Addressing health inequalities in times of austerity: implementation of a place-based approach in multitiered local government.

AIMS: This article focuses on how local authorities in England are tackling wider determinants of health and inequalities in their population's outcomes while budgets for public services are diminishing. METHODS: It reports the experience from one case study engaged in rolling out a devolved, place- and asset-based strategy over multiple tiers of local government. Relating these findings to relevant social theory, we draw out aspects of context and mechanisms of change. We offer plausible hypotheses for the experiences observed, which supports transferability and implementation of place-based strategies in other local authority areas struggling with similar challenges. RESULTS: Findings highlight the importance of high-level and political buy-in, as well as the role of the COVID-19 pandemic as a potential catalyst to rollout. Creating the foundations for a new, place-based working was important for achieving coherence among partners around what local government was trying to achieve. These included investment in infrastructure, both relational and tangible inputs such as organisational and human resources, to establish the conditions for systemic change towards early intervention and prevention. CONCLUSION: This study identified clear foundations for place-based action, plus enablers and barriers to significant transformation of practice towards asset-based approaches between local authorities, partners and the public.

Examining the effectiveness of place-based interventions to improve public health and reduce health inequalities: an umbrella review.

BACKGROUND: Locally delivered, place-based public health interventions are receiving increasing attention as a way of improving health and reducing inequalities. However, there is limited evidence on their effectiveness. This umbrella review synthesises systematic review evidence of the health and health inequalities impacts of locally delivered place-based interventions across three elements of place and health: the physical, social, and economic environments. METHODS: Systematic review methodology was used to identify recent published systematic reviews of the effectiveness of place-based interventions on health and health inequalities (PROGRESS+) in high-income countries. Nine databases were searched from 1st January 2008 to 1st March 2020. The quality of the included articles was determined using the Revised Assessment of Multiple Systematic Reviews tool (R-AMSTAR). RESULTS: Thirteen systematic reviews were identified - reporting 51 unique primary studies. Fifty of these studies reported on interventions that changed the physical environment and one reported on changes to the economic environment. Only one primary study reported cost-effectiveness data. No reviews were identified that assessed the impact of social interventions. Given heterogeneity and quality issues, we found tentative evidence that the provision of housing/home modifications, improving the public realm, parks and playgrounds, supermarkets, transport, cycle lanes, walking routes, and outdoor gyms - can all have positive impacts on health outcomes - particularly physical activity. However, as no studies reported an assessment of variation in PROGRESS+ factors, the effect of these interventions on health inequalities remains unclear. CONCLUSIONS: Place-based interventions can be effective at improving physical health, health behaviours and social determinants of health outcomes. High agentic interventions indicate greater improvements for those living in greater proximity to the intervention, which may suggest that in order for interventions to reduce inequalities, they should be implemented at a scale commensurate with the level of disadvantage. Future research needs to ensure equity data is collected, as this is severely lacking and impeding progress on identifying interventions that are effective in reducing health inequalities. TRIAL REGISTRATION: PROSPERO CRD42019158309.

Blood flow restriction augments the skeletal muscle response during very low-load resistance exercise to volitional failure.

The purpose of this study was to compare the acute muscular response with resistance exercise between the following conditions [labeled (% one-repetition maximum/% arterial occlusion pressure)]: high-load (70/0), very low-load (15/0), very low-load with moderate (15/40), and high (15/80) blood flow restriction pressures. Twenty-three participants completed four sets of unilateral knee extension to failure (up to 90 repetitions) with each condition, one condition per leg, each day. Muscle thickness and maximal voluntary contraction (MVC) were measured before (Pre), immediately after (Post-0), and 15 min after (Post-15) exercise and electromyography (EMG) amplitude during exercise. Pre to Post-0 muscle thickness changes in cm [95% CI] were greater with 15/40 [0.57 (0.41, 0.73)] and 15/80 [0.49 (0.35, 0.62)] compared to 70/0 [0.33 (0.25, 0.40)]. Pre to Post-0 MVC changes in Nm [95% CI] were higher with 15/40 [-127.0 (-162.1, -91.9)] and 15/80 [-133.6 (-162.8, -104.4)] compared to 70/0 [-48.4 (-70.1, -26.6)] and 15/0 [-98.4 (-121.9, -74.9)], which were also different. Over the first three repetitions, EMG increased across sets, whereas in the last three repetitions it did not. EMG was also different between conditions and was generally greater during 70/0. Repetitions decreased across sets reaching the lowest for 70/0, and for very low loads decreased with increased pressure. In trained participants exercising to failure, lower load and the application of restriction pressure augment changes in muscle thickness and torque. The EMG amplitude was augmented by load. Training studies should compare these conditions, as the results herein suggest some muscular adaptations may differ.

The affective and behavioral responses to repeated "strength snacks".

Background A training program consisting of only one-repetition maximum (1RM) training results in similar strength adaptations as traditional resistance exercise. However, little is known regarding the affective or behavioral responses to this type of training. Aim To examine the affective and behavioral response to either a traditional resistance exercise program or a biweekly 1RM-training program. Methods Participants were trained for 8 weeks (2× per week). The HYPER group completed four sets of 8-12 repetitions; the 1RM group (TEST) worked up to a single maximal repetition. Results The TEST group felt more revitalized and had an increase in positive engagement during their first visit, whereas the HYPER group showed an increase in feelings of physical exhaustion during their first and last visits. There were no pre to post differences for the change in behavior or self-efficacy between groups. Conclusion 1RM training appears to elicit a more favorable affective response, compared with HYPER training, which may ultimately improve adherence to resistance-type exercise.

Are higher blood flow restriction pressures more beneficial when lower loads are used?

The application of blood flow restriction during low-load resistance exercise has been shown to induce muscle growth with high or low restriction pressures, however, loads lower than 20% one-repetition maximum (1RM) remain unexplored. Fourteen trained individuals completed six elbow flexion protocols involving three different loads (10%, 15%, and 20% 1RM) each of which was performed with either a low (40% arterial occlusion) or high (80% arterial occlusion) pressure. Pre- and post-measurements of surface electromyography (sEMG), isometric torque, and muscle thickness were analyzed. An interaction was present for torque (p < 0.001) and muscle thickness (p < 0.001) illustrating that all increases in pressure and/or load resulted in a greater fatigue and muscle thickness. There was no interaction for sEMG (p = 0.832); however, there were main effects of condition (p = 0.002) and time (p = 0.019) illustrating greater sEMG in the 20% 1RM conditions. Higher blood flow restriction pressures may be more beneficial for muscle growth when very low loads are used.

The acute muscular response to two distinct blood flow restriction protocols.

The purpose of this study was to determine acute physiological and perceptual responses to two commonly implemented blood flow restriction protocols. Using a within-subject design, 15 participants (age ∼25) performed four sets of unilateral elbow flexion with each arm. One arm exercised using a 3-cm elastic cuff inflated to 160 mmHg, whereas the other arm exercised using a 5-cm nylon cuff inflated to 40% of the individual's arterial occlusion pressure. While both protocols elicited increases in acute muscle thickness [pre: 4.5 (0.2) cm, post: 5.0 (0.2) cm; p < 0.001] and electromyography amplitude [first 3 reps: 55 ( 5 ) %MVC; last 3 reps: 87 ( 10 ) %MVC], there were no differences between conditions. Both protocols produced decreases in post-exercise strength (pre: 70 Nm, post: 51 Nm; p < 0.001) with no difference between conditions. The nylon protocol resulted in more repetitions during sets 2 [13 ( 2 ) vs. 9 ( 4 ); p = 0.001] and 3 [10 ( 2 ) vs. 7 ( 4 ); p = 0.05], while producing lower levels of discomfort following each set (average 3 vs. 4; p < 0.05). In conclusion, both protocols produced similar acute responses thought to be important for promoting muscle growth. However, the use of arbitrary pressures may place some individuals under complete arterial occlusion which may increase the potential risk of an adverse event.

Four weeks of high- versus low-load resistance training to failure on the rate of torque development, electromechanical delay, and contractile twitch properties.

The purpose of this study was to investigate the effects of 4-weeks of high- versus low-load resistance training to failure on rate of torque development (RTD), electromechanical delay (EMD), and contractile twitch characteristics. Fifteen men (mean±SD; age=21.7±2.4 yrs) were randomly assigned to either a high- (80% 1RM; n=7) or low-load (30% 1RM; n=8) training group and completed elbow flexion resistance training to failure 3 times per week for 4 weeks. The participants were tested at baseline, 2-, and 4-weeks of training. Peak RTD (pRTDV) and RTD at 0-30 (RTD30V), 0-50 (RTD50V), 0-100 (RTD100V), and 0-200 (RTD200V) ms, integrated EMG amplitude (iEMG) at 0-30, 0-50, and 0-100 ms, and EMD were quantified during maximal voluntary isometric muscle actions. Peak twitch torque, peak RTD, time to peak twitch, 1/2 relaxation time and the peak relaxation rate were quantified during evoked twitches. Four weeks of high-load, but not low-load resistance training, increased RTD200V. There were also increases in iEMG during the first 30 ms of muscle activation for the high- and low-load groups, which may have indirectly indicated increases in early phase motor unit recruitment and/or firing frequency. There were no significant training-induced adaptations in EMD or contractile twitch properties.

An automated method for the simultaneous measurement of azole antifungal drugs in human plasma or serum using turbulent flow liquid chromatography-tandem mass spectrometry.

Azole antifungal drugs are important in the prophylaxis and treatment of invasive aspergillosis. Therapeutic drug monitoring may be indicated to (1) monitor adherence, (2) guide dosage and (3) minimise the risk of drug-drug interactions and dose-related toxicity. TurboFlow(TM) technology offers online, automated sample preparation. An Aria Transcend(TM) TLX-II coupled with a TSQ Vantage(TM) MS was used. Centrifuged samples (25 µL) were mixed with internal standard solution (975 µL) and 30 µL injected directly onto a C18-P-XL TurboFlow column. Analytes were focussed onto a Phenomenex Gemini Phenyl analytical column and eluted using a methanol/water gradient (flow-rate, 0.8 mL/min). Analytes were monitored in selected reaction monitoring mode (two transitions per analyte, positive mode APCI). Calibration ranges were as follows: itraconazole, hydroxyitraconazole, and posaconazole 0.05-5.0 mg/L; voriconazole and fluconazole 0.1-10 mg/L. Total analysis time was 12 min. TurboFlow column recovery was >77% for all analytes. Calibration was linear (R (2) > 0.99) for all analytes. Inter- and intra-assay imprecision (% RSD) was <8% and accuracy (nominal internal quality control values) 90-105% for all analytes. The limit of detection was 0.01 mg/L for all analytes. No matrix effects were observed. This method is simple, robust and suitable for measuring these compounds at concentrations attained during therapy.

A-272651, a nonpeptidic blocker of large-conductance Ca2+-activated K+ channels, modulates bladder smooth muscle contractility and neuronal action potentials.

BACKGROUND AND PURPOSE: The large-conductance Ca(2+)-activated K(+) channel (BK(Ca), K(Ca)1.1) links membrane excitability with intracellular Ca(2+) signaling and plays important roles in smooth muscle contraction, neuronal firing, and neuroendocrine secretion. This study reports the characterization of a novel BK(Ca) channel blocker, 2,4-dimethoxy-N-naphthalen-2-yl-benzamide (A-272651). EXPERIMENTAL APPROACH: (86)Rb(+) efflux in HEK-293 cells expressing BK(Ca) was measured. Effects of A-272651 on BK(Ca) alpha- and BK(Ca) alphabeta1-mediated currents were evaluated by patch-clamp. Effects on contractility were assessed using low-frequency electrical field stimulated pig detrusor and spontaneously contracting guinea pig detrusor. Effects of A-272651 on neuronal activity were determined in rat small diameter dorsal root ganglia (DRG). KEY RESULTS: A-272651 (10 microM) inhibited (86)Rb(+) efflux evoked by NS-1608 in HEK-293 cells expressing BK(Ca) currents. A-272651 concentration-dependently inhibited BK(Ca) currents with IC(50) values of 4.59 microM (Hill coefficient 1.04, measured at +40 mV), and 2.82 microM (Hill coefficient 0.89), respectively, for BK(Ca) alpha and BK(Ca) alphabeta1-mediated currents. Like iberiotoxin, A-272651 enhanced field stimulated twitch responses in pig detrusor and spontaneous contractions in guinea pig detrusor with EC(50) values of 4.05+/-0.05 and 37.95+/-0.12 microM, respectively. In capsaicin-sensitive DRG neurons, application of A-272651 increased action potential firing and prolonged action potential duration. CONCLUSIONS AND IMPLICATIONS: These data demonstrate that A-272651 modulates smooth muscle contractility and neuronal firing properties. Unlike previously reported peptide BK(Ca) blockers, A-272651 represents one of the first small molecule BK(Ca) channel blockers that could serve as a useful tool for further characterization of BK(Ca) channels in physiological and pathological states.

Characterization of a novel ATP-sensitive K+ channel opener, A-251179, on urinary bladder relaxation and cystometric parameters.

BACKGROUND AND PURPOSE: ATP-sensitive K(+) channels (K(ATP)) play a pivotal role in contractility of urinary bladder smooth muscle. This study reports the characterization of 4-methyl-N-(2,2,2-trichloro-1-(3-pyridin-3-ylthioureido)ethyl)benzamide (A-251179) as a K(ATP) channel opener. EXPERIMENTAL APPROACH: Glyburide-sensitive membrane potential, patch clamp and tension assays were employed to study the effect of A-251179 in vitro. The in vivo efficacy of A-251179 was characterized by suppression of spontaneous contractions in obstructed rat bladder and by measuring urodynamic function of urethane-anesthetized rat models. KEY RESULTS: A-251179 was about 4-fold more selective in activating SUR2B-Kir6.2 derived K(ATP) channels compared to those derived from SUR2A-Kir6.2. In pig bladder smooth muscle strips, A-251179 suppressed spontaneous contractions, about 27- and 71-fold more potently compared to suppression of contractions evoked by low-frequency electrical stimulation and carbachol, respectively. In vivo, A-251179 suppressed spontaneous non-voiding bladder contractions from partial outlet-obstructed rats. Interestingly, in the neurogenic model where isovolumetric contractions were measured by continuous transvesical cystometry, A-251179 at a dose of 0.3 micromol kg(-1), but not higher, was found to increase bladder capacity without affecting either the voiding efficiency or changes in mean arterial blood pressure. CONCLUSIONS AND IMPLICATIONS: The thioureabenzamide analog, A-251179 is a potent novel K(ATP) channel opener with selectivity for SUR2B/Kir6.2 containing K(ATP) channels relative to pinacidil. The pharmacological profile of A-251179 is to increase bladder capacity and to prolong the time between voids without affecting voiding efficiency and represents an interesting characteristic to be explored for further investigations of K(ATP) channel openers for the treatment of overactive bladder.

Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia.

In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).

Two novel and potent 3-[(o-methoxyphenyl)piperazinylethyl]-5-phenylthien.

The synthesis and in vitro characterization of A-119637 and A-123189, two novel, selective and potent alpha1D antagonists, are described.

Functional implication of spare ATP-sensitive K(+) channels in bladder smooth muscle cells.

ATP-sensitive K(+) (K(ATP)) channels play important roles in the regulation of excitability in urinary bladder smooth muscle cells. Patch-clamp studies revealed that the current density was about 9-fold higher in the pig bladder smooth muscle cells, compared with guinea pig, although the rank order of potencies for suppression of electrical field-stimulated contraction of bladder strips by K(ATP) channel openers (KCOs) showed a nearly 1:1 correlation between pig and guinea pig. To investigate the existence of spare K(ATP) channels, P1075-evoked current and membrane potential responses were studied in bladder smooth muscle cells. During a 10-min exposure to P1075 (10 microM), K(ATP) currents ran down by approximately 30.5%, whereas membrane hyperpolarization remained constant. P1075 evoked membrane hyperpolarization with an EC(50) value of 0.20 +/- 0.02 microM, comparable to that required for smooth muscle relaxation (EC(50) = 0.11 +/- 0.01 microM). However, these potencies are 6-fold higher than those required for current activation (EC(50) = 0.73 +/- 0.4 microM). These findings demonstrate that the reduction in membrane excitability by KCOs is associated with membrane hyperpolarization, and that a low amount of K(ATP) channel opening is sufficient to suppress bladder smooth muscle contraction.

Characteristics of a telecytology consultation service.

Although numerous reports describe the application of remote video microscopy to pathologic diagnosis (telepathology), only a few address some of the special issues surrounding remote cytologic diagnosis (telecytology). These studies have generally suggested a high correlation between telecytologic diagnoses and those arising from direct examination of the glass slides, but factors affecting the clinical utility of routine cytologic diagnosis have not been examined. In this report, we describe our experience in telecytologic consultation on 99 cases seen at the Armed Forces Institute of Pathology between October 1995 and November 1999. The mean time between receipt of the telecytologic images and the contributor receipt of the faxed report was 9.9 hours (median, 5.13 hours). Using stringent criteria for agreement, we find fair to good (48%) concordance between the contributor's impression and the consultant's opinion. The concordance between the consultant's telecytologic diagnosis and the subsequent glass slide diagnosis is imperfect; in 8 (31%) of 26 cases in which the glass slide was sent after the telecytology consultation, a minor discrepancy between these diagnoses was found. No major discrepancies were found between the consultant's telecytologic and glass slide diagnoses.

Pharmacological properties of A-204176, a novel and selective alpha1A adrenergic agonist, in in vitro and in vivo models of urethral function.

A-204176 (N-[5-(1H-imidazol-4-y1)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide) is a potent and selective alpha1A adrenoceptor agonist that binds with 17-fold and 9-fold greater affinity to the alpha1A (Ki=176 nM) than the alpha1b and alpha1d subtypes, respectively. In functional studies A-204176 is potent (pD2=6.4) and efficacious (83% of maximum control phenylephrine response) at rabbit urethra alpha1A receptors, with weaker potency and greatly reduced efficacy at rat spleen alpha1B (pD2=5.3, 11%) and rat aorta alpha1D (pD2=4.4, 10%) subtypes. In anesthetized female dogs, A-204176 is more potent than the non-selective alpha1 adrenoceptor agonist phenylpropanolamine (PPA) to increase measures of urethral tone and is more efficacious to increase pressure in the proximal region of the urethra. Significant increases on parameters of the urethral pressure profilometry were induced at 100 and 300 nmol/kg, i.v., by A-204176 and PPA, respectively. A-204176 was more potent than PPA to increase the abdominal pressure required to produce leakage. In the simultaneous measurement of intraurethral pressure and mean arterial blood pressure, A-204176 displays enhanced urethral selectivity relative to PPA. However, despite its selectivity for alpha1A versus alpha1B and alpha1D adrenoceptors in vitro, A-204176 did not display the degree of urethral selectivity in vivo that would have been expected. The observed effect of A-204176 on blood pressure may be due to the presence of extra-synaptic alpha1A adrenoceptors in the vasculature or to activation of spinal and supraspinal alpha1A adrenoceptors. These data indicate that A-204176 may represent a useful pharmacological tool to investigate the functional role of the alpha1A adrenoceptor in the urethra and to elucidate the lack of uroselectivity observed in vivo.

Directions in urological research and drug therapies.

This meeting report summarizes advances and notable developments in the pharmaceutical management of urological diseases presented at various sessions during the Annual Meeting of the American Urological Association held in Anaheim, California, June 2-7, 2001. More than 10,000 attendees drawn from clinical and preclinical research deliberated on the latest trends in surgical and pharmacotherapeutic management in diverse areas of urology. In particular, several forums were dedicated to reviewing scientific trends, emerging concepts and therapies in urological diseases, such as overactive bladder, erectile dysfunction and lower urinary tract symptoms, which are the focus of this report.

A-315456: a selective alpha(1D)-adrenoceptor antagonist with minimal dopamine D(2) and 5-HT(1A) receptor affinity.

In functional assays, A-315456, N-[3-(cyclohexylidene-(1H-imidazol-4-ylmethyl))phenyl]ethanesulfonamide, behaved as an alpha(1D)-adrenoceptor subtype selective antagonist (pA(2)=8.34) in the rat aorta. It was 83-fold less potent at the alpha(1B)-adrenoceptor subtype expressed in the rat spleen, and was inactive at the alpha(1A)-adrenoceptor subtype expressed in the rat vas deferens. Radioligand binding assays also revealed high affinity (pK(i)=8.71) for the alpha(1D)-adrenoceptor subtype and weaker affinities at the alpha(1A)-adrenoceptor (pK(i)=6.23) and alpha(1B)-adrenoceptor (pK(i)=7.86). In comparison to its potent affinity at the alpha(1D)-adrenoceptor subtype, A-315456 was 3020-, 794- and 38-fold weaker at the dopamine D(2)-, 5-HT(1A)-, and alpha(2a)-adrenoceptors, respectively. These studies indicate that A-315456 is a potent and selective alpha(1D)-antagonist that may serve as a useful pharmacological ligand to probe the physiological role of the alpha(1D)-adrenoceptor subtype in normal and disease states.

Pharmacological and molecular analysis of ATP-sensitive K(+) channels in the pig and human detrusor.

The pharmacological and molecular properties of ATP-sensitive K(+) channels present in pig detrusor smooth muscle were investigated. In isolated pig detrusor strips, ATP-sensitive K(+) channel openers inhibited contractions elicited by low frequency field-stimulation in a concentration-dependent manner. The inhibitory effects of P1075 [N-cyano-N'-(1,1-dimethylpropyl)-N"-3-pyridylguanidine] were attenuated by glyburide with a pA(2) value of 7.38 (slope=1.08). The potency of the inhibitory effects of the K(+) channel openers on the field-stimulated contractions correlated well with those evoked by the muscarinic receptor agonist, carbachol (r=0.93) and furthermore, to relaxation of the pre-contracted (25 mM potassium chloride, KCl) human detrusor (r=0.95). Reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed the presence of mRNA for sulfonylurea receptors SUR1 and SUR2B in both pig and human detrusor. Considering the similarities in the molecular and pharmacological profile of ATP-sensitive K(+) channels between the pig and the human detrusor, it is concluded that the pig detrusor may serve as a suitable in vitro model for the evaluation of novel K(+) channel openers with potential use in urological disorders in humans.

Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH).

In search of a uroselective agent that exhibits a high level of selectivity for the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.