The effects of alternate-day fasting on sleep and physical activity in poor sleeping adults: A randomized control trial.

Utilizing a randomized control design, 42 healthy adults (22.5 ± 2.8 years) participated in alternate-day modified fasting over a 12-day treatment period. Assessments of sleep included sleep time, efficiency, latency and wake after sleep onset, and assessments of physical activity included steps, energy expenditure, sedentary time, time spent in light physical activity and time spent in moderate-to-vigorous activity. Additional measurements included body composition and mood. The alternate-day modified fasting group consumed 25.8% ± 0.3% fewer calories compared with the control group (p = 0.03). There were no differences between groups for change in body mass index (p = 0.87), total fat mass (p = 0.91) or total lean mass (p = 0.88). Daily energy expenditure did not differ between groups (p = 0.11). On fast days, participants spent 34.5 ± 12.7 more minutes sedentary (p = 0.01), took 1100 ± 362 fewer steps (p < 0.01), and engaged in 27.2 ± 8.4 fewer minutes of moderate-to-vigorous physical activity (p = 0.00) compared with non-fasting days. Sleep duration, efficiency, latency or wake after sleep onset were not different between conditions (p = 0.92, p = 0.10, p = 0.09 and p = 0.66, respectively). We conclude that alternate-day modified fasting does not alter sleep time, efficiency, latency or wake after sleep onset in people reporting poor sleep quality, and does not alter overall physical activity. Although average daily physical activity is not altered, fasting in this manner does tend to result in more sedentary time and less physical activity with compensation on non-fasting days.

Outcomes of Reverse Total Shoulder Arthroplasty Were Not Adversely Affected by the COVID-19 Pandemic.

Introduction: The objective was to investigate outcomes in reverse total shoulder arthroplasty (RTSA) in patients affected by the COVID-19 pandemic shutdown. We hypothesized that patients undergoing RTSA in early 2020 would have decreased access to physical therapy (PT) and worse postoperative outcomes compared to historical controls. Materials and Methods: Patients who received primary RTSA between 1/1/2020 to 3/17/2020 were included and patients who received primary RTSA between 1/1/2019 to 3/17/2019 were used as a control group. Retrospective chart review was performed, and patient reported outcomes were recorded at an average of 2.69 ± 0.06 years and a minimum of 1 year postoperatively. Patient data were collected and statistically analyzed using the 2-sample t-test and Chi-square test. The Mann Whitney U test and Fisher's Exact test were used when appropriate. Results: 38 patients in 2020 were included in this study and compared to 31 patients in 2019. RTSA performed in 2019 had improvements in forward elevation (FE) (95.7º ± 47.2º to 144.7º ± 17.2º, p<0.001), but not in external rotation (ER) (32.5º ± 20.3º to 41.0º ± 13.3º, p=0.15), or internal rotation (IR) (S1 to L5, p=0.76). RTSA 2020 cases had improvements in FE (111.5º ± 40.3 to 132.8º ± 30.6, p=0.016), but not ER (31.9º ± 18.2 to 35.7º ± 15.9, p=0.36) or IR (S1 to L5, p=0.13). Patients in 2019 (FE: 4 to 5-, p<0.001; ER: 4+ to 5-, p=0.003; IR: 5- to 5, p<0.001) and 2020 (FE: 4 to 5-, p<0.001; ER: 4+ to 5, p<0.001; IR: 5- to 5, p=0.02) both experienced improvements in strength. Patients in 2020 initiated PT later (2019: 39.3 ± 27.3 days, 2020: 57.1 ± 35.5 days, p=0.028) and completed less PT sessions (2019: 20.7 ± 11.1, 2020: 12.9 ± 6.6, p<0.001) than patients in 2019. In the 2020 cohort, 10.5% (4/38) did not complete any PT, 34.2% (13/38) reported a delay in initiating PT, and 47.4% (18/38) reported that their recovery was negatively affected by the COVID-19 pandemic. At final follow-up, patients in 2020 reported a mean SANE score of 73.6 ± 17.5 on their affected shoulder and a mean VAS score of 1.68 ± 1.23. Discussion: Despite a delay in initiating PT and completing less PT overall, patients who received RTSA in 2020 experienced significant improvements in ROM and strength at final follow-up and were comparable to the 2019 patients.

Bridging Zirconia Nodes within a Metal-Organic Framework via Catalytic Ni-Hydroxo Clusters to Form Heterobimetallic Nanowires.

Metal-organic frameworks (MOFs), with their well-ordered pore networks and tunable surface chemistries, offer a versatile platform for preparing well-defined nanostructures wherein functionality such as catalysis can be incorporated. Notably, atomic layer deposition (ALD) in MOFs has recently emerged as a versatile approach to functionalize MOF surfaces with a wide variety of catalytic metal-oxo species. Understanding the structure of newly deposited species and how they are tethered within the MOF is critical to understanding how these components couple to govern the active material properties. By combining local and long-range structure probes, including X-ray absorption spectroscopy, pair distribution function analysis, and difference envelope density analysis, with electron microscopy imaging and computational modeling, we resolve the precise atomic structure of metal-oxo species deposited in the MOF NU-1000 through ALD. These analyses demonstrate that deposition of NiOxHy clusters occurs selectively within the smallest pores of NU-1000, between the zirconia nodes, serving to connect these nodes along the c-direction to yield heterobimetallic metal-oxo nanowires. This bridging motif perturbs the NU-1000 framework structure, drawing the zirconia nodes closer together, and also underlies the sintering resistance of these clusters during the hydrogenation of light olefins.

Anatomic Total Shoulder Arthroplasty Outcomes Were Not Negatively Affected by the COVID-19 Pandemic.

Objective To investigate whether patients undergoing anatomic total shoulder arthroplasty (ATSA) between January and March 2020 experienced different postoperative outcomes than patients in 2019. We hypothesized that patients in 2020 would have less access to physical therapy (PT) and experience different postoperative outcomes. Methods Records from patients who received ATSA between January 1st, 2019, and March 17th, 2019, and January 1st, 2020, to March 17th, 2020, were analyzed. Patient data, including demographic information, range of motion (ROM), strength, and PT was collected and compared between the two groups. The 2020 patients were contacted by phone during October 2022 and patient-reported metrics were gathered. Results The present study identified 24 patients in 2019 and 27 patients in 2020 who underwent ATSA during the specified time frame and had a minimum 1-year follow-up. Patients in 2019 experienced improvements in forward elevation (FE) ROM (125.4° to 146.7°; p = 0.008), external rotation (ER; 33.0° to 47.7°; p < 0.001), and internal rotation (IR; S1 to L4; p = 0.019). Patients in 2020 also experienced significant improvements in FE (120.2° to 141.1°; p = 0.009), ER (32.9° to 42.0°; p = 0.037), and IR (S1 to L3; p = 0.002). Patients in 2020 terminated PT earlier (2019: 125.8 days; 2020: 91.1 days; p = 0.046) and completed fewer sessions (2019: 21.4 sessions; 2020: 13.1 sessions; p = 0.003). At the final follow-up, patients in 2020 reported an average Visual Analogue Scale (VAS) pain score of 1.67 ± 1.1. Conclusion Despite decreased PT, patients who underwent ATSA in 2020 had significant improvements in ROM and strength and were comparable to patients in 2019.

Hip, knee, and shoulder arthroplasty in patients with a history of solid organ transplant: A review.

Solid organ transplants (SOT) have evolved into life-saving interventions for end-stage diseases affecting vital organs. Advances in transplantation techniques, donor selection, and immunosuppressive therapies have enhanced outcomes, leading to a growing demand for SOT. Patients with a solid organ transplant are living long enough to develop the same pathologies which are indicated for joint replacement surgery in the general population. SOT patients who undergo a total hip, knee, or shoulder arthroplasty do similarly in the context of clinical outcomes and implant survival when compared to the general population. These immunosuppressed patients tend to have higher complication rates in the short-term following surgery. Prudent management of these patients in the short-term may be necessary, but patients can expect to do well otherwise.

Lateral Femoral Condyle Allograft in the Treatment of Elbow Capitellar Avascular Necrosis: A Case Report.

CASE: A 27-year-old woman developed capitellar osteonecrosis after long-term corticosteroid use to treat non-Hodgkin lymphoma. She underwent an osteochondral reconstruction using a lateral femoral condyle (LFC) allograft. This graft was selected because it has a similar radius of curvature to the capitellum. The patient had osseous integration, painless, near full range of motion of her elbow 6 months postoperatively and good shoulder function 1.0 year postoperatively. CONCLUSION: The LFC allograft should be considered a viable option in treating capitellar osteonecrosis.

Modern Applications of Machine Learning in Shoulder Arthroplasty: A Review.

¼ There is increased integration of machine learning (ML) to aid clinical decision-making in orthopaedic surgery.¼ ML has the ability to predict both clinical outcomes such as range of motion and complications in total shoulder arthroplasty patients.¼ An increased area of focus is the ability for ML to identify implants to aid in revision surgery planning.¼ In this article, we review the current applications of ML in shoulder arthroplasty and discuss future areas where it may enhance orthopaedic practice.

Shoulder arthroplasty following solid organ transplant: A systematic review and meta-analysis.

Introduction: The purpose of this study is to report a systematic review and meta-analysis of solid organ transplant (SOT) patients undergoing shoulder arthroplasty to compare functional and radiographic outcomes, demographics, and complications with non-transplant patients. Methods: Studies were included if they examined patients undergoing shoulder arthroplasty in the setting of prior solid organ transplantation and included post operative range of motion, patient-reported outcomes, complications, or revisions. Studies were excluded if they were national database analyses or lacked clinical data. Pubmed, MEDLine, Scopus, and Web of Science were queried using relevant search terms in July 2022. Data was pooled, weighted, and a paired t-test and chi-square analysis was performed. Results: There were 71 SOT and 159 non-SOT shoulders included in the study. The most common indication for surgery was avascular necrosis (n = 26) in the solid organ transplant group and osteoarthritis (n = 60) in the non-SOT group. Forward elevation, external rotation, ASES, and VAS pain scores improved significantly in both cohorts following surgery. There was no significant difference in age at surgery (p-value = 0.20), postoperative forward elevation (p-value = 0.08), postoperative external rotation (0.84), and postoperative ASES scores (p-value = 0.11) between the two cohorts. VAS pain scores were significantly lower in the SOT cohort (p-value<0.01). The risk of death was significantly higher in the SOT group (p-value<0.01). but the rate of overall complications (p = 0.47), surgical complication (p-value = 0.79), or revision surgery (p-value = 1.00) was not significantly different between the two cohorts. Conclusion: Shoulder arthroplasty is a safe, effective option in patients following solid organ transplant. There is not an increased risk of adverse outcomes, and SOT patients had comparable range of motion and patient-reported outcomes when compared to their non-SOT peers. Level of evidence: III.

Weekend admission to hospital has a higher risk of death in the elective setting than in the emergency setting: a retrospective database study of national health service hospitals in England.

BACKGROUND: Although acute hospitals offer a twenty-four hour seven day a week service levels of staffing are lower over the weekends and some health care processes may be less readily available over the weekend. Whilst it is thought that emergency admission to hospital on the weekend is associated with an increased risk of death, the extent to which this applies to elective admissions is less well known. We investigated the risk of death in elective and elective patients admitted over the weekend versus the weekdays. METHODS: Retrospective statistical analysis of routinely collected acute hospital admissions in England, involving all patient discharges from all acute hospitals in England over a year (April 2008-March 2009), using a logistic regression model which adjusted for a range of patient case-mix variables, seasonality and admission over a weekend separately for elective and emergency (but excluding zero day stay emergency admissions discharged alive) admissions. RESULTS: Of the 1,535,267 elective admissions, 91.7% (1,407,705) were admitted on the weekday and 8.3% (127,562) were admitted on the weekend. The mortality following weekday admission was 0.52% (7,276/1,407,705) compared with 0.77% (986/127,562) following weekend admission. Of the 3,105,249 emergency admissions, 76.3% (2,369,316) were admitted on the weekday and 23.7% (735,933) were admitted on the weekend. The mortality following emergency weekday admission was 6.53% (154,761/2,369,316) compared to 7.06% (51,922/735,933) following weekend admission. After case-mix adjustment, weekend admissions were associated with an increased risk of death, especially in the elective setting (elective Odds Ratio: 1.32, 95% Confidence Interval 1.23 to 1.41); vs emergency Odds Ratio: 1.09, 95% Confidence Interval 1.05 to 1.13). CONCLUSIONS: Weekend admission appears to be an independent risk factor for dying in hospital and this risk is more pronounced in the elective setting. Given the planned nature of elective admissions, as opposed to the unplanned nature of emergency admissions, it would seem less likely that this increased risk in the elective setting is attributable to unobserved patient risk factors. Further work to understand the relationship between weekend processes of care and mortality, especially in the elective setting, is required.

Antigiardial Activity of Novel Guanidine Compounds.

From four focused compound libraries based on the known anticoccidial agent robenidine, 44 compounds total were synthesised and screened for antigiardial activity. All active compounds were counter-screened for antibiotic and cytotoxic action. Of the analogues examined, 21 displayed IC50 <5 µM, seven with IC50 <1.0 µM. Most active were 2,2'-bis{[4-(trifluoromethoxy)phenyl]methylene}carbonimidic dihydrazide hydrochloride (30), 2,2'-bis{[4-(trifluoromethylsulfanyl)phenyl]methylene}carbonimidic dihydrazide hydrochloride (32), and 2,2'-bis[(2-bromo-4,5-dimethoxyphenyl)methylene]carbonimidic dihydrazide hydrochloride (41) with IC50 =0.2 µM. The maximal observed activity was a 5 h IC50 value of 0.2 µM for 41. The clinically used metronidazole was inactive at this timepoint at a concentration of 25 µM. Robenidine off-target effects at bacteria and cell line toxicity were removed. Analogue 41 was well tolerated in mice treated orally (100 mg/kg). Following 5 h treatment with 41, no Giardia regrowth was noted after 48 h.

Minimising damage in high resolution scanning transmission electron microscope images of nanoscale structures and processes.

Beam damage caused during acquisition of the highest resolution images is the current limitation in the vast majority of experiments performed in a scanning transmission electron microscope (STEM). While the principles behind the processes of knock-on and radiolysis damage are well-known (as are other contributing effects, such as heat and electric fields), understanding how and especially when beam damage is distributed across the entire sample volume during an experiment has not been examined in detail. Here we use standard models for damage and diffusion to elucidate how beam damage spreads across the sample as a function of the microscope conditions to determine an "optimum" sampling approach that maximises the high-resolution information in any image acquisition. We find that the standard STEM approach of scanning an image sequentially accelerates damage because of increased overlap of diffusion processes. These regions of accelerated damage can be significantly decelerated by increasing the distance between the acquired pixels in the scan, forming a "spotscan" mode of acquisition. The optimum distance between these pixels can be broadly defined by the fundamental properties of each material, allowing experiments to be designed for specific beam sensitive materials. As an added bonus, if we use inpainting to reconstruct the sparse distribution of pixels in the image we can significantly increase the speed of the STEM process, allowing dynamic phenomena, and the onset of damage, to be studied directly.

Evaluating Relationships Between Sleep and Next-Day Physical Activity in Young Women.

BACKGROUND: To evaluate the relationship between sleep and next-day physical activity (PA) under free-living conditions in women. METHODS: Sleep and PA were measured objectively for 7 consecutive days by accelerometry in 330 young adult women (aged 17-25 y). A structural equation model was used to evaluate the relationship between the driving factor of sleep (total sleep or morning wake time) and the amount of nonsleep sedentary (SED) and moderate to vigorous physical activity (MVPA) each day. RESULTS: With sleep duration as the driving factor, the estimates of ßSED and ßMVPA were -0.415 and -0.093, respectively (P ≤ .05). For every hour slept, a 24.9-minute reduction in SED time and a 5.58-minute reduction in MVPA were observed. With wake time as the driving factor, the estimates of ßSED and ßMVPA were -0.636 and -0.149, respectively. For every wake time that was 1 hour later, a 38.2-minute decrease in SED and a 8.9-minute decrease in MVPA (P ≤ .05) were observed. CONCLUSIONS: Women who wake later or who sleep longer tend to get less MVPA throughout the day. Getting up earlier and going to bed earlier may support behaviors that improve PA and lifestyle.

Aminoguanidines: New leads for treatment of Giardia duodenalis infection.

Giardia duodenalis is an ubiquitous parasitic pathogen that causes significant morbidity and mortality worldwide. Failures in drug therapy are commonly due to poor patient compliance as a result of the need for repeated administration, off target drug effects and increasing parasite drug resistance. In this study the in vitro efficacy and selectivity of the aminoguanidine compound robenidine and 2 structural analogues against Giardia were determined. After 5 h exposure to each compound the IC50 was as low as 0.2 µM with corresponding MLCs as low as 2.8 µM. This is in contrast to metronidazole which required 24 h to exhibit inhibitory activity. A modified adherence assay, developed for this study, demonstrated that three of the compounds inhibited in vitro adherence of the parasite. The lead compound exhibited rapid giardicidal activity (<5hr). In addition, microscopy studies demonstrated damage to the plasma membrane of trophozoites. In conclusion, a class of aminoguanidines, represented by robenidine, has shown antigiardial activity warranting further investigation.

Anatomic Total Shoulder Arthroplasty Outcomes Were Not Negatively Affected by the COVID-19 Pandemic / Os desfechos da artroplastia anatômica total do ombro não foram afetados negativamente pela pandemia de Covid-19

Abstract Objective To investigate whether patients undergoing anatomic total shoulder arthroplasty (ATSA) between January and March 2020 experienced different postoperative outcomes than patients in 2019. We hypothesized that patients in 2020 would have less access to physical therapy (PT) and experience different postoperative outcomes. Methods Records from patients who received ATSA between January 1st, 2019, and March 17th, 2019, and January 1st, 2020, to March 17th, 2020, were analyzed. Patient data, including demographic information, range of motion (ROM), strength, and PT was collected and compared between the two groups. The 2020 patients were contacted by phone during October 2022 and patient-reported metrics were gathered. Results The present study identified 24 patients in 2019 and 27 patients in 2020 who underwent ATSA during the specified time frame and had a minimum 1-year follow-up. Patients in 2019 experienced improvements in forward elevation (FE) ROM (125.4° to 146.7°; p = 0.008), external rotation (ER; 33.0° to 47.7°; p < 0.001), and internal rotation (IR; S1 to L4; p = 0.019). Patients in 2020 also experienced significant improvements in FE (120.2° to 141.1°; p = 0.009), ER (32.9° to 42.0°; p = 0.037), and IR (S1 to L3; p = 0.002). Patients in 2020 terminated PT earlier (2019: 125.8 days; 2020: 91.1 days; p = 0.046) and completed fewer sessions (2019: 21.4 sessions; 2020: 13.1 sessions; p = 0.003). At the final follow-up, patients in 2020 reported an average Visual Analogue Scale (VAS) pain score of 1.67 ± 1.1. Conclusion Despite decreased PT, patients who underwent ATSA in 2020 had significant improvements in ROM and strength and were comparable to patients in 2019.

Resumo Objetivo Investigar se os pacientes submetidos à artroplastia total anatômica do ombro (ATAO) entre janeiro e março de 2020 tiveram resultados pós-operatórios diferentes dos pacientes operados em 2019. Nossa hipótese é a de que os pacientes de 2020 teriam menos acesso à fisioterapia (FT) e apresentariam desfechos pós-opera-tórios diferentes. Métodos Foram analisados os prontuários de pacientes submetidos à ATAO de 1° de janeiro de 2019 a 17 de março de 2019 e de 1° de janeiro de 2020 a 17 de março de 2020. Os dados dos pacientes, incluindo informações demográficas, amplitude de movimento (ADM), força e FT foram coletados e comparados entre os dois grupos. Os pacientes de 2020 foram contatados por telefone durante outubro de 2022, e as métricas relatadas por eles pacientes foram coletadas. Resultados Este estudo identificou 24 pacientes em 2019 e 27 pacientes em 2020 que foram submetidos à ATAO durante o período especificado e tiveram acompanhamento mínimo de 1 ano. Os pacientes em 2019 apresentaram melhoras na ADM de elevação anterior (EA; 125,4° a 146,7°; p = 0,008), rotação externa (RE; 33,0° a 47,7°; p < 0,001) e rotação interna (RI; S1 a L4; p = 0,019). Os pacientes em 2020 também apresentaram melhoras significativas de EA (120,2° a 141,1°; p = 0,009), RE (32,9° a 42,0°; p = 0,037) e RI (S1 a L3; p = 0,002). Os pacientes de 2020 terminaram a FT mais cedo (2019: 125,8 dias; 2020: 91,1 dias; p = 0,046) e fizeram menos sessões (2019: 21,4 sessões; 2020: 13,1 sessões; p = 0,003). No acompanhamento final, os pacientes de 2020 relataram uma pontuação média de dor na Escala Visual Analógica (EVA) de 1,67 ± 1,1. Conclusão Apesar da menor realização de FT, os pacientes submetidos à ATAO em 2020 apresentaram melhoras significativas na ADM e na força e foram comparáveis aos pacientes de 2019.

Home-based exercise rehabilitation in addition to specialist heart failure nurse care: design, rationale and recruitment to the Birmingham Rehabilitation Uptake Maximisation study for patients with congestive heart failure (BRUM-CHF): a randomised controlled trial.

BACKGROUND: Exercise has been shown to be beneficial for selected patients with heart failure, but questions remain over its effectiveness, cost-effectiveness and uptake in a real world setting. This paper describes the design, rationale and recruitment for a randomised controlled trial that will explore the effectiveness and uptake of a predominantly home-based exercise rehabilitation programme, as well as its cost-effectiveness and patient acceptability. METHODS/DESIGN: Randomised controlled trial comparing specialist heart failure nurse care plus a nurse-led predominantly home-based exercise intervention against specialist heart failure nurse care alone in a multiethnic city population, served by two NHS Trusts and one primary care setting, in the United Kingdom.169 English speaking patients with stable heart failure, defined as systolic impairment (ejection fraction < or = 40%). with one or more hospital admissions with clinical heart failure or New York Heart Association (NYHA) II/III within previous 24-months were recruited.Main outcome measures at 1 year: Minnesota Living with Heart Failure Questionnaire, incremental shuttle walk test, death or admission with heart failure or myocardial infarction, health care utilisation and costs. Interviews with purposive samples of patients to gain qualitative information about acceptability and adherence to exercise, views about their treatment, self-management of their heart failure and reasons why some patients declined to participate. The records of 1639 patients managed by specialist heart failure services were screened, of which 997 (61%) were ineligible, due to ejection fraction>40%, current NYHA IV, no admission or NYHA II or more within the previous 2 years, or serious co-morbidities preventing physical activity. 642 patients were contacted: 289 (45%) declined to participate, 183 (39%) had an exclusion criterion and 169 (26%) agreed to randomisation. DISCUSSION: Due to safety considerations for home-exercise less than half of patients treated by specialist heart failure services were eligible for the study. Many patients had co-morbidities preventing exercise and others had concerns about undertaking an exercise programme.

Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent.

The spread of multidrug resistance among bacterial pathogens poses a serious threat to public health worldwide. Recent approaches towards combating antimicrobial resistance include repurposing old compounds with known safety and development pathways as new antibacterial classes with novel mechanisms of action. Here we show that an analog of the anticoccidial drug robenidine (4,6-bis(2-((E)-4-methylbenzylidene)hydrazinyl)pyrimidin-2-amine; NCL195) displays potent bactericidal activity against Streptococcus pneumoniae and Staphylococcus aureus by disrupting the cell membrane potential. NCL195 was less cytotoxic to mammalian cell lines than the parent compound, showed low metabolic degradation rates by human and mouse liver microsomes, and exhibited high plasma concentration and low plasma clearance rates in mice. NCL195 was bactericidal against Acinetobacter spp and Neisseria meningitidis and also demonstrated potent activity against A. baumannii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Enterobacter spp. in the presence of sub-inhibitory concentrations of ethylenediaminetetraacetic acid (EDTA) and polymyxin B. These findings demonstrate that NCL195 represents a new chemical lead for further medicinal chemistry and pharmaceutical development to enhance potency, solubility and selectivity against serious bacterial pathogens.

Secular trends and evaluation of complex interventions: the rising tide phenomenon.

Evaluations of service delivery interventions with contemporaneous controls often yield null results, even when the intervention appeared promising in advance. There can be many reasons for null results. In this paper we introduce the concept of a 'rising tide' phenomenon being a possible explanation of null results. We note that evaluations of service delivery interventions often occur when awareness of the problems they intend to address is already heightened, and pressure to tackle them is mounting throughout a health system. An evaluation may therefore take place in a setting where the system as a whole is improving - where there is a pronounced temporal trend or a 'rising tide causing all vessels to rise'. As a consequence, control sites in an intervention study will improve. This reduces the difference between intervention and control sites and predisposes the study to a null result, leading to the conclusion that the intervention has no effect. We discuss how a rising tide may be distinguished from other causes of improvement in both control and intervention groups, and give examples where the rising tide provides a convincing explanation of such a finding. We offer recommendations for interpretation of research findings where improvements in the intervention group are matched by improvements in the control group. Understanding the rising tide phenomenon is important for a more nuanced interpretation of null results arising in the context of system-wide improvement. Recognition that a rising tide may have predisposed to a null result in one health system cautions against generalising the result to another health system where strong secular trends are absent.

Robenidine Analogues as Gram-Positive Antibacterial Agents.

Robenidine, 1 (2,2'-bis[(4-chlorophenyl)methylene]carbonimidic dihydrazide), was active against MRSA and VRE with MIC's of 8.1 and 4.7 µM, respectively. SAR revealed tolerance for 4-Cl isosteres with 4-F (8), 3-F (9), 3-CH3 (22), and 4-C(CH3)3 (27) (23.7-71 µM) and with 3-Cl (3), 4-CH3 (21), and 4-CH(CH3)2 (26) (8.1-13.0 µM). Imine carbon alkylation identified a methyl/ethyl binding pocket that also accommodated a CH2OH moiety (75; 2,2'-bis[1-(4-chlorophenyl)-2-hydroxyethylidene]carbonimidic dihydrazide). Analogues 1, 27 (2,2'-bis{[4-(1,1-dimethylethyl)phenyl]methylene}carbonimidic dihydrazide), and 69 (2,2'-bis[1-(4-chlorophenyl)ethylidene]carbonimidic dihydrazide hydrochloride) were active against 24 clinical MRSA and MSSA isolates. No dose-limiting cytotoxicity at ≥2× MIC or hemolysis at ≥8× MIC was observed. Polymyxin B addition engendered Escherichia coli and Pseudomonas aeruginosa Gram-negative activity MIC's of 4.2-21.6 µM. 1 and 75 displayed excellent microsomal stability, intrinsic clearance, and hepatic extraction ratios with T1/2 > 247 min, CLint < 7 µL/min/mg protein, and EH < 0.22 in both human and mouse liposomes for 1 and in human liposomes for 75.

Recruitment of ethnic minority patients to a cardiac rehabilitation trial: the Birmingham Rehabilitation Uptake Maximisation (BRUM) study [ISRCTN72884263].

BACKGROUND: Concerns have been raised about low participation rates of people from minority ethnic groups in clinical trials. However, the evidence is unclear as many studies do not report the ethnicity of participants and there is insufficient information about the reasons for ineligibility by ethnic group. Where there are data, there remains the key question as to whether ethnic minorities more likely to be ineligible (e.g. due to language) or decline to participate. We have addressed these questions in relation to the Birmingham Rehabilitation Uptake Maximisation (BRUM) study, a randomized controlled trial (RCT) comparing a home-based with a hospital-based cardiac rehabilitation programme in a multi-ethnic population in the UK. METHODS: Analysis of the ethnicity, age and sex of presenting and recruited subjects for a trial of cardiac rehabilitation in the West-Midlands, UK. PARTICIPANTS: 1997 patients presenting post-myocardial infarction, percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery. DATA COLLECTED: Exclusion rates, reasons for exclusion and reasons for declining to participate in the trial by ethnic group. RESULTS: Significantly more patients of South Asian ethnicity were excluded (52% of 'South Asian' v 36% 'White European' and 36% 'Other', p < 0.001). This difference in eligibility was primarily due to exclusion on the basis of language (i.e. the inability to speak English or Punjabi). Of those eligible, similar proportions were recruited from the different ethnic groups (white, South Asian and other). There was a marked difference in eligibility between people of Indian, Pakistani or Bangladeshi origin. CONCLUSION: Once eligible for this trial, people from different ethnic groups were recruited in similar proportions. The reason for ineligibility in the BRUM study was the inability to support the range of minority languages.

Trends in clinical development timeframes for antiviral drugs launched in the UK, 1981-2014: a retrospective observational study.

OBJECTIVES: Recent decades have witnessed the development of highly innovative new antiviral drug therapies. However, there are concerns that rising costs and lengthening development times could have implications for future patient access to innovative new drugs. We sought to establish whether the time taken for the clinical development of new antiviral drugs launched in the UK had increased since the 1980s. DESIGN AND SETTING: Retrospective observational study of all new antiviral drugs licensed for use in the UK. PRIMARY AND SECONDARY OUTCOME MEASURES: Duration of clinical development (from initiation of studies in humans to receipt of Marketing Authorisation), subdivided into clinical trial and regulatory approval periods by the date of Marketing Authorisation Application. RESULTS: 48 new antiviral drugs were licensed for use in the UK between 1981 and 2014 (inclusive), over half (54%) initially for HIV infection. The overall mean duration of clinical development was 77.2 months, of which 64.6 months was spent in clinical trials before regulatory submission. The total time in clinical development increased from 41.7 months for drugs licensed 1981-1992 to 91.7 months for drugs licensed 2004-2014. This increase was accounted for by an increase in the clinical trials period and not the regulatory approval period, for which there was no observable trend. Drugs initially licensed to treat hepatitis C had a longer duration of clinical development than those indicated for other viral infections. However, the, initially shorter clinical development durations of drugs indicated for HIV infection increased more rapidly across the study period than those indicated for other viral infections. CONCLUSIONS: The time spent by antiviral drugs in clinical development has increased markedly in recent decades despite many initiatives to speed access to innovative new drugs. However, this represents only one part of the translational research pathway, and a complete picture of development timeframes is lacking.