Search

Background: Specialized proresolution molecules (SPMs) halt the transition to chronic pathogenic inflammation. We aimed to quantify serum levels of pro- and anti-inflammatory bioactive lipids in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients, and to identify potential relationships with innate responses and clinical outcome., Methods: Serum from 50 hospital admitted inpatients (22 female, 28 male) with confirmed symptomatic SARS-CoV-2 infection and 94 age- and sex-matched controls collected prior to the pandemic (SARS-CoV-2 negative), were processed for quantification of bioactive lipids and anti-nucleocapsid and anti-spike quantitative binding assays., Results: SARS-CoV-2 serum had significantly higher concentrations of omega-6-derived proinflammatory lipids and omega-6- and omega-3-derived SPMs, compared to the age- and sex-matched SARS-CoV-2-negative group, which were not markedly altered by age or sex. There were significant positive correlations between SPMs, proinflammatory bioactive lipids, and anti-spike antibody binding. Levels of some SPMs were significantly higher in patients with an anti-spike antibody value >0.5. Levels of linoleic acid and 5,6-dihydroxy-8Z,11Z,14Z-eicosatrienoic acid were significantly lower in SARS-CoV-2 patients who died., Conclusions: SARS-CoV-2 infection was associated with increased levels of SPMs and other pro- and anti-inflammatory bioactive lipids, supporting the future investigation of the underlying enzymatic pathways, which may inform the development of novel treatments., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

Purpose: The world's population is ageing. Therefore, every doctor should receive geriatric medicine training during their undergraduate education. This review aims to summarise recent developments in geriatric medicine that will potentially inform developments and updating of undergraduate medical curricula for geriatric content., Methods: We systematically searched the electronic databases Ovid Medline, Ovid Embase and Pubmed, from 1st January 2009 to 18th May 2021. We included studies related to (1) undergraduate medical students and (2) geriatric medicine or ageing or older adults and (3) curriculum or curriculum topics or learning objectives or competencies or teaching methods or students' attitudes and (4) published in a scientific journal. No language restrictions were applied., Results: We identified 2503 records and assessed the full texts of 393 records for eligibility with 367 records included in the thematic analysis. Six major themes emerged: curriculum, topics, teaching methods, teaching settings, medical students' skills and medical students' attitudes. New curricula focussed on minimum Geriatrics Competencies, Geriatric Psychiatry and Comprehensive Geriatric Assessment; vertical integration of Geriatric Medicine into the curriculum has been advocated. Emerging or evolving topics included delirium, pharmacotherapeutics, healthy ageing and health promotion, and Telemedicine. Teaching methods emphasised interprofessional education, senior mentor programmes and intergenerational contact, student journaling and reflective writing, simulation, clinical placements and e-learning. Nursing homes featured among new teaching settings. Communication skills, empathy and professionalism were highlighted as essential skills for interacting with older adults., Conclusion: We recommend that future undergraduate medical curricula in Geriatric Medicine should take into account recent developments described in this paper. In addition to including newly emerged topics and advances in existing topics, different teaching settings and methods should also be considered. Employing vertical integration throughout the undergraduate course can usefully supplement learning achieved in a dedicated Geriatric Medicine undergraduate course. Interprofessional education can improve understanding of the roles of other professionals and improve team-working skills. A focus on improving communication skills and empathy should particularly enable better interaction with older patients. Embedding expected levels of Geriatric competencies should ensure that medical students have acquired the skills necessary to effectively treat older patients., (© 2021. The Author(s).)

Background: Older people who are non-weight-bearing after a lower limb fracture are at risk of poor outcomes but there are no clinical guidelines for this group of patients. Given the paucity of the research evidence base, we conducted a consensus exercise to ascertain expert opinion about the management of this group., Methods: A three-round e-Delphi technique was planned to use the online JISC survey tool with a multidisciplinary panel of health professionals. Panellists were invited by email via professional organisations and UK NHS Trusts. The initial statements for this study were prepared by the authors based upon the findings of their scoping review. Consensus required >/= 70% agreement with statements., Results: Only 2 survey rounds were required. Ninety panellists, representing seven clinical disciplines, reached consensus for 24 statements about general issues (osteoporosis detection and management, falls risk reduction and nutrition) and specific non-weight bearing issues (such as the need for activity to be promoted during this period)., Conclusions: These findings can be used in the generation of a clinical guideline for this group of patients.

Background: sarcopenia is the loss of muscle mass and quality and is diagnosed using measures of muscle strength, size and mass. We evaluated the literature on whether sarcopenia measures are predictive of motor outcomes in older people in clinical settings., Methods: electronic databases (MEDLINE Ovid, EMBASE, CINAHL and Web of Science) were searched for articles on measures of muscle mass, volume, thickness or strength, in older people in clinical settings, which reported cross-sectional or longitudinal associations with motor outcomes. Clinical cohorts included geriatric medical inpatients and outpatients, patients with hip fracture, geriatric rehabilitation and care home residents. Motor outcomes were mobility, falls, balance and activities of daily living (ADL). Due to high study heterogeneity, standardised mean differences were used to compare strength of associations., Results: in total, 83 articles were identified. The most frequently studied measures were grip strength (47 studies), knee extension strength (21 studies) and bioelectrical impedance analysis (18 studies). Handgrip strength (HGS) had evidence for cross-sectional associations with mobility (14 of 16 studies, 2,088 participants), balance (6 of 6 studies, 1,177 participants) and ADL independence (10 of 11 studies, 3,228 participants), and evidence of longitudinal associations with mobility (3 of 3 studies, 883 participants) and ADL independence (7 of 10 studies, 1,511 participants). There was no conclusive evidence for association with falls., Conclusions: HS was the most studied measure and was associated with mobility, balance and ADL outcomes. There was a paucity of studies, particularly with longitudinal follow-up, measuring muscle mass, volume or thickness using gold-standard approaches., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Falls and polypharmacy are both common in care home residents. Deprescribing of medications in residents with increased falls risk is encouraged. Psychotropic medications are known to increase falls risk in older adults. These drugs are often used in care home residents for depression, anxiety, and behavioural and psychological symptoms of dementia. However, a few studies have explored the link between polypharmacy, psychotropic medications, and falls risk in care home residents., Methods: This was a prospective cohort study of residents from 84 UK care homes. Data were collected from residents' care records and medication administration records. Age, diagnoses, gender, number of medications, and number of psychotropic medications were collected at baseline and residents were monitored over three months for occurrence of falls. Logistic regression models were used to assess the effect of multiple medications and psychotropic medication on falls whilst adjusting for confounders., Results: Of the 1655 participants, mean age 85 (SD 8.9) years, 67.9% female, 519 (31%) fell in 3 months. Both the total number of regular drugs prescribed and taking ≥ 1 regular psychotropic medication were independent risk factors for falling (adjusted odds ratio (OR) 1.06 (95% CI 1.03-1.09, p < 0.01) and 1.39 (95% CI 1.10-1.76, p < 0.01), respectively). The risk of falls was higher in those taking antidepressants (p < 0.01) and benzodiazepines (p < 0.01) but not antipsychotics (p > 0.05)., Conclusion: In UK care homes, number of medications and psychotropic medications (particularly antidepressants and benzodiazepines) predicted falls. This information can be used to inform prescribing and deprescribing decisions.

We investigated whether osteoporotic fractures declined during lockdown, among adults aged 50 years and older. We showed that fewer outpatients attended the Fracture Clinic, for non-hip fractures, during lockdown; in contrast, no change in admissions for hip fractures was observed. This could be due to fewer outdoors falls, during lockdown., Purpose: Many countries implemented a lockdown to control the spread of the COVID-19 pandemic. We explored whether outpatient attendances to the Fracture Clinic for non-hip fragility fracture and inpatient admissions for hip fracture declined during lockdown, among adults aged 50 years and older, in a large secondary care hospital., Methods: In our observational study, we analysed the records of 6681 outpatients attending the Fracture Clinic, for non-hip fragility fractures, and those of 1752 inpatients, admitted for hip fracture, during the time frames of interest. These were weeks 1st to 12th in 2020 ("prior to lockdown"), weeks 13th to 19th in 2020 ("lockdown") and corresponding periods over 2015 to 2019. We tested for differences in mean numbers (standard deviation (SD)) of outpatients and inpatients, respectively, per week, during the time frames of interest, across the years., Results: Prior to lockdown, in 2020, 63.1 (SD 12.6) outpatients per week attended the Fracture Clinic, similar to previous years (p value 0.338). During lockdown, 26.0 (SD 7.3) outpatients per week attended the Fracture Clinic, fewer than previous years (p value < 0.001); similar findings were observed in both sexes and age groups (all p values < 0.001). During lockdown, 16.1 (SD 5.6) inpatients per week were admitted for hip fracture, similar to previous years (p value 0.776)., Conclusion: During lockdown, fewer outpatients attended the Fracture Clinic, for non-hip fragility fractures, while no change in inpatient admissions for hip fracture was observed. This could reflect fewer non-hip fractures and may inform allocation of resources during pandemic.

Background: chair-based pedal exercises potentially offer a simple method of improving physical activity in older people admitted to hospital., Objective: to assess the feasibility of using chair-based pedal exercisers on acute medical wards for older people. To study if there is any effect on muscle strength, mobility and time spent physically active., Subjects: fifty participants ≥65 years who were able to pedal admitted to acute medical wards for older people in a UK hospital., Methods: participants were randomised to either pedal for 5 min three times a day with minimal supervision; or standard care. Outcome data (compliance with exercise and change in lower limb muscle strength, mobility and level of physical activity) were collected on day 7 or on discharge, whichever came 1st., Results: there were no significant differences in baseline characteristics between the intervention and standard care group. Participants remained in the study for an average of 5 days. None in the intervention group adhered to the prescribed exercise duration. The intervention group completed a median of 152 revolutions, or a median total pedal time of 5 min during the entire study period. There were no differences in change in lower limb muscle strength, mobility score or the percentage of time spent active between the two groups., Conclusion: pedal exercises with minimal supervision are not feasible as a single intervention to improve physical activity in older people admitted to hospital. There may be a role for it as part of a multifaceted strategy to improve physical activity in hospital.

The preparation of 3-(2-chlorethyl)-4-oxo-3H-imidazo[5,1-d]-1,2,3,5- tetrazine-8-carboxylic acid, a key derivative of mitozolomide in our exploration of the structure-activity relationships of this class of antitumor agents, is described. The facile conversion to the 8-carbonyl chloride gave a derivative that reacted preferentially with nucleophiles at the 8-position rather than at the reactive 4-oxo group, allowing the preparation of a wide range of ester, thioester, amide (including an amide derived from an amino acid), hydroxamic acid, hydrazide and sulfoximide, azide and diazoacetyl derivatives. The in vivo activity is presented of a range of these compounds against TLX5 lymphoma and L1210 leukemia cell lines.

The synthesis and antiallergic activity in the rat passive cutaneous anaphylactic reaction of a series of 2-phenyl-8-azapurin-6-ones are described. Early in the investigation, a linear free-energy equation was established in which the activity was related to the size and hydrogen bonding capacity of the ortho substituent in the phenyl ring. This relationship was used to provide guidance and limits for subsequent work leading to 2-o-propoxyphenyl-8-azapurin-6-one which is 40 times more potent than disodium cromoglycate. It is suggested that good antiallergic activity in this series is associated with coplanarity of the phenyl group with the azapurin-6-one which would be favored by a high degree of hydrogen bonding.

8-Carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H) -one (mitozolomide) demonstrates curative action against a range of murine tumor model systems. At single doses of between 20 and 40 mg/kg, the latter of which approximates the 10% lethal dose value in mice, the compound elicited cures against the L1210 and P388 leukemias irrespective of the route of tumor and/or drug administration; in these tests, animals receiving 10(5) cells i.p. survived greater than 60 days after treatment. Potent effects were also observed against the TLX5 lymphoma (s.c.) and B16 melanoma (i.p.). In other experiments, 7 of 10 animals implanted with 2 X 10(5) Lewis lung carcinoma cells survived greater than 60 days while 10 of 10 animals survived greater than 60 days after implantation of the Colon 26 tumor. Potent inhibition of the solid tumor models was also observed with complete cures of the Colon 38, M5076 sarcoma, and ADJ/PC6A plasmacytoma. In cross-resistance studies, the compound was ineffective against an L1210 leukemia made resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea and against a TLX5 lymphoma resistant to dimethyltriazenes but cured animals bearing the L1210 leukemia with derived resistance to cyclophosphamide.

The systematic variation of the potent antitumor agent mitozolomide (1) is extended to cover alteration of substituents at positions 6 and 8 and to change the imidazo[5,1-d]-1,2,3,5-tetrazinone (1) skeleton to the isomeric pyrazolo-[5,1-d]-1,2,3,5-tetrazinone (17) skeleton. The series of eight 6-alkyl and 6-aralkyl derivatives of 1 showed optimal antitumor activity when the group was small or linear, but activity diminished as size and branching of this substituent increased. This may reflect altered transport characteristics, or failure of the enlarged derivatives to fit a binding site, or possibly a reduced tendency for the derivatives having bulky groups at position 6 to hydrolytically generate the putatively active triazenes (21). Testing of 14 derivatives of 1 differently substituted at position 8 revealed a complex structure-activity relationship, with good antitumor activity obtained for carbamoyl and sulfamoyl groups bearing small substituents. The 8-methylsulfonyl compound had noteworthy activity, but the 8-cyano, 8-nitro, and 8-phenyl derivatives were devoid of useful antitumor activity in these tests. From the limited number of pyrazolotetrazinones (17) reported here, it is suggested that the same conclusions as regards activity also hold true for this ring system.

The in vitro cytotoxicity, stability, and metabolism of the 8-(N,N-dimethylcarboxamide) and 8-(N-methylcarboxamide) analogues of the experimental antitumor drug mitozolomide have been investigated in conjunction with their in vivo murine pharmacokinetics and metabolism. When tested against the TLX5 lymphoma in vitro the ID50 values for dimethylmitozolomide, methylmitozolomide, and mitozolomide were 14.6, 3.0, and 2.3 microM, respectively. The cytotoxicity of dimethylmitozolomide was dramatically increased when it was incubated with murine hepatic microsomes. There was no significant difference in the in vitro stabilities of dimethylmitozolomide and methylmitozolamide with half-lives of 43.5 and 45.8 min, respectively, in RPMI at 37 degrees C. The in vitro microsomal incubation of dimethylmitozolomide produced significant amounts of methylmitozolomide, which suggests that methylmitozolomide contributed to the cytotoxicity of dimethylmitozolomide in the presence of microsomes. The pharmacokinetics of both dimethylmitozolomide and methylmitozolomide, given i.p. at 10 mg/kg, were investigated in CBA/Ca mice bearing the s.c. solid TLX5 lymphoma. Methylmitozolomide was absorbed rapidly with maximum plasma and tumor concentrations of 10.66 mg/liter and 8.01 mg/kg, respectively, achieved 0.17 h following dosing. Dimethylmitozolomide was also rapidly absorbed with maximum plasma and tumor concentrations of 9.34 mg/liter and 5.00 mg/kg, respectively, achieved within 0.18 h of dosing. Following administration of dimethylmitozolomide, methylmitozolomide was found in both plasma and tumor tissue. The plasma and tumor area under the curves of methylmitozolomide were 87.7% and 120.8%, respectively, of those seen when mice were dosed with authentic methylmitozolomide. By comparison of the area under the curves and clearance values, it was demonstrated that 89% of the administered dimethylmitozolomide was metabolized via methylmitozolomide.

The synthesis and antiallergic activity of a series of 2-hydroxy-N-1H-tetrazol-5-ylbenzamides and isomeric N-(2-hydroxyphenyl)-1H-tetrazole-5-carboxamides is described. A relationship between structure and intravenous antiallergic activity in the rat passive cutaneous anaphylaxis (PCA) test has been established using a Hansch/Free-Wilson model and used to direct studies toward potent derivatives. The contribution of physicochemical properties to activity is discussed. One member of this series, N-(3-acetyl-5-fluoro-2-hydroxyphenyl)-1H-tetrazole-5-carboxamide (3f), which was selected for further evaluation, has an ID50 value of 0.16 mg/kg po and is 130 times more potent than disodium cromoglycate (DSCG) on intravenous administration.

Interaction of 5-diazoimidazole-4-carboxamide and alkyl and aryl isocyanates in the dark affords 8-carbamoyl-3-substituted-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-on es. In cold methanol or ethanol, the 3-(2-chloroethyl) derivative 7a decomposes to afford 2-azahypoxanthine (14) and methyl and ethyl N-(2-chloroethyl)carbamates, respectively. Compound 7a has curative activity against L-1210 and P388 leukemia and may act as a prodrug modification of the acyclic triazene 5-[3-(2-chloroethyl)triazen-1-yl]imidazole-4-carboxamide (MCTIC), since it ring opens to form the triazene in aqueous sodium carbonate.