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OBJECTIVE: To describe the Port Delivery System with ranibizumab implant insertion procedure. METHODS: A surgical procedure based on the clinical trial program in patients with retinal diseases. RESULTS: An infusion line is placed in the infero-temporal quadrant; a superotemporal quadrant corneal traction suture is recommended. The superotemporal quadrant peritomy of 6 × 6 mm is executed with gentle, purposeful tissue handling. Generous posterior and lateral sub-Tenon's capsule dissection creates laxity for the subsequent closure. Adequate scleral hemostasis is achieved with wet-field cautery to maintain a clean field. The implant is filled under magnification with a customized formulation of ranibizumab. A precise 3.5-mm-long scleral incision (4 mm posterior and parallel to the limbus) is created to ensure proper implant fit. The exposed pars plana undergoes laser ablation to reduce vitreous hemorrhage risk. A pars plana incision is made, and the implant is inserted perpendicular to the globe and seated flush against the sclera. Complete closure of both the conjunctiva and Tenon's capsule with scleral anchoring and mild tissue overhang at the anterior limbus is performed to reduce conjunctival erosion and retraction risks. CONCLUSION: The procedure is straightforward yet requires precise preoperative and intraoperative preparation and standardized surgical techniques. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:249–256.]

PURPOSE: To describe the Port Delivery System with ranibizumab refill-exchange procedure. METHODS: Procedure based on the clinical trial program in patients with retinal diseases. RESULTS: The refill-exchange procedure is performed under topical anesthesia and strict aseptic conditions. Supplemental task lighting and magnification are recommended throughout the procedure. Ranibizumab is aseptically transferred from the vial with the filter needle and air is removed from the syringe. The filter needle is then replaced with the refill needle; any remaining air is removed from the syringe and the plunger is advanced to the 0.1-mL mark. Targeting the implant septum center, the refill needle is inserted perpendicularly to the globe until the soft stop contacts the conjunctiva (perpendicular orientation and conjunctival contact are maintained throughout the procedure); a cotton-tipped applicator is recommended for globe stabilization. The entire syringe contents are slowly injected over 5–10 seconds while existing solution fills the fluid collection reservoir. Once completed, the needle is carefully withdrawn while maintaining perpendicularity. The procedure can be successfully performed in rare, specific cases, including subconjunctival thickening or fibrous capsule formation, fluid-filled bleb formation, and corneal patch grafts. CONCLUSION: The procedure is straightforward but distinct from intravitreal injections and requires adherence to standardized techniques. With appropriate preparation, the procedure can be performed in specific cases. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:257–265.]

OBJECTIVES: To describe conjunctiva and Tenon's capsule handling during the Port Delivery System with ranibizumab (PDS) implant insertion procedure including up-front assessments, planning, and instrumentation, with emphasis placed on the peritomy, scleral dissection, and closure steps. METHODS: Surgical pearls based on experience accumulated in the PDS clinical trial program in patients with retinal diseases. RESULTS: Preoperative preparation, specific instruments, and meticulous techniques are key to optimizing surgical outcomes. Before surgery, assessment of factors that affect conjunctival integrity and an in-office conjunctiva examination are conducted. Gentle, purposeful conjunctiva and Tenon's capsule handling with nontoothed forceps and suturing with a BV needle are recommended to prevent tissue damage. The peritomy is 6 mm by 6 mm, centered around the planned implant location in the superotemporal quadrant. A complete sub-Tenon's capsule dissection is achieved using a wide, robust lateral and posterior dissection technique to free tissue from the sclera and minimize tension. The globe is stabilized during scleral cutdown by grasping the sclera with fine-toothed forceps away from the incision edge to prevent tissue delamination. When closing the peritomy, both the conjunctiva and Tenon's capsule are completely captured and sutured with scleral anchoring at the apex of the peritomy to help prevent conjunctival retraction and erosion. Mitigation and detection of adverse events is critical to successful surgical outcomes. CONCLUSIONS: The PDS implant insertion procedure is straightforward, but it requires planned preoperative preparation, specific instruments, and meticulous techniques. The surgical pearls described here offer insights for optimizing outcomes. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:266–273.]

Manufacturing firms are increasingly seeking cost and other competitive advantages by tightly coupling and managing their relationship with suppliers. Among other mechanisms, interorganizational systems (IOS) that facilitate boundary‐spanning activities of a firm enable them to effectively manage different types of buyer–supplier relationships. This study integrates literature from the operations and information systems fields to create a joint perspective in understanding the linkages between the nature of the IOS, buyer–supplier relationships, and manufacturing performance at the dyadic level. External integration, breadth, and initiation are used to capture IOS functionality, and their effect on process efficiency and sourcing leverage is examined. The study also explores the differences in how manufacturing firms use IOS when operating under varying levels of competitive intensity and product standardization. In order to test the research models and related hypothesis, empirical data on buyer–supplier dyads is collected from manufacturing firms. The results show that only higher levels of external integration that go beyond simple procurement systems, as well as who initiates the IOS, allow manufacturing firms to enhance process efficiency. In contrast, IOS breadth and IOS initiation enable manufacturing firms to enhance sourcing leverage over their suppliers. In addition, firms making standardized products in highly competitive environments tend to achieve higher process efficiencies and have higher levels of external integration. The study shows how specific IOS decisions allow manufacturing firms to better manage their dependence on the supplier for resources and thereby select system functionalities that are consistent with their own operating environments and the desired supply chain design.

BackgroundONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201.MethodsPatients ≥ 18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of weekly ONC201, which was confirmed in an 11-patient dose expansion cohort.ResultsTwenty patients were enrolled: three at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients.ConclusionsWeekly, oral ONC201 is well-tolerated and results in enhanced immunostimulatory activity that warrants further investigation.Trial registration NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors).

Introduction Non-alcoholic fatty liver disease (NAFLD) has become a widespread cause of chronic liver disease, ranging from simple steatosis to severe conditions like non-alcoholic steatohepatitis (NASH) and cirrhosis. Despite its similarity to alcohol-induced liver damage, NAFLD affects individuals with no significant alcohol consumption. This study explores the association between NAFLD, bone mineral density (BMD), insulin resistance, and subclinical inflammation, focusing on the Asian Indian population. The primary objective was to investigate the relationship between NAFLD and BMD, insulin levels, and markers of subclinical inflammation, hypothesizing that patients with NAFLD exhibit lower BMD, possibly linked to insulin resistance and inflammation. Methodology A cross-sectional study with 100 subjects aged 18-50 years (50 cases with NAFLD and 50 controls) was conducted. Exclusion criteria included excessive alcohol consumption, drug-induced fatty liver, severe organ dysfunction, infections, pregnancy, and acute or chronic illness. Data were collected through clinical examinations, anthropometric measurements, biochemical investigations, ultrasound diagnosis of NAFLD, and dual-energy X-ray absorptiometry (DEXA) scans for BMD assessment. Statistical analysis employed the chi-squared tests, t-tests, and Wilcoxon rank-sum tests. Results NAFLD patients had higher body mass index (BMI), waist-to-hip ratio, and markers of insulin resistance and inflammation compared to non-NAFLD controls. DEXA scans revealed significantly lower BMD in NAFLD cases, along with a higher prevalence of osteopenia. Positive correlations were observed between BMD and insulin resistance. The study contributes to understanding the link between NAFLD and lower BMD in the Asian Indian population, emphasizing the impact of insulin resistance and inflammation on bone health. The literature review supports the relevance of exploring NAFLD as an independent risk factor for low BMD. Conclusion This case-control study underscores the significant association between NAFLD and lower BMD in the Asian Indian population. Despite limitations, the findings highlight the importance of further research with larger samples and comprehensive assessments to elucidate the interplay between NAFLD, metabolic factors, and bone health.

Stationary cycling is the popular, preferred, and convenient form of exercise. During exercise, autonomic modulation is seen which can be assessed by heart rate variability (HRV). The aim of the study was to evaluate the changes in HRV during mild-intensity cycling exercise. An observational cross-sectional study was done on 20 healthy male volunteers with the age (35.44 ± 4.12), height (71.12 ± 11.98), and weight (161.23 ± 11.65), BMI (27.12 ± 3.49) attending various YOGA sessions in AYUSH OPD. Volunteers underwent an exercise program at the mild intensity of 30% to 50% of maximal heart rate on a stationary cycle for 20 min. HRV was recorded by the HRV mobile unit Dynamika Machine at rest, every 5 min (4×) over 20 min and during the recovery period. Repeated measures of analysis of variance with post-hoc analysis with Bonferroni and Holm's multiple comparisons. Significant change was observed in mean heart rate and time domain parameters. Frequency domain parameters that showed significant change were total power, High Frequency- HF (ms ), Very Low Frequency -VLF (ms ), Low Frequency -LF (ms ), and Very Low Frequency %-VLF (%). The HRV parameters conclusively point towards cardiac parasympathetic withdrawal and sympathetic dominance at the initiation of exercise. With the progression of exercise, the sympathetic influence is retained. In the recovery period parasympathetic reactivation gains control over heart rate as well as HRV. The HRV response to exercise challenges may be helpful in designing exercise programs based on variations in the autonomic response.

Background Verbal autopsy (VA) has been proposed to determine the cause of death (COD) distributions in settings where most deaths occur without medical attention or certification. We develop performance criteria for VA-based COD systems and apply these to the Registrar General of India’s ongoing, nationally-representative Indian Million Death Study (MDS). Methods Performance criteria include a low ill-defined proportion of deaths before old age; reproducibility, including consistency of COD distributions with independent resampling; differences in COD distribution of hospital, home, urban or rural deaths; age-, sex- and time-specific plausibility of specific diseases; stability and repeatability of dual physician coding; and the ability of the mortality classification system to capture a wide range of conditions. Results The introduction of the MDS in India reduced the proportion of ill-defined deaths before age 70 years from 13% to 4%. The cause-specific mortality fractions (CSMFs) at ages 5 to 69 years for independently resampled deaths and the MDS were very similar across 19 disease categories. By contrast, CSMFs at these ages differed between hospital and home deaths and between urban and rural deaths. Thus, reliance mostly on urban or hospital data can distort national estimates of CODs. Age-, sex- and time-specific patterns for various diseases were plausible. Initial physician agreement on COD occurred about two-thirds of the time. The MDS COD classification system was able to capture more eligible records than alternative classification systems. By these metrics, the Indian MDS performs well for deaths prior to age 70 years. The key implication for low- and middle-income countries where medical certification of death remains uncommon is to implement COD surveys that randomly sample all deaths, use simple but high-quality field work with built-in resampling, and use electronic rather than paper systems to expedite field work and coding. Conclusions Simple criteria can evaluate the performance of VA-based COD systems. Despite the misclassification of VA, the MDS demonstrates that national surveys of CODs using VA are an order of magnitude better than the limited COD data previously available.

Background Acute Encephalitis Syndrome (AES) is a critical public health issue, contributing significantly to morbidity and mortality in India, particularly among children. Despite ongoing vaccination efforts, Japanese Encephalitis (JE) remains a major cause of AES. This study analyzes the epidemiology of AES and JE in India from 2014 to 2023, using data from the Virus Research and Diagnostic Laboratory Network (VRDLN). Methods A cross-sectional analysis was conducted on AES cases reported by 159 VRDLN laboratories between 2014 and 2023. Standardized diagnostic tests such as polymerase chain reaction were used to identify causative pathogens, including JE virus. All the labs in the network followed BSL-2 standards. Descriptive analyses were performed on AES cases by year, etiology, and demographic factors. JE cases were further analyzed for geographic distribution, age, sex, and clinical characteristics. Results Over the study period, 124,890 AES cases were reported, with 16.3% testing positive for at least one pathogen, including 10% confirmed as JE. The highest JE positivity was observed in the northeastern states. An increasing trend in the number of cases tested and JE detections was noted, alongside a shift in the age distribution towards younger populations. The median (IQR) annual test positivity for JEV among tested was 16.2% (14.5%, 18.4%). Conclusions The VRDLN has substantially enhanced India’s capacity to diagnose and monitor AES and JE. Despite progress, JE transmission persists, particularly in endemic regions, posing significant public health challenges. Strengthened surveillance, improved diagnostic coverage, and integrated pathogen testing are essential for effective interventions. Targeted strategies and sustained public health efforts are critical to reducing the burden of AES and JE in India.

We report results of the studies relating to development of an aptamer-based electrochemical biosensor for detection of human lung adenocarcinoma A549 cells. The aminated 85-mer DNA aptamer probe specific for the A549 cells has been covalently immobilized onto silane self assembled monolayer (SAM) onto ITO surface using glutaraldehyde as the crosslinker. The results of cyclic voltammetry and differential pulse voltammetry studies reveal that the aptamer functionalized bioelectrode can specifically detect lung cancer cells in the concentration range of 103 to 107 cells/ml with detection limit of 103 cells/ml within 60 s. The specificity studies of the bioelectrode have been carried out with control KB cells. No significant change in response is observed for control KB cells as compared to that of the A549 target cells.