Dosing Schedule Research Articles

Hydrogel-based Drug Delivery System in Diabetes Management.

It is estimated that there are over 200 million people living with diabetes mellitus (DM) all over the world. It is a metabolic condition caused by decreased insulin action or secretion. Diabetes Mellitus is also known as Type 2 Diabetes Mellitus. Type 1 diabetes mellitus and type 2 diabetes mellitus are the two most common types of DM. Treatment for type 1 diabetes often consists of insulin replacement therapy, while treatment for type 2 diabetes typically consists of oral hypoglycemics. Conventional dosing schedules for the vast majority of these medications come with a number of drawbacks, the most common of which are frequent dosing, a short half-life, and low bioavailability. Thus, innovative and regulated oral hypoglycemic medication delivery methods have been developed to reduce the limitations of standard dose forms. The studies and reviews published under the title were looked up in several databases (including PubMed, Elsevier, and Google Scholar). Hydrogels made from biopolymers are three-dimensional polymeric networks that can be physically or chemically crosslinked. These networks are based on natural polymers and have an inherent hydrophilic quality because of the functional groups they contain. They have a very high affinity for biological fluids in addition to a high water content, softness, flexibility, permeability, and biocompatibility. The fact that these features are similar to those of a wide variety of soft living tissues paves the way for several potentials in the field of biomedicine. In this sense, hydrogels offer excellent platforms for the transport of medications and the controlled release of those drugs. Additionally, biopolymer-based hydrogels can be put as coatings on medical implants in order to improve the biocompatibility of the implants and to prevent medical diseases. The current review focuses on the most recent advancements made in the field of using biopolymeric hydrogels that are physically and chemically crosslinked, in addition to hydrogel coatings, for the purpose of providing sustained drug release of oral hypoglycemics and avoiding problems that are associated with the traditional dosage forms of oral hypoglycemics.

Client preferences for the design and delivery of injectable opioid agonist treatment services: Results from a best-worst scaling task.

Clinical trials support injectable opioid agonist treatment (iOAT) for individuals with opioid use disorder (OUD) for whom other pharmacological management approaches are not well-suited. However, despite substantial research indicating that person-centered care improves engagement, retention and health outcomes for individuals with OUD, structural requirements (e.g. drug policies) often dictate how iOAT must be delivered, regardless of client preferences. This study aimed to quantify clients' iOAT delivery preferences to improve client engagement and retention. Cross-sectional preference elicitation survey. Metro Vancouver, British Columbia, Canada. 124 current and former iOAT clients. Participants completed a demographic questionnaire package and an interviewer-led preference elicitation survey (case 2 best-worst scaling task). Latent class analysis was used to identify distinct preference groups and explore demographic differences between preference groups. Most participants (n = 100; 81%) were current iOAT clients. Latent class analysis identified two distinct groups of client preferences: (1) autonomous decision-makers (n = 73; 59%) and (2) shared decision-makers (n = 51; 41%). These groups had different preferences for how medication type and dosage were selected. Both groups prioritized access to take-home medication (i.e. carries), the ability to set their own schedule, receiving iOAT in a space they like and having other services available at iOAT clinics. Compared with shared decision-makers, fewer autonomous decision-makers identified as a cis-male/man and reported flexible preferences. Injectable opioid agonist treatment (iOAT) clients surveyed in Vancouver, Canada, appear to prefer greater autonomy than they currently have in choosing OAT medication type, dosage and treatment schedule.

PH-Sensitive In Situ Gel of Mirtazapine Invasomes for Rectal Drug Delivery: Protruded Bioavailability and Anti-Depressant Efficacy.

The present research emphasizes fabrication alongside the assessment of an innovative nano-vesicular membranous system known as invasomes (NVMs) laden with Mirtazapine for rectal administration. This system could circumvent the confines of orally administered counterparts regarding dose schedules and bioavailability. Mirtazapine invasomes were tailored by amalgamating phospholipid, cineole, and ethanol through a thin-film hydration approach rooted in the Box-Behnken layout. Optimization of composition parameters used to fabricate desired NVMs' physicochemical attributes was undertaken using the Design-Expert® program. The optimal MRZ-NVMs were subsequently transformed to a pH-triggered in situ rectal gel followed by animal pharmacodynamic and pharmacokinetic investigations relative to rectal plain gel and oral suspension. The optimized NVMs revealed a diameter size of 201.3 nm, a z potential of -28.8 mV, an entrapment efficiency of 81.45%, a cumulative release within 12 h of 67.29%, and a cumulative daily permeated quantity of 468.68 µg/cm2. Compared to the oral suspension, pharmacokinetic studies revealed a 2.85- and 4.45-fold increase in calculated rectal bioavailability in circulation and brain, respectively. Pharmacodynamic and immunohistopathology evaluations exposed superior MRZ-NVMs attributed to the orally administered drug. Consequently, rectal MRZ-NVMs can potentially be regarded as a prospective nanoplatform with valuable pharmacokinetics and tolerability assets.

Stated preferences for new HIV prevention technologies among men who have sex with men in India: A discrete choice experiment.

India has the second largest HIV epidemic in the world. Despite successes in epidemic control at the population level, a concentrated epidemic persists among gay and other men who have sex with men (MSM). However, India lags in implementation of biomedical prevention technologies, such as HIV pre-exposure prophylaxis (PrEP). In order to inform scale-up of new HIV prevention technologies, including those in the development pipeline, we assessed willingness to use oral PrEP, rectal microbicides, and HIV vaccines, and choices among product characteristics, among MSM in two major Indian cities. A cross-sectional survey was conducted with a discrete choice experiment (DCE), an established methodology for quantitively estimating end-user preferences in healthcare. Survey participants were randomly assigned to one of three questionnaire versions, each of which included a DCE for one prevention technology. Participants were recruited using chain-referral sampling by peer outreach workers, beginning with seeds in community-based organizations and public sex environments, in Chennai and Mumbai. DCE data were analyzed using random-parameters (mixed) logit (RPL) models. Among participants (n = 600), median age was 25 years, with median monthly income of INR 9,000 (~US$125). Nearly one-third (32%) had completed a college degree and 82% were single/never married. A majority of participants (63%) reported condomless anal sex in the past month. The acceptability of all three products was universally high (≥90%). Across all three products, four attributes were significant predictors of acceptability-with efficacy consistently the most important attribute, and in decreasing order of preference, side-effects, dosing schedule, and venue. MSM varied in their preferences for product attributes in relation to their levels of education and income, and engagement in sex work and HIV risk behavior. This study provides empirical evidence to facilitate the integration of end users' preferences throughout design, testing, and dissemination phases of HIV prevention technologies. The findings also suggest action points and targets for interventions for diverse subgroups to support the effectiveness of combination HIV prevention among MSM in India.

Description of COVID-19 Vaccination Behavior in Rural and Urban Communities in Serang District

Public health status in Indonesia can be influenced by the implementation of healthy behavior in the community. There are differences in behavior between people in rural and urban areas and factors that can cause vaccine delays that have the potential to affect COVID-19 vaccination coverage in Indonesia. This study aims to determine the behavior of COVID-19 vaccination in rural and urban communities in Serang Regency. This study used a descriptive research design with a quantitative approach which was conducted in October−November 2021 with a sample of 334 people aged 18−59 years. The results showed that the vaccination status of the respondents was complete dose (rural 65.3% and urban 70.3%), waiting for dose 2 (rural 22.4% and urban 18.6%), and dose 1 had been received but the dosing schedule 2 had passed (rural 12.3% and urban 11.1%). Three perceptions that are still low in percentage are perceptions of vulnerability, perceptions of obstacles, and cues to act. Some of the reasons for stopping the termination of COVID-19 in the community are not yet feeling that they will have severe symptoms if exposed to COVID-19, feeling confused about information related to COVID-19, not being able to carry out COVID-19 vaccinations because the schedule for COVID-19 vaccination program coincides with other activities, did not receive an invitation from the local government to vaccinate against COVID-19, vaccinate because people in their environment had vaccinated against COVID-19, did not receive support from cadres or religious leaders for the COVID-19 vaccination. Improved policy behavior can be improved by changing perceptions of vulnerability to COVID-19, reducing barriers, and also providing cues according to education through social media with the key message of spending the full dose of vaccine.

Suitability and Usefulness of a Flexible Dosing Timing of Oral Semaglutide to Maximize Benefit in Clinical Practice: An Expert Panel.

From clinical trials and observational data, oral semaglutide has proven to be the most effective second-line oral therapy for the management of patients with type 2 diabetes. This review aims to describe the perspective of an Italian expert panel that addressed the potential challenges arising during the use of oral semaglutide in the free-living conditions of routine clinical care. A group of Italian experts discussed and generated insights into the use of oral semaglutide in clinical practice. Key topics included the effectiveness of oral semaglutide in clinical practice, the positioning of the agent to optimize the treatment benefits, the possibility to adopt flexibility in the administration schedule, critical issues encountered, the role of patient communication and information in the importance of dose escalation and management of adverse events. Available data on efficacy and effectiveness of oral semaglutide from randomized clinical trials and real-world studies were reported, along with factors that determine tolerability and persistence on treatment. The debate over a fixed versus a flexible dosing schedule was critically addressed, providing anecdotical clues from a small case series and a real-world database. Additionally, a set of recommendations for clinicians to consider when prescribing oral semaglutide and during the process of patient monitoring were provided.

A Prospective Randomised Comparative Study to Evaluate the Effect of Single Dose (6.25Gy Vs 8Gy) Palliative Radiotherapy with Zoledronic Acid in Patients with Painful Bone Metastases

Background: To assess the effectiveness of a single fraction dose of radiotherapy (6.25Gy versus 8 Gy) with zoledronic acid in cancer patients with painful bone metastases in treating pain; quality of life; duration of pain response and incidence of skeletal related events (SREs). Material and methods: A total of 80 patients with bone metastases presented in the department of Radiation Oncology, S.M.S hospital were randomly assigned to: Group A, received single dose of 6.25Gy with Zoledronic acid 4mg and Group B, received single dose of 8Gy with Zoledronic acid 4mg. The main variable was pain which was assessed with 11 point Numeric pain Rating Score (NRS). Results: There were total 80 patients, 40 in each group, with mean age 54.6 years and 54.5 years in group A and B respectively. Most frequent primary malignant sites were lung (36.2%), breast (28.7%), and prostate (8.7%). At 4 weeks post radiotherapy, complete response was 25% in group A, 27.5% in group B and overall response was 82.5% in group A, 85% in group B. At 2 months post radiotherapy complete response was observed in 25% of patients in group A, while 30% in group B and overall response in 85 % in group A and 87.5% in group B. Quality of life improved in both groups. Mean duration of pain relief was 13.5 weeks vs. 14.5 weeks respectively in group A and group B. Conclusion: There was improvement in pain relief and quality of life post radiotherapy in both the groups. On comparison between 2 groups, the overall pain relief was insignificant between the two dose schedules. So a lower dose 6.25Gy is almost as effective as 8 Gy single fractions for treatment of painful bone metastases.

Population Pharmacokinetic Modeling of Adavosertib (AZD1775) in Patients with Solid Tumors.

Adavosertib (AZD1775) is a potent small-molecule inhibitor of Wee1 kinase. This analysis utilized pharmacokinetic data from 8 Phase I/II studies of adavosertib to characterize the population pharmacokinetics of adavosertib in patients (n = 538) with solid tumors and evaluate the impact of covariates on exposure. A nonlinear mixed-effects modeling approach was employed to estimate population and individual parameters from the clinical trial data. The model for time dependency of apparent clearance (CL) was developed in a stepwise manner and the final model validated by visual predictive checks (VPCs). Using an adavosertib dose of 300 mg once daily on a 5 days on/2 days off dosing schedule given 2 weeks out of a 3-week cycle, simulation analyses evaluated the impact of covariates on the following exposure metrics at steady state: maximum concentration during a 21-day cycle, area under the curve (AUC) during a 21-day cycle, AUC during the second week of a treatment cycle, and AUC on day 12 of a treatment cycle. The final model was a linear 2-compartment model with lag time into the dosing compartment and first-order absorption into the central compartment, time-varying CL, and random effects on all model parameters. VPCs and steady-state observations confirmed that the final model satisfied all the requirements for reliable simulation of randomly sampled Phase I and II populations with different covariate characteristics. Simulation-based analyses revealed that body weight, renal impairment status, and race were key factors determining the variability of drug-exposure metrics.

Treatment outcomes of surgery followed by short-course every other day radiotherapy in keloid

BackgroundPostoperative radiotherapy can significantly reduce keloid recurrence. However, consensus on the optimal radiotherapy dose and treatment schedule remains elusive. This study aims to evaluate the effectiveness of surgery followed by a short-course of radiotherapy administered every other day for keloid treatment.Materials/MethodsWe conducted a retrospective analysis of 498 patients with keloids treated at our institution between January 2010 and December 2017. All patients underwent electron beam irradiation at a dose of 16 Gy, delivered in four fractions every other day, starting within 24 h post-surgery. The primary endpoint of the study was the local control rate.ResultsA total of 130 (26.5%) keloids recurred after a median follow-up of 68.1months (42.6-129.9 months). The local control rates at 1 year, 3 years and 5 years for all patients were 89.5%, 82.5% and 81%, respectively. The highest recurrence rate was observed in keloids located in the chest region (50.8%), followed by the suprapubic (47.8%), head and neck (38.8%), limbs (33.3%) and ear (14%). Both multivariate and univariate analyses identified the presence of pain and or pruritus as an independently prognostic factor for keloid recurrence (p<0.0001). The local control rates at 1-year, 3-years and 5-years for patients with or without symptom of pain or pruritus were 45% vs. 98.8%, 12.5% vs. 95.9%, and 8.8% vs. 95%, respectively (HR:37.829, 95%CI: 24.385–58.686, p<0.001). In the ear keloid subgroup, the 1-year, 3-year and 5-year local control rates for patients with pruritus were significantly lower than those without pain or pruritus (60.0% vs. 97.9%, 26.7% vs. 94.7%, 26.7% vs. 94.3%, HR:30.209, 95% CI:14.793–61.69, p<0.001). The same results were found in other location(p<0.001). During treatment and follow-up, two patients experienced infections, and one patient developed a cutaneous fibroblastoma.ConclusionThis study suggests that a combination of surgery followed by short-course, every-other-day radiotherapy can yield satisfactory local control rates for keloids. Pain and or pruritus symptom was an independently prognostic factors for recurrence of keloid. To further validate these results, a prospective randomized controlled trial is recommended.

Homologous but not heterologous COVID-19 vaccine booster elicits IgG4+ B-cells and enhanced Omicron subvariant binding

Booster vaccinations are recommended to improve protection against severe disease from SARS-CoV-2 infection. With primary vaccinations involving various adenoviral vector and mRNA-based formulations, it remains unclear if these differentially affect the immune response to booster doses. We examined the effects of homologous (mRNA/mRNA) and heterologous (adenoviral vector/mRNA) vaccination on antibody and memory B cell (Bmem) responses against ancestral and Omicron subvariants. Healthy adults who received primary BNT162b2 (mRNA) or ChAdOx1 (vector) vaccination were sampled 1-month and 6-months after their 2nd and 3rd dose (homologous or heterologous) vaccination. Recombinant spike receptor-binding domain (RBD) proteins from ancestral, Omicron BA.2 and BA.5 variants were produced for ELISA-based serology, and tetramerized for immunophenotyping of RBD-specific Bmem. Dose 3 boosters significantly increased ancestral RBD-specific plasma IgG and Bmem in both cohorts. Up to 80% of ancestral RBD-specific Bmem expressed IgG1+. IgG4+ Bmem were detectable after primary mRNA vaccination, and expanded significantly to 5–20% after dose 3, whereas heterologous boosting did not elicit IgG4+ Bmem. Recognition of Omicron BA.2 and BA.5 by ancestral RBD-specific plasma IgG increased from 20% to 60% after the 3rd dose in both cohorts. Reactivity of ancestral RBD-specific Bmem to Omicron BA.2 and BA.5 increased following a homologous booster from 40% to 60%, but not after a heterologous booster. A 3rd mRNA dose generates similarly robust serological and Bmem responses in homologous and heterologous vaccination groups. The expansion of IgG4+ Bmem after mRNA priming might result from the unique vaccine formulation or dosing schedule affecting the Bmem response duration and antibody maturation.

The future of cancer treatment: combining radiotherapy with immunotherapy.

Radiotherapy (RT) and immunotherapy (IT) are the powerful tools for cancer treatment which act through the stimulation of immune response, and evidence suggest that combinatorial actions of these therapies may augment each other's beneficial effect through complex synergistic mechanisms. These molecular strategies are designed to target rapidly dividing cancer cells by either directly or indirectly inducing DNA damage. However, when cells detect DNA damage, they activate a range of signalling pathways known as the DNA damage response (DDR) to repair. Strategies are being developed to interfere with the DDR pathways in cancer cells to ensure their damage-induced degeneration. The stability of a cell's genetic material is largely dependent on the efficacy of DNA repair and therefore, an in-depth understanding of DNA damages and repair mechanism(s) in cancer cells is important to develop a promising therapeutic strategies for ensuring the efficacy of damage-induced tumor cell death. In recent years, a wide range of small molecule drugs have been developed which are currently being employed to combat the DNA repair deficiencies associated with tumor cells. Sequential or concurrent use of these two modalities significantly enhances the anti-tumor response, however with a concurrent probability of increased incidence of symptomatic adverse effects. With advent of newer IT agents, and administration of higher doses of radiation per fraction, such effects are more difficult to predict owing to the paucity of randomized trial data. It is well established that anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4), anti- Programmed cell death protein 1(PD-1), anti-Programmed cell death one ligand 1 (PD-L1) can be safely administered with RT and many studies have demonstrated survival benefit with such combination for patients with metastatic malignancy. However, the biology of radioimmunotherapy (RT/IT) is still an open area where research need to be focused to determine optimum dosage specially the interaction of the RT/IT pathways to determine optimum dosing schedule. In the current article we have summarised the possible intracellular immunological events that might be triggered when RT and IT modalities are combined with the DDR antagonists and highlighted present clinical practices, outcome, and toxicity profile of this novel treatment strategy.

What are the benefits of therapeutic drug monitoring in the optimization of adalimumab therapy? a systematic review and meta-analysis up to 2022.

Persistent uncertainties exist surrounding the therapeutic drug monitoring (TDM) of adalimumab in clinical settings. To address these issues, we conducted a systematic review to assess the current evidence regarding the benefits of TDM for adalimumab. PubMed, EMBASE, and Cochrane Databases were searched from inception to October 2022. The trials regarding to the list three key questions were considered: 1) Could routine proactive TDM assist in improving outcomes in patients receiving adalimumab? 2) Could reactive TDM assist in guiding subsequent treatment strategies for patients with treatment failure to adalimumab? 3) Could TDM assist in informing dose reduction or discontinuation in patients with low disease activity or in remission treated with adalimumab? Two reviewers independently selected the studies and extracted the data. Meta-analysis was performed to calculate the relative risk (RR) and 95% confidence interval (CI). A total of 9 studies was included in this review. For proactive TDM, meta-analysis indicated that proactive TDM (n = 163/257, 63.42%) showed no significant superiority over reactive TDM and/or conventional management (n = 336/606, 55.44%) in achieving and/or maintaining clinical remission by random effects model (RR: 1.24, 95% CI 0.98-1.58, I 2 = 73%). There were three studies that supporting the reactive TDM, low drug levels in the absence of anti-drug antibodies (ADA) strongly indicate the need for dose intensification, and infliximab is a feasible choice for patients with low drug levels and ADA positivity. While swapping to another class should be considered in patients with adequate drug levels. In addition, TDM can help clinicians optimize dosing schedules and prevent overtreatment in patients who have achieved low disease activity and sufficient drug concentrations, with no predictive value for successful adalimumab discontinuation. Current evidence suggests that proactive TDM is numerically but not statistically significant superiority over reactive TDM and/or conventional management. Reactive TDM can aid in understanding treatment failure and developing subsequent therapy. For patients reaching low disease activity and remission, TDM can help successful dose reduction, while it cannot inform the successful drug discontinuation. However, existing trials are limited, and more well-designed trials are necessary to clarify the role of TDM in adalimumab treatment.

"Fast but not so furious": A condensed step-up dosing schedule of teclistamab for relapsed/refractory multiple myeloma.

Teclistamab is a B-cell maturation antigen (BCMA)-directed bispecific T-cell engager approved for relapsed-refractory multiple myeloma (RRMM). Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) are well-documented treatment -related adverse events of teclistamab. The prescribing information recommends step-up dosing on days 1, 4, and 7 with 48-72 h of inpatient observation after each dose to monitor for CRS. This leads to a more than weeklong hospital stay, adding to the cost of therapy, resource utilization, and patient inconvenience. Here, we present a single center retrospective analysis addressing the safety and utility of a condensed step-up dosing schedule for teclistamab. All patients who were treated with teclistamab from November 2022 to August 2023 at the Medical University of South Carolina were included in the analysis. Patients received subcutaneous (SC) teclistamab with step-up doses (0.06 and 0.3 mg/kg) separated by either 2 or 3 (48-72 h) before the administration of the first full (1.5 mg/kg) dose (days 1, 3, and 5 'condensed' schedule or days 1, 4, and 7 'standard' schedule, respectively). All patients were hospitalized for the two step-up doses and first full dose of teclistamab and received pre-medications prior to each dose. Patients could be discharged after a minimum of 24 h following the full dose, if they did not have any CRS or ICANS. Relevant data regarding incidence, severity, and onset of CRS was collected. Statistical analysis was completed to assess the probability of fever with the first full dose of teclistamab based on incidence of fever with previous doses. A total of 25 patients were included in the analysis. Twenty-eight percent (7/25) of patients underwent the standard step up while the remaining 72% (18/25) underwent a condensed step up of teclistamab. More than half (53%, 13/25) of the patients experienced CRS during step up dosing. Grades 1 and 2 CRS occurred in 48% (12/25) and 4% (1/25) patients, respectively. Of the 13 patients that experienced CRS, 30% (4/13) fevered with the first dose, 84% (11/13) fevered with the second dose, and one patient developed fever after the third dose. The negative predictive value of being 'fever free' after doses 1 and 2 and remaining 'fever free' throughout hospitalization was 0.92. The median length of hospital stay among the 1, 3, and 5 step up group was 6 days (6-25) and 70% (14/20) of patients were discharged from the hospital within 7 days of treatment initiation. This report demonstrates the utility of a condensed step-up schedule for teclistamab initiation. The schedule was found to be safe and reduced hospital length of stay. These results should prompt consideration of shorter hospital stays for patients who do not experience CRS and raise the possibility of outpatient administration with close observation.

Serial Assessment of Hemodynamic and Cerebrovascular Changes After Administration of Mannitol in Postoperative Neurosurgical Patients in the Intensive Care Unit: A Combined Transthoracic and Transcranial Color Doppler Study.

Mannitol is widely used in neurosurgical units to mitigate raised intracranial pressure and cerebral edema, crucial in postoperative management. Its hyperosmolar properties reduce brain extracellular fluid, thereby altering cerebral perfusion and cardiac dynamics. However, the temporal and combined effects of mannitol on cardiovascular and cerebrovascular parameters remain inadequately explored in postoperative settings. This prospective observational study enrolled 20 adult patients who underwent elective craniotomies for tumor excision. Mannitol was administered to the patients at a dose of 0.5 mg/kg/dose as a bolus dose over 20 to 30 minutes. The time interval was eight hours between the doses (scheduled dosing). Patients received their first dose of mannitol in the ICU after eight hours of intraoperative dose. The patients were given mannitol for two postoperative days and followed up for two days in the postoperative period. Transthoracic echocardiography and transcranial color Doppler were used to assess cardiovascular and cerebrovascular parameters at multiple intervals post-mannitol administration. Significant increases in mean flow velocities were observed bilaterally immediately post-mannitol administration on the first postoperative day, indicative of improved cerebral blood flow. However, these changes were transient, with no significant variations noted on the second postoperative day. Cerebrovascular resistance, as measured by the pulsatility index, showed non-significant changes bilaterally across both days. Cardiovascular parameters, including stroke volume and cardiac output, remained stable throughout the study period. Mannitol administration at 0.5 g/kg in postoperative neurosurgical patients transiently improves cerebral perfusion without causing significant hemodynamic instability. This study underscores the importance of monitoring both cerebrovascular and cardiovascular parameters post-mannitol administration to optimize patient management and outcomes.

Effets indésirables de l’association tezacaftor/ivacaftor/elexacaftor pouvant mener à un arrêt de traitement : à propos d’une série de 10 cas

Cystic fibrosis transmembrane regulator (CFTR) channel modulators (ivacaftor, lumacaftor, tezacaftor and elexacaftor) represent a major advance in the management of cystic fibrosis. However, few data are available on the real-life safety profile of these medications, in particular on adverse events that may lead to their discontinuation. The aim of this study is to describe the characteristics and evolution of adverse reactions to the tezacaftor/ivacaftor/elexacaftor combination that led to discontinuation and were reported to the Centre régional de pharmacovigilance (CRPV) in Rennes (France). A retrospective study was conducted from December 2021 to May 2023, focusing on cases of discontinuation of the tezacaftor/ivacaftor/elexacaftor combination due to the occurrence of one or more adverse effects, and reported to the CRPV of Rennes, France. Ten cases of drug discontinuation were reported to the Rennes CRPV (6 women/4 men). Adverse effects mainly involved neuropsychiatric disorders (n=6), followed by liver disorders (n=2), ear, nose and throat disorders (n=1), and digestive disorders (n=1). The average duration of treatment at discontinuation was 339.8 [39-668] days. The drug was reintroduced in 7 patients on average 48.7 [7-123] days after discontinuation, with a dosage adjustments (n=4) consisting of changes in dosing times or a reduction in daily doses, with varying success in alleviating adverse symptoms depending on the case. This small case series suggests that neuropsychiatric adverse effects may occur more frequently than initially described after initiation of tezacaftor/ivacaftor/elexacaftor, and should be carefully screened and monitored. Dosage or administration schedule modifications may be considered for patients experiencing these adverse effects. Further pharmacovigilance studies are needed to better understand the adverse effect profiles of "caftors", their possible risk factors, and the impact of adjusting dosing modalities.

Evidence for an HPV one-dose schedule

The World Health Organization has recently updated their dosing schedule recommendations for the human papillomavirus (HPV) vaccine to include a single-dose schedule. We review the biologic plausibility of a single dose, the evidence from clinical trials, post-licensure observational studies, and mathematical modeling for a single-dose schedule. We also discuss the implications of countries switching to a single-dose program from a two or three-dose schedule. Finally, we review the countries that have currently switched to or introduced the vaccine with a single-dose schedule.

Impact of dosing schedules on performance of rotavirus vaccines in Ghana.

Available live-oral rotavirus vaccines are associated with low to moderate performance in low- and middle-income settings. There is limited evidence relating to how the vaccine dosing schedule might be adjusted to improve vaccine performance in these settings. We used mathematical models fitted to rotavirus surveillance data for children <5 years of age from three different hospitals in Ghana (Korle-Bu Teaching Hospital in Accra, Komfo Anokye Teaching Hospital in Kumasi and War Memorial Hospital in Navrongo) to project the impact of rotavirus vaccination over a 10-year period (April 2012-March 2022). We quantified and compared the impact of the previous vaccination program in Ghana to the model-predicted impact for other vaccine dosing schedules across the three hospitals and the entire country, under different assumptions about vaccine protection. To project the rotavirus vaccine impact over Ghana, we sampled from the range of model parameters for Accra and Navrongo, assuming that these two settings represent the "extremes" of rotavirus epidemiology within Ghana. For the previously implemented 6/10-week monovalent Rotarix vaccine (RV1) schedule, the model-estimated average annual incidence of moderate-to-severe rotavirus-associated gastroenteritis (RVGE) ranged between 1,151 and 3,002 per 100,000 people per year over the 10-year period for the three sites. Compared to no vaccination, the model-estimated median percentage reductions in RVGE ranged from 28-85% and 12-71% among children <1 year and <5 years of age respectively, with the highest and lowest percentage reductions predicted using model parameters estimated for Accra and Navrongo, respectively. The median predicted reductions in RVGE for the whole country ranged from 57-66% and 35-45% among children <1 year and <5 years of age, respectively. The 1/6/10- and 6/10/14-week schedules provided the best and comparable reductions in RVGE compared to the original 6/10-week schedule, whereas there was no improvement in impact for the 10/14-week schedule. We found that administering an additional dose of RV1 might be an effective strategy to improve rotavirus vaccine impact, particularly in settings with low vaccine effectiveness. The results could be extrapolated to other countries using a 2-dose vaccine schedule with low to moderate vaccine performance.

Assessing alimentary tract radiation in liver cancer treatment with proton beam therapy: a PET/CT imaging study.

Proton beams deposit energy along their path, abruptly stopping and generating various radioactive particles, including positrons, along their trajectory. In comparison with traditional proton beam therapy, scanning proton beam therapy is effective in delivering proton beams to irregularly shaped tumors, reducing excessive radiation exposure to the alimentary tract during the treatment of liver cancer. In this study, we utilized positron emission tomography/computed tomography (PET/CT) imaging to assess the total amount of radiation to the alimentary tract during liver cancer treatment with proton beam therapy, involving the administration of complex irradiation in 13 patients. This approach resulted in the prevention of excess radiation. The planned radiation restraint doses for the colon exhibited a significant correlation with the PET values of the colon (correlation coefficient 0.8384, P=.0003). Likewise, the scheduled radiation restraint doses for the gastroduodenum were correlated with the PET values of the gastroduodenum (correlation coefficient 0.5397, P=.0569). PET/CT conducted after proton beam therapy is useful for evaluating excess radiation in the alimentary tract. Proton beam therapy in liver cancer, assessed via PET/CT, effectively reduced alimentary tract radiation, which is vital for optimizing treatments and preventing excess exposure.

Smart Medi Box

This paper addresses the prevalent issue of medication mismanagement among older individuals in families, a problem observed not only in our personal context but also widespread across various demographics. Many elderly family members struggle with the complexity of multiple medications, leading to missed doses and inadvertent intake of incorrect medicines. Recognizing the urgency of this concern, we embarked on a mission to devise a solution, resulting in the conceptualization and development of a Smart Medi Box. This innovative device aims to streamline medication management by incorporating smart technology to facilitate accurate dosage scheduling and timely reminders. The impetus for this initiative stems from the staggering statistic that 16 crore (160 million) Indians rely on daily medications. Through the Smart Medi Box, we aspire to enhance medication adherence, mitigate risks associated with incorrect usage, and ultimately improve the overall well-being of individuals managing chronic illnesses. Key Words: Medication management, Smart Medi Box, adherence, medication scheduling, elderly care, health technology, chronic illnesses, reminder system, healthcare innovation, Indian population.

Efficacy, effectiveness and immunogenicity of reduced HPV vaccination schedules: A review of available evidence.

Current National Advisory Committee on Immunization (NACI) guidance recommends human papillomavirus (HPV) vaccines be administered as a two or three-dose schedule. Recently, several large clinical trials have reported the clinical benefit of a single HPV vaccine dose. As a result, the World Health Organization released updated guidance on HPV vaccines in 2022, recommending a two-dose schedule for individuals aged 9-20 years, and acknowledging the use of an alternative off-label single dose schedule. The objective of this overview is to provide a detailed account of the available evidence comparing HPV vaccination schedules, which was considered by NACI when updating recommendations on HPV vaccines. To identify relevant evidence, existing systematic reviews were leveraged where possible. Individual studies were critically appraised, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence. Available evidence suggests that a one, two, or three-dose HPV vaccine schedule may provide similar protection from HPV infection. While antibody levels against HPV vaccine types were statistically significantly lower with a single dose schedule compared to two or three doses, titres were sustained for up to 16 years. The clinical significance of lower antibody titres is unknown, as there is no established immunologic correlate of protection. While the available evidence on single-dose HPV vaccination schedules shows a one-dose schedule is highly effective, continued follow-up of single-dose cohorts will be critical to understanding the relative duration of protection for reduced dose schedules and informing future NACI guidance on HPV vaccines.