Cost-Effectiveness of Poly ADP-Ribose Polymerase Inhibitors in Cancer Treatment: A Systematic Review

Background: PARP inhibitors have shown significant improvement in progression-free survival, but their costs cast a considerable financial burden. In line with value-based oncology, it is important to evaluate whether drug prices justify the outcomes. / Objectives: The aim of the study was to systematically evaluate PARP inhibitors on 1) cost-effectiveness against the standard care, 2) impact on cost-effectiveness upon stratification for genetic characteristics, and 3) identify factors determining their cost-effectiveness, in four cancer types. / Methods: We systematically searched PubMed, EMBASE, Web of Science, and Cochrane Library using designated search terms, updated to 31 August 2021. Trial-based or modeling cost-effectiveness analyses of four FDA-approved PARP inhibitors were eligible. Other studies known to authors were included. Reference lists of selected articles were screened. Eligible studies were assessed for methodological and reporting quality before review. / Results: A total of 20 original articles proceeded to final review. PARP inhibitors were not cost-effective as recurrence maintenance in advanced ovarian cancer despite improved performance upon genetic stratification. Cost-effectiveness was achieved when moved to upfront maintenance in a new diagnosis setting. Limited evidence indicated non–cost-effectiveness in metastatic breast cancer, mixed conclusions in metastatic pancreatic cancer, and cost-effectiveness in metastatic prostate cancer. Stratification by genetic testing displayed an effect on cost-effectiveness, given the plummeting ICER values when compared to the “treat-all” strategy. Drug cost was a strong determinant for cost-effectiveness in most models. / Conclusions: In advanced ovarian cancer, drug use should be prioritized for upfront maintenance and for patients with BRCA mutation or BRCAness at recurrence. Additional economic evaluations are anticipated for novel indications

CHEMICAL INVESTIGATION AND ANTIPROLIFERATIVE STUDIES OF ISOLATED POLYISOPRENYLATED BENZOPHENONES FROM STEM-BARK OF Garcinia maingayi

In the current study, sequential solvents extraction from the stem bark of Garcinia maingayi, a native plant to Malaysia has led to the isolation of four polyisoprenylated benzophenones: 30-epi-cambogin (GB 1), 14-deoxy-30-epi-cambogin (GB 2), guttiferone F (GB 3), and 14-deoxy-guttiferone F (GB 4). The structures were elucidated using IR, optical rotation, and NMR spectral data. The compounds were evaluated for antiproliferative effect using MTT assay, apoptosis using Annexin V/7-AAD flow cytometry, cell cycle progression, and activation of caspases 3/7, 8 and 9 and BCL2 mRNA expression in MCF-7, HeLa, and HepG2 cancer cell lines. Compounds GB 1 to GB 4 exhibited a remarkable antiproliferative effect on HeLa, MCF-7, and HepG2 cells with IC50 values ranging from 5 to 45 µM. Compounds GB 1 to GB 4 induced significant cell cycle arrest in the G1 phase corroborated with the decrease in the number of MCF-7 and HepG2 cells in S and G2/M phases (P<0.05). Compounds GB 1 to GB 4 induced apoptosis at 48 h. Further, among these, compounds GB 1 and GB 2 induced significant levels of caspases 3 and 9 in HeLa cells, while GB 3 induced caspase 9 activities in both MCF-7 and HepG2 cells. No significant induction of caspase 8 was observed suggesting that the apoptotic effects are mainly mediated through the intrinsic pathway. Only compound GB 1 inhibited the BCL2 mRNA expression significantly in all treated cancer cells. In conclusion, these compounds possess anticancer properties and thus further investigation is crucial on the mechanistic study, structure-activity relationship, and identification of putative molecular targets

Tuning the Photocycle Kinetics of Bacteriorhodopsin in Lipid Nanodiscs

AbstractMonodisperse lipid nanodiscs are particularly suitable for characterizing membrane protein in near-native environment. To study the lipid-composition dependence of photocycle kinetics of bacteriorhodopsin (bR), transient absorption spectroscopy was utilized to monitor the evolution of the photocycle intermediates of bR reconstituted in nanodiscs composed of different ratios of the zwitterionic lipid (DMPC, dimyristoyl phosphatidylcholine; DOPC, dioleoyl phosphatidylcholine) to the negatively charged lipid (DOPG, dioleoyl phosphatidylglycerol; DMPG, dimyristoyl phosphatidylglycerol). The characterization of ion-exchange chromatography showed that the negative surface charge of nanodiscs increased as the content of DOPG or DMPG was increased. The steady-state absorption contours of the light-adapted monomeric bR in nanodiscs composed of different lipid ratios exhibited highly similar absorption features of the retinal moiety at 560 nm, referring to the conservation of the tertiary structure of bR in nanodiscs of different lipid compositions. In addition, transient absorption contours showed that the photocycle kinetics of bR was significantly retarded and the transient populations of intermediates N and O were decreased as the content of DMPG or DOPG was reduced. This observation could be attributed to the negatively charged lipid heads of DMPG and DOPG, exhibiting similar proton relay capability as the native phosphatidylglycerol (PG) analog lipids in the purple membrane. In this work, we not only demonstrated the usefulness of nanodiscs as a membrane-mimicking system, but also showed that the surrounding lipids play a crucial role in altering the biological functions, e.g., the ion translocation kinetics of the transmembrane proteins

Anti-obesity effect of phenylcoumarins from two Calophyllum spp in 3T3-L1 adipocytes

Purpose: To evaluate the anti-obesity effects of five compounds isolated from Calophyllum andersonnii and Calophyllum sclerophyllum, viz, friedelin (CP1), friedelinol (CP2), isodispar B (CP3), 5,7-dihydroxy-6-(3-methybutyryl)-4-phenylcoumarin (CP4) and 5,7-dihydroxy-6-(2-methybutyryl)-4-phenylcoumarin (CP5) in 3T3-L1 mouse pre-adipocytes.Methods: Maximum non-toxic doses (MNTDs) of CP1 - CP5 were obtained by conducting 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Intracellular lipid droplet accumulation was determined by Oil Red O (ORO) staining. The effects of CP1 - 5 on the expression of adipogenesis transcriptional factors, namely, C/ebpα, Pparγ1, aP2 and on cellular glucose uptake and adipokine (adiponectin, leptin, resistin) secretion were assessed by commercial colorimetric and ELISA kits, respectively.Results: MNTDs for CP1-CP5 were 3.0, 1.4, 1.0, 29.0 and 25.0 μM, respectively. 3T3-L1 cells treated with CP1 - CP3 showed increased lipid accumulation (p < 0.05) and decreased glucose uptake (p < 0.05), compared with untreated cells; cells treated with CP4 and CP5 had opposite effects. Cells treated with CP4 and CP5 also showed downregulated Pparγ1, C/ebpα and aP2 expression (p < 0.05), compared with untreated cells. The anti-adipogenic property exerted by CP4 and CP5 manifested as increased secretion of adiponectin as well as reduced leptin and resistin levels.Conclusion: CP4 and CP5 isolated from Calophyllum sclerophyllum show promising anti-obesity properties, and could serve as candidate hits for further investigation at in vivo level to provide additional mechanistic evidence.Keywords: Phenylcoumarin, Calophyllum, Adipogenesis, Adipocyte, Adipokine, Obesit

Impact of COVID-19 pandemic on depression incidence and healthcare service use among patients with depression: an interrupted time-series analysis from a nine-year population-based study

Background: Most studies on the impact of COVID-19 pandemic on depression burden focused on the earlier pandemic phase specific to lockdowns, but the longer-term impact of pandemic is less well-studied. In this population-based cohort study, we examined the short-term and long-term impacts of COVID-19 on depression incidence and healthcare service use among patients with depression. Methods: Using the territory-wide electronic medical records in Hong Kong, we identified all patients aged 10 years with new diagnoses of depression from 2014 to 2022. We performed an interrupted time-series (ITS) analysis to examine changes in incidence of medically attended depression before and during the pandemic. We then divided all patients into nine cohorts based on year of depression incidence and studied their initial and ongoing service use patterns until the end of 2022. We applied generalized linear modelling to compare the rates of healthcare service use in the year of diagnosis between patients newly diagnosed before and during the pandemic. A separate ITS analysis explored the pandemic impact on the ongoing service use among prevalent patients with depression. Results: We found an immediate increase in depression incidence (RR=1.21, 95% CI:1.10-1.33, p<0.001) in the population after the pandemic began with non-significant slope change, suggesting a sustained effect until the end of 2022. Subgroup analysis showed that the increases in incidence were significant among adults and the older population, but not adolescents. Depression patients newly diagnosed during the pandemic used 11% fewer resources than the pre-pandemic patients in the first diagnosis year. Pre-existing depression patients also had an immediate decrease of 16% in overall all-cause service use since the pandemic, with a positive slope change indicating a gradual rebound over a three-year period. Conclusions: During the pandemic, service provision for depression was suboptimal in the face of increased demand generated by the increasing depression incidence during the COVID-19 pandemic. Our findings indicate the need to improve mental health resource planning preparedness for future public health crises

H0LiCOW XII. Lens mass model of WFI2033-4723 and blind measurement of its time-delay distance and H0H_0

We present the lens mass model of the quadruply-imaged gravitationally lensed quasar WFI2033-4723, and perform a blind cosmographical analysis based on this system. Our analysis combines (1) time-delay measurements from 14 years of data obtained by the COSmological MOnitoring of GRAvItational Lenses (COSMOGRAIL) collaboration, (2) high-resolution $\textit{Hubble Space Telescope}$ imaging, (3) a measurement of the velocity dispersion of the lens galaxy based on ESO-MUSE data, and (4) multi-band, wide-field imaging and spectroscopy characterizing the lens environment. We account for all known sources of systematics, including the influence of nearby perturbers and complex line-of-sight structure, as well as the parametrization of the light and mass profiles of the lensing galaxy. After unblinding, we determine the effective time-delay distance to be $4784_{-248}^{+399}~\mathrm{Mpc}$, an average precision of $6.6\%$. This translates to a Hubble constant $H_{0} = 71.6_{-4.9}^{+3.8}~\mathrm{km~s^{-1}~Mpc^{-1}}$, assuming a flat $\Lambda$CDM cosmology with a uniform prior on $\Omega_\mathrm{m}$ in the range [0.05, 0.5]. This work is part of the $H_0$ Lenses in COSMOGRAIL's Wellspring (H0LiCOW) collaboration, and the full time-delay cosmography results from a total of six strongly lensed systems are presented in a companion paper (H0LiCOW XIII).Comment: Version accepted by MNRAS. 29 pages including appendix, 17 figures, 6 tables. arXiv admin note: text overlap with arXiv:1607.0140

Publishing patterns within the UK accounting and finance academic community

This study reports on publishing patterns in the UK and Irish accounting and finance academic community for the 2-year period 1998-1999 using the data contained in the BAR Research Register. It is found that the community has been growing modestly since 1991, with a doubling in the number of PhD-qualified staff (to 30%) and a reduction in the number with a professional qualification (from 81 to 58%). Nearly half of all outputs appear in other than academic journals. The mean number of publications is 1.76 per capita, with significantly more staff active in publishing than in 1991 (44% compared to 35%). However, only 17% publish in a subset of 60 'top' journals. Just over half of all articles are published in the core discipline journals, the rest appearing mainly in management, economics, sociology, education and IT journals. This may indicate a growing maturity in the disciplines, whereby applied research findings are flowing back into related foundation and business disciplines. Nearly two-thirds of academic articles are co-authored, with 25% of contributions coming from outside the community, indicating an openness to interdisciplinary collaboration, collaboration with overseas academics and collaboration with individuals in practice. The findings of this study will be of assistance to those making career decisions (either their own career or decisions involving other people's careers). They also raise awareness of the way in which the accounting and finance disciplines are developing

Evaluation of TRMM Product for Monitoring Drought in the Kelantan River Basin, Malaysia

Assessment of satellite precipitation products’ capability for monitoring drought is relatively new in tropical regions. The purpose of this paper is to evaluate the reliability of the Tropical Rainfall Measuring Mission (TRMM) Multisatellite Precipitation Analysis (TMPA) 3B43 product in estimating the standardized precipitation index (SPI) in the Kelantan River Basin, Malaysia from 1998 to 2014, by comparing it with data from 42 rain gauges. Overall, the TMPA-3B43 performed well in the monthly precipitation estimation, but performed moderately in the seasonal scale. Better performance was found in the northeast monsoon (wet season) than in the southwest monsoon (dry season). The product is more reliable in the northern and north-eastern regions (coastal zone) compared to the central, southern and south-eastern regions (mountainous area). For drought assessment, the correlations between the TMPA-3B43 and ground observations are moderate at various time-scales (one to twelve months), with better performance at shorter time-scales. The TMPA-3B43 shows similar temporal drought behavior by capturing most of the drought events at various time-scales, except for the 2008–2009 drought. These findings show that the TMPA-3B43 is not suitable to be used directly for SPI estimation in this basin. More bias correction and algorithm improvement work are needed to improve the accuracy of the TMPA-3B43 in drought monitoring

Projecting the 10-year costs of care and mortality burden of depression until 2032: a Markov modelling study developed from real-world data

Background Based on real-world data, we developed a 10-year prediction model to estimate the burden among patients with depression from the public healthcare system payer's perspective to inform early resource planning in Hong Kong. Methods We developed a Markov cohort model with yearly cycles specifically capturing the pathway of treatment-resistant depression (TRD) and comorbidity development along the disease course. Projected from 2023 to 2032, primary outcomes included costs of all-cause and psychiatric care, and secondary outcomes were all-cause deaths, years of life lived, and quality-adjusted life-years. Using the territory-wide electronic medical records, we identified 25,190 patients aged ≥10 years with newly diagnosed depression from 2014 to 2016 with follow-up until 2020 to observe the real-world time-to-event pattern, based on which costs and time-varying transition inputs were derived using negative binomial modelling and parametric survival analysis. We applied the model as both closed cohort, which studied a fixed cohort of incident patients in 2023, and open cohort, which introduced incident patients by year from 2014 to 2032. Utilities and annual new patients were from published sources. Findings With 9217 new patients in 2023, our closed cohort model projected the 10-year cumulative costs of all-cause and psychiatric care to reach US$309.0 million and US$58.3 million, respectively, with 899 deaths (case fatality rate: 9.8%) by 2032. In our open cohort model, 55,849–57,896 active prevalent cases would cost more than US$322.3 million and US$60.7 million, respectively, with more than 943 deaths annually from 2023 to 2032. Fewer than 20% of cases would live with TRD or comorbidities but contribute 31–54% of the costs. The greatest collective burden would occur in women aged above 40, but men aged above 65 and below 25 with medical history would have the highest costs per patient-year. The key cost drivers were relevant to the early disease stages. Interpretation A limited proportion of patients would develop TRD and comorbidities but contribute to a high proportion of costs, which necessitates appropriate attention and resource allocation. Our projection also demonstrates the application of real-world data to model long-term costs and mortality, which aid policymakers anticipate foreseeable burden and undertake budget planning to prepare for the care need in alternative scenarios

Perubahan sosioekonomi komuniti orang Asli Jakun akibat Rancangan Penempatan Semula: satu kajian kes di RPS Runchang, Pahang

Masyarakat orang Asli merupakan masyarakat peribumi di Semenanjung Malaysia. Sehubungan itu, dalam menentukan indeks Kesejahteraan Hidup Malaysia, indeks kesejahteraan orang Asli perlu dikira bersama. Dalam usaha untuk mencapai kesejahteraan hidup masyarakat orang Asli, Rancangan Penempatan Semula (RPS) telah memindahkan mereka dari kawasan pendalaman ke kawasan pinggir bandar bermula pada Rancangan Malaysia Keempat (1980-1985). Program ini telah menyusun dan membangunkan pembangunan sosial dan ekonomi di penempatan orang Asli. Penempatan semula orang Asli ini membawa perubahan dalam kehidupan mereka terutamanya aspek ekonomi, kesihatan dan pendidikan. Pembangunan sosioekonomi ini menyebabkan berlakunya kemusnahan sumber hutan yang sebelum ini menjadi kebergantungan hidup kepada komuniti orang Asli. Kajian ini bertujuan untuk mengenal pasti perubahan sosial, ekonomi dan kesan RPS kepada komuniti orang Asli Jakun di RPS Runchang, Pekan, Pahang. Bagi mencapai tujuan tersebut, temu bual mendalam telah dilakukan terhadap 11 informan untuk mengetahui perubahan kehidupan yang dialami oleh penduduk di RPS Runchang. Analisis data kajian ini menunjukkan terdapat perubahan sosioekonomi dalam aspek ekonomi, kesihatan dan pendidikan setelah program penempatan semula dilaksanakan. Aspek kesihatan mengalami perubahan secara menyeluruh berbanding dengan aspek ekonomi dan pendidikan. Sehubungan itu, bersama-sama dengan aspek kesihatan, aspek sosioekonomi yang lain ini perlu diberikan perhatian dalam proses pembangunan orang Asli di negara ini bagi memastikan peningkatan dalam indeks Kesejahteraan Hidup masyarakat orang Asli dan indeks kesejahteraan hidup Malaysia umumnya