Budget impact analysis for three glucagon-like peptide-1 receptor agonist-based therapies for type 2 diabetes mellitus management in Saudi Arabia.

BACKGROUND AND OBJECTIVES: This study presents a budget impact analysis (BIA) conducted in Saudi Arabia, evaluating the cost implications of adopting semaglutide, tirzepatide, or dulaglutide in the management of type 2 diabetes mellitus (T2DM) patients. The analysis aims to assess the individual budgetary impact of these treatment options on healthcare budgets and provide insights for decision-makers. METHODS: A prevalence-based BIA was developed using real-world and clinical trials data. The model considered disease epidemiology, medication prices, diabetes management expenses, cardiovascular (CV) complications costs, and weight reduction savings over a 5-year time horizon. One-way and probabilistic sensitivity analyses (OWSA, PSA) were performed to assess the robustness of the results. RESULTS: Over a 5-year period, the cumulative budget impact for semaglutide, tirzepatide, and dulaglutide were 85,923,089 USD, 169,790,195 USD, and 94,558,356 USD, respectively. Hypothetical scenarios considering price parity between semaglutide and tirzepatide are associated with financial impacts of 85,923,091 USD and 86,475,335 USD, respectively. In the public sector, semaglutide showed the lowest incidence of 3-point major adverse CV events (3P-MACE), with tirzepatide leading in weight loss and HbA1c reduction, and dulaglutide presenting the highest 3P-MACE rates and least improvements in HbA1c and weight. A breakeven analysis suggested that tirzepatide's list price would need to be $199.91 lower than its current list price to achieve budget impact parity with semaglutide based on currently available evidence. Results from the OWSA suggested that risk reductions for CV events were key drivers of budget impact. PSA results were confirmatory of base-case analyses. CONCLUSIONS: CV cost-offsets and drug acquisition considerations may make semaglutide a favorable use of resources for Saudi budget planners and decision-makers. These results were robust to assumptions regarding the list price of tirzepatide.

Quality of Care for Prostate Cancer in Kashmir, India: A Real-World Study.

Purpose Despite the importance of quality care for patients with prostate cancer, significant gaps exist in healthcare delivery, including diagnosis and treatment. Our objective was to assess the quality of care (QoC) using retrospective data from prostate care patients in our center. Methods We performed a retrospective study of prostate cancer patients registered at a dedicated cancer care center in the Kashmir region from 2012 to 2020. A set of 15 quality indicators representing crucial facets of diagnosis, pathology, and treatment was identified from a comprehensive list developed and validated by other researchers. Results The final analysis of all indicators was conducted on 46 patients with a median age of 70 years (52-92 years). In the majority of patients, the diagnosis (89.1%) was made through a prostatic biopsy, while only five patients were diagnosed solely based on the prostate-specific antigen. Transrectal ultrasound (TRUS) or transurethral resection (TURP)-guided biopsy was documented in 84.8% of patients, with Gleason grading documented in 87.5% of patients. However, the number of positive cores was mentioned for only 25.7% of patients. Radical prostatectomy was the primary treatment for most patients with localized prostate cancer (58.3%). The majority of patients with metastatic prostate cancer were treated with orchidectomy (55%), owing to easy access and the lower cost of surgical castration. Conclusion The study demonstrated a lack of compliance with many QoC indicators at the diagnostic and therapeutic levels. However, large-scale, population-based studies are needed to establish the compliance of prostate cancer QoC in Kashmir. The quality indicator assessment can guide the necessary actions required to improve QoC for prostate cancer patients.

Phytoconstituents and Medicinal Plants for Anticancer Drug Discovery: Computational Identification of Potent Inhibitors of PIM1 Kinase.

Natural products, medicinal plants, and phytoconstituents serve as important sources and accelerators for anticancer drug discovery, especially when they are combined with virtual screening and molecular simulations against molecular drug targets. Proto-oncogene serine/threonine-protein kinase Pim1 (PIM1) is involved in cell survival and proliferation, with great relevance for oncogenesis. PIM1 plays a major role in the progression of various common complex human cancers, including prostate cancer, acute myeloid leukemia, and other hematopoietic malignancies. The overexpression of PIM1 leads to cancer progression, and thus it is considered as a potential target for drug design and development purposes. Here, we report original in silico findings by employing structure-based virtual screening to discover potential phytoconstituents from the medicinal plants-based compounds, which could inhibit the PIM1 activity, using the IMPPAT (a curated database of Indian Medicinal Plants, Phytochemistry And Therapeutics) database. The initial hits were selected based on their binding affinity toward PIM1 calculated through the molecular docking approach. Subsequently, interaction analyses and molecular dynamics (MD) simulation for 100 ns was carried out to study the conformational dynamics and complex stability of PIM1 with the identified compounds. Importantly, we found that PIM1 forms stable protein-ligand complexes with the phytoconstituents Dehydrotectol and Nordracorubin in particular. Our findings suggest that identified phytoconstituents Dehydrotectol and Nordracorubin bind to PIM1 in ATP-competitive binding mode. These findings and the compounds reported herein warrant further exploration as promising scaffolds for anticancer drug design, discovery, and development.

Discovery of Natural Compounds as Potential Inhibitors of Human Carbonic Anhydrase II: An Integrated Virtual Screening, Docking, and Molecular Dynamics Simulation Study.

Carbonic anhydrase II (CAII) is one of the zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide, leading to the formation of bicarbonate and proton. CAII plays a significant role in health and disease. For example, CAII helps to maintain eye pressure while regulating the pH of the tumor microenvironment, and by extension, contributing to cancer progression. Owing to its remarkable role in cancer, visual health, and other human diseases, CAII can serve as an attractive therapeutic target. We report an original study based on high-throughput virtual screening of natural compounds from the ZINC database in search of potential inhibitors of CAII. We selected the hits based on the physicochemical, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, pan-assay interference compound (PAINS) patterns, and interaction analysis. Importantly, two natural compounds were identified, ZINC08918123 and ZINC00952700, bearing considerable affinity and specific interactions to the residues of the CAII-binding pocket with well-organized conformational fitting compatibility. We investigated the conformational dynamics of CAII in complex with the identified compounds through molecular dynamics simulation, which revealed the formation of a stable complex preserved throughout the 100 ns trajectories. The stability of the protein/ligand complexes is maintained by significant numbers of noncovalent interactions throughout the simulations. In conclusion, natural compounds identified in the present study specifically and computer-assisted drug design broadly offer a reliable resource and strategy to discover potential promising therapeutic inhibitors of CAII to cure various cancers and glaucoma after further experimental validation and clinical studies.

Migrated Intravesical Intrauterine Contraceptive Devices: A Case Series and a Suggested Algorithm for Management.

Introduction Intrauterine contraceptive devices (IUCD) are a commonly used, reversible, contraceptive method. Complications from insertion rarely include migration into the bladder. We report on two cases of intravesical migrated IUCD and present an algorithm for management based on recently published data. Materials and Methods The case records of two patients who underwent surgical procedures for migrated IUCD into the bladder were reviewed. A Pubmed search was performed to identify similar studies. A total of 25 papers met the criteria for inclusion. Results Both cases were managed with laparotomy and partial cystectomy. A review of literature suggests recently reported cases of IUCD migration are rising, with most cases having been reported in the last decade. Bladder calculus developing over the migrated IUCD is the most common presentation. Most cases have been managed using endourological techniques. A small number of cases have required open vesicolithotomy or laparoscopic surgery. Rarely, laparotomy has been required.  Discussion IUCD migration into the bladder remains rare, however, recently the number of reported cases has risen. A thorough physical examination and radiological evaluation are warranted. Management is surgical in all cases. Most cases can be managed with endourological techniques. A treatment algorithm has been suggested in this paper based on recent data. Conclusion With the rising use of contraception worldwide, the incidence of IUCD migration is possibly going to increase. Treating doctors need to be aware of the possible complications that may arise from a migrated IUCD, including bladder calculi.

Hepatocellular carcinoma and other complications of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in Japan: A structured review of published works.

AIMS: Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality in Japan. As the treatment of viral hepatitis improves, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are rapidly becoming leading causes of HCC in Japan. This structured review aims to characterize the morbidity and mortality of HCC and other malignant and non-malignant complications among Japanese NAFLD and NASH patients. METHODS: An English and Japanese structured search of published works was undertaken in PubMed, Embase, and Ichushi Web databases, identifying 6553 studies, 34 of which met predefined inclusion criteria. RESULTS: Hepatocellular carcinoma was the most common incident malignancy among NAFLD/NASH patients, with higher incidence in patients with advanced/severe fibrosis (F3/F4) of 10.5%-20.0%. Although NASH results in a lower HCC cumulative incidence than hepatitis C virus (HCV) (11.3% vs. 30.5%), they have similar impacts on health outcomes, including overall mortality. Among Japanese NASH patients, HCC was found to be the main driver of mortality (40.0% in 2.7 years in NASH-HCC). With longer follow-up, higher mortality rates are observed in F3/4 patients: 25.0% in NASH F3/F4 versus 0.0% in NASH F0/2 over 7.7 years. The NASH-HCC patients also have a higher post-operative mortality than HCV-HCC patients. Additionally, NAFLD/NASH patients had higher rates of cardiovascular disease than non-NAFLD/NASH controls, and slightly higher rates of gastric cancer than HCV patients. CONCLUSION: Hepatocellular carcinoma is the most common malignancy and cause of death among NAFLD/NASH patients in Japan, with higher mortality observed among those with advanced disease and complications. Early identification and effective treatments are needed.

Epidemiology of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in Japan: A focused literature review.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) represent a growing unmet medical need and an increasingly prevalent cause of cirrhosis, hepatocellular carcinoma (HCC), and death in Japan. The aim of this review was to characterize the epidemiology of NAFLD and NASH in Japan. An English and Japanese literature search was conducted in PubMed, Embase, and ICHUSHI Web, identifying 6553 studies, 67 of which were included. Prevalence of NAFLD in the Japanese population rose from the early 1990s (12.6-12.9%) to the early 2000s (24.6-34.7% of the population). Japanese NASH prevalence is estimated to be 1.9-2.7%. NAFLD and NASH are more common among males than females; however, females experience more severe disease than males. While obese patients had higher prevalence of NAFLD/NASH, nonobese individuals (body mass index [BMI] <25 kg/m2) consistently comprised 20% to >35% of NAFLD and NASH patients. The evidence shows that, despite obesity being linked with worse disease stages, "lean-NASH" also plays an important role in NASH epidemiology. Besides obesity, diabetes and metabolic syndrome appeared to be reliably associated with disease severity. The prevalence of advanced fibrosis or cirrhotic disease was the highest in patients with NASH-HCC (44-80% with stage F3/F4 disease), while 21-50% of patients with NASH had F3/F4 disease. NAFLD/NASH is common in the Japanese population, and the prevalence of these conditions has tripled in the last two decades. Furthermore, these NAFLD/NASH patients have a high comorbidity burden. Early and efficient identification of safe and effective treatments for NAFLD/NASH patients is urgently needed.

Non-invasive diagnosis of non-alcoholic steatohepatitis and advanced fibrosis in Japan: A targeted literature review.

Despite the invasive nature of liver biopsy, it remains the current standard for diagnosing non-alcoholic steatohepatitis (NASH) and fibrosis staging. Given the rising prevalence of non-alcoholic fatty liver disease (NAFLD) in Japan, there is a need for reliable non-invasive tests to accurately and efficiently identify NASH and advanced (F3/F4) fibrosis. A review of published works from English and Japanese sources was undertaken in PubMed, Embase, and Ichushi Web to identify studies reporting diagnostic characteristics of NITs in biopsy-proven Japanese NAFLD/NASH patients including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve. The performance of non-invasive tests for two diagnostic questions were assessed, namely: (i) identifying NASH cases among NAFLD; and (ii) distinguishing advanced fibrosis (F3-4) from milder fibrosis (F0-2). Twenty-five studies reported outcomes for serum biomarkers, imaging, scoring systems, and novel complex techniques (based on multivariable regression models) for both diagnostic questions. Serum biomarkers were the most commonly assessed method for NASH identification, whereas scoring systems and imaging techniques were most commonly studied for fibrosis staging. In general, tests for NASH identification showed higher PPVs than NPVs, suggesting their usefulness in identifying probable NASH cases. The reverse was observed for fibrosis staging, with higher NPVs than PPVs, suggesting their use in excluding patients at low risk of F3/F4 disease rather than identifying definite F3/F4 fibrosis. In Japanese studies, simple scoring systems and imaging techniques showed particular usefulness in prediction of fibrosis staging, and combinations of serum biomarkers showed diagnostic potential for NASH screening.

A Study of the Role of 180W XPS Lithium Triborate Laser in the Treatment of Patients With Lower Urinary Tracts Symptoms Due to Benign Prostatic Hyperplasia.

Introduction: Benign prostatic hyperplasia (BPH) is a disease of the prostate commonly seen in elderly males known to cause lower urinary tract symptoms (LUTS) that may require surgery as a part of treatment. Transurethral resection of the prostate (TURP) is considered the gold standard of surgical treatment, but it is not without complications. Laser photoselective vaporisation of the prostate (PVP), introduced in 1998 as an 80 W Nd:YAG laser which passed through a KTP (potassium-titanylphosphate) crystal, emerged as a safe alternative to TURP in selected cases. A recent upgrade to the Greenlight XPS 180 W powered with an LBO (lithium triborate) crystal has been available for use since 2012. Data on the use of this new upgrade is still being collected and analysed, especially in patients with large prostates or high risk cases. We analysed cases done at Jaslok Hospital over a 2-year period. Methods: A total of 34 patients who underwent Laser PVP using XPS 180W for LUTS due to BPH at Jaslok Hospital were part of this study. We analysed the pre- and postoperative variables and the intraoperative parameters of all patients. Results: The XPS 180W was found to be safe and efficacious. Eighteen patients were high-risk cases, classified as ASA (American Society of Anesthesiologists) Classes 3 and 4. Average postoperative catheter duration was 40.18 hours. In prostates of size <80 mL, an average of 229 kJ of energy was used. In large prostates (>80 mL), an average of 390 kJ of energy was used. No major complications were seen in any of the high-risk patients, classified as Clavien Dindo Class 3 and 4. The postoperative drop in IPSS (International Prostate Symptom Score) was 8.7. Conclusion: We found that Green Light Laser XPS 180W may be used for large (>80 g) prostates, hitherto an indication for open surgery, and that it may be used in high-risk patients, who were otherwise unfit for TURP. It is safe and efficacious. Further, multicenter trials are required to confirm the findings.

Syringomyelia-associated scoliosis with and without the Chiari I malformation.

Although there may be a hereditary component to true idiopathic scoliosis, the condition has no known cause and is not associated with dysraphism. However, scoliosis with an associated syrinx, with or without the Chiari I malformation, sometimes presents as an idiopathic-type curve. Physical examination findings and subtle clues on diagnostic imaging may help the orthopaedic surgeon diagnose scoliosis associated with syringomyelia. Examination findings include asymmetric reflexes and presentation at ages younger than those of patients who present with adolescent idiopathic curves (i.e., 10 to 14 years). Radiologic findings include kyphosis at the apex of the curve. Indications for surgical decompression include progressive neurologic deficits, weakness, pain, and progressive curves. Most orthopaedic surgeons agree that a syrinx should be evaluated neurosurgically before any planned spinal arthrodesis to decrease the risk of neurologic injury connected with surgical correction. The indications for arthrodesis in these patients compared with those with idiopathic curves are evolving.