bims-minfam 2021-11-21 papers

Issue of 2021–11–21
twenty papers selected by
Ayesh Seneviratne, University of Toronto

J Cell Physiol. 2021 Nov 17.

Mario Barilani, Christopher Lovejoy, Roberta Piras, Andrey Y Abramov, Lorenza Lazzari, Plamena R Angelova.

Aging is a physiological process that leads to a higher risk for the most devastating diseases. There are a number of theories of human aging proposed, and many of them are directly or indirectly linked to mitochondria. Here, we used mesenchymal stem cells (MSCs) from young and older donors to study age-related changes in mitochondrial metabolism. We have found that aging in MSCs is associated with a decrease in mitochondrial membrane potential and lower NADH levels in mitochondria. Mitochondrial DNA content is higher in aged MSCs, but the overall mitochondrial mass is decreased due to increased rates of mitophagy. Despite the higher level of ATP in aged cells, a higher rate of ATP consumption renders them more vulnerable to energy deprivation compared to younger cells. Changes in mitochondrial metabolism in aged MSCs activate the overproduction of reactive oxygen species in mitochondria which is compensated by a higher level of the endogenous antioxidant glutathione. Thus, energy metabolism and redox state are the drivers for the aging of MSCs/mesenchymal stromal cells.

Keywords: MSC; aging; bioenergetics; bone marrow; cellular senescence; mitochondria

DOI: https://doi.org/10.1002/jcp.30638

Age Ageing. 2021 Nov 14. pii: afab198. [Epub ahead of print]

Olive oil consumption is associated with lower frailty risk: a prospective cohort study of community-dwelling older adults.

Carolina Donat-Vargas, Ligia J Domínguez, Helena Sandoval-Insausti, Belén Moreno-Franco, Jimena Rey-Garcia, José R Banegas, Fernando Rodríguez-Artalejo, Pilar Guallar-Castillón.

BACKGROUND: There is no evidence on the specific beneficial association of the main types of olive oil consumption with frailty.
OBJECTIVE: The aim was to assess the relationship between olive oil consumption and incident frailty in community-dwelling older adults.
DESIGN: Prospective cohort.
SETTING: Participants were recruited in 2008-10 and follow-up through 2013.
SUBJECTS: In total, 1,896 older adults aged 60+.
METHODS: At baseline, olive oil and other food consumption was collected using a validated dietary history. Incident frailty was defined as having at least three of the following five Fried-based criteria: low physical activity, fatigue, slow walking, muscle weakness and unintentional weight loss. Analyses were performed with logistic regression and adjusted for the major confounders.
RESULTS: Over a mean follow-up of 3.5 years, 135 incident frailty cases were identified. The odds ratio (95% confidence interval) of frailty across sex-specific tertiles of total olive oil consumption (12.7, 20 and 30.8 g/day, respectively) were: 1 (ref.), 0.52 (0.32, 0.83) and 0.47 (0.29, 0.78), P trend 0.003. When differentiating by olive oil types, the results held for virgin but did not for common (refined) olive oil.
CONCLUSION: The highest total olive oil consumption (~3 tablespoons), especially if virgin, was associated with half the risk of frailty as the lowest consumption (~1 tablespoon) among older adults. This study suggests that virgin olive oil should be the preferent culinary olive oil type for frailty prevention. If confirmed in other settings, small doses of virgin olive oil could be added as a simple geriatric nutritional advice on the prevention of frailty.

Keywords: frailty prevention; healthy ageing; nutritional epidemiology; older people; prospective cohort; virgin olive oil

DOI: https://doi.org/10.1093/ageing/afab198

Front Nutr. 2021 ;8 749320

Editorial: Ageing-Related Symptoms, Kampo Medicine, and Treatment.

Masahiro Ohsawa, Yasuhito Uezono, Akio Inui.

Keywords: Japanese Kampo medicine; aging-related disease; frail; herbal medicine; longevity

DOI: https://doi.org/10.3389/fnut.2021.749320

Analyst. 2021 Nov 15.

DO-SRS imaging of metabolic dynamics in aging Drosophila.

Yajuan Li, Wenxu Zhang, Anthony A Fung, Lingyan Shi.

Emerging studies have shown that lipid metabolism plays an important role in aging. High resolution in situ imaging of lipid metabolic dynamics inside cells and tissues affords a novel and potent approach for understanding many biological processes such as aging. Here we established a new optical imaging platform that combines D2O-probed stimulated Raman scattering (DO-SRS) imaging microscopy and a Drosophila model to directly visualize metabolic activities in situ during aging. The sub-cellular spatial distribution of de novo lipogenesis in the fat body was quantitatively imaged and examined. We discovered a dramatic decrease in lipid turnover in 35-day-old flies. Decreases in protein turnover occurred earlier than lipids (25-day vs. 35-day), and there are many proteins localized on the cell and lipid droplet membrane. This suggests that protein metabolism may act as a prerequisite for lipid metabolism during aging. This alteration of maintenance of protein turnover indicates disrupted lipid metabolism. We further found a significantly higher lipid turnover rate in large LDs, indicating more active metabolism in large LDs, suggesting that large and small LDs play different roles in metabolism to maintain cellular homeostasis. This is the first study that directly visualizes spatiotemporal alterations of lipid (and protein) metabolism in Drosophila during the aging process. Our study not only demonstrates a new imaging platform for studying lipid metabolism, but also unravels the important interconnections between lipid metabolism and aging.

DOI: https://doi.org/10.1039/d1an01638e

EMBO Rep. 2021 Nov 15. e53054

Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR-Cas9 screen.

Mara Mennuni, Roberta Filograna, Andrea Felser, Nina A Bonekamp, Patrick Giavalisco, Oleksandr Lytovchenko, Nils-Göran Larsson.

Cancer cells depend on mitochondria to sustain their increased metabolic need and mitochondria therefore constitute possible targets for cancer treatment. We recently developed small-molecule inhibitors of mitochondrial transcription (IMTs) that selectively impair mitochondrial gene expression. IMTs have potent antitumor properties in vitro and in vivo, without affecting normal tissues. Because therapy-induced resistance is a major constraint to successful cancer therapy, we investigated mechanisms conferring resistance to IMTs. We employed a CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats)-(CRISP-associated protein 9) whole-genome screen to determine pathways conferring resistance to acute IMT1 treatment. Loss of genes belonging to von Hippel-Lindau (VHL) and mammalian target of rapamycin complex 1 (mTORC1) pathways caused resistance to acute IMT1 treatment and the relevance of these pathways was confirmed by chemical modulation. We also generated cells resistant to chronic IMT treatment to understand responses to persistent mitochondrial gene expression impairment. We report that IMT1-acquired resistance occurs through a compensatory increase of mitochondrial DNA (mtDNA) expression and cellular metabolites. We found that mitochondrial transcription factor A (TFAM) downregulation and inhibition of mitochondrial translation impaired survival of resistant cells. The identified susceptibility and resistance mechanisms to IMTs may be relevant for different types of mitochondria-targeted therapies.

Keywords: CRISPR-Cas9 screen; cancer; chemoresistance; inhibitor of mitochondrial transcription; mtDNA

DOI: https://doi.org/10.15252/embr.202153054

Clin Nutr Res. 2021 Oct;10(4): 303-313

Effects of Calcium Fortified Beverage Intake on Insulin Sensitivity and Antioxidant Metabolism in Healthy Elderly.

Seonjeong Kim, Eunju Park, Jae-Hee Park.

Calcium, one of the most important nutrients, determines the quality of life of the elderly. It has been reported that 7 out of 10 people over the age of 60 have insufficient calcium intake. The purpose of this study was to evaluate the effect of calcium fortified beverage (CFB) intake on insulin sensitivity and antioxidant metabolism in healthy elderly. A crossover clinical trial was performed and antioxidant status of healthy elderly (age above 65 years, n = 8) was analyzed. Subjects did not take CFB for 0-3 weeks. They then took it for 3-6 weeks. CFB supplementation decreased insulin levels (Δ3-6 weeks: 1.19 ± 0.65 μ IU/mL → Δ0-3 weeks: -0.58 ± 0.38 μ IU/mL). Increasing degree of fasting blood glucose level was suppressed by intake of CFB, although the suppression was not statistically significant. Except for insulin, there were no significant differences in results of biochemical analysis between 0-3 weeks and 3-6 weeks. Catalase activity was significantly increased by CFB supplementation (Δ3-6 weeks: 3.50 ± 5.30 K g/Hb) compared to the no CFB supplementation period (Δ0-3 weeks: -12.48 ± 4.37 K g/Hb). However, the activity of superoxide dismutase and glutathione-peroxidase were not significantly different between 0-3 weeks and 3-6 weeks. H2O2-induced DNA oxidative damage was also decreased significantly by CFB supplementation. Taken together, these results indicate that CFB has beneficial effect on insulin sensitivity and some antioxidant enzymes in healthy elderly.

Keywords: Antioxidant activity; Beverage; Calcium; Healthy aging; Insulin sensitivity

DOI: https://doi.org/10.7762/cnr.2021.10.4.303

Cancer Discov. 2021 Nov 17. pii: candisc.0030.2021. [Epub ahead of print]

Fasting-mimicking diet is safe and reshapes metabolism and antitumor immunity in cancer patients.

In tumor-bearing mice, cyclic fasting or fasting-mimicking diets (FMDs) enhance the activity of antineoplastic treatments by modulating systemic metabolism and boosting antitumor immunity. Here we conducted a clinical trial to investigate the safety and biological effects of cyclic, five-day FMD in combination with standard antitumor therapies. In 101 patients, the FMD was safe, feasible, and resulted in a consistent decrease of blood glucose and growth factor concentration, thus recapitulating metabolic changes that mediate fasting/FMD anticancer effects in preclinical experiments. Integrated transcriptomic and deep-phenotyping analyses revealed that FMD profoundly reshapes anticancer immunity by inducing the contraction of peripheral blood immunosuppressive myeloid and regulatory T-cell compartments, paralleled by enhanced intratumor T-helper 1/cytotoxic responses and an enrichment of interferon-gamma and other immune signatures associated with better clinical outcomes in cancer patients. Our findings lay the foundations for phase II/III clinical trials aimed at investigating FMD antitumor efficacy in combination with standard antineoplastic treatments.

DOI: https://doi.org/10.1158/2159-8290.CD-21-0030

Expert Rev Clin Pharmacol. 2021 Nov 18.

Keeping up with venetoclax for leukemic malignancies: key findings, optimal regimens and clinical considerations.

Maria Siddiqui, Marina Konopleva.

INTRODUCTION: Venetoclax has transformed the treatment landscape in hematologic malignancies, especially in elderly population. With high rates of remission, deep and durable responses, and safe toxicity profile, venetoclax in combination therapy has been extremely effective, garnering accelerated approval and becoming standard of care in lymphoid and myeloid malignancies.
AREAS COVERED: The role of venetoclax in the intrinsic apoptotic pathway is covered. This includes preclinical and clinical experience of venetoclax monotherapy and combination therapy in relapsed/refractory and frontline CLL, AML, ALL and high-risk MDS, with an emphasis on key clinical trials and efficacy of combination regimens in distinct mutational landscapes. Strategies to mitigate myelosuppression, manage dose adjustments and infectious complications are addressed.
EXPERT OPINION: Targeting BCL-2 offers a safe and highly effective adjunct to available therapies in hematologic malignancies. Despite success and frequent utilization of venetoclax, several resistance mechanisms have been elucidated, prompting development of novel combinatorial strategies. Further, on-target myelosuppression of venetoclax is a key obstacle in clinical practice, requiring diligent monitoring and practice-based knowledge of dose modifications. Despite these limitations, venetoclax has gained tremendous popularity in hematologic-oncology, becoming an integral component of numerous combination regimes, with ongoing plethora of clinical trials encompassing standard chemotherapy, targeted agents and immune-based approaches.

Keywords: acute lymphoblastic leukemia; acute myeloid leukemia; chronic lymphocytic leukemia; myelodysplastic syndrome; venetoclax

DOI: https://doi.org/10.1080/17512433.2021.2008239

J Clin Oncol. 2021 Nov 18. JCO2102286

Donor Clonal Hematopoiesis and Recipient Outcomes After Transplantation.

PURPOSE: Clonal hematopoiesis (CH) can be transmitted from a donor to a recipient during allogeneic hematopoietic cell transplantation. Exclusion of candidate donors with CH is controversial since its impact on recipient outcomes and graft alloimmune function is uncertain.
PATIENTS AND METHODS: We performed targeted error-corrected sequencing on samples from 1,727 donors age 40 years or older and assessed the effect of donor CH on recipient clinical outcomes. We measured long-term engraftment of 102 donor clones and cytokine levels in 256 recipients at 3 and 12 months after transplant.
RESULTS: CH was present in 22.5% of donors, with DNMT3A (14.6%) and TET2 (5.2%) mutations being most common; 85% of donor clones showed long-term engraftment in recipients after transplantation, including clones with a variant allele fraction < 0.01. DNMT3A-CH with a variant allele fraction ≥ 0.01, but not smaller clones, was associated with improved recipient overall (hazard ratio [HR], 0.79; P = .042) and progression-free survival (HR, 0.72; P = .003) after adjustment for significant clinical variables. In patients who received calcineurin-based graft-versus-host disease prophylaxis, donor DNMT3A-CH was associated with reduced relapse (subdistribution HR, 0.59; P = .014), increased chronic graft-versus-host disease (subdistribution HR, 1.36; P = .042), and higher interleukin-12p70 levels in recipients. No recipient of sole DNMT3A or TET2-CH developed donor cell leukemia (DCL). In seven of eight cases, DCL evolved from donor CH with rare TP53 or splicing factor mutations or from donors carrying germline DDX41 mutations.
CONCLUSION: Donor CH is closely associated with clinical outcomes in transplant recipients, with differential impact on graft alloimmune function and potential for leukemic transformation related to mutated gene and somatic clonal abundance. Donor DNMT3A-CH is associated with improved recipient survival because of reduced relapse risk and with an augmented network of inflammatory cytokines in recipients. Risk of DCL in allogeneic hematopoietic cell transplantation is driven by somatic myelodysplastic syndrome-associated mutations or germline predisposition in donors.

DOI: https://doi.org/10.1200/JCO.21.02286

Eur J Ageing. 2021 Dec;18(4): 537-547

Successful ageing in the oldest old: objectively and subjectively measured evidence from a population-based survey in Germany.

Marina Plugge.

Despite rapid increase of people aged 80 and over, concepts of successful ageing (SA) are primarily examined for people below that age. Therefore, successful ageing was examined in a population-based representative sample of N = 1863 people aged 80 to 102 (NRW80+) with 11% living in institutionalized settings. In this survey on quality of life and well-being, multiple linear and logistic regression models were used to calculate the distribution of successful agers. According to Rowe and Kahn's objective definition, 9% of the sample aged successfully, but one-third (33%) still met four to five SA criteria. This is in line with the theoretical a priori criterion of 10% in a normal distribution of a sample, while 80% age normally and 10% pathologically. However, averages of life satisfaction, affective well-being, positive ageing experience and valuation of life were high. The majority of the oldest old (65%) are successful agers in their own subjective perception, which is not in line with objective measurements. Moreover, 11% of objectively measured successful agers do not meet subjective criteria. These empirical findings reveal a remarkable discrepancy between objective and subjective criteria of SA. Future research on concepts that define successful ageing for the oldest old should consider more holistic markers of success, e.g., outcomes of productive social engagement.
Supplementary Information: The online version contains supplementary material available at 10.1007/s10433-021-00609-7.

Keywords: Oldest old; Subjective well-being; Successful ageing

DOI: https://doi.org/10.1007/s10433-021-00609-7

Nutr J. 2021 11 13. 20(1): 91

Curcuma longa extract improves serum inflammatory markers and mental health in healthy participants who are overweight: a randomized, double-blind, placebo-controlled trial.

Ryusei Uchio, Kengo Kawasaki, Chinatsu Okuda-Hanafusa, Ryosuke Saji, Koutarou Muroyama, Shinji Murosaki, Yoshihiro Yamamoto, Yoshitaka Hirose.

BACKGROUND: The dietary spice Curcuma longa, also known as turmeric, has various biological effects. Both a water extract and a supercritical carbon dioxide extract of C. longa showed anti-inflammatory activities in animal studies. However, the anti-inflammatory effect in humans of a mixture of these two C. longa extracts (CLE) is poorly understood. Therefore, we investigated the effect of CLE containing anti-inflammatory turmeronols on chronic inflammation and general health.
METHODS: We performed a randomized, double-blind, placebo-controlled study in healthy subjects aged 50 to 69 years with overweight. Participants took two capsules containing CLE (CLE group, n = 45) or two placebo capsules (placebo group, n = 45) daily for 12 weeks, and serum inflammatory markers were measured. Participants also completed two questionnaires: the Medical Outcomes Study (MOS) 36-Item Short-Form Health Survey (SF-36) and the Profile of Mood States (POMS) scale. Treatment effects were analyzed by two way analysis of variance followed by a t test (significance level, p < 0.05).
RESULTS: After the intervention, the CLE group had a significantly lower body weight (p < 0.05) and body mass index (p < 0.05) than the placebo group and significantly lower serum levels of C-reactive protein (p < 0.05) and complement component 3 (p < 0.05). In addition, the CLE group showed significant improvement of the MOS SF-36 mental health score (p < 0.05) and POMS anger-hostility score (p < 0.05).
CONCLUSION: CLE may ameliorate chronic low-grade inflammation and thus help to improve mental health and mood disturbance.
TRIAL REGISTRATION: UMIN-CTR, UMIN000037370. Registered 14 July 2019, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000042607.

Keywords: 36-item short-form health survey (SF-36); Bisacurone; Body mass index (BMI); C-reactive protein (CRP); Chronic inflammation; Complement component 3 (C3); Profile of mood states (POMS); Turmeric (Curcuma longa); Turmeronol

DOI: https://doi.org/10.1186/s12937-021-00748-8

J Aging Stud. 2021 Dec;pii: S0890-4065(21)00064-5. [Epub ahead of print]59 100974

"Better be dead than grow older:" A qualitative study on subjective aging among older Koreans.

Eun Young Choi, Sung Hyun Ko, Yuri Jang.

While a large body of evidence suggests potential cultural variations in the experiences of subjective aging, very little is known about how members of Asian cultures feel about their aging. This study aims to acquire an in-depth understanding of subjective aging and its cultural/societal contexts among older Korean adults. In-depth face-to-face interviews were conducted with 20 community-dwelling Korean adults over age 65. Guided by the Stereotype Embodiment Theory, open-ended questions were asked to address how exposure to cultural/societal views about older adults relate to individuals' subjective aging. Data were analyzed using the constant comparative method. Seven categories were identified, which were grouped into three primary themes: 1) exposure to negative views on aging/older persons; 2) salience gain from self-relevance; and 3) influence on older adults' subjective aging. Most participants were generally not satisfied with their aging, felt they were a burden, and were prone to experience intergenerational conflicts. This may be attributed in part to their exposure to widespread negative age stereotypes and disrespect for older adults. Awareness of age-related changes and experience of age discrimination appear to be triggers through which the negative cultural/societal views on aging/older persons influence one's subjective perceptions and experience of aging. This in-depth data from an understudied population contributes to the existing literature by suggesting that the dominant-negative experience of aging among older Koreans may be better understood from socio-cultural contexts. Our findings can inform culture-specific intervention strategies to promote positive subjective aging.

Keywords: Asian culture; Older Koreans; Stereotype embodiment theory; Subjective aging

DOI: https://doi.org/10.1016/j.jaging.2021.100974

Curr Opin Infect Dis. 2021 Nov 18.

Frailty in people living with HIV: an update.

Howell T Jones, Tom Levett, Tristan J Barber.

PURPOSE OF REVIEW: The HIV population is ageing with rising rates of frailty though strategies of how best to manage it remain ill-defined. It also remains unclear what the prevalence of frailty is within this cohort, how best to diagnose it and what factors are associated.
RECENT FINDINGS: The prevalence of frailty remains unclear because of heterogenous results. Routine screening in those 50+ is recommended and whilst the Fried Frailty Phenotype is currently preferred the Clinical Frailty Scale could be considered. No biomarkers are currently recommended. Looking at associated factors, HIV neurocognitive impairment and long-term alcohol usage has been shown to be associated with developing frailty whilst those who are frail have been shown to be less active and more likely to fall. NAFLD with fibrosis has been shown to be an indicator of metabolic age and the Pooled Cohort Equations has been shown to be more effective in diagnosing cardiovascular risk in frail people living with HIV.
SUMMARY: Whilst the prevalence of frailty differs between countries, with the addition of prefrailty, this represents a large proportion of people living with HIV. Services must ensure strategies are in place to support those living with HIV and frailty. Further longitudinal studies are required.

DOI: https://doi.org/10.1097/QCO.0000000000000798

Cochrane Database Syst Rev. 2021 Nov 16. 11 CD012775

Antiemetics for adults for prevention of nausea and vomiting caused by moderately or highly emetogenic chemotherapy: a network meta-analysis.

Vanessa Piechotta, Anne Adams, Madhuri Haque, Benjamin Scheckel, Nina Kreuzberger, Ina Monsef, Karin Jordan, Kathrin Kuhr, Nicole Skoetz.

BACKGROUND: About 70% to 80% of adults with cancer experience chemotherapy-induced nausea and vomiting (CINV). CINV remains one of the most distressing symptoms associated with cancer therapy and is associated with decreased adherence to chemotherapy. Combining 5-hydroxytryptamine-3 (5-HT₃) receptor antagonists with corticosteroids or additionally with neurokinin-1 (NK₁) receptor antagonists is effective in preventing CINV among adults receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). Various treatment options are available, but direct head-to-head comparisons do not allow comparison of all treatments versus another. OBJECTIVES: • In adults with solid cancer or haematological malignancy receiving HEC - To compare the effects of antiemetic treatment combinations including NK₁ receptor antagonists, 5-HT₃ receptor antagonists, and corticosteroids on prevention of acute phase (Day 1), delayed phase (Days 2 to 5), and overall (Days 1 to 5) chemotherapy-induced nausea and vomiting in network meta-analysis (NMA) - To generate a clinically meaningful treatment ranking according to treatment safety and efficacy • In adults with solid cancer or haematological malignancy receiving MEC - To compare whether antiemetic treatment combinations including NK₁ receptor antagonists, 5-HT₃ receptor antagonists, and corticosteroids are superior for prevention of acute phase (Day 1), delayed phase (Days 2 to 5), and overall (Days 1 to 5) chemotherapy-induced nausea and vomiting to treatment combinations including 5-HT₃ receptor antagonists and corticosteroids solely, in network meta-analysis - To generate a clinically meaningful treatment ranking according to treatment safety and efficacy SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, conference proceedings, and study registries from 1988 to February 2021 for randomised controlled trials (RCTs).
SELECTION CRITERIA: We included RCTs including adults with any cancer receiving HEC or MEC (according to the latest definition) and comparing combination therapies of NK₁ and 5-HT₃ inhibitors and corticosteroids for prevention of CINV.
DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We expressed treatment effects as risk ratios (RRs). Prioritised outcomes were complete control of vomiting during delayed and overall phases, complete control of nausea during the overall phase, quality of life, serious adverse events (SAEs), and on-study mortality. We assessed GRADE and developed 12 'Summary of findings' tables. We report results of most crucial outcomes in the abstract, that is, complete control of vomiting during the overall phase and SAEs. For a comprehensive illustration of results, we randomly chose aprepitant plus granisetron as exemplary reference treatment for HEC, and granisetron as exemplary reference treatment for MEC.
MAIN RESULTS: Highly emetogenic chemotherapy (HEC) We included 73 studies reporting on 25,275 participants and comparing 14 treatment combinations with NK₁ and 5-HT₃ inhibitors. All treatment combinations included corticosteroids. Complete control of vomiting during the overall phase We estimated that 704 of 1000 participants achieve complete control of vomiting in the overall treatment phase (one to five days) when treated with aprepitant + granisetron. Evidence from NMA (39 RCTs, 21,642 participants; 12 treatment combinations with NK₁ and 5-HT₃ inhibitors) suggests that the following drug combinations are more efficacious than aprepitant + granisetron for completely controlling vomiting during the overall treatment phase (one to five days): fosnetupitant + palonosetron (810 of 1000; RR 1.15, 95% confidence interval (CI) 0.97 to 1.37; moderate certainty), aprepitant + palonosetron (753 of 1000; RR 1.07, 95% CI 1.98 to 1.18; low-certainty), aprepitant + ramosetron (753 of 1000; RR 1.07, 95% CI 0.95 to 1.21; low certainty), and fosaprepitant + palonosetron (746 of 1000; RR 1.06, 95% CI 0.96 to 1.19; low certainty). Netupitant + palonosetron (704 of 1000; RR 1.00, 95% CI 0.93 to 1.08; high-certainty) and fosaprepitant + granisetron (697 of 1000; RR 0.99, 95% CI 0.93 to 1.06; high-certainty) have little to no impact on complete control of vomiting during the overall treatment phase (one to five days) when compared to aprepitant + granisetron, respectively. Evidence further suggests that the following drug combinations are less efficacious than aprepitant + granisetron in completely controlling vomiting during the overall treatment phase (one to five days) (ordered by decreasing efficacy): aprepitant + ondansetron (676 of 1000; RR 0.96, 95% CI 0.88 to 1.05; low certainty), fosaprepitant + ondansetron (662 of 1000; RR 0.94, 95% CI 0.85 to 1.04; low certainty), casopitant + ondansetron (634 of 1000; RR 0.90, 95% CI 0.79 to 1.03; low certainty), rolapitant + granisetron (627 of 1000; RR 0.89, 95% CI 0.78 to 1.01; moderate certainty), and rolapitant + ondansetron (598 of 1000; RR 0.85, 95% CI 0.65 to 1.12; low certainty). We could not include two treatment combinations (ezlopitant + granisetron, aprepitant + tropisetron) in NMA for this outcome because of missing direct comparisons. Serious adverse events We estimated that 35 of 1000 participants experience any SAEs when treated with aprepitant + granisetron. Evidence from NMA (23 RCTs, 16,065 participants; 11 treatment combinations) suggests that fewer participants may experience SAEs when treated with the following drug combinations than with aprepitant + granisetron: fosaprepitant + ondansetron (8 of 1000; RR 0.23, 95% CI 0.05 to 1.07; low certainty), casopitant + ondansetron (8 of 1000; RR 0.24, 95% CI 0.04 to 1.39; low certainty), netupitant + palonosetron (9 of 1000; RR 0.27, 95% CI 0.05 to 1.58; low certainty), fosaprepitant + granisetron (13 of 1000; RR 0.37, 95% CI 0.09 to 1.50; low certainty), and rolapitant + granisetron (20 of 1000; RR 0.57, 95% CI 0.19 to 1.70; low certainty). Evidence is very uncertain about the effects of aprepitant + ondansetron (8 of 1000; RR 0.22, 95% CI 0.04 to 1.14; very low certainty), aprepitant + ramosetron (11 of 1000; RR 0.31, 95% CI 0.05 to 1.90; very low certainty), fosaprepitant + palonosetron (12 of 1000; RR 0.35, 95% CI 0.04 to 2.95; very low certainty), fosnetupitant + palonosetron (13 of 1000; RR 0.36, 95% CI 0.06 to 2.16; very low certainty), and aprepitant + palonosetron (17 of 1000; RR 0.48, 95% CI 0.05 to 4.78; very low certainty) on the risk of SAEs when compared to aprepitant + granisetron, respectively. We could not include three treatment combinations (ezlopitant + granisetron, aprepitant + tropisetron, rolapitant + ondansetron) in NMA for this outcome because of missing direct comparisons. Moderately emetogenic chemotherapy (MEC) We included 38 studies reporting on 12,038 participants and comparing 15 treatment combinations with NK₁ and 5-HT₃ inhibitors, or 5-HT₃ inhibitors solely. All treatment combinations included corticosteroids. Complete control of vomiting during the overall phase We estimated that 555 of 1000 participants achieve complete control of vomiting in the overall treatment phase (one to five days) when treated with granisetron. Evidence from NMA (22 RCTs, 7800 participants; 11 treatment combinations) suggests that the following drug combinations are more efficacious than granisetron in completely controlling vomiting during the overall treatment phase (one to five days): aprepitant + palonosetron (716 of 1000; RR 1.29, 95% CI 1.00 to 1.66; low certainty), netupitant + palonosetron (694 of 1000; RR 1.25, 95% CI 0.92 to 1.70; low certainty), and rolapitant + granisetron (660 of 1000; RR 1.19, 95% CI 1.06 to 1.33; high certainty). Palonosetron (588 of 1000; RR 1.06, 95% CI 0.85 to 1.32; low certainty) and aprepitant + granisetron (577 of 1000; RR 1.06, 95% CI 0.85 to 1.32; low certainty) may or may not increase complete response in the overall treatment phase (one to five days) when compared to granisetron, respectively. Azasetron (560 of 1000; RR 1.01, 95% CI 0.76 to 1.34; low certainty) may result in little to no difference in complete response in the overall treatment phase (one to five days) when compared to granisetron. Evidence further suggests that the following drug combinations are less efficacious than granisetron in completely controlling vomiting during the overall treatment phase (one to five days) (ordered by decreasing efficacy): fosaprepitant + ondansetron (500 of 100; RR 0.90, 95% CI 0.66 to 1.22; low certainty), aprepitant + ondansetron (477 of 1000; RR 0.86, 95% CI 0.64 to 1.17; low certainty), casopitant + ondansetron (461 of 1000; RR 0.83, 95% CI 0.62 to 1.12; low certainty), and ondansetron (433 of 1000; RR 0.78, 95% CI 0.59 to 1.04; low certainty). We could not include five treatment combinations (fosaprepitant + granisetron, azasetron, dolasetron, ramosetron, tropisetron) in NMA for this outcome because of missing direct comparisons. Serious adverse events We estimated that 153 of 1000 participants experience any SAEs when treated with granisetron. Evidence from pair-wise comparison (1 RCT, 1344 participants) suggests that more participants may experience SAEs when treated with rolapitant + granisetron (176 of 1000; RR 1.15, 95% CI 0.88 to 1.50; low certainty). NMA was not feasible for this outcome because of missing direct comparisons. Certainty of evidence Our main reason for downgrading was serious or very serious imprecision (e.g. due to wide 95% CIs crossing or including unity, few events leading to wide 95% CIs, or small information size). Additional reasons for downgrading some comparisons or whole networks were serious study limitations due to high risk of bias or moderate inconsistency within networks.
AUTHORS' CONCLUSIONS: This field of supportive cancer care is very well researched. However, new drugs or drug combinations are continuously emerging and need to be systematically researched and assessed. For people receiving HEC, synthesised evidence does not suggest one superior treatment for prevention and control of chemotherapy-induced nausea and vomiting. For people receiving MEC, synthesised evidence does not suggest superiority for treatments including both NK₁ and 5-HT₃ inhibitors when compared to treatments including 5-HT₃ inhibitors only. Rather, the results of our NMA suggest that the choice of 5-HT₃ inhibitor may have an impact on treatment efficacy in preventing CINV. When interpreting the results of this systematic review, it is important for the reader to understand that NMAs are no substitute for direct head-to-head comparisons, and that results of our NMA do not necessarily rule out differences that could be clinically relevant for some individuals.

DOI: https://doi.org/10.1002/14651858.CD012775.pub2

Front Public Health. 2021 ;9 655831

Age and Ageing During the COVID-19 Pandemic; Challenges to Public Health and to the Health of the Public.

A Mark Clarfield, Tzvi Dwolatzky.

The distribution of the SARS-CoV-2 virus has reached pandemic proportions. While COVID-19 can affect anyone, it is particularly hazardous for those with "co-morbidities." Older age is an especially strong and independent risk factor for hospital and ICU admission, mechanical ventilation and death. Health systems must protect persons at any age while paying particular attention to those with risk factors. However, essential freedoms must be respected and social/psychological needs met for those shielded. The example of the older population in Israel may provide interesting public health lessons. Relatively speaking, Israel is a demographically young country, with only 11.5% of its population 65 years and older as compared with the OECD average of >17%. As well, a lower proportion of older persons is in long-term institutions in Israel than in most other OECD countries. The initiation of a national program to protect older residents of nursing homes and more latterly, a successful vaccine program has resulted in relatively low rates of serious COVID-19 related disease and mortality in Israel. However, the global situation remains unstable and the older population remains at risk. The rollout of efficacious vaccines is in progress but it will probably take years to cover the world's population, especially those living in low- and middle-income countries. Every effort must be made not to leave these poorer countries behind. Marrying the principles of public health (care of the population) with those of geriatric medicine (care of the older individual) offers the best way forward.

Keywords: COVID-19 pandemic; age; ageism; geriatric medicine; pandemic

DOI: https://doi.org/10.3389/fpubh.2021.655831

Blood Adv. 2021 Nov 18. pii: bloodadvances.2021004934. [Epub ahead of print]

Differential impact of IDH1/2 mutational subclasses on outcome in adult AML: Results from a large multicenter study.

Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are amongst the most frequent alterations in acute myeloid leukemia (AML) and can be found in ~20% of patients at diagnosis. Among 4930 patients (median age 56 years, interquartile range 45-66) with newly diagnosed, intensively treated AML, we have identified IDH1 mutations (mIDH1) in 423 (8.6%) and IDH2 mutations (mIDH2) in 575 (11.7%) patients. Overall, there were no differences in response rates or survival for patients with mIDH1 or mIDH2 compared to patients without mutated IDH1/2. However, distinct clinical and co-mutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with significantly increased age, lower white blood cell count (WBC), less frequent co-mutation of NPM1 and FLT3-ITD as well as lower rate of complete remissions and a trend for reduced overall survival (OS) compared to other mIDH1 variants and wtIDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC, more karyotype abnormalities, and less frequent co-mutations of NPM1 and/or FLT3-ITD. Among patients within the ELN2017 intermediate- and adverse-risk groups, RFS and OS were significantly better for patients with IDH2-R172K compared to wtIDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific co-mutation pattern and favorable outcome. In summary, the presented data from a large cohort of IDH1/2 mutant AML patients indicate novel and clinically relevant findings for the most common IDH-mutation subtypes.

DOI: https://doi.org/10.1182/bloodadvances.2021004934

J Neurol. 2021 Nov 17.

The role of frailty in Parkinson's disease: a cross-sectional study.

Daniele Belvisi, Marco Canevelli, Matteo Costanzo, Margherita Giangrosso, Andrea Fabbrini, Andrea Borraccino, Giuseppe Bruno, Alfredo Berardelli, Giovanni Fabbrini.

BACKGROUND: Frailty is an age-related state of increased risk for health-related adverse outcomes that reflects multisystem physiological changes and likely influences the clinical expression and disease progression of neurodegenerative disorders. The aim of the present study was to assess the potential relationship between frailty, as assessed by a frailty index (FI), and motor symptom severity, motor subtypes, and non-motor domains in Parkinson's disease (PD).
METHODS: We consecutively enrolled 150 PD patients. We administered an FI specifically designed for PD that included 50 age-related multidimensional biological deficits. Patients underwent a clinical assessment that evaluated motor and non-motor manifestations of PD. Using the FI score, we classified PD patients as relatively fit (FI ≤ 0.10), less fit (0.10 < FI ≤ 0.21), or frail (FI > 0.21). A linear regression model was designed to explore possible associations between frailty level and PD motor and non-motor manifestations.
RESULTS: Frail patients showed greater motor symptom severity and motor complications than fitter patients. A trend towards a higher prevalence of the postural instability/gait disorder subtype was also observed in frail versus relatively fit and less fit patients. The global burden of non-motor symptoms was higher in frail patients. Increased frailty was associated with more severe motor and non-motor symptoms, as well as with more pronounced cognitive deficits. These associations remained significant even when "traditional" predictors of PD severity (age, disease duration, and levodopa equivalent daily dose) were considered.
CONCLUSIONS: The present findings indicate that the FI is associated with both motor and non-motor features of PD.

Keywords: Frailty index; Motor symptoms; Non-motor symptoms; Parkinson’s disease; Subtypes

DOI: https://doi.org/10.1007/s00415-021-10873-3