showed a globular, dark brown-coloured mass near the temporal limbus at 4 to 5 o'clock position, measuring 3 × 3 × 2 mm. There were a few scattered flat pigmented lesions near the mass and also a few prominent vessels. The mass underwent wide local excision, with a clear margin, followed by double freeze cryotherapy of the conjunctival margins along with the application of Mitomycin C. The bare sclera was covered by amniotic membrane. Histology surprisingly revealed a nodular basal cell carcinoma (BCC) containing melanin. The melanin was present in the tumour cell cytoplasm, within melanophages and within dendritic, Melan A-positive melanocytes. The BCC was immunohistochemically positive for BerEP4 and negative for EMA. The clinically observed smaller nodules flanking the main pigmented BCC corresponded histologically to pigmented superficial growth pattern BCC connected to the under surface of the conjunctival epithelium. This is the first report of a pigmented BCC of the conjunctiva, mimicking a conjunctival melanoma. Pigmented BCC should be considered in the differential diagnosis of pigmented tumours of the conjunctiva.

Specific stabilization of promoter G-Quadruplex DNA by 2,6-disubstituted amidoanthracene-9,10-dione based dimeric distamycin analogues and their selective cancer cell cytotoxicity.

We have designed and synthesized anthraquinone containing compounds which have oligopyrrole side chains of varying lengths. These compounds stabilized the G-quadruplex DNA formed in the promoter regions of c-MYC oncogenes selectively over the duplex DNA. These observations were recorded using UV-vis spectroscopic titrations, fluorescence measurements and circular dichroism (CD) spectral titrations. The potency of the compounds to stabilize the G4 DNA has been shown from the thermal denaturation experiments. The compound interacts with c-MYC G-quadruplex DNA through stacking mode as obtained from ethidium bromide displacement assay, cyclic voltammetric titration, and docking experiments. Molecular modeling studies suggested that the stacking of the anthraquinone moiety over the G-tetrad of the G4 structures are responsible for the stability of such quadruplex secondary structure. Furthermore, polymerase stop assay also supported the formation of stable G4 structures in the presence of the above-mentioned compounds. The compounds have shown selective cancer cell (HeLa and HEK293T) cytotoxicity over normal cells (NIH3T3 and HDFa) under in vitro conditions as determined from MTT based cell viability assay. Apoptosis was found to be the mechanistic pathway underlying the cancer cell cytotoxicity as obtained from Annexin V-FITC and PI dual staining assay which was further substantiated by nuclear morphological changes as observed by AO/EB dual staining assay. Cellular morphological changes, as well as nuclear condensation and fragmentation upon treatment with these compounds, were observed under bright field and confocal microscopy.

Geometry of the Poincaré plot can segregate the two arms of autonomic nervous system - A hypothesis.

Autonomic Nervous System (ANS) operates to achieve the optimum physiological functioning and maintains homeostasis in a tonic and continuous manner. Evaluation of ANS profile is crucial in assessing autonomic dysfunction. Conventional ANS evaluation procedures fail to capture minute dynamic alterations of ANS activities. The ANS output pattern is appropriately reflected in the fine alteration of the resting heart rate (HR). HR is a non-stationary variable, results from the dynamic interplay between the multiple physiologic mechanisms. The control of cardiac rate or the chronotropic regulation of heart is considered as a coupled network of oscillators, each representing a specific facet of the cardiovascular reflex. The slower vasomotor oscillation via sympathetic system is combined with rapid respiratory oscillation by parasympathetic system to modulate the intrinsic oscillation pattern of the SA Node. Heart Rate Variability (HRV) is used to understand the autonomic influence on cardiovascular system in health and disease. Fourier decomposition of HRV offers us mainly two different frequency components. High frequency (HF) variation indicates parasympathetic variability due to respiration and Low frequency (LF) mainly implicates tonic sympathetic influence, due to slower vasomotor modulation of heart rate. However, different studies show conflicting results and direct recording of sympathetic nerve activity also failed to correlate with LF power in either healthy subjects or in patients with increased cardiac sympathetic drive. A scatter-plot where each R-R interval is plotted against the preceding R-R interval forms a distributed elliptic point cloud in two dimensional plane. The phase space realization of this plot with dimension two and delay one is referred to as Poincaré plot analysis, an emerging quantitative-visual technique where the shape of the plot is categorized into different functional classes. The plot provides summary as well as detailed beat-to-beat information of the heart. This plot can be extended to three dimensions and with multi-lag, offering more insight and information. A mathematical expression was developed by an interventional study by Toichi et al., using pharmacological blockers during different physiological variables that calculated the lengths of transverse and longitudinal axes of the Poincaré plot to derive two quantitative expressions of sympathetic and vagal influence on HRV: 'cardiac sympathetic index' (CSI)) and 'cardiac vagal index' (CVI). In the present study, we emulate Poincaré plot patterns seen in normal range of sympatho-vagal balances and also in Diabetes Mellitus (DM), known to cause autonomic dysfunction. The emerging pattern of R-R interval time series would provide valuable insight into the altered temporal dynamics and also extract crucial features embedded within. DM is a major public health crisis globally and particularly in Indian population. We hypothesize that, CSI and CVI will effectively segregate the two arms of ANS and can be utilized as an effective evaluation tool to explore the disease status in patients of Diabetes Mellitus. We also propose that, the dynamics of fluctuations in physiological rhythms that exhibit long-term correlation and memory, can also be explored and expressed quantitatively by incorporating various degrees of 'lag' in these recurrence plots.

A pilot randomized controlled trial (RCT) of daily versus weekly interactive voice response calls to support adherence among antiretroviral treatment patients in India.

BACKGROUND: There are more than two million people living with HIV (PLH) in India, with more than 30% on antiretroviral treatment (ART) estimated to be non-adherent. This study aimed to (I) document adherence rates and related factors among ART patients in a large ART clinic in India, and (II) pilot test daily and weekly interactive voice response (IVR) calls to improve ART adherence and related outcomes. METHODS: ART patients reporting missing at least one dose in prior 6 months (N=362) were enrolled and assessed via self-report and medical record review. Participants were randomized to one of two conditions: (I) twice-daily IVR call reminders with self-management support messaging, plus a weekly IVR adherence assessment; or (II) an attention control, with only weekly IVR adherence assessment. Participants completed study assessments at baseline, 2-, 4-, and 6-months with high retention (88% to 96%). RESULTS: Intention-to-treat analyses found limited support for intervention effects for improving or maintaining ART adherence or CD4 counts between the two study arms over 6-months follow-up. Adherence increased significantly in the six months prior to baseline from about 65% to >95% with perfect adherence based on pill counts from medical records and consistent with patient self-report measures, which presented ceiling effects for detecting improvements in ART adherence in response to IVR intervention exposure. There was also limited support for intervention effects on secondary, self-management outcomes. CONCLUSIONS: High levels of adherence were sustained throughout the 6-month RCT. IVR regulation changes in India delayed study launch for 6 months, which likely allowed mobilization of improved adherence at the clinic, provider and patient levels in anticipation of the study launch. Therefore, ceiling effects limited inferences on intervention effects to improve adherence. Results suggest that clinic-level adherence monitoring may be sufficient to mobilize adherence improvements by providers and patients. TRIAL REGISTRATION: ClinicalTrials.gov registration #NCT02118454.