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Hip arthroplasties are cost-effective procedures; however, instability and leg length discrepancy are common complications that can lead to higher revision rates and patient dissatisfaction. Preoperative planning aids surgeons in choosing the right offset and neck length before surgery. Nonetheless, intraoperative measures are still necessary due to the differences dictated by the surgical procedure. Several hip trials might be needed to reach the optimum choice of implants. We have introduced a technique that utilizes the trunnion as a reference point to the hip centre of rotation, matching it with the acetabulum centre of rotation after applying the necessary soft tissue tension. This serves as a proximal reference point. Using the trunnion, as opposed to the trial head, allows for a better assessment of tissue tension within the acetabular void, avoiding constraints imposed by the applied trial head. Additionally, determining the acetabulum's centre of rotation is challenging if obscured by the trial head. Matching the two tibial tuberosities indicates the correct leg length, serving as the distal reference point. Both reference points should be considered together to select the right neck length and offset for optimal tissue tension. This technique has been tested on hip arthroplasty patients over five years. All hip surgeons who used this technique agree that it gives a better representation of the tissue tension, easing the challenges when preparing the acetabulum as well as reducing the need for multiple trials.

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Introduction E-health, defined as the utilization of information and communication technologies for health services, has become integral in enhancing healthcare delivery and accessibility. This study focuses on user satisfaction and perceptions of e-health applications in rural health centers, with special focus on Tamil Nadu, India. E-health technologies have proven to be effective in addressing challenges to healthcare accessibility and improving patient outcomes, at reduced costs. Despite these benefits, there is a need to understand user experiences in rural settings to optimize the implementation of e-health solutions. Methods A cross-sectional study was conducted among 383 patients registered in a non-communicable disease (NCD) clinic and specialty clinic in the rural health center of a tertiary care hospital in Tiruvallur district. Participants were selected using a consecutive sampling method from the NCD and specialty clinic registers. A semi-structured questionnaire was used to collect data on their perception and satisfaction with e-health applications. Data was entered in (Microsoft) MS Excel (Microsoft Corporation, Redmond, Washington, United States) and analyzed using IBM SPSS Statistics for Windows, Version 25 (Released 2017; IBM Corp., Armonk, New York, United States). Results The overall mean age was 49.45 ± 7 years. Among the study participants, females constituted 57.3% compared to males who constituted 42.7%. 58.3% of the participants had comorbid conditions. More than half of the study participants were educated up to the high school level. According to BG Prasad's classification, 86.9 % of the participants belonged to middle class and below. Among the study participants, more than half of them use their smartphones as devices for internet access to use e-health applications. The study participants who had no co-morbid conditions were 3.3 times the odds of having poor perception and satisfaction when compared to the other categories (OR = 3.3, CI = 2.1 - 5.1) in using e-health applications, and this difference was found to be statistically significant (p = 0.01). Conclusion This study's findings reveal that gender, socio-economic status, occupation, and the presence of comorbid illnesses play significant roles in shaping users' perceptions and satisfaction levels. This study's findings underscore the importance of tailored e-health interventions to address these barriers and enhance healthcare delivery in rural areas.

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Bispecific T-cell engagers (Bi-TCEs) have revolutionized the treatment and management of both hematological and solid tumor indications with opportunities to become best-in-class therapeutics for cancer. However, defining the dose and dosing regimen for the first-in-human (FIH) studies of Bi-TCEs can be challenging, as a high starting dose can expose subjects to serious toxicity while a low starting dose based on traditional minimal anticipated biological effect level (MABEL) approach could lead to lengthy dose escalations that exposes seriously ill patients to sub-therapeutic dosing. Leveraging our in-depth and broad clinical development experience across three generations of Bi-TCEs across both liquid and solid tumor indications, we developed an innovative modified MABEL approach for starting dose selection that integrates knowledge based on the target biology, indication, toxicology, in vitro, in vivo pharmacological evaluations, and translational pharmacokinetic/pharmacodynamic (PK/PD) modeling, together with anticipated safety profile. Compared to the traditional MABEL approach in which high effector to target (E:T) cell ratios are typically used, our innovative approach utilized an optimized E:T cell ratio that better reflects the tumor microenvironment. This modified MABEL approach was successfully applied to FIH dose selection for a half-life extended (HLE) Bi-TCE for gastric cancer. This modified MABEL approach enabled a 10-fold higher starting dose that was deemed safe and well tolerated and saved at least two dose-escalation cohorts before reaching the projected efficacious dose. This approach was successfully accepted by global regulatory agencies and can be applied for Bi-TCEs across both hematological and solid tumor indications for accelerating the clinical development for Bi-TCEs.

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Introduction Diabetes mellitus (DM) is one of the leading causes of death and disability, in addition to its rapidly increasing prevalence in developing countries. The key element of managing diabetes is quality of life (QoL). It is a factor that is positively related to treatment adherence, and QoL motivates the patient to manage their disease and achieve health and happiness in the long term. We undertook this study in a district of South India among patients with type 2 diabetes mellitus (T2DM) to assess their QoL. Methodology A cross-sectional study was conducted among T2DM patients registered in a noncommunicable disease (NCD) clinic in an urban health center in Tiruvallur District, Tamil Nadu. Participants were selected using a systematic random sampling method from the NCD clinic register. Sociodemographic details of the participants were collected using a pretested, semistructured questionnaire, following which the World Health Organization Quality of Life-Brief Version Scale (WHOQOL-BBREF) questionnaire was used to assess the QoL. Data was entered in MS Excel (Microsoft Corporation, Redmond, Washington, United States) and analyzed using IBM SPSS Statistics for Windows, Version 25.0 (Released 2017; IBM Corp., Armonk, New York, United States). Results The mean age of the study participants was 53.5 ± 9.2 years. Females constituted 63.81% of the study population compared to males (36.19%). Domain-wise, 55.83% had good physical QoL, 49.1% had good psychological QoL, 49.69% had good social QoL, and 57.1% had good environmental QoL. Overall, 52.8% had a good QoL across all the domains. Conclusion The current study found that patients with diabetes had a good QoL with the exception in educational category. However, it is essential to create an awareness among the diabetic patients about the QoL and also the measures that they can practice to improve their QoL, which should be emphasized through health education, information education communication (IEC), and counselling in NCD clinics.

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The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current practices, provide recommendations for improvement, develop a clinical toolkit, and engage Health Authorities. Historically, dose selection for cytotoxic chemotherapeutics has focused on the maximum tolerated dose, a paradigm that is less relevant for targeted therapies and new treatment modalities. A survey conducted by this group gathered insights from member companies regarding industry practices in oncology dose optimization. Given oncology drug development is a complex effort with multidimensional optimization and high failure rates due to lack of clinically relevant efficacy, this Working Group advocates for a case-by-case approach to inform the timing, specific quantitative targets, and strategies for dose optimization, depending on factors such as disease characteristics, patient population, mechanism of action, including associated resistance mechanisms, and therapeutic index. This white paper highlights the evolving nature of oncology dose optimization, the impact of Project Optimus, and the need for a tailored and evidence-based approach to optimize oncology drug dosing regimens effectively.

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A recent industry perspective published in this journal describes the benefits received by drug companies from participation in the MIDD Pilot Program. Along with the primary objectives of supporting good decision-making in drug development, there were substantial savings in time and development costs. Furthermore, many sponsors reported qualitative benefits such as new learnings and clarity on MIDD strategies and methodology that could be applied to other development programs. Based on the success of the Pilot Program, the FDA recently announced the continuation of the MIDD Paired Meeting Program as part of the Prescription Drug User Fee Act (PDUFA VII). In this report, we describe the collective experiences of industry participants in the MIDD Program to date, including all aspects of the process from meeting request submission to follow-up actions. The purpose is to provide future participants with information to optimize the value of the MIDD Program.

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Approved and emerging siRNA therapeutics are primarily designed for targeted delivery to liver where the therapeutic gene silencing effects occurs. Impairment of hepatic/renal function and its impact on siRNA pharmacokinetics/pharmacodynamics (PKs/PDs) are yet to be mechanistically evaluated to describe the unanticipated clinical observations for this novel modality. We developed pathophysiologically relevant models for organ impairment within a physiologically-based PK-PD (PBPK-PD) modeling framework focusing on modality-specific mechanistic factors to evaluate impact on siRNA PKs and PDs. PBPK-PD models for two US Food and Drug Administration (FDA) approved siRNAs inclisiran and vutrisiran were developed as case studies leveraging available tissue-specific data and translated to humans. Key determinants of the clinical PK and PD of N-acetylgalactosamine conjugated siRNAs (GalNAc-siRNAs) with varying sequences were also identified to inform effective clinical translation strategies for emerging GalNAc-siRNA candidates. A 30-70% reduction in hepatic asialoglycoprotein receptors concentrations still allowed for sufficient amount of free cytoplasmic siRNA for RISC-loading to produce PD effects comparable in extent and duration to normal liver function. This included severe hepatic impairment for which no clinical data are available. Inclusion of other modality agnostic physiological changes relevant to organ impairment did not alter the findings. Changes in renal physiologies, including changes in GFR across various degrees of impairment, well predicted minimal changes in PD for inclisiran and vutrisiran. This work provides a quantitative mechanistic framework and insights on modality-specific factors that drive clinical translation and patient/disease-related factors that impact specific dosing considerations and clinical outcomes to help accelerate the optimal development of siRNA therapeutics.

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With the promise of a potentially single-dose curative regimen, CAR-T cell therapies have brought a paradigm shift in the treatment and management of hematological malignancies with 6 approved products in the USA. However, there are no approved CAR-T cell therapies for solid tumors. Herein, we report the clinical pharmacology profile of AMG 119, the first CAR-T cell therapy targeting delta-like ligand 3 (DLL3), in patients with relapsed/refractory (R/R) small cell lung cancer (SCLC). AMG 119 demonstrated robust cellular expansion with long-lasting cell persistence and a favorable exposure-response relationship. AMG 119 has been demonstrated to be clinically safe and well tolerated at the doses tested, with no dose-limiting toxicities (DLTs) reported. This is the first publication of the clinical pharmacology profile of a CAR-T cell therapy in SCLC, with encouraging cellular kinetics data supporting the potential for CAR-T cell therapy in solid tumor space.

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Bispecific T cell engagers (Bi-TCEs) have revolutionized the treatment of oncology indications across both liquid and solid tumors. Bi-TCEs are rapidly evolving from conventional intravenous (i.v.) to more convenient subcutaneous (s.c.) administrations and extending beyond adults to also benefit pediatric patients. Leveraging clinical development experience across three generations of Bi-TCE molecules across both liquid and solid tumor indications from i.v./s.c. dosing in adults and pediatric subjects, we developed a mechanistic-physiologically-based pharmacokinetic (PBPK) platform model for Bi-TCEs. The model utilizes a full PBPK model framework and was successfully validated for PK predictions following i.v. and s.c. dosing across both liquid and solid tumor space in adults for eight Bi-TCEs. After refinement to incorporate physiological ontogeny, the model was successfully validated to predict pediatric PKs in 1 month - < 2 years, 2-11 years, and 12-17 years old subjects following i.v. dosing. Following s.c. dosing in pediatric subjects, the model predicted similar bioavailability, however, a shorter time to maximum concentration (Tmax ) for the three age groups compared with adults. The model was also applied to guide the dosing strategy for first generation of Bi-TCEs for organ impairment, specifically renal impairment, and was able to accurately predict the impact of renal impairment on PK for these relatively small-size Bi-TCEs. This work highlights a novel mechanistic platform model for accurately predicting the PK in adult and pediatric patients across liquid and solid tumor indications from i.v./s.c. dosing and can be used to guide optimal dose and dosing regimen selection and accelerating the clinical development for Bi-TCEs.

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CAR-T therapies have shown remarkable efficacy against hematological malignancies in the clinic over the last decade and new studies indicate that progress is being made to use these novel therapies to target solid tumors as well as treat autoimmune disease. Innovation in the field, including TCR-T, allogeneic or "off the shelf" CAR-T, and autoantigen/armored CAR-Ts are likely to increase the efficacy and applications of these therapies. The unique aspects of these cell-based therapeutics; patient-derived cells, intracellular expression, in vivo expansion, and phenotypic changes provide unique bioanalytical challenges to develop pharmacokinetic and immunogenicity assessments. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Translational and ADME Sciences Leadership Group (TALG) has brought together a group of industry experts to discuss and consider these challenges. In this white paper, we present the IQ consortium perspective on the best practices and considerations for bioanalytical and immunogenicity aspects toward the optimal development of CAR-T and TCR-T cell therapies.

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Aim: The present study aimed to assess the clinical outcome of root coverage following coronally advanced flap with or without amniotic membrane in Miller's class I or class II localized gingival recession in relation to anteriors. Methods: Five patients with bilaterally symmetrical Miller's class I or class II localized gingival recession were included in the study. Each patient was divided into control (without amniotic membrane) and test sites (with amniotic membrane) arbitrarily. Clinical parameters including plaque index, probing pocket depth (PPD), clinical attachment level (CAL), and depth and width of the gingival recession were recorded in a pro forma at baseline and in the 2nd, 4th, 12th week. The results were tabulated and subjected to statistical analysis using analysis of variance (ANOVA). Results: A 0.600-mm, 0.400-mm, 2.630-mm, and 2.616-mm reduction in PPD and gain in CAL were observed at control and test sites in the 12th week postoperatively and was found to be statistically insignificant (P = 0.580 and P = 0.871, respectively). Changes in depth and width of the gingival recession were observed and found to be maximum between base line (2.28 mm, 3.01 mm, 2.71, and 3.09 mm) and 2nd week (0.00, 0.00 mm, 0.23, and 0.20 mm) but without statistical significance. Conclusion: From the above results of the study, it could be concluded that the use of amniotic membrane as a barrier along with coronally advanced flap did not influence the clinical outcome of root coverage procedure.

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Interest and efforts to use recombinant adeno-associated viruses (AAV) as gene therapy delivery tools to treat disease have grown exponentially. However, gaps in understanding of the pharmacokinetics/pharmacodynamics (PK/PD) and disposition of this modality exist. This position paper comes from the Novel Modalities Working Group (WG), part of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ). The pan-industry WG effort focuses on the nonclinical PK and clinical pharmacology aspects of AAV gene therapy and related bioanalytical considerations.Traditional PK concepts are generally not applicable to AAV-based therapies due to the inherent complexity of a transgene-carrying viral vector, and the multiple steps and analytes involved in cell transduction and transgene-derived protein expression. Therefore, we explain PK concepts of biodistribution of AAV-based therapies and place key terminologies related to drug exposure and PD in the proper context. Factors affecting biodistribution are presented in detail, and guidelines are provided to design nonclinical studies to enable a stage-gated progression to Phase 1 testing. The nonclinical and clinical utility of transgene DNA, mRNA, and protein analytes are discussed with bioanalytical strategies to measure these analytes. The pros and cons of qPCR vs. ddPCR technologies for DNA/RNA measurement and qualitative vs. quantitative methods for transgene-derived protein are also presented. Last, best practices and recommendations for use of clinical and nonclinical data to project human dose and response are discussed. Together, the manuscript provides a holistic framework to discuss evolving concepts of PK/PD modeling, bioanalytical technologies, and clinical dose selection in gene therapy.

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With the promise of a potentially "single dose curative" paradigm, CAR-T cell therapies have brought a paradigm shift in the treatment and management of hematological malignancies. Both CAR-T and TCR-T cell therapies have also made great progress toward the successful treatment of solid tumor indications. The field is rapidly evolving with recent advancements including the clinical development of "off-the-shelf" allogeneic CAR-T therapies that can overcome the long and difficult "vein-to-vein" wait time seen with autologous CAR-T therapies. There are unique clinical pharmacology, pharmacometric, bioanalytical, and immunogenicity considerations and challenges in the development of these CAR-T and TCR-T cell therapies. Hence, to help accelerate the development of these life-saving therapies for the patients with cancer, experts in this field came together under the umbrella of International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) to form a joint working group between the Clinical Pharmacology Leadership Group (CPLG) and the Translational and ADME Sciences Leadership Group (TALG). In this white paper, we present the IQ consortium perspective on the best practices and considerations for clinical pharmacology and pharmacometric aspects toward the optimal development of CAR-T and TCR-T cell therapies.

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Achieving high zT in n-type and p-type thermoelements in similar compounds is a great challenge for device construction. Herein, we report a high-power factor of 480 µW/mK2 in Ga and Mn co-doped Bi2Se3 along with a maximum zT of 0.25 at 303 K as a p-type thermoelement. The co-doped Ga and Mn play distinct roles in enhancing the hole concentration to 1.6 × 1019 cm-3 with a maximized effective mass. In addition, a drastic reduction in lattice thermal conductivity of 0.5 W/mK is attained due to point defects of mass and strain field fluctuation scattering in Bi2Se3.

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OBJECTIVES: To describe the implementation of screening for cryptococcal antigenaemia by point-of-care (POC) serum cryptococcal antigen (CrAg) lateral flow assay, measure the prevalence and factors associated with serum cryptococcal antigenaemia in the routine programmatic setting. DESIGN: Cross-sectional study. SETTING: Seventeen publicly funded antiretroviral therapy (ART) centres in Mumbai, India. PARTICIPANTS: Serum CrAg screening was offered to all adolescents (>10 years of age) and adults with advanced HIV disease (AHD) (CD4 <200 cells/mm3 or with WHO clinical stage III/IV) regardless of symptoms of cryptococcal meningitis. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was to describe the implementation of serum CrAg screening and secondary outcome was to measure the prevalence of serum cryptococcal antigenaemia and its risk factors. RESULTS: A total of 2715 patients with AHD were tested for serum CrAg by POC assay. Of these, 25 (0.9%) had a CrAg positive result. Among CrAg-positive patients, only one had symptoms. Serum CrAg positivity was 3.6% (6/169) and 1.6% (6/520) among those presenting with CD4 <100 cells/mm3 in the treatment naïve and treatment experienced group, respectively. On multivariable analysis, CD4 count <100 cells/mm3 (OR: 2.3, 95% CI 1.01 to 5.3; p=0.05) and people living with HIV who were treatment naïve (OR: 2.5, 95% CI 1.04 to 6.0; p=0.04) were significantly associated with a positive serum CrAg result. Lumbar puncture was obtained in 20/25 patients within 4 days (range: 1-4 days) of positive serum CrAg result and one person was confirmed to have meningitis. All serum CrAg-positive patients who had a negative cerebrospinal fluid CrAg were offered pre-emptive therapy. CONCLUSIONS: Implementation of a POC CrAg assay was possible with existing ART centre staff. Initiation of pre-emptive therapy and management of cryptococcal antigenaemia are operationally feasible at ART centres. The Indian National AIDS Control Programme may consider reflexive CrAg screening of all AHD patients with CD4 <100 cells/mm3.

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Rhinolith is an uncommon condition that usually happens due to mineralisation of calcium and magnesium salts over a retained foreign body inside the nasal cavity for long period of time. Here we report one such case of a 33-year-old lady who presented to us with long standing intermittent epistaxis and on examination rhinolith was discovered.

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BACKGROUND: Carfilzomib is an irreversible second-generation proteasome inhibitor that has a short elimination half-life but much longer pharmacodynamic (PD) effect based on its irreversible mechanism of action, making it amenable to longer dosing intervals. A mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was built using a bottom-up approach, based on the mechanism of action of carfilzomib and the biology of the proteasome, to provide further evidence of the comparability of once-weekly and twice-weekly dosing. METHODS: The model was qualified using clinical data from the phase III ENDEAVOR study, where the safety and efficacy of bortezomib (a reversible proteasome inhibitor) and carfilzomib were compared. Simulations were performed to compare the average proteasome inhibition across five cycles of treatment for the 20/70 mg/m2 once-weekly (70 QW) and 20/56 mg/m2 twice-weekly (56 BIW) regimens. RESULTS: Results indicated that while 70 QW had a higher maximum concentration (Cmax) and lower steady-state area under the concentration-time curve (AUC) than 56 BIW, the average proteasome inhibition after five cycles of treatment between the regimens was comparable. Presumably, the higher Cmax of carfilzomib from 70 QW compensates for the lower overall AUC compared with 56 BIW, and hence 70 QW is expected to have comparable proteasome inhibition, and therefore comparable efficacy, to 56 BIW. The comparable model-predicted proteasome inhibition between 70 QW and 56 BIW also translated to comparable clinical response, in terms of overall response rate and progression-free survival. CONCLUSION: This work provides a framework for which mechanistic PK/PD modeling can be used to guide optimization of dosing intervals for therapeutics with significantly longer PD effects than PK, and help further justify patient-convenient, longer dosing intervals.

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Generally, the pattern formed by individual particles trapped inside a microfluidic chamber by a two-dimensional standing acoustic wave field has been considered only the result of the acoustic radiation force. Previous studies showed that particles can be trapped at the local minima and maxima of the first-order pressure and velocity fields. Thus, either a rectangular or a diamond pattern can be formed solely depending on the particle size, when the acoustic field is unchanged, and the material properties of the particles and the fluid are fixed. In this paper, we report about the co-existence of different patterns with particles of the same size. The actual shape of the patterns depends mainly on the ratio between particle diameter and wavelength. In addition, particles were found to be trapped at locations that coincide with the position of antinodes, even though the particles have a positive acoustic contrast factor. These phenomena imply that the trapping of individual particles cannot be described by the acoustic radiation force solely. Hence, further research is required, taking the viscous drag force caused by the fluid flow induced by the acoustic streaming effect into account.

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Bismuth Selenide is a Tellurium free topological insulator in V-VI compounds with an excellent thermoelectric performance from room temperature to mid-temperature region. Herein, hydrothermally prepared polycrystalline Bi2AgxSe3 nanostructures have been reported for thermoelectric application. The crystal structure identification and morphology with the elemental presence were analyzed by XRD (X-ray diffraction), HR-SEM with EDS (High resolution scanning electron microscope with energy dispersive X-ray), and HR-TEM (High-resolution transmission electron microscope) measurements. The reduced lattice thermal conductivity and enhanced electrical transport properties synergistically boost the thermoelectric properties through the highly-dense stacking faults with the presence of dislocations. The IFFT (Inverse Fast Fourier Transform) pattern reveals the existence of stacking faults and dislocations. These highly dense stacking faults and dislocations act as active phonon scattering centers, which can contribute to effective phonon scattering resultsin extremely low lattice thermal conduction of 0.3 W/mK at 543 K. On the other hand, the involvement of phonon-phonon scattering primarily reduced the lattice thermal conductivity at elevated temperatures. In addition, phonon-carrier scattering was less compared to phonon-phonon scattering at elevated temperature region. Moreover, the enhancement of electrical conductivity and controlled reduction of the Seebeck coefficient plays a vital role in achieving the maximum power factor of 335 µW/mK2 at 543 K due to the energy filtering effect. The synergistic combination of low thermal conduction and the maximum power factor helps to achieve the high peak zT of 0.3 at 543 K.