Exploring management and outcomes of elderly patients with glioblastoma using data from two randomised trials (GEINO1401/EX-TEM).

PURPOSE: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. METHODS: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. RESULTS: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. CONCLUSION: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.

A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

"They will only remember us during elections": The culture of government support to Nigerian older adults and policy implications.

Governments are obliged to ensure the healthy living, well-being, and life satisfaction of every citizen. This, however, has not been achieved in Nigeria, especially with regard to older adults. Despite the notable shift in the country's demographic stance, few studies have investigated the government's roles in addressing the support to Nigerian older adults given that inadequate support is a risk factor for general poor health conditions and high mortality rates. This study, therefore, sought to investigate views on available government support to older adults in Nnewi, South-East Nigeria. Focus Group Discussion and In-depth interviews were adopted to collect data from older adults. The generated data were subjected to a thematic method of analysis. Findings show that Nigerian older adults are usually remembered during political activities, such as electioneering and election. However, the support is not all-inclusive but reserved for those who could actively participate in these political activities. To achieve the African Union and the 2030 global agenda's commitment to "leave no one behind," the study recommends social policies that address all-inclusive support and care for Nigeria older adults. Social workers' intervention will also be crucial to facilitate the formulation and implementation of welfare policies and programmes for the support and well-being of older adults.

Mortality and AIDS-defining events among young people following transition from paediatric to adult HIV care in the UK.

OBJECTIVES: To investigate risk of AIDS and mortality after transition from paediatric to adult care in a UK cohort of young people with perinatally acquired HIV. METHODS: Records of people aged ≥ 13 years on 31 December 2015 in the UK paediatric HIV cohort (Collaborative HIV Paediatric Study) were linked to those of adults in the UK Collaborative HIV Cohort (CHIC) cohort. We calculated time from transition to a new AIDS event/death, with follow-up censored at the last visit or 31 December 2015, whichever was the earliest. Cumulative incidence of and risk factors for AIDS/mortality were assessed using Kaplan-Meier and Cox regression. RESULTS: At the final paediatric visit, the 474 participants [51% female, 80% black, 60% born outside the UK, median (interquartile range) age at antiretroviral therapy (ART) initiation = 9 (5-13) years] had a median age of 18 (17-19) years and CD4 count of 471 (280-663) cell/µL; 89% were prescribed ART and 60% overall had a viral load ≤ 400 copies/mL. Over median follow-up in adult care of 3 (2-6) years, 35 (8%) experienced a new AIDS event (n = 25) or death (n = 14) (incidence = 1.8/100 person-years). In multivariable analyses, lower CD4 count at the last paediatric visit [adjusted hazard ratio = 0.8 (95% confidence interval: 0.7-1.0)/100 cells/µL increment] and AIDS diagnosis in paediatric care [2.7 (1.4-5.5)] were associated with a new AIDS event/mortality in adult care. CONCLUSIONS: Young people with perinatally acquired HIV transitioning to adult care with markers of disease progression in paediatric care experienced poorer outcomes in adult care. Increased investment in multidisciplinary specialized services is required to support this population at high risk of morbidity and mortality.

Measuring the quality of cancer care in the Barwon South Western region, Victoria, Australia.

OBJECTIVE: The implementation of clinical quality indicators for monitoring cancer care in regional, rural and remote areas. DESIGN: Retrospective data from a population-based Clinical Quality Registry for lung, colorectal and breast cancers. SETTING: All major health services in the Barwon South Western region, Victoria, Australia. PARTICIPANTS: All patients who were diagnosed with cancer and who presented to a health service. INTERVENTION(S): Clinical subgroups to review variations. MAIN OUTCOME MEASURES(S): Clinical quality indicators for lung, colorectal and breast cancers. RESULTS: Clinical indicators included the following: discussion at multidisciplinary meetings, the timeliness of care provided and the type of care for different stages of the disease and survival outcomes. Many of the derived clinical indicator targets were reached. However, variations led to an improvement in the tumour stage being recorded in the medical record; an improved awareness of the need for adjuvant chemotherapy for colorectal cancer; a reduction in time to treatment for lung cancer and a reduced time to surgery for breast cancer, and the 30-day mortality post-treatment for all of the tumour streams was highlighted. CONCLUSIONS: Clinical quality indicators allow for valuable insights into patterns of care. These indicators are easily reproduced and may be of use to other cancer centres and health services.

Salvage of failed odontoid fixation through anterior C1/C2 transarticular screws.

Odontoid fracture fixation allows for early mobilisation out of orthosis. Both anterior and posterior fixation techniques have been described but anterior surgery has less post-operative morbidity through the use of natural cleavage planes. We described the use of anterior transarticular stabilisation as a salvage procedure following a failed odontoid screw fixation.

The Impacts of Spirituality and Religious Participation on the Emotional Well-Being of Widowed Older Adults in Southeast Nigeria.

Background and Objectives: The population of older individuals in Africa is increasing, and at a rapid rate. Although the numbers of these individuals increase, many African countries, including Nigeria, are devoid of state-sponsored welfare systems that address their well-being. This situation has placed the bulk of support on the family members including spouses. Studies have shown that spouses are considered to be veritable sources of support in later life. However, spousal death tends to reduce the perceived support including emotional support, which usually occasions lower well-being, life dissatisfaction, and higher mortality rates. This study ascertains the impact of spirituality/religious participation on the emotional well-being of widowed older adults. Research Design and Methods: The study was conducted in Enugu State, southeast Nigeria. The study implemented a qualitative approach to collect data from 71 widowed older adults, aged 60 and older. The thematic analytical method was used to analyze the generated data. Results: Participating in spiritual/religious activities like prayers, church programs/activities reading, studying, and meditating on the word of God have enabled the widowed older adults to buffer some of the emotional challenges. Discussion and Implications: Older adults should be encouraged to participate in spiritual and religious activities. Religious leaders should also make every effort to organize activities that will address the emotional needs of these individuals.

Cognitive-behaviour intervention for critical thinking disposition of religion and social science students.

BACKGROUND: The dispositions of students towards critical thinking (CT) no doubt improve their clinical practice and performance. Hence, efforts to explore ways to help students become aware and conscious of the need for CT are imperative for their self-actualization, development, and improved professional practice. It is worrisome that in spite of the limited intervention addressing CT disposition challenges, scholars are yet to study the problem, especially in developing countries. METHODS: In view of that, we assessed how CT disposition can be improved among students enrolled in cognitive-behavioral reflective training programme (CBRT-P) using a group-randomized control study with three months follow-up. To achieve this, 163 students were allocated to different groups. The recruited participants were exposed to CBRT-P. RESULTS: Repeated-measures analysis performed shows that at the posttest, the mean CT disposition scores of the participants enrolled in CBRT-programme (treatment group) were significantly greater compared to the counterpart group that is the comparison group. At the third assessment, the mean score of the dependent measure consistently remained higher in favor of the experimental group. CONCLUSION: Given the results, it is concluded that the treatment programme improves the CT disposition of students over time.

Strategies for fertility preservation after chemotherapy: awareness among Irish cancer specialists.

The potential effect on fertility for patients undergoing cancer treatments is an important issue. The aim of this study was to assess awareness of fertility preservation strategies among cancer specialists involved in the management of young women with malignancy. A 10 question survey was sent to 94 cancer specialists in Ireland, comprising 28 medical oncologists, 32 haematologists and 34 breast surgeons, assessing awareness of; guidelines, facilities in Ireland, and potential barriers to referral. Fifty of 94 responded (53% response rate). Awareness of current success rates associated with assisted reproductive therapy was poor. Ten respondents (20%) identified the estimated time delay to the delivery of chemotherapy due to fertility preservation. Three important potential barriers to referral were identified; time delays, poor prognosis disease and clinical features of the cancer. Awareness of the impact of reduced fertility is important in these patients but early consideration is vital.

Reactions of aryl dimethylphosphinothioate esters with anionic oxygen nucleophiles: transition state structure in 70% water-30% ethanol.

Aryl dimethylphosphinates, 2, react with anionic oxygen nucleophiles in water via a concerted (ANDN) mechanism. With EtO- in anhydrous ethanol, the mechanism is associative (AN + DN), with rate-limiting pentacoordinate intermediate formation. This change in mechanism with solvent change has been ascribed to changes in the nucleophile and leaving group basicities accompanying solvent change. This paper reports on a kinetic analysis of the reactions of the aryl dimethylphosphinothioates, 3a-g, with oxygen nucleophiles in 70% water-30% ethanol (v/v) solvent at 25 °C, reactions known to proceed by a concerted mechanism in water, to test the rationalization stated above, since the nucleophiles and LGs of interest are more basic in aqueous ethanol than in water. The change in solvent causes an ca. 14 to 320-fold decrease in rate. Hammett and Brønsted-type correlations characterize a concerted TS with less P-LG bonding in aqueous ethanol than in water. Two opposing consequences are associated with the solvent change: (a) increased basicity of nucleophiles and LGs, which lead to a modest tightening of the TS; and (b) better stabilization of the IS relative to the TS in aqueous ethanol, which results in a slower reaction with a more product-like TS. Hammond and anti-Hammond effects on the TS arising from better stabilization of the IS over the TS dominate over the effects of increased nucleophile and LG basicity in determining the looser TS structure in aqueous ethanol. An altered TS structure is consistent with an altered reaction potential energy surface, in this case caused by a change in solvent polarity.

Regulation of the Extracellular Matrix by Ciliary Machinery.

The primary cilium is an organelle involved in cellular signalling. Mutations affecting proteins involved in cilia assembly or function result in diseases known as ciliopathies, which cause a wide variety of phenotypes across multiple tissues. These mutations disrupt various cellular processes, including regulation of the extracellular matrix. The matrix is important for maintaining tissue homeostasis through influencing cell behaviour and providing structural support; therefore, the matrix changes observed in ciliopathies have been implicated in the pathogenesis of these diseases. Whilst many studies have associated the cilium with processes that regulate the matrix, exactly how these matrix changes arise is not well characterised. This review aims to bring together the direct and indirect evidence for ciliary regulation of matrix, in order to summarise the possible mechanisms by which the ciliary machinery could regulate the composition, secretion, remodelling and organisation of the matrix.

Real-world impact of anti-HER2 therapy-related cardiotoxicity in patients with advanced HER2-positive breast cancer.

BACKGROUND: Anti-HER2 therapy-related cardiotoxicity is well described in the context of clinical trials, particularly in the setting of early stage disease, but there is more limited data in advanced breast cancer and in the real world setting. MATERIAL AND METHODS: A prospectively-maintained registry database with 312 consecutive patients diagnosed with HER2 positive advanced breast cancer in Australia was analysed. RESULTS: 287 patients (92%) received anti-HER2 therapy, 17 (6%) experienced anti-HER2 therapy-related cardiotoxicity. Patients who experienced cardiotoxicity were more likely to have ≥2 risk factors for cardiotoxicity (OR 3.9 95% CI 1.4-11.3 p = 0.01). A prior diagnosis of cardiovascular disease was significantly associated with cardiotoxicity (OR 7.1 95% CI 1.3-39.5). Cardiotoxicity resolved on imaging in 65% of patients; there was no association between severity and resolution. 11 patients (65%) received cardiologist input. Of the patients who developed cardiotoxicity, 12 patients (71%) received further anti-HER2 therapy in the first- or second-line setting without recurrent cardiotoxicity. DISCUSSION AND CONCLUSION: Therapy-related cardiotoxicity is an uncommon complication of anti-HER2 therapy in the real world setting. Cardiac toxicity resolved in the majority of affected patients, and further anti-HER2 therapy was administered without recurrence of cardiac issues. Our data suggests anti-HER2 therapy can be safely given in routine care, even in patients with risk factors for toxicity.

Waiting times for access, diagnosis and treatment in a cancer centre.

We analysed the waiting times for patients in a Dublin hospital from 2001 to 2006, and evaluated trends in each of 4 cancer diagnoses; breast, lung, colorectal and upper gastrointestinal (gastric and oesophageal). Measured times were; time from referral to first seen, time from first seen to diagnosis and time from diagnosis to treatment. Patient numbers increased 39% from 529 in 2001 to 737 in 2006. As a result waiting times have increased over the 6 years. While median time from referral to first seen for breast cancer was 7 days, it rose from 2 to 5 days for lung cancer, 1 to 2 days for colorectal cancer, and 1 to 6 days for upper GI cancers. The time from diagnosis to treatment rose from 8 to 15 days (breast), 10 days to 25 (lung), 6 to 14 days (colorectal) and 7 to 13 days (Upper GI). Waiting times however, remain within international standards.

Consumer and clinician perspectives on personalising breast cancer prevention information.

BACKGROUND: Personalised prevention of breast cancer has focused on women at very high risk, yet most breast cancers occur in women at average, or moderately increased risk (≤moderate risk). OBJECTIVES: To determine; 1) interest of women at ≤ moderate risk (consumers) in personalised information about breast cancer risk; 2) familial cancer clinicians' (FCCs) perspective on managing women at ≤ moderate risk, and; 3) both consumers' and FCCs reactions to iPrevent, a personalised breast cancer risk assessment and risk management decision support tool. METHODS: Seven focus groups on breast cancer risk were conducted with 49 participants; 27 consumers and 22 FCCs. Data were analysed thematically. RESULTS: Consumers reported some misconceptions, low trust in primary care practitioners for breast cancer prevention advice and frustration that they often lacked tailored advice about breast cancer risk. They expressed interest in receiving personalised risk information using iPrevent. FCCs reported an inadequate workforce to advise women at ≤ moderate risk and reacted positively to the potential of iPrevent to assist. CONCLUSIONS: While highlighting a potential role for iPrevent, several outstanding issues remain. For personalised prevention of breast cancer to extend beyond women at high risk, we must harness women's interest in receiving tailored information about breast cancer prevention and identify a workforce willing to advise women.

A comparative study of mechanisms of the adsorption of CO2 confined within graphene-MoS2 nanosheets: a DFT trend study.

The space within the interlayer of 2-dimensional (2D) nanosheets provides new and intriguing confined environments for molecular interactions. However, atomic level understanding of the adsorption mechanism of CO2 confined within the interlayer of 2D nanosheets is still limited. Herein, we present a comparative study of the adsorption mechanisms of CO2 confined within graphene-molybdenum disulfide (MoS2) nanosheets using density functional theory (DFT). A comprehensive analysis of CO2 adsorption energies (E AE) at various interlayer spacings of different multilayer structures comprising graphene/graphene (GrapheneB) and MoS2/MoS2 (MoS2B) bilayers as well as graphene/MoS2 (GMoS2) and MoS2/graphene (MoS2G) hybrids is performed to obtain the most stable adsorption configurations. It was found that 7.5 Å and 8.5 Å interlayer spacings are the most stable conformations for CO2 adsorption on the bilayer and hybrid structures, respectively. Adsorption energies of the multilayer structures decreased in the following trend: MoS2B > GrapheneB > MoS2G > GMoS2. By incorporating van der Waals (vdW) interactions between the CO2 molecule and the surfaces, we find that CO2 binds more strongly on these multilayer structures. Furthermore, there is a slight discrepancy in the binding energies of CO2 adsorption on the heterostructures (GMoS2, MoS2G) due to the modality of the atom arrangement (C-Mo-S-O and Mo-S-O-C) in both structures, indicating that conformational anisotropy determines to a certain degree its CO2 adsorption energy. Meanwhile, Bader charge analysis shows that the interaction between CO2 and these surfaces causes charge transfer and redistributions. By contrast, the density of states (DOS) plots show that CO2 physisorption does not have a substantial effect on the electronic properties of graphene and MoS2. In summary, the results obtained in this study could serve as useful guidance in the preparation of graphene-MoS2 nanosheets for the improved adsorption efficiency of CO2.

Ultrasonic and hydrothermal mediated synthesis routes for functionalized Mg-Al LDH: Comparison study on surface morphology, basic site strength, cyclic sorption efficiency and effectiveness.

Amine functionalized layered double hydroxide (LDHs) adsorbents prepared using three different routes: co-precipitation, sono-chemical and ultrasonic-assisted high pressure hydrothermal. The prepared adsorbent samples were characterized using X-ray diffraction (XRD), X-ray Photoelectron Spectroscopy (XPS), Scanning electron microscope-Energy dispersive X-ray spectroscopy (SEM-EDX), Temperature Programmed Desorption (TPD), Brunauer-Emmett-Teller (BET), and Thermogravimetric analysis (TGA), respectively. The performance of the prepared adsorbents was tested in a controlled thermal-swing adsorption process to measure its adsorption capacity, regeneration and cyclic efficiencies subsequently. The characterisation results were compared with those obtained using the conventional preparation routes but taking into account of the impact of sonochemical and hydrothermal pre-treatment on textural properties, adsorption capacity, regeneration and cyclic efficiencies. Textural results depicts a surge in surface area of the adsorbent synthesised by hydrothermal route (311m2/g) from 25 to 171m2/g for conventional and ultrasonic routes respectively. Additionally, it has been revealed from the present study that adsorbents prepared using ultrasonic-assisted hydrothermal route exhibit a better CO2 uptake capacity than that prepared using sonochemical and conventional routes. Thus, the ultrasonic-assisted hydrothermal treatment can effectively promote the adsorption capacity of the adsorbent. This is probably due to the decrease of moderate (M-O) and weak (OH- groups) basic sites with subsequent surge in the number of strong basic sites (O2-) resulting from the hydrothermal process. Moreover, the cyclic adsorption efficiency of the ultrasonic mediated process was found to be 76% compared with 60% for conventional and 53% for hydrothermal routes, respectively. According to the kinetic model analysis, adsorption mechanism is mostly dominated by physisorption before amine modification and by chemisorption after the modification process.

Correlating ultrasonic impulse and addition of ZnO promoter with CO2 conversion and methanol selectivity of CuO/ZrO2 catalysts.

The thermal characteristics of Cu-based catalysts for CO2 utilization towards the synthesis of methanol were analysed and discussed in this study. The preparation process were varied by adopting ultrasonic irradiation at various impulses for the co-precipitation route and also, by introducing ZnO promoters using the solid-state reaction route. Prepared catalysts were characterised using XRD, TPR, TPD, SEM, BET and TG-DTA-DSC. In addition, the CO2 conversion and CH3OH selectivity of these samples were assessed. Calcination of the catalysts facilitated the interaction of the Cu catalyst with the respective support bolstering the thermal stability of the catalysts. The characterisation analysis clearly reveals that the thermal performance of the catalysts was directly related to the sonication impulse and heating rate. Surface morphology and chemistry was enhanced with the aid of sonication and introduction of promoters. However, the impact of the promoter outweighs that of the sonication process. CO2 conversion and methanol selectivity showed a significant improvement with a 270% increase in methanol yield.

Transcriptional consequences of topoisomerase inhibition.

In principle, the generation, transmission, and dissipation of supercoiling forces are determined by the arrangement of the physical barriers defining topological boundaries and the disposition of enzymes creating (polymerases and helicases, etc.) or releasing (topoisomerases) torsional strain in DNA. These features are likely to be characteristic for individual genes. By using topoisomerase inhibitors to alter the balance between supercoiling forces in vivo, we monitored changes in the basal transcriptional activity and DNA conformation for several genes. Every gene examined displayed an individualized profile in response to inhibition of topoisomerase I or II. The expression changes elicited by camptothecin (topoisomerase I inhibitor) or adriamycin (topoisomerase II inhibitor) were not equivalent. Camptothecin generally caused transcription complexes to stall in the midst of transcription units, while provoking little response at promoters. Adriamycin, in contrast, caused dramatic changes at or near promoters and prevented transcription. The response to topoisomerase inhibition was also context dependent, differing between chromosomal or episomal c-myc promoters. In addition to being well-characterized DNA-damaging agents, topoisomerase inhibitors may evoke a biological response determined in part from transcriptional effects. The results have ramifications for the use of these drugs as antineoplastic agents.

Chromosomal DNA replication initiates at the same origins in meiosis and mitosis.

Autonomously replicating sequence (ARS) elements are identified by their ability to promote high-frequency transformation and extrachromosomal replication of plasmids in the yeast Saccharomyces cerevisiae. Six of the 14 ARS elements present in a 200-kb region of Saccharomyces cerevisiae chromosome III are mitotic chromosomal replication origins. The unexpected observation that eight ARS elements do not function at detectable levels as chromosomal replication origins during mitotic growth suggested that these ARS elements may function as chromosomal origins during premeiotic S phase. Two-dimensional agarose gel electrophoresis was used to map premeiotic replication origins in a 100-kb segment of chromosome III between HML and CEN3. The pattern of origin usage in premeiotic S phase was identical to that in mitotic S phase, with the possible exception of ARS308, which is an inefficient mitotic origin associated with CEN3. CEN3 was found to replicate during premeiotic S phase, demonstrating that the failure of sister chromatids to disjoin during the meiosis I division is not due to unreplicated centromeres. No origins were found in the DNA fragments without ARS function. Thus, in both mitosis and meiosis, chromosomal replication origins are coincident with ARS elements but not all ARS elements have chromosomal origin function. The efficiency of origin use and the patterns of replication termination are similar in meiosis and in mitosis. DNA replication termination occurs over a broad distance between active origins.