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Per- and polyfluoroalkyl substances (PFAS) are a group of recalcitrant molecules that have been used since the 1940s in a variety of applications. They are now linked to a host of negative health outcomes and are extremely resistant to degradation under environmental conditions. Currently, membrane technologies or adsorbents are used to remediate contaminated water. These techniques are either inefficient at capturing smaller PFAS molecules, have high energy demands, or result in concentrated waste that must be incinerated at high temperatures. This Review focuses on what role metal-organic frameworks (MOFs) may play in addressing the PFAS problem. Specifically, how the unique properties of MOFs such as their well-defined pore sizes, ultra-high internal surface area, and tunable surface chemistry may be a sustainable solution for PFAS contamination.

BackgroundEvidence on heterogeneity in outcomes of surgical quality interventions in low-income and middle-income countries is limited. We explored factors driving performance in the Safe Surgery 2020 intervention in Tanzania’s Lake Zone to distil implementation lessons for low-resource settings.MethodsWe identified higher (n=3) and lower (n=3) performers from quantitative data on improvement from 14 safety and teamwork and communication indicators at 0 and 12 months from 10 intervention facilities, using a positive deviance framework. From 72 key informant interviews with surgical providers across facilities at 1, 6 and 12 months, we used a grounded theory approach to identify practices of higher and lower performers.ResultsPerformance experiences of higher and lower performers differed on the following themes: (1) preintervention context, (2) engagement with Safe Surgery 2020 interventions, (3) teamwork and communication orientation, (4) collective learning orientation, (5) role of leadership, and (6) perceived impact of Safe Surgery 2020 and beyond. Higher performers had a culture of teamwork which helped them capitalise on Safe Surgery 2020 to improve surgical ecosystems holistically on safety practices, teamwork and communication. Lower performers prioritised overhauling safety practices and began considering organisational cultural changes much later. Thus, while also improving, lower performers prioritised different goals and trailed higher performers on the change continuum.ConclusionFuture interventions should be tailored to facility context and invest in strengthening teamwork, communication and collective learning and facilitate leadership engagement to build a receptive climate for successful implementation of safe surgery interventions.

Background: Headache diaries are recommended for migraine management in primary care.\ud \ud Objective: Determine the acceptability and use of a digital headache diary app for migraine.\ud \ud Methods: Evaluative prospective primary care cohort study in North of England. Part 1 was a postal survey; if responders were interested, in Part 2 participants trialled the digital N1-Headache App headache diary for 90 days, followed by survey feedback on the App’s usability.\ud \ud Results: A total of 637 out of 2189 invited patients (29%) completed the initial survey, and 32% of respondents had previously used a headache diary; 437 out of 637 patients (69%) were interested in using the App. Regression analysis showed that interested patients were those with more severe migraines that limit physical/intellectual activities, and who indicate to not know enough about their migraine. Actual registration numbers and compliance with the App was very modest; 53 out of 173 participants (23%), who ultimately activated their personal N1-Headache App account, were able to generate a personalised trigger and protector map & report. Furthermore, at the end of the 90 day app trial period there was a non-significant trend towards improvements in participants’ health confidence levels.\ud \ud Conclusion: Migraine patients – particularly those with more severe and frequent migraines - show an interest in using a digital headache diary app, ultimately, consistent daily use is very modest. The challenge is to improve app usage and compliance rates to allow interpretation of more patients’ migraine trigger and/or protector patterns, and wider use amongst patients.

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.FUNDING: US National Institutes of Health and Operation Warp Speed.

Fat embolism syndrome is a rare but underdiagnosed complication of sickle cell disease associated with high morbidity and mortality. It affects predominantly patients with a previously mild course of their illness and those of non-SS genotypes while there is possibly an association with infection with human parvovirus B19 (HPV B19). Here, we present the mortality rates and autopsy findings of all reported cases to date. A systematic review has revealed 99 published cases in the world literature with a mortality rate of 46%. Mortality varied greatly according to the time of reported cases with no survivors in the 1940s, 1950s or 1960s and no deaths since 2020. 35% of cases had previously undiagnosed sickle cell disease and the latter was only identified at autopsy after developing fat embolism with a fatal outcome. 20% of cases reported after 1986 tested positive for HPV B19 with an associated mortality of 63% whereas in cases that have not documented HPV B19 infection the mortality was 32%. The organs most often staining positive for fat were the kidneys, lungs, brain and heart whereas ectopic haematopoietic tissue was found in 45% of the examined lung specimens.

Millions of patients worldwide suffer disability and death due to complications related to surgery. Many of these complications can be reduced by the use of the World Health Organization (WHO) Surgical Safety Checklist (SSC), a simple tool that can enhance teamwork and communication and improve patient safety. Despite the evidence on benefits of its use, introducing and sustaining the use of the checklist are challenging. We present a team-based approach employed in a low-resource setting in Tanzania, which resulted in high checklist utilization and compliance rates. We reviewed reported data from facility registers supplemented by direct observation data by mentors to evaluate the use of the WHO SSC across 40 health facilities in two regions of Tanzania between January and December 2018. We analyzed the self-reported monthly data on total number of major surgeries performed and proportion of surgeries where the checklist was used. We also analyzed the use of the SSC during direct observation by external mentors and completion rates of the SSC in a random selection of patient files during two mentorship visits between June and December 2018. During the review period, the average self-reported checklist utilization rate was 79.3% (11,564 out of 14,580 major surgeries). SSC utilization increased from 0% at baseline in January 2018 to 98% in December 2018. The proportion of checklists that were completely and correctly filled out increased between the two mentor visits from 82.1 to 92.8%, but the gain was significantly greater at health centers than at hospitals (p

Background Safe, high-quality surgical care in many African countries is a critical need. Challenges include availability of surgical providers, improving quality of care, and building workforce capacity. Despite growing evidence that mentoring is effective in African healthcare settings, less is known about its role in surgery. We examined a multimodal approach to mentorship as part of a safe surgery intervention (Safe Surgery 2020) to improve surgical quality. Our goal was to distill lessons for policy makers, intervention designers, and practitioners on key elements of a successful surgical mentorship program. Methods We used a convergent, mixed-methods design to examine the experiences of mentees, mentors, and facility leaders with mentorship at 10 health facilities in Tanzania’s Lake Zone. A multidisciplinary team of mentors worked with surgical providers over 17 months using in-person mentorship, telementoring, and WhatsApp. We conducted surveys, in-depth interviews, and focus groups to capture data in four categories: (1) satisfaction with mentorship; (2) perceived impact; (3) elements of a successful mentoring program; and (4) challenges to implementing mentorship. We analyzed quantitative data using frequency analysis and qualitative data using the constant comparison method. Recurrent and unifying concepts were identified through merging the qualitative and quantitative data. Results Overall, 96% of mentees experienced the intervention as positive, 88% were satisfied, and 100% supported continuing the intervention in the future. Mentees, mentors, and facility leaders perceived improvements in surgical practice, the surgical ecosystem, and in reducing postsurgical infections. Several themes related to the intervention’s success emerged: (1) the intervention’s design, including its multimodality, side-by-side mentorship, and standardization of practices; (2) the mentee–mentor relationship, including a friendly, safe, non-hierarchical, team relationship, as well as mentors’ understanding of the local context; and (3) mentorship characteristics, including non-judgmental feedback, experience, and accessibility. Challenges included resistance to change, shortage of providers, mentorship dose, and logistics. Conclusions Our study suggests a multimodal mentorship approach is promising in building the capacity of surgical providers. By distilling the experiences of the mentees, mentors, and facility leaders, our lessons provide a foundation for future efforts to establish effective surgical mentorship programs that build provider capacity and ultimately improve surgical quality.

Summary There is limited evidence from 11 randomised controlled trials on the effect of rehabilitation interventions which incorporate outdoor mobility on ambulatory ability and/or self-efficacy after hip fracture. Outdoor mobility should be central (not peripheral) to future intervention studies targeting improvements in ambulatory ability. Purpose Determine the extent to which outdoor mobility is incorporated into rehabilitation interventions after hip fracture. Synthesise the evidence for the effectiveness of these interventions on ambulatory ability and falls-related self-efficacy. Methods Systematic search of MEDLINE, Embase, PsychInfo, CINAHL, PEDro and OpenGrey for published and unpublished randomised controlled trials (RCTs) of community-based rehabilitation interventions incorporating outdoor mobility after hip fracture from database inception to January 2021. Exclusion of protocols, pilot/feasibility studies, secondary analyses of RCTs, nonrandomised and non-English language studies. Duplicate screening for eligibility, risk of bias, and data extraction sample. Random effects meta-analysis. Statistical heterogeneity with inconsistency-value (I2). Results RCTs (n = 11) provided limited detail on target or achieved outdoor mobility intervention components. There was conflicting evidence from 2 RCTs for the effect on outdoor walking ability at 1–3 months (risk difference 0.19; 95% confidence intervals (CI): 0.21, 0.58; I2 = 92%), no effect on walking endurance at intervention end (standardised mean difference 0.05; 95% CI: − 0.26, 0.35; I2 = 36%); and suggestive (CI crosses null) of a small effect on self-efficacy at 1–3 months (standardised mean difference 0.25; 95% CI: − 0.29, 0.78; I2 = 87%) compared with routine care/sham intervention. Conclusion It was not possible to attribute any benefit observed to an outdoor mobility intervention component due to poor reporting of target or achieved outdoor mobility and/or quality of the underlying evidence. Given the low proportion of patients recovering outdoor mobility after hip fracture, future research on interventions with outdoor mobility as a central component is warranted. Trial registration PROSPERO registration: CRD42021236541

Background Evidence-based strategies for improving surgical quality and patient outcomes in low-resource settings are a priority. Objective To evaluate the impact of a multicomponent safe surgery intervention (Safe Surgery 2020) on (1) adherence to safety practices, teamwork and communication, and documentation in patient files, and (2) incidence of maternal sepsis, postoperative sepsis, and surgical site infection. Methods We conducted a prospective, longitudinal study in 10 intervention and 10 control facilities in Tanzania’s Lake Zone, across a 3-month pre-intervention period in 2018 and 3-month post-intervention period in 2019. SS2020 is a multicomponent intervention to support four surgical quality areas: (i) leadership and teamwork, (ii) evidence-based surgery, anesthesia and equipment sterilization practices, (iii) data completeness and (iv) infrastructure. Surgical team members received training and mentorship, and each facility received up to a $10 000 infrastructure grant. Inpatients undergoing major surgery and postpartum women were followed during their stay up to 30 days. We assessed adherence to 14 safety and teamwork and communication measures through direct observation in the operating room. We identified maternal sepsis (vaginal or cesarean delivery), postoperative sepsis and SSIs prospectively through daily surveillance and assessed medical record completeness retrospectively through chart review. We compared changes in surgical quality outcomes between intervention and control facilities using difference-in-differences analyses to determine areas of impact. Results Safety practices improved significantly by an additional 20.5% (95% confidence interval (CI), 7.2–33.7%; P = 0.003) and teamwork and communication conversations by 33.3% (95% CI, 5.7–60.8%; P = 0.02) in intervention facilities compared to control facilities. Maternal sepsis rates reduced significantly by 1% (95% CI, 0.1–1.9%; P = 0.02). Documentation completeness improved by 41.8% (95% CI, 27.4–56.1%; P Conclusion Our findings demonstrate the benefit of the SS2020 approach. Improvement was observed in adherence to safety practices, teamwork and communication, and data quality, and there was a reduction in maternal sepsis rates. Our results support the emerging evidence that improving surgical quality in a low-resource setting requires a focus on the surgical system and culture. Investigation in diverse contexts is necessary to confirm and generalize our results and to understand how to adapt the intervention for different settings. Further work is also necessary to assess the long-term effect and sustainability of such interventions.

Importance Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed. Objective To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19. Design, Setting, and Participants This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients. Interventions Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). Main Outcomes and Measures The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality. Results Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, −0.2% [95% CI, −5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]). Conclusions and Relevance Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults. Trial Registration ClinicalTrials.gov:NCT04332991

Objective We sought to discover secreted biomarkers to monitor the recovery of physiological adiponectin levels with metabolic surgery, focusing on epigenetic changes that might predict adiponectin function. Design We conducted a prospective observational study of patients undergoing metabolic surgery by Roux-en-Y Gastric Bypass (RYGB) for weight loss in a single center (IRB GHS # 1207-27). Methods All patients (n = 33; 27 females; 6 males) signed informed consent. Metabolites, adiponectin and MIR148A were measured in fasting plasma. We followed MIQE for transcript profiles. Results Patients lost on average 47 ± 12% excess BMI (%EBMI) after 12 weeks. Adiponectin pre, post or delta (post minus pre) did not correlate with %EBMIL. A decrease in adiponectin following weight loss surgery was observed in a subset of patients, chi-square test of independence rejects the null hypotheses that the liver DNA methyltransferase 1 (DNMT1) and delta adiponectin are independent (chi-square statistics χ2 = 6.9205, P = 0.00852, n = 33), as well as MIR148A and delta adiponectin are independent (chi-square statistics χ2 = 9.6823, P = 0.00186, n = 33). The presence of plasma MIR148A allows identification of patients that appear to be adiponectin insensitive at baseline. Conclusion We combined the presence of plasma MIR148A, the concentration of total adiponectin and the expression of DNA methyltransferase 1 (DNMT1) in liver biopsy tissue to identify patients with non-physiological adiponectin. Weight loss and physical activity interventions complemented with the new method presented here could serve to monitor the physiological levels of adiponectin, thought to be important for long-term weight loss maintenance.

IntroductionDespite ongoing maternal health interventions, maternal deaths in Tanzania remain high. One of the main causes of maternal mortality includes postoperative infections. Surgical site infection (SSI) rates are higher in low/middle-income countries (LMICs), such as Tanzania, compared with high-income countries. We evaluated the impact of a multicomponent safe surgery intervention in Tanzania, hypothesising it would (1) increase adherence to safety practices, such as the WHO Surgical Safety Checklist (SSC), (2) reduce SSI rates following caesarean section (CS) and (3) reduce CS-related perioperative mortality rates (POMRs).MethodsWe conducted a pre-cross-sectional/post-cross-sectional study design to evaluate WHO SSC utilisation, SSI rates and CS-related POMR before and 18 months after implementation. Our interventions included training of inter-professional surgical teams, promoting use of the WHO SSC and introducing an infection prevention (IP) bundle for all CS patients. We assessed use of WHO SSC and SSI rates through random sampling of 279 individual CS patient files. We reviewed registers and ward round reports to obtain the number of CS performed and CS-related deaths. We compared proportions of individuals with a characteristic of interest during pre-implementation and post implementation using the two-proportion z-test at p≤0.05 using STATA V.15.ResultsThe SSC utilisation rate for CS increased from 3.7% (5 out of 136) to 95.1% (136 out of 143) with pConclusionOur findings show that our intervention led to improved utilisation of the WHO SSC, reduced SSIs and a drop in CS-related POMR. We recommend replication of the interventions in other LMICs.

The oboe and clarinet are relatively similar instruments in their size and shape yet create such a different sound. This study is an exploration of the reasoning behind their differences through a detailed acoustical analysis and geometrical study of these instruments, comparing and contrasting their properties. The oboe and clarinet are comparable in size but have some key differences. The oboe’s conical shape allows for all the harmonics to be present, while the clarinet is mostly cylindrical, except for the bell, so that mostly odd harmonics are present. The oboe’s keys have holes much smaller than those of the clarinet. Looking to find differences in acoustical spectra based on their geometric differences, samples of low, medium, and high ranges on both instruments using the same concert pitches have been taken. Data has been taken in a regular lab setting as well as an anecoic chamber in order to look for differences in harmonic content for each instrument. The data are consistent with the notion that the shape of the instruments does contribute to the spectra.

This study presents data from the first observation of labor, childbirth and immediate newborn care in a clinical setting in Sindh, the second most populous province of Pakistan. Trained midwives observed 310 births at 126 district level referral facilities and primary health care facilities in 10 districts of Sindh where the USAID-funded Maternal Child Health Integrated Program (MCHIP) was implemented. The facility participation rate was 78%. The findings show that monitoring vital signs during the initial examination was conducted for less than one-in-ten women. Infection prevention practices were only observed for one-in-four women. Modesty was preserved for less than half of women. In spite of an absence of monitoring during the first and second stages of labor, providers augmented labor with oxytocin in two-thirds of births. To prevent post-partum hemorrhage, oxytocin was administered within a minute of birth in 51% of cases. Immediate drying of the baby was nearly universal and eight out of ten babies were wrapped in a dry towel. Newborn vital signs and the baby's weight were taken in one-in-ten cases. Breastfeeding was initiated during the first hour of birth in 18% of cases. A support-person was present during labor and birth for 90% of women. While quality of care is poor across all facilities, the provision of care at district-level referral facilities was even lower quality than at primary health care facilities. This is because dais or assistants without formal training provided labor, birth, and newborn care for 40% of deliveries during night shifts at referral facilities. This study found many examples of suboptimal practice by skilled birth attendants across all levels of health facilities. There remains an urgent need to improve quality of service provision among skilled birth attendants in Pakistan.

The oboe and clarinet are relatively similar instruments in their size and shape yet create such different sounds. This study is an exploration of the reasoning behind their differences through a detailed acoustical analysis and geometrical study of these instruments, comparing and contrasting their properties. The oboe and clarinet are comparable in size but have some key differences. The oboe’s conical shape allows for all the harmonics to be present, while the clarinet is mostly cylindrical, except for the bell, so that mostly odd harmonics are present. The oboe’s keys have holes much smaller than those of the clarinet. Looking to find differences in acoustical spectra based on their geometric differences, samples of low, medium, and high ranges on both instruments using the same concert pitches have been taken. Data have been taken in a regular lab setting as well as an anechoic chamber in order to look for differences in harmonic content for each instrument. The data are consistent with the notion that the shape of the instruments does contribute to the spectra.

Intracellular calcium response and resulting calcium signaling to an agonist-GPCR interaction are important for the measurement of compound activity in the GPCR drug development. The increase in cytosol calcium concentration can be measured by the fluorescent calcium indicator dye such as Fluo-4 in a quick assay (in 3-5 minutes) using the fluorescence imaging plate reader. The calcium signaling through the transcription factors such as NFAT that induces gene expression can be measured by the reporter gene assay that links to the expression of reporter enzyme such as the beta-lactamase that requires 5-hour incubation. We have evaluated a multiplexed assay that sequentially measures the calcium response to a GPCR agonist in a rapid fluorescent calcium dye assay, followed by a NFAT beta-lactamase assay, and compared them in the single assay format. We found that the agonist activity determined in the multiplexed assay were comparable with these determined in the single assay format and the Z’ factors were all >0.5. Five active compounds were identified that were active in both calcium dye assay and beta-lactamase assay. Therefore, our results demonstrated the utility of this multiplexed calcium assay for screening of GPCR compounds that can cross validate the primary hits and help to eliminate the false positive compounds.

A series of aminomethylpyrazoles were prepared and evaluated using cell-based Smoothened β-lactamase reporter assay and Smoothened binding assay. Potent Smoothened antagonists 10k and 10l were found to inhibit hair growth in vivo in the C3H/HeN mouse hair growth model. The more selective compound 10l was tested negative in the 3T3 NRU assay, indicating a low risk for causing photo-irritation and was efficacious using the C3H/HeN mouse hair growth model although it was slightly less efficacious than that of the reference compound eflornithine (7).

A novel α7 nAChR agonist, N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (3a, PHA-709829), has been identified for the potential treatment of cognitive deficits in schizophrenia. The compound shows potent and selective α7 in vitro activity, excellent brain penetration, good rat oral bioavailability and robust in vivo efficacy in a rat auditory sensory gating model.

A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.

Background Voluntary medical male circumcision (VMMC) reduces HIV acquisition among heterosexual men by approximately 60%. VMMC is a surgical procedure and some adverse events (AEs) are expected. Swaziland’s Ministry of Health established a toll-free hotline to provide general information about VMMC and to manage post-operative clinical AEs through telephone triage. Methods We retrospectively analyzed a dataset of telephone calls logged by the VMMC hotline during a VMMC campaign. The objectives were to determine reasons clients called the VMMC hotline and to ascertain the accuracy of telephone-based triage for VMMC AEs. We then analyzed VMMC service delivery data that included date of surgery, AE type and severity, as diagnosed by a VMMC clinician as part of routine post-operative follow-up. Both datasets were de-identified and did not contain any personal identifiers. Proportions of AEs were calculated from the call data and from VMMC service delivery data recorded by health facilities. Sensitivity analyses were performed to assess the accuracy of phone-based triage compared to clinically confirmed AEs. Results A total of 17,059 calls were registered by the triage nurses from April to December 2011. Calls requesting VMMC education and counseling totaled 12,492 (73.2%) and were most common. Triage nurses diagnosed 384 clients with 420 (2.5%) AEs. According to the predefined clinical algorithms, all moderate and severe AEs (153) diagnosed through telephone-triage were referred for clinical management at a health facility. Clinicians at the VMMC sites diagnosed 341 (4.1%) total clients as having a mild (46.0%), moderate (47.8%), or severe (6.2%) AE. Eighty-nine (26%) of the 341 clients who were diagnosed with AEs by clinicians at a VMMC site had initially called the VMMC hotline. The telephone-based triage system had a sensitivity of 69%, a positive predictive value of 83%, and a negative predictive value of 48% for screening moderate or severe AEs of all the AEs. Conclusions The use of a telephone-based triage system may be an appropriate first step to identify life-threatening and urgent complications following VMMC surgery.

The seven-transmembrane protein Smoothened (Smo) mediates the cellular response to the Hedgehog protein signal and is involved in cell growth and differentiation during embryonic development. Stimulation of the Smo pathway is directly implicated in tissue maintenance and repair, but overactivation of Smo could lead to tumorigenesis. We developed a robust and sensitive functional cell-based assay that measures the activity of endogenous Smo using a beta-lactamase transcriptional readout. This is the first Smo reporter assay that utilizes beta-lactamase reporter technology. This assay type has distinct advantages over other reporter technologies and can be used in a high-throughput mode to search for therapeutically relevant downstream Smo target effectors.

Health care practitioners are all impacted by globalization: instant global communication the increasing ease of travel global population shifts epidemics and looming global pandemics. Among health care providers midwives in particular tend to serve disadvantaged communities. In addition to caring for underserved American women midwives also see increasing numbers of recent emigres. It is critical that community practitioners know how to evaluate the risks of those diseases endemic to patients homelands including malaria tuberculosis and HIV/AIDS. (excerpt)