Core requirements of frailty screening in the emergency department: an international Delphi consensus study.

INTRODUCTION: Frailty is associated with adverse outcomes among patients attending emergency departments (EDs). While multiple frailty screens are available, little is known about which variables are important to incorporate and how best to facilitate accurate, yet prompt ED screening. To understand the core requirements of frailty screening in ED, we conducted an international, modified, electronic two-round Delphi consensus study. METHODS: A two-round electronic Delphi involving 37 participants from 10 countries was undertaken. Statements were generated from a prior systematic review examining frailty screening instruments in ED (logistic, psychometric and clinimetric properties). Reflexive thematic analysis generated a list of 56 statements for Round 1 (August-September 2021). Four main themes identified were: (i) principles of frailty screening, (ii) practicalities and logistics, (iii) frailty domains and (iv) frailty risk factors. RESULTS: In Round 1, 13/56 statements (23%) were accepted. Following feedback, 22 new statements were created and 35 were re-circulated in Round 2 (October 2021). Of these, 19 (54%) were finally accepted. It was agreed that ideal frailty screens should be short (<5 min), multidimensional and well-calibrated across the spectrum of frailty, reflecting baseline status 2-4 weeks before presentation. Screening should ideally be routine, prompt (<4 h after arrival) and completed at first contact in ED. Functional ability, mobility, cognition, medication use and social factors were identified as the most important variables to include. CONCLUSIONS: Although a clear consensus was reached on important requirements of frailty screening in ED, and variables to include in an ideal screen, more research is required to operationalise screening in clinical practice.

Design and Synthesis of Multi-Functional Ligands through Hantzsch Reaction: Targeting Ca2+ Channels, Activating Nrf2 and Possessing Cathepsin S Inhibitory, and Antioxidant Properties.

This work relates to the design and synthesis of a series of novel multi-target directed ligands (MTDLs), i.e., compounds 4a-l, via a convenient one-pot three-component Hantzsch reaction. This approach targeted calcium channel antagonism, antioxidant capacity, cathepsin S inhibition, and interference with Nrf2 transcriptional activation. Of these MTDLs, 4i emerged as a promising compound, demonstrating robust antioxidant activity, the ability to activate Nrf2-ARE pathways, as well as calcium channel blockade and cathepsin S inhibition. Dihydropyridine 4i represents the first example of an MTDL that combines these biological activities.

Calcium channel blockers' contribution to overcoming Current drug discovery challenges in Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a progressive, irreversible, and multifactorial brain disorder that gradually and insidiously destroys individual's memory, thinking, and other cognitive abilities. AREAS COVERED: In this perspective, the authors examine the complex and multifactorial nature of Alzheimer's disease and believe that the best approach to develop new drugs is the MTDL strategy, which obviously faces several challenges. These challenges include identifying the key combination of targets and their suitability for coordinated actions, as well as developing an acceptable pharmacokinetic and toxicological profile to deliver a drug candidate. EXPERT OPINION: Since calcium plays a crucial role in the pathology of AD, a polypharmacological approach with calcium channel blockers reinforced by activities targeting other factors involved in AD is a serious option in our opinion. This is exemplified by a phase III clinical trial using a drug combination approach with Losartan, Amlodipine (a calcium channel blocker), and Atorvastatin, as well as several MTDL-based calcium channel blockade approaches with a promising in vitro and in vivo profile.

Exploring the Potential of Sulfonamide-Dihydropyridine Hybrids as Multitargeted Ligands for Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that has a heavy social and economic impact on all societies and for which there is still no cure. Multitarget-directed ligands (MTDLs) seem to be a promising therapeutic strategy for finding an effective treatment for this disease. For this purpose, new MTDLs were designed and synthesized in three steps by simple and cost-efficient procedures targeting calcium channel blockade, cholinesterase inhibition, and antioxidant activity. The biological and physicochemical results collected in this study allowed us the identification two sulfonamide-dihydropyridine hybrids showing simultaneous cholinesterase inhibition, calcium channel blockade, antioxidant capacity and Nrf2-ARE activating effect, that deserve to be further investigated for AD therapy.

Getting a handle on rat familiarization: The impact of handling protocols on classic tests of stress in Rattus norvegicus.

Experimenter familiarization with laboratory rodents through handling prior to experimentation is an important practice in neurobehavioral research and is implicated in stress, study variability, and replicability. Unfortunately, different handling protocols have not been thoroughly examined. Determining optimal experimenter familiarization protocols is expected to reduce animal stress and thus improve welfare and data consistency. The impact of different handling protocols was determined through behavioral assessments (i.e. elevated plus maze, light/dark box, open field) as well as via analysis of fecal boli counts, ultrasonic vocalizations, and blood corticosterone. Male and female Sprague Dawley rats were distributed among three groups: never handled, picked-up, and handled for 5 min once daily over five days. Handled and picked-up rats spent more time in open arms and less time in closed arms of the elevated plus maze and more time in the center and less time at the perimeter of the open field compared to rats that were never handled, indicating that handled and picked-up rats were less anxious than those that were never handled. Male rats consistently defecated more frequently throughout the handling process and throughout behavioral testing, whereas females showed greater concentrations of blood corticosterone. Female rats were found to emit more 50-kHz calls and fewer 22-kHz calls compared to males. The results observed suggest that picking animals up may suffice as a handling method compared to time-intensive handling procedures, and that there are significant sex differences in response to handling.

"Older People Want to Be in Their Own Homes": A Service Evaluation of Patient and Carer Feedback after Pathfinder Responded to Their Emergency Calls.

OBJECTIVE: Older people experience high rates of adverse outcomes following emergency department (ED) presentation. There is growing evidence to support alternative care pathways for certain types of emergency medical services (EMS) calls. Pathfinder is one such service and targets patients aged 65 years and over, whose presenting issues can be safely managed at home by immediate paramedic, occupational therapy, and/or physiotherapy interventions. The aim of this service evaluation was to understand how older people feel about being treated at home as a result of EMS calls and to understand their experiences of the Pathfinder service. METHODS: This was a thematic analysis of open-ended responses recorded from telephone interviews during routine service evaluation with service users (patients or their next-of-kin). RESULTS: Of 573 service users, telephone interviews were conducted with 429 (75%). Five primary themes were identified: (1) professionalism of the multidisciplinary clinical team; (2) "the right service, in the right place, at the right time"; (3) role of Pathfinder in "getting the ball rolling"; (4) lasting effects of the experience on the patient and his or her next-of-kin; (5) value of skilled communication with the older person. CONCLUSION: Older people and their next-of-kin voiced a clear preference for hospital avoidance, and strongly valued the opportunity to be treated in their homes at the time of an EMS call rather than default conveyance to the ED. They appreciated the importance of a skilled multidisciplinary team with a follow-up service that effectively positions itself between the acute hospital and community services.

Benzochromenopyrimidines: Synthesis, Antiproliferative Activity against Colorectal Cancer and Physicochemical Properties.

Ten new differently substituted 3-benzyl-5-aryl-3,5-dihydro-4H-benzo[6,7]chromeno[2,3-d]pyrimidin-4,6,11-triones 3 were synthesized by a simple and cost-efficient procedure in a one-pot, three-component reaction from readily available ethyl 2-amino-4-aryl-5,10-dioxo-5,10-dihydro-4H-benzo[g]chromene-3-carboxylates, benzylamine and triethyl orthoformate under solvent- and catalyst-free conditions. All the new compounds were screened for their antiproliferative activity against two colorectal-cancer-cell lines. The results showed that the compounds 3-benzyl-5-phenyl-3,5-dihydro-4H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11-trione (3a) and 3-benzyl-5-(3-hydroxyphenyl)-3,5-dihydro-4H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11-trione (3g) exhibited the most potent balanced inhibitory activity against human LoVo and HCT-116 cancer cells.

The Effects of Rearing in a Shelved Environment on Behavioral and Physiological Markers of Welfare in Rats (Rattus norvegicus).

Early-life experiences are critical modifiers of development. An important component of early-life experience is the nature of maternal interactions, which can be modified by stress. During rearing, mothers are typically allocated to single-level cages where they are readily accessible to pups, a potentially stressful scenario not reflective of nature. Accordingly, mothers regularly removed from the rearing environment interact differently with their offspring, leading to long-term changes in offspring physiology and behavior. Such changes commonly include modifications within the hypothalamic-pituitary-adrenal axis, of which corticosterone is a major component. Modifications in the hypothalamic-pituitary-adrenal axis may also be manifested through changes in affective behavior and assessed via tests such as the open field and elevated plus maze as well as via ultrasonic vocalization (USV) analysis. As a means of assessing the impact of rearing in a shelved environment, we allocated mothers to standard single-level cages or cages with an integrated shelf, which allowed the mother to temporarily escape pups. While there were no differences in fecal cortico-sterone, behavior in the elevated plus maze, or USVs, male rats reared in standard cages weighed more, and all standard single-level housed rats spent more time in the center of the open field. The observed differences indicate that allocating nursing mothers to shelved environments throughout the postnatal period has long-lasting effects on offspring behavior that must be considered when establishing dam enrichment protocols.

A modified TOF-ratio to assess rocuronium-induced neuromuscular block: a comparison with the usual TOF-ratio.

BACKGROUND: The TOFscan is an acceleromyographic neuromuscular monitor that calculates and displays two measurements: first, a train-of-four (TOF) ratio, or ratio of the fourth twitch in the TOF-sequence, T4, and the first twitch, T1 (T4/T1). In addition, a second, modified ratio is displayed (T4/Tr), which refers to the ratio between T4 and a reference twitch (Tr), calculated as the mean value of the four twitches in a TOF-sequence [Tr = (T1 + T2 + T3 + T4)/4]. T4/Tr is calculated before establishment of neuromuscular block. METHODS: This prospective observational study included 35 adult patients. NMB induced by a rocuronium bolus of 0.6 mg/kg was continuously monitored at the adductor pollicis with the TOFscan and both TOF-ratios were simultaneously assessed. Primary outcome was the comparison of recovery to a TOF-ratio ≥ 0.9 calculated as T4/T1 and T4/Tr. RESULTS: The first value of the T4/T1 ≥ 90% was 90.9 (1.1) % and the simultaneously calculated T4/Tr was 69.6 (9.3) %, P < 0.001. The first value of the T4/Tr ≥ 90% was 90.5 (1.1) %, the simultaneously T4/T1 was 97.3 (2.5) %, P < 0.001. Time from injection of rocuronium to a TOF-ratio ≥ 90% was 56.2 ± 17.1 min for the T4/T1 and 65.3 ± 19.3 min for the T4/Tr, P < 0.001. During onset, a TOF ratio ≤ 20% was reached 145.5 (50.5) s after rocuronium when considering T4/T1, and 114.5 (45) s with the T4/Tr, P < 0.001. CONCLUSION: The present study shows the limitations of the usually determined acceleromyographic TOF ratio (T4/T1) in determining adequate neuromuscular recovery. The T4/T1 ratio significantly overestimates recovery compared with the T4/Tr ratio. Clinical decisions of adequate neuromuscular recovery based on the new T4/Tr ratio may reduce the incidence of residual paralysis and improve patient safety.

Ultrasonic Vocalization Analysis as a Novel Metric to Assess Cage Enrichment in Rats.

Laboratory rodent housing conditions vary significantly across laboratories and facilities. Variation in housing can be associated with animal stress leading to study variability and the subsequent inability to replicate experimental findings. Optimization and standardization of animal housing are necessary to promote animal welfare and data consistency, thereby reducing the number of animals necessary to detect treatment effects. While interest in environmental enrichment is increasing, many studies do not examine the behavior of animals in the home cage, neglecting important aspects of enrichment. To determine how increased vertical home cage area affects animal welfare, double-decker cages (enriched), which allow rats to upright stand, were compared with standard single-level cages, which impede the ability to upright stand. Home cage welfare was assessed by analyzing ultrasonic vocalizations, fecal corticosterone, upright standing, and fighting. Ultrasonic vocalization was further explored by analyses of call type as defined by a 14 call-type schematic. Rats housed in enriched cages spent more time fighting, produced fewer 50 kHz calls, and had higher levels of fecal corticosterone. Rats in standard cages attempted to upright stand more often but remained upright for a shorter amount of time due to the height limitation imposed by standard cages. In addition, standard cages restrict some naturalistic behaviors such as upright standing and reduce fighting, which may be attributable to their single-tier organization and floor space. Enriched cages permit rats to engage in normal ethological behavior but also increase fighting. This study demonstrates that housing conditions have a meaningful impact on multiple measures of animal affect. When considering study design, researchers should be aware of how housing conditions affect animal subjects.

Early-life seizures modify behavioral response to ultrasonic vocalization playback in adult rats.

Early-life seizures (ELS) are associated with autism spectrum disorder (ASD); however, due to a lack of effective treatments for ELS, it is not clear whether ELS plays a causal role, potentiates the ASD phenotype, or is the result of a common pathophysiology. Deficits in communications are a core feature of ASD. To isolate the impact of ELS on communication, we probed the behavioral consequences of a single episode of kainic acid-induced early-life seizures (KA-ELS) in male and female Sprague-Dawley (CD) rats. Deficits in auditory communication were observed in adult male rats as assessed by behavioral response to ultrasonic vocalization (USV) playback. Ultrasonic vocalizations are classified into two major categories - 50-kHz (positive) calls and 22-kHz (aversive) calls. Behavioral response was assessed via rat preference for different USV playback in a radial arm maze. Response to 22-kHz calls was not impacted by ELS while response to 50-kHz calls was impacted. All rats demonstrated positional preference for the arms adjacent to where 50-kHz calls were playing compared to background noise; however, male ELS rats demonstrated a greater positional preference for the arms adjacent to where 50-kHz calls were playing compared to male control rats. These studies demonstrate that responses to socially relevant auditory cues are chronically altered in adult male rats following a single episode of ELS. We speculate that these changes contribute to previously reported social deficits associated with ELS.

Biginelli Reaction Synthesis of Novel Multitarget-Directed Ligands with Ca2+ Channel Blocking Ability, Cholinesterase Inhibition, Antioxidant Capacity, and Nrf2 Activation.

Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software.

Neuromuscular block in patients 80 years and older: a prospective, controlled study.

BACKGROUND: An increasing number of patients older than 80 years are undergoing anesthesia, but little information is available regarding pharmacodynamic effects of myorelaxants in this population. This study aims to compare the time course of rocuronium neuromuscular block in patients ≥ 80 years with those of younger adults. METHODS: Under total intravenous anesthesia with propofol and sufentanil, time course of a bolus of rocuronium 0.6 mg/kg neuromuscular block was assessed with acceleromyography in patients ≥ 80 and in patients 20-50 years old. Onset time, clinical duration, duration until 90% and 100% recovery of baseline were determined. RESULTS: Data from 32 patients were analyzed, 16 were ≥ 80 years and 16 were 20-50 years old. Demographic data are shown in Table 1. In the group ≥ 80, onset time was 190 s ± 46 s compared to 123 s ± 40 s in the group 20-50, P < 0.001 and the clinical duration was 52 [48-69.5] min and 36 [34-41] min, respectively, P < 0.001. Duration to 90% recovery of baseline was 77.5 [71-88.5] min and duration to 100% recovery of baseline was 91.2 [82.2-98] min in patients ≥ 80 years and the corresponding values in the patients 20-50 years old were 53.5 [49-55.5] min and 59.5 [56.5-70.25] min, respectively, P < 0.001. CONCLUSION: Compared to younger adults rocuronium shifted in patients ≥ 80 years from a rapid onset, intermediate acting compound to a slower onset, long-acting compound. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03551652 (29/05/2018).

The Impact of COVID-19 on Hospitalised COPD Exacerbations in Malta.

METHOD: Data was collected retrospectively from electronic hospital records during the periods 1st March until 10th May in 2019 and 2020. RESULTS: There was a marked decrease in AECOPD admissions in 2020, with a 54.2% drop in admissions (n = 119 in 2020 vs. n = 259 in 2019). There was no significant difference in patient demographics or medical comorbidities. In 2020, there was a significantly lower number of patients with AECOPD who received nebulised medications during admission (60.4% in 2020 vs. 84.9% in 2019; p ≤ 0.001). There were also significantly lower numbers of AECOPD patients admitted in 2020 who received controlled oxygen via venturi masks (69.0% in 2020 vs. 84.5% in 2019; p = 0.006). There was a significant increase in inpatient mortality in 2020 (19.3% [n = 23] and 8.4% [n = 22] for 2020 and 2019, respectively, p = 0.003). Year was found to be the best predictor of mortality outcome (p = 0.001). The lack of use of SABA pre-admission treatment (p = 0.002), active malignancy (p = 0.003), and increased length of hospital stay (p = 0.046) were also found to be predictors of mortality for AECOPD patients; however, these parameters were unchanged between 2019 and 2020 and therefore could not account for the increase in mortality. CONCLUSIONS: There was a decrease in the number of admissions with AECOPD in 2020 during the COVID-19 pandemic, when compared to 2019. The year 2020 proved to be a significant predictor for inpatient mortality, with a significant increase in mortality in 2020. The decrease in nebuliser and controlled oxygen treatment noted in the study period did not prove to be a significant predictor of mortality when corrected for other variables. Therefore, the difference in mortality cannot be explained with certainty in this retrospective cohort study.

Is Pathfinder a safe alternative to the emergency department for older patients? An observational analysis.

BACKGROUND: many patients brought to emergency departments (EDs) following an emergency medical services (EMS) call have non-urgent needs that could be treated elsewhere. Older people are particularly vulnerable to adverse events while attending the ED. Alternative care pathway models can reduce ED crowding and improve outcomes. Internationally, there is no consensus on which model is recommended. AIM: the aim of this study is to investigate the impact of the Pathfinder model on ED conveyance rates and patient safety. METHODS: the Pathfinder service is a collaboration between the National Ambulance Service and Beaumont Hospital Occupational Therapy and Physiotherapy Departments. It is supported by the Government of Ireland's Sláintecare Integration fund. This is a retrospective cohort study of the Pathfinder service over a 5-month period. RESULTS: one-hundred and seventy-eight patients were responded to by the Pathfinder 'Rapid Response Team'. Average age was 79.6 years (standard deviation 7.6), median clinical frailty score was 6 (interquartile range: 5-6). Sixty-four percent remained at home following initial review. None re-presented to the ED within 24 hours, and 10% re-presented within 7 days. The majority (67%) of patients required follow-up by the Pathfinder 'Follow-Up Team' and/or another community-based service. Feedback demonstrates 99% patient satisfaction with the service. CONCLUSION: the Pathfinder service is a safe alternative to ED conveyance for older people following an EMS call. It is the first model of this kind to be evaluated in Ireland. The overwhelmingly positive feedback confirms that older people want this service. This model could expand, with local adaptation, nationally and internationally.

Single Amino Acid Replacements in RocA Disrupt Protein-Protein Interactions To Alter the Molecular Pathogenesis of Group A Streptococcus.

Group A Streptococcus (GAS) is a human-specific pathogen and major cause of disease worldwide. The molecular pathogenesis of GAS, like many pathogens, is dependent on the coordinated expression of genes encoding different virulence factors. The control of virulence regulator/sensor (CovRS) two-component system is a major virulence regulator of GAS that has been extensively studied. More recent investigations have also involved regulator of Cov (RocA), a regulatory accessory protein to CovRS. RocA interacts, in some manner, with CovRS; however, the precise molecular mechanism is unknown. Here, we demonstrate that RocA is a membrane protein containing seven transmembrane helices with an extracytoplasmically located N terminus and cytoplasmically located C terminus. For the first time, we demonstrate that RocA directly interacts with itself (RocA) and CovS, but not CovR, in intact cells. Single amino acid replacements along the entire length of RocA disrupt RocA-RocA and RocA-CovS interactions to significantly alter the GAS virulence phenotype as defined by secreted virulence factor activity in vitro and tissue destruction and mortality in vivo In summary, we show that single amino acid replacements in a regulatory accessory protein can affect protein-protein interactions to significantly alter the virulence of a major human pathogen.

The Effectiveness of Mindfulness-Based Cognitive Therapy (MBCT) in Real-World Healthcare Services.

Depression is common with a high risk of relapse/recurrence. There is evidence from multiple randomised controlled trials (RCTs) demonstrating the efficacy of mindfulness-based cognitive therapy (MBCT) for the prevention of depressive relapse/recurrence, and it is included in several national clinical guidelines for this purpose. However, little is known about whether MBCT is being delivered safely and effectively in real-world healthcare settings. In the present study, five mental health services from a range of regions in the UK contributed data (n = 1554) to examine the impact of MBCT on depression outcomes. Less than half the sample (n = 726, 47%) entered with Patient Health Questionnaire (PHQ-9) scores in the non-depressed range, the group for whom MBCT was originally intended. Of this group, 96% sustained their recovery (remained in the non-depressed range) across the treatment period. There was also a significant reduction in residual symptoms, consistent with a reduced risk of depressive relapse. The rest of the sample (n = 828, 53%) entered treatment with PHQ-9 scores in the depressed range. For this group, 45% recovered (PHQ-9 score entered the non-depressed range), and overall, there was a significant reduction in depression severity from pre-treatment to post-treatment. For both subgroups, the rate of reliable deterioration (3%) was comparable to other psychotherapeutic interventions delivered in similar settings. We conclude that MBCT is being delivered effectively and safely in routine clinical settings, although its use has broadened from its original target population to include people experiencing current depression. Implications for implementation are discussed.

The glucocorticoid receptor in osteoprogenitors regulates bone mass and marrow fat.

Excess fat within bone marrow is associated with lower bone density. Metabolic stressors such as chronic caloric restriction (CR) can exacerbate marrow adiposity, and increased glucocorticoid signaling and adrenergic signaling are implicated in this phenotype. The current study tested the role of glucocorticoid signaling in CR-induced stress by conditionally deleting the glucocorticoid receptor (GR) in bone marrow osteoprogenitors (Osx1-Cre) of mice subjected to CR and ad libitum diets. Conditional knockout of the GR (GR-CKO) reduced cortical and trabecular bone mass as compared to wildtype (WT) mice under both ad libitum and CR conditions. No interaction was detected between genotype and diet, suggesting that the GR is not required for CR-induced skeletal changes. The lower bone mass in GR-CKO mice, and the further suppression of bone by CR, resulted from suppressed bone formation. Interestingly, treatment with the -adrenergic receptor antagonist propranolol mildly but selectively improved metrics of cortical bone mass in GR-CKO mice during CR, suggesting interaction between adrenergic and glucocorticoid signaling pathways that affects cortical bone. GR-CKO mice dramatically increased marrow fat under both ad libitum and CR-fed conditions, and surprisingly propranolol treatment was unable to rescue CR-induced marrow fat in either WT or GR-CKO mice. Additionally, serum corticosterone levels were selectively elevated in GR-CKO mice with CR, suggesting the possibility of bone-hypothalamus-pituitary-adrenal crosstalk during metabolic stress. This work highlights the complexities of glucocorticoid and ß-adrenergic signaling in stress-induced changes in bone mass, and the importance of GR function in suppressing marrow adipogenesis while maintaining healthy bone mass.