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Micro electro-mechanical systems (MEMS) are used to record training and match play of intermittent team sport athletes. Paired with estimates of internal responses or adaptations to exercise, practitioners gain insight into players' dose-response relationship which facilitates the prescription of the training stimuli to optimize performance, prevent injuries, and to guide rehabilitation processes. A systematic review on the relationship between external, wearable-based, and internal parameters in team sport athletes, compliant with the PRISMA guidelines, was conducted. The literature research was performed from earliest record to 1 September 2020 using the databases PubMed, Web of Science, CINAHL, and SportDISCUS. A total of 66 full-text articles were reviewed encompassing 1541 athletes. About 109 different relationships between variables have been reviewed. The most investigated relationship across sports was found between (session) rating of perceived exertion ((session-)RPE) and PlayerLoad™ (PL) with, predominantly, moderate to strong associations (r = 0.49-0.84). Relationships between internal parameters and highly dynamic, anaerobic movements were heterogenous. Relationships between average heart rate (HR), Edward's and Banister's training impulse (TRIMP) seem to be reflected in parameters of overall activity such as PL and TD for running-intensive team sports. PL may further be suitable to estimate the overall subjective perception. To identify high fine-structured loading-relative to a certain type of sport-more specific measures and devices are needed. Individualization of parameters could be helpful to enhance practicality.

Background: Previous WHO guidance on tenofovir disoproxil fumarate-based oral pre-exposure prophylaxis (PrEP) suggests measuring creatinine levels at PrEP initiation and regularly afterwards, which might represent barriers to PrEP implementation and uptake. We aimed to systematically review published literature on kidney toxicity among tenofovir disoproxil fumarate-based oral PrEP users and conducted an individual participant data meta-analysis (IPDMA) on kidney function among PrEP users in a global implementation project dataset., Methods: In this systematic review and meta-analysis we searched PubMed up to June 30, 2021, for randomised controlled trials (RCTs) or cohort studies that reported on graded kidney-related adverse events among oral PrEP users (tenofovir disoproxil fumarate-based PrEP alone or in combination with emtricitabine or lamivudine). We extracted summary data and conducted meta-analyses with random-effects models to estimate relative risks of grade 1 and higher and grade 2 and higher kidney-related adverse events, measured by elevated serum creatinine or decline in estimated creatinine clearance or estimated glomerular filtration rate. The IPDMA included (largely unpublished) individual participant data from 17 PrEP implementation projects and two RCTs. Estimated baseline creatinine clearance and creatinine clearance change after initiation were described by age, gender, and comorbidities. We used random-effects regressions to estimate the risk in decline of creatinine clearance to less than 60 mL/min., Findings: We identified 62 unique records and included 17 articles reporting on 11 RCTs with 13 523 participants in meta-analyses. PrEP use was associated with increased risk of grade 1 and higher kidney adverse events (pooled odds ratio [OR] 1·49, 95% CI 1·22-1·81; I 2 =25%) and grade 2 and higher events (OR 1·75, 0·68-4·49; I 2 =0%), although the grade 2 and higher association was not statistically significant and events were rare (13 out of 6764 in the intervention group vs six out of 6782 in the control group). The IPDMA included 18 676 individuals from 15 countries (1453 [7·8%] from RCTs) and 79 (0·42%) had a baseline estimated creatinine clearance of less than 60 mL/min (increasing proportions with increasing age). Longitudinal analyses included 14 368 PrEP users and 349 (2·43%) individuals had a decline to less than 60 mL/min creatinine clearance, with higher risks associated with increasing age and baseline creatinine clearance of 60·00-89·99 mL/min (adjusted hazard ratio [aHR] 8·49, 95% CI 6·44-11·20) and less than 60 mL/min (aHR 20·83, 12·83-33·82)., Interpretation: RCTs suggest that risks of kidney-related adverse events among tenofovir disoproxil fumarate-based oral PrEP users are increased but generally mild and small. Our global PrEP user analysis found varying risks by age and baseline creatinine clearance. Kidney function screening and monitoring might focus on older individuals, those with baseline creatinine clearance of less than 90 mL/min, and those with kidney-related comorbidities. Less frequent or optional screening among younger individuals without kidney-related comorbidities may reduce barriers to PrEP implementation and use., Funding: Unitaid, Bill & Melinda Gates Foundation, WHO., Competing Interests: Declaration of interests J-MM declares that his institution has received grants from Gilead Sciences; receiving consulting fees from Gilead Sciences, Merck & Co, and ViiV Healthcare; and payments for expert testimony from Merck & Co, unrelated to the present work. KG declares receipt of travel grants by IAS and WHO to attend meetings unrelated to the present work. All other authors declare no competing interests., (© 2022 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products, or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Introduction: Faced with the coronavirus disease (COVID-19) pandemic, governments worldwide instituted lockdowns to curtail virus spread. Health facility closures and travel restrictions disrupted access to antiretroviral (ARV) therapy for people living with HIV. This report describes how HIV programs in Indonesia, Laos, Nepal, and Nigeria supported treatment continuation by introducing home delivery of ARVs., Methods: Staff supporting the programs provided accounts of when and how decisions were taken to support ARV home delivery. They captured programmatic information about home delivery implementation using an intervention documentation tool. The 4 country experiences revealed lessons learned about factors favoring successful expansion of ARV home delivery., Results: Three of the countries relied on existing networks of community health workers for ARV delivery; the fourth country, Indonesia, relied on a private sector courier service. Across the 4 countries, between 19% and 51% of eligible clients were served by home delivery. The experiences showed that ARV home delivery is feasible and acceptable to health service providers, clients, and other stakeholders. Essential to success was rapid mobilization of stakeholders who led the design of the home delivery mechanisms and provided leadership support of the service innovations. Timely service adaptation was made possible by pre-existing differentiated models of care supportive of community-based ARV provision by outreach workers. Home delivery models prioritized protection of client confidentiality and prevention measures for COVID-19. Sustainability of the innovation depends on reinforcement of the commodity management infrastructure and investment in financing mechanisms., Conclusion: Home delivery of ARVs is a feasible client-centered approach to be included among the options for decentralized drug distribution. It serves as a measure for expanding access to care both when access to health services is disrupted and under routine circumstances., (© Hoke et al.)

Introduction: The advent of COVID-19 has put pressure on health systems as they implement measures to reduce the risk of transmission to people living with HIV (PLHIV) and healthcare workers. For two out-of-facility individual differentiated service delivery (DSD) models, we assessed acceptability of antiretroviral therapy (ART) distribution through private pharmacies and reach of home delivery of ART through courier services during the COVID-19 pandemic in Botswana., Methods: From 24 July to 24 August 2020, we conducted exit interviews with PLHIV receiving ART from 10 high-volume public facilities in Gaborone, and mapped and conducted an online survey with private pharmacies to assess willingness and capacity to dispense ART to PLHIV enrolled in the Botswana national ART program. We piloted ART home delivery from September 2020 to January 2021 in Gaborone and Kweneng East districts for PLHIV accessing ART at two Tebelopele Wellness Clinics. We used cascade analysis to measure the enrolment and eventual reach (percentage of those reached amongst those who are eligible) of ART home delivery., Results: Sixty-one PLHIV and 42 private pharmacies participated. Of the PLHIV interviewed, 37 (61%) indicated willingness to access ART from private pharmacies and pay BWP50 (∼US$4) per refill for a maximum of two refills per year. All private pharmacies surveyed were willing to provide ART, and 26 (62%) would charge a dispensing fee (range = BWP50-100; ∼US$4-8) per refill. All pharmacies operated 12 h/day, 6 days/week and on public holidays. In the home delivery pilot, 650 PLHIV were due for refills, 69.5% (n = 452) of whom were eligible for home delivery. Of these, 361 were successfully offered home delivery and 303 enrolled (enrolment = 83.9%: female = 87.2%, male = 77.8%, p = 0.013). A total of 276 deliveries were made, a reach of 61%., Conclusions: Providing ART through private pharmacies and home delivery was acceptable in Botswana during COVID-19. Surveyed pharmacies were willing and able to dispense ART to PLHIV attending public sector facilities for free or for a nominal fee. Additionally, using courier services for ART home delivery is a novel and viable model in countries with a reliable courier service like Botswana and should be scaled up, particularly in urban areas., (© 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Chromatin signaling relies on a plethora of posttranslational modifications (PTM) of the histone proteins which package the long DNA molecules of our cells in reoccurring units of nucleosomes. Determining the biological function and molecular working mechanisms of different patterns of histone PTMs requires access to various chromatin substrates of defined modification status. Traditionally, these are achieved by individual reconstitution of single nucleosomes or arrays of nucleosomes in conjunction with modified histones produced by means of chemical biology. Here, we report an alternative strategy for establishing a library of differentially modified nucleosomes that bypasses the need for many individual syntheses, purification and assembly reactions by installing modified histone tails on ligation-ready, immobilized nucleosomes reconstituted in a single batch. Using the ligation-ready nucleosome strategy with sortase-mediated ligation for histone H3 and intein splicing for histone H2A, we generated libraries of up to 280 individually modified nucleosomes in 96-well plate format. Screening these libraries for the effects of patterns of PTMs onto the recruitment of a well-known chromatin factor, HP1 revealed a previously unknown long-range cross-talk between two modifications. H3S28 phosphorylation enhances recruitment of the HP1 protein to the H3K9 methylated H3-tail only in nucleosomal context. Detailed structural analysis by NMR measurements implies negative charges at position 28 to increase nucleosomal H3-tail dynamics and flexibility. Our work shows that ligation-ready nucleosomes enable unprecedented access to the ample space and complexity of histone modification patterns for the discovery and dissection of chromatin regulatory principles., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The aim of this study was to determine possible influences, including data processing and sport-specific demands, on the validity of acceleration measures by an inertial measurement unit (IMU) in indoor environments. IMU outputs were compared to a three-dimensional (3D) motion analysis (MA) system and processed with two sensor fusion algorithms (Kalman filter, KF; Complementary filter, CF) at temporal resolutions of 100, 10, and 5 Hz. Athletes performed six team sport-specific movements whilst wearing a single IMU. Mean and peak acceleration magnitudes were analyzed. Over all trials ( n = 1093), KF data overestimated MA resultant acceleration by 0.42 ± 0.31 m∙s -2 for mean and 4.18 ± 3.68 m∙s -2 for peak values, while CF processing showed errors of up to 0.57 ± 0.41 m∙s -2 and -2.31 ± 2.25 m∙s -2 , respectively. Resampling to 5 Hz decreased the absolute error by about 14% for mean and 56% for peak values. Still, higher acceleration magnitudes led to a large increase in error. These results indicate that IMUs can be used for assessing accelerations in indoor team sports with acceptable means. Application of a CF and resampling to 5 Hz is recommended. High-acceleration magnitudes impair validity to a large degree and should be interpreted with caution.

Background: Complex health interventions must incorporate user preferences to maximize their potential effectiveness. Discrete choice experiments (DCEs) quantify the strength of user preferences and identify preference heterogeneity across users. We present the process of using a DCE to supplement conventional qualitative formative research in the design of a demand creation intervention for voluntary medical male circumcision (VMMC) to prevent HIV in Tanzania., Methods: The VMMC intervention was designed within a 3-month formative phase. In-depth interviews (n = 30) and participatory group discussions (n = 20) sought to identify broad setting-specific barriers to and facilitators of VMMC among adult men. Qualitative results informed the DCE development, identifying the role of female partners, service providers' attitudes and social stigma. A DCE among 325 men in Njombe and Tabora, Tanzania, subsequently measured preferences for modifiable VMMC service characteristics. The final VMMC demand creation intervention design drew jointly on the qualitative and DCE findings., Results: While the qualitative research informed the community mobilization intervention, the DCE guided the specific VMMC service configuration. The significant positive utilities (u) for availability of partner counselling (u = 0.43, p < 0.01) and age-separated waiting areas (u = 0.21, p < 0.05) led to the provision of community information booths for partners and provision of age-separated waiting areas. The strong disutility of female healthcare providers (u = - 0.24, p < 0.01) led to re-training all providers on client-friendliness., Conclusion: This is, to our knowledge, the first study documenting how user preferences from DCEs can directly inform the design of a complex intervention. The use of DCEs as formative research may help increase user uptake and adherence to complex interventions.

Highly potent cannabis concentrates obtained by butane or by supercritical carbon dioxide-extraction are gaining popularity. These extracts called butane hash oil (BHO) with Δ 9 -tetrahydrocannabinolic acid A (THCA) contents above 60% are consumed by flash vaporization on a glowing titanium nail, followed by inhalation of the resulting vapor through a water pipe in a single puff - a technique referred to as "dabbing". We herein investigated the decarboxylation rate of THCA during artificial smoking of cannabis plant material and simulated dabbing, and the lung availability of Δ 9 -tetrahydrocannabinol (THC) which we define as the recovery of THC in the smoke and vapor condensates. Preliminary smoking and dabbing experiments were performed using an apparatus built in-house. Due to availability of cannabidiol (CBD)-rich hemp in Switzerland, we included a sample of CBD flowers in our experiments and investigated the decarboxylation and recovery of cannabidiolic acid (CBDA) and CBD, respectively. Decarboxylation of THCA and CBDA during combustion of the plant material and vaporization of the BHO, respectively, was complete. The high recovery of total THC (75.5%) by dabbing cannot be achieved by smoking marijuana. Lung availability ranged from 12% for mixed cannabis material with a rather low THC content, to approximately 19-27% for marijuana flowers, similar for THC in marijuana as for CBD in CBD-rich marijuana. In reality, when smoking a joint, further losses in recovery must be assumed by additional sidestream smoke. The rather high lung availability of THC via dabbing can explain the increased psychoactive and adverse effects associated with this new trend of cannabis consumption., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: To determine whether multiple viewings of one's ultraviolet (UV) facial photo differentially affects subsequent sun protection behaviors relative to a single viewing., Study Design: Pretest-posttest control group., Methods: Southern California college students (N = 151) were randomly assigned to be shown their UV facial photo one time, multiple times over the course of 2 weeks, or not at all. Emotional reactions, perceived susceptibility to skin damage, and sun protection intentions were assessed immediately, and sun protection behaviors were assessed during a surprise telephonic follow-up 1 month later., Results: Immediately after viewing a UV photo of their face, participants reported significantly greater perceived susceptibility to skin damage, greater intentions to engage in future sun protection, and more negative emotions than those who had not seen a UV photo. Moreover, 1 month later, those who had viewed their UV photo were less likely to report having sunbathed and reported significantly greater sun protection than did controls. There were no differences in sun protection behaviors between those who had been shown their UV photo only once during the initial intervention session and those who had been sent their UV photo several times thereafter. However, among those who had been sent their UV photo several times, those who reported having viewed their photo on additional occasions reported significantly greater sun protection behaviors than those who had not., Conclusions: Being randomly assigned to view a UV facial photo multiple times generally neither strengthened nor weakened effects on subsequent sun protection behaviors relative to being shown the photo just once. However, among those who were sent their photo and thus had the option of viewing it more often than they had been assigned to, those who chose to view their photo more frequently also engaged in more sun protection behaviors., (Copyright © 2018 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Background: Although voluntary medical male circumcision (VMMC) reduces the risk of HIV acquisition, demand for services is lower among men in most at-risk age groups (ages 20-34 years). A randomized controlled trial was conducted to assess the effectiveness of locally-tailored demand creation activities (including mass media, community mobilization, and targeted service delivery) in increasing uptake of campaign-delivered VMMC among men aged 20-34 years. We conducted an economic evaluation to understand the intervention's cost and cost-effectiveness., Setting: Tanzania (Njombe and Tabora regions)., Methods: Cost data were collected on surgery, demand creation activities, and monitoring and supervision related to VMMC implementation across clusters in both trial arms, as well as start-up activities for the intervention arms. The Decision Makers' Program Planning Tool was used to estimate the number of HIV infections averted and related cost savings, given the total VMMCs per cluster. Disability-adjusted life years were calculated and used to estimate incremental cost-effectiveness ratios., Results: Client load was higher in the intervention arms than in the control arms: 4394 vs. 2901 in Tabora and 1797 vs. 1025 in Njombe, respectively. Despite additional costs of tailored demand creation, demand increased more than proportionally: mean costs per VMMC in the intervention arms were $62 in Tabora and $130 in Njombe, and in the control arms $70 and $191, respectively. More infections were averted in the intervention arm than in the control arm in Tabora (123 vs. 67, respectively) and in Njombe (164 vs. 102, respectively). The intervention dominated the control because it was both less costly and more effective. Cost savings were observed in both regions stemming from the antiretroviral treatment costs averted as a result of the VMMCs performed., Conclusions: Spending more to address local preferences as a way to increase uptake of VMMC can be cost-saving.

The increasing interest in assessing physical demands in team sports has led to the development of multiple sports related monitoring systems. Due to technical limitations, these systems primarily could be applied to outdoor sports, whereas an equivalent indoor locomotion analysis is not established yet. Technological development of inertial measurement units (IMU) broadens the possibilities for player monitoring and enables the quantification of locomotor movements in indoor environments. The aim of the current study was to validate an IMU measuring by determining average and peak human acceleration under indoor conditions in team sport specific movements. Data of a single wearable tracking device including an IMU (Optimeye S5, Catapult Sports, Melbourne, Australia) were compared to the results of a 3D motion analysis (MA) system (Vicon Motion Systems, Oxford, UK) during selected standardized movement simulations in an indoor laboratory ( n = 56). A low-pass filtering method for gravity correction (LF) and two sensor fusion algorithms for orientation estimation [Complementary Filter (CF), Kalman-Filter (KF)] were implemented and compared with MA system data. Significant differences ( p < 0.05) were found between LF and MA data but not between sensor fusion algorithms and MA. Higher precision and lower relative errors were found for CF (RMSE = 0.05; CV = 2.6%) and KF (RMSE = 0.15; CV = 3.8%) both compared to the LF method (RMSE = 1.14; CV = 47.6%) regarding the magnitude of the resulting vector and strongly emphasize the implementation of orientation estimation to accurately describe human acceleration. Comparing both sensor fusion algorithms, CF revealed slightly lower errors than KF and additionally provided valuable information about positive and negative acceleration values in all three movement planes with moderate to good validity (CV = 3.9 - 17.8%). Compared to x- and y-axis superior results were found for the z-axis. These findings demonstrate that IMU-based wearable tracking devices can successfully be applied for athlete monitoring in indoor team sports and provide potential to accurately quantify accelerations and decelerations in all three orthogonal axes with acceptable validity. An increase in accuracy taking magnetometers in account should be specifically pursued by future research.

Despite risk for secondary skin cancers, many adolescent and young adult (AYA) cancer survivors do not practice recommended sun protection (SP). Ultraviolet light photography (UVP), which demonstrates the negative impact of sun exposure on physical appearance, has been shown to increase SP in community AYA samples. This study of 58 AYA cancer survivors demonstrates that UVP is acceptable and not distressing to this population. Follow-up data on 23 AYAs demonstrated that those given UVP significantly improve their SP behaviors, while those receiving standard educational materials do not. Results demonstrate UVP is a promising tool for increasing SP in AYA survivors.

The relationship between the time duration of movement (t(dur)) and related maximum possible power output has been studied and modeled under many conditions. Inspired by the so-called power profiles known for discontinuous endurance sports like cycling, and the critical power concept of Monod and Scherrer, the aim of this study was to evaluate the numerical characteristics of the function between maximum horizontal movement velocity (HSpeed) and t(dur) in soccer. To evaluate this relationship, GPS data from 38 healthy soccer players and 82 game participations (≥30 min active playtime) were used to select maximum HSpeed for 21 distinct t(dur) values (between 0.3 s and 2,700 s) based on moving medians with an incremental t(dur) window-size. As a result, the relationship between HSpeed and Log(t(dur)) appeared reproducibly as a sigmoidal decay function, and could be fitted to a five-parameter equation with upper and lower asymptotes, and an inflection point, power and decrease rate. Thus, the first three parameters described individual characteristics if evaluated using mixed-model analysis. This study shows for the first time the general numerical relationship between t(dur) and HSpeed in soccer games. In contrast to former descriptions that have evaluated speed against power, HSpeed against t(dur) always yields a sigmoidal shape with a new upper asymptote. The evaluated curve fit potentially describes the maximum moving speed of individual players during the game, and allows for concise interpretations of the functional state of team sports athletes.

Uncircumcised adolescent males in sub-Saharan Africa are an important group to reach with voluntary medical male circumcision (VMMC) services due to high HIV burden occurring among this age group. Appropriateness of the content and delivery of sexual health and HIV prevention messages to adolescent VMMC clients has not been extensively described. A study was conducted in Tanzania to examine quality, delivery and content of messages provided to adolescent (aged 15-19) and adult (aged 20+) VMMC clients (n = 320). Results show that counseling of mixed age groups during group education lacked selected key messages, compared to more age-homogeneous groups. Additionally, adolescents received more comprehensive information in individual counseling compared to group education. We recommend that health care providers are provided with skills and job aides to assist them to segment VMMC clients by age; provide age-appropriate messages; and increase use of individual counseling as a means to communicate with adolescent clients.

Objective: We evaluated a demand-creation intervention to increase voluntary medical male circumcision (VMMC) uptake among men aged 20-34 years in Tanzania, to maximise short-term impact on HIV incidence., Methods: A cluster randomized controlled trial stratified by region was conducted in 20 outreach sites in Njombe and Tabora regions. The sites were randomized 1 : 1 to receive either a demand-creation intervention package in addition to standard VMMC outreach, or standard VMMC outreach alone. The intervention package included enhanced public address messages, peer promotion by recently circumcised men, facility setup to increase privacy, and engagement of female partners in demand creation. The primary outcome was the proportion of VMMC clients aged 20-34 years., Findings: Overall, 6251 and 3968 VMMC clients were enrolled in intervention and control clusters, respectively. The proportion of clients aged 20-34 years was slightly greater in the intervention than control arm [17.7 vs. 13.0%; prevalence ratio = 1.36; 95% confidence intervals (CI):0.9-2.0]. In Njombe region, the proportion of clients aged 20-34 years was similar between arms but a significant two-fold difference was seen in Tabora region (P value for effect modification = 0.006). The mean number of men aged 20-34 years (mean difference per cluster = 97; 95% CI:40-154), and of all ages (mean difference per cluster = 227, 95% CI:33-420) were greater in the intervention than control arm., Conclusion: The intervention was associated with a significant increase in the proportion of clients aged 20-34 years in Tabora but not in Njombe. The intervention may be sensitive to regional factors in VMMC programme scale-up, including saturation.

Background: Uptake of voluntary medical male circumcision (VMMC) among adult men has fallen short of targets in Tanzania. We evaluated a smartphone raffle intervention designed to increase VMMC uptake in three regions., Methods: Among 7 matched pairs of health facilities, 1 in each pair was randomly assigned to the intervention, consisting of a weekly smartphone raffle for clients returning for follow-up and monthly raffle for peer promoters and providers. VMMC records of clients aged 20 and older were analyzed over three months, with the number performed compared with the same months in the previous year. In multivariable models, the intervention's effect on number of VMMCs was adjusted for client factors and clustering. Focus groups with clients and peer promoters explored preferences for VMMC incentives., Results: VMMCs increased 47% and 8% in the intervention and control groups, respectively; however, the changes were not significantly different from one another. In the Iringa region subanalysis, VMMCs in the intervention group increased 336% (exponentiated coefficient of 3.36, 95% CI: 1.14 to 9.90; P = 0.028), after controlling for facility pair, percentage of clients ≥ age 30, and percentage testing HIV positive; the control group had a more modest 63% significant increase (exponentiated coefficient 1.63, 95% CI: 1.18 to 2.26; P = 0.003). The changes were not significantly different. Focus group respondents expressed mixed opinions about smartphone raffles; some favored smaller cash incentive or transportation reimbursement., Implications: A smartphone raffle might increase VMMC uptake in some settings by helping late adopters move from intention to action; however, there is no recommendation for this intervention more generally., Competing Interests: The authors have no funding or conflicts of interest to disclose.

Background: Since its launch in 2010, the Tanzania National Voluntary Medical Male Circumcision (VMMC) Program has focused efforts on males ages 10-34 in 11 priority regions. Implementers have noted that over 70% of VMMC clients are between the ages of 10 and 19, raising questions about whether additional efforts would be required to recruit men age 20 and above. This analysis uses mathematical modeling to examine the economic and epidemiological consequences of scaling up VMMC among specific age groups and priority regions in Tanzania., Methods and Findings: Analyses were conducted using the Decision Makers' Program Planning Tool Version 2.0 (DMPPT 2.0), a compartmental model implemented in Microsoft Excel 2010. The model was populated with population, mortality, and HIV incidence and prevalence projections from external sources, including outputs from Spectrum/AIDS Impact Module (AIM). A separate DMPPT 2.0 model was created for each of the 11 priority regions. Tanzania can achieve the most immediate impact on HIV incidence by circumcising males ages 20-34. This strategy would also require the fewest VMMCs for each HIV infection averted. Circumcising men ages 10-24 will have the greatest impact on HIV incidence over a 15-year period. The most cost-effective approach (lowest cost per HIV infection averted) targets men ages 15-34. The model shows the VMMC program is cost saving in all 11 priority regions. VMMC program cost-effectiveness varies across regions due to differences in projected HIV incidence, with the most cost-effective programs in Njombe and Iringa., Conclusions: The DMPPT 2.0 results reinforce Tanzania's current VMMC strategy, providing newfound confidence in investing in circumcising adolescents. Tanzanian policy makers and program implementers will continue to focus scale-up of VMMC on men ages 10-34 years, seeking to maximize program impact and cost-effectiveness while acknowledging trends in demand among the younger and older age groups.

Iringa region of Tanzania has had great success reaching targets for voluntary medical male circumcision (VMMC). Looking to sustain high coverage of male circumcision, the government introduced a pilot project to offer early infant male circumcision (EIMC) in Iringa in 2013. From April 2013 to December 2014, a total of 2,084 male infants were circumcised in 8 health facilities in the region, representing 16.4% of all male infants born in those facilities. Most circumcisions took place 7 days or more after birth. The procedure proved safe, with only 3 mild and 3 moderate adverse events (0.4% overall adverse event rate). Overall, 93% of infants were brought back for a second-day visit and 71% for a seventh-day visit. These percentages varied significantly by urban and rural residence (97.4% urban versus 84.6% rural for day 2 visit; 82.2% urban versus 49.9% rural for day 7 visit). Mothers were more likely than fathers to have received information about EIMC. However, fathers tended to be key decision makers regarding circumcision of their sons. This suggests the importance of addressing fathers with behavioral change communication about EIMC. Successes in scaling up VMMC services in Iringa did not translate into immediate acceptability of EIMC. EIMC programs will require targeted investments in demand creation to expand and thrive in traditionally non-circumcising settings such as Iringa., (© Amuri et al.)

Formation of singlet oxygen ((1)O2) has been implicated with damaging photosystem II (PSII) that needs to undergo continuous repair to maintain photosynthetic electron transport. In addition to its damaging effect, (1)O2 has also been shown to act as a signal that triggers stress acclimation and an enhanced stress resistance. A signaling role of (1)O2 was first documented in the fluorescent (flu) mutant of Arabidopsis It strictly depends on the chloroplast protein EXECUTER1 (EX1) and happens under nonphotoinhibitory light conditions. Under severe light stress, signaling is initiated independently of EX1 by (1)O2 that is thought to be generated at the acceptor side of active PSII within the core of grana stacks. The results of the present study suggest a second source of (1)O2 formation in grana margins close to the site of chlorophyll synthesis where EX1 is localized and the disassembly of damaged and reassembly of active PSII take place. The initiation of (1)O2 signaling in grana margins depends on EX1 and the ATP-dependent zinc metalloprotease FtsH. As FtsH cleaves also the D1 protein during the disassembly of damaged PSII, EX1- and (1)O2-mediated signaling seems to be not only spatially but also functionally associated with the repair of PSII.

Dual-chamber systems can offer self-administration and home care use for lyophilized biologics. Only a few products have been launched in dual-chamber systems so far-presumably due to dual-chamber systems' complex and costly drug product manufacturing process. Within this paper, two improved processes (both based on tray filling technology) for freeze-drying pharmaceuticals in dual-chamber systems are described. Challenges with regards to heat transfer were tackled by (1) performing the freeze-drying step in a needle-down orientation in combination with an aluminum block, or (2) freeze-drying the drug product "externally" in a metal cartridge with subsequent filling of the lyophilized cake into the dual-chamber system. Metal-mediated heat transfer was shown to be efficient in both cases and batch (unit-to-unit) homogeneity with regards to sublimation rate was increased. It was difficult to influence ice crystal size using different methods when in use with an aluminum block due to its heat capacity. Using such a metal carrier implies a large heat capacity leading to relatively small ice crystals. Compared to the established process, drying times were reduced by half using the new processes. The drying time was, however, longer for syringes compared to vials due to the syringe design (long and slim). The differences in drying times were less pronounced for aggressive drying cycles. The proposed processes may help to considerably decrease investment costs into dual-chamber system fill-finish equipment., Lay Abstract: Dual-chamber syringes offer self-administration and home care use for freeze-dried pharmaceuticals. Only a few products have been launched in dual-chamber syringes so far-presumably due to their complex and costly drug product manufacturing process. In this paper two improved processes for freeze-drying pharmaceuticals in dual-chamber syringes are described. The major challenge of freeze-drying is to transfer heat through a vacuum. The proposed processes cope with this challenge by (1) freeze-drying the drug product in the syringe in an orientation in which the product is closest to the heat source, or (2) freeze-drying the drug product outside the syringe in a metal tube. The latter requires filling the freeze-dried product subsequently into the dual-chamber syringe. Both processes were very efficient and promised to achieve similar freeze-drying conditions for all dual-chamber syringes within one production run. The proposed processes may help to considerably decrease investment costs into dual-chamber syringe fill-finish equipment., (© PDA, Inc. 2016.)

Assessing an individual's physical fitness can usually be achieved through evaluating lactate or ventilatory thresholds. Unfortunately, the detection of ventilatory thresholds still requires uncomfortable mass flow sensors and a laboratory setting. Therefore, this study aimed to evaluate a ventilatory inflection point (VIP) derived from thorax expansion as a useful surrogate to assess an individual's physical fitness under field conditions. 348 and 107 ramp tests have been selected respectively to examine validity and retest variability of VIP. The individual anaerobic threshold (IAT) determined by means of blood lactate sampling was used as reliable rationale for evaluation. Calibrated respiratory inductance plethysmography (RIP) was utilized to derive ventilation from thorax expansion during the ramp test. An automated software routine was applied to detect the VIP. Speed, heart rate and ventilation at the VIP correlated significantly to corresponding values at IAT (r=0.840, 0.876, 0.933). Non-systematic differences between repeated testing ranged within ±1.15 km·h(-1), ±8.74 b·min(-1) and ±12.69 l·min(-1) (±1.96 SD). The timing of VIP is not solely dependent on the aerobic capacity and might instead quantify an individual's physical fitness in terms of the efficiency of the compensative and supportive ventilatory response during increased exercise intensities., (© Georg Thieme Verlag KG Stuttgart · New York.)

The aim of this study was to evaluate the predictive potential provided by two ventilatory inflection points (VIP1 and VIP2) examined in field without using gas analysis systems and uncomfortable facemasks. A calibrated respiratory inductance plethysmograph (RIP) and a computerised routine were utilised, respectively, to derive ventilation and to detect VIP1 and VIP2 during a standardised field ramp test on a 400 m running track on 81 participants. In addition, average running speed of a competitive 1000 m run (S1k) was observed as criterion. The predictive value of running speed at VIP1 (SVIP1) and the speed range between VIP1 and VIP2 in relation to VIP2 (VIPSPAN) was analysed via regression analysis. VIPSPAN rather than running speed at VIP2 (SVIP2) was operationalised as a predictor to consider the covariance between SVIP1 and SVIP2. SVIP1 and VIPSPAN, respectively, provided 58.9% and 22.9% of explained variance in regard to S1k. Considering covariance, the timing of two ventilatory inflection points provides predictive value in regard to a competitive 1000 m run. This is the first study to apply computerised detection of ventilatory inflection points in a field setting independent on measurements of the respiratory gas exchange and without using any facemasks.

Purpose: Antimicrobial preservatives are known to interact with proteins and potentially affect their stability in aqueous solutions. In this systematic study, the interactions of a model peptide with three commonly used preservatives, benzyl alcohol, phenol and m-cresol, were evaluated., Methods: The impact on peptide oligomerization was studied using GC-MALS, SEC-MALS and DLS, antimicrobial efficiency of different formulations were studied using the Ph. Eur. antimicrobial efficacy test, and the molecular adsorption of preservative molecules on reversible peptide oligomers was monitored using NMR., Results: The hydrodynamic radius and molar mass of the peptide oligomers was shown to clearly increase in the presence of m-cresol but less significantly with phenol and benzyl alcohol. The increase in size was most likely caused by peptide self-interactions becoming more attractive, leading to reversible oligomerization. On the other hand, increasing the concentration of peptide in multi-dose formulations led to reduced molecular mobility and decreased antimicrobial efficacy of all preservatives., Conclusions: Peptide-preservative interactions not only affect peptide self-interactions, but also antimicrobial efficiency of the preservatives and are thus of significant relevance. Adsorption of preservatives on oligomeric states of peptides is proposed as a mechanism to explain this reduced antimicrobial efficacy.

Voluntary Medical Male Circumcision (VMMC) for HIV prevention in Tanzania was introduced by the Ministry of Health and Social Welfare in 2010 as part of the national HIV prevention strategy. A qualitative study was conducted prior to a cluster randomized trial which tested effective strategies to increase VMMC up take among men aged ≥20 years. During the formative qualitative study, we conducted in-depth interviews with circumcised males (n = 14), uncircumcised males (n = 16), and participatory group discussions (n = 20) with men and women aged 20-49 years in Njombe and Tabora regions of Tanzania. Participants reported that mothers and female partners have an important influence on men's decisions to seek VMMC both directly by denying sex, and indirectly through discussion, advice and providing information on VMMC to uncircumcised partners and sons. Our findings suggest that in Tanzania and potentially other settings, an expanded role for women in VMMC communication strategies could increase adult male uptake of VMMC services.

Background: Based on the established protective effect of voluntary medical male circumcision (VMMC) in reducing female-to-male HIV transmission, Tanzania's Ministry of Health and Social Welfare (MOHSW) embarked on the scale-up of VMMC services in 2009. The Maternal and Child Health Integrated Project (MCHIP) supported the MOHSW to roll out VMMC services in Iringa and Njombe, 2 regions of Tanzania with among the highest HIV and lowest circumcision prevalence. With ambitious targets of reaching 264,990 males aged 10-34 years with VMMC in 5 years, efficient and innovative program approaches were necessary., Program Description: Outreach campaigns, in which mobile teams set up temporary services in facilities or non-facility settings, are used to reach lesser-served areas with VMMC. In 2012, MCHIP began using geographic information systems (GIS) to strategically plan the location of outreach campaigns. MCHIP gathered geocoded data on variables such as roads, road conditions, catchment population, staffing, and infrastructure for every health facility in Iringa and Njombe. These data were uploaded to a central database and overlaid with various demographic and service delivery data in order to identify the VMMC needs of the 2 regions., Findings: MCHIP used the interactive digital maps as decision-making tools to extend mobile VMMC outreach to "the last kilometer." As of September 2014, the MOHSW with MCHIP support provided VMMC to 267,917 men, 259,144 of whom were men were aged 10-34 years, an achievement of 98% of the target of eligible males in Iringa and Njombe. The project reached substantially more men through rural dispensaries and non-health care facilities each successive year after GIS was introduced in 2012, jumping from 48% of VMMCs performed in rural areas in fiscal year 2011 to 88% in fiscal year 2012 and to 93% by the end of the project in 2014., Conclusion: GIS was an effective tool for making strategic decisions about where to prioritize VMMC service delivery, particularly for mobile and outreach services. Donors may want to consider funding mapping initiatives that support numerous interventions across implementing partners to spread initial start-up costs., (© Mahler et al.)

Among the new psychoactive substances (NPS), most frequently synthetic cannabinoids (SCBs) have been found in Europe. These are sold as active compounds in e. g. so-called "herbal blends". When inhaled or ingested, besides intoxication symptoms, as they occur with heavy cannabis use (e. g., tachycardia, myocardial infarction, confusion, hallucinations, panic attacks, and paranoia), harmful effects (severe agitation, coma, catatonic stupor, hypertension, cardiac arrhythmia, dyspnoea, seizures, myoclonus, rhabdomyolysis, hyperthermia, diaphoresis, acute kidney injury, vomiting, headache, and hypokalemia) arise, which are mostly unusual about cannabis use. In addition, the first cases of addiction and death related to SCBs have been reported. Taking into account the newest literature and using an algorithm with two main criteria (addiction potential, toxicity), the authors made a first attempt to rank the personal health hazard of SCBs in comparison to that of other psychoactive drugs. Accordingly, the relative health hazard of SCBs is found to be somewhat higher than that of cannabis and lower than that of synthetic cathinones ("bath salts"). However, the toxicity of SCBs, is significantly greater than the toxicity of cannabis, thus being similar to that of synthetic cathinones and benzodiazepines. The addiction potential appears to be lower than that of synthetic cathinones, benzodiazepines, or cannabis. Due to the fluctuation of substances and the availability in internet resources, legislation is facing a serious "hare-hedgehog" problem to control the manufacture, trade and possession of SCBs., (© Georg Thieme Verlag KG Stuttgart · New York.)

The abuse of drugs such as street cocaine is known to cause a variety of toxic effects, some of which involve the lungs and often induce lethal complications. While the toxicity of cocaine itself is reviewed well, the influence of toxic effects of its adulterants on the human body is not thoroughly studied. Therefore, we examined heart blood, femoral vein blood and lung tissue from 11 cases for typically used adulterants in cocaine preparations and check whether if the concentrations in the lung tissue are higher than in the blood. The adulterants were isolated using solid-phase (SPE) and liquid-liquid extraction (LLE) and quantified via high-pressure-liquid-chromatography-time-of-flight-mass spectrometry (LC/TOF-MS). Five adulterants, i.e., phenacetin, lidocaine, diltiazem, levamisole and hydroxyzine, were detected. We found out that the concentration of these substances was often higher in the lung than in the analogous analysed body fluids. It should therefore be considered whether - for the determination in the cause of death - the lung should be examined in addition to heart blood, urine or brain tissue., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The between-days variability in ascertained gain factors for calibration of a wearable respiratory inductance plethysmograph (RIP) and validity thereof for the repeated use during exercise were examined. Consecutive 5-min periods of standing still, slow running at 8 km·h(-1), fast running at 14 km·h(-1) (male) or 12 km·h(-1) (female) and recovery were repeated by 10 healthy subjects on 5 days. Breath-by-breath data were recorded simultaneously by flow meter and RIP. Gain factors were determined individually for each trial (CALIND) via least square regression. Reliability and variability in gain factors were quantified respectively by intraclass correlation coefficients (ICC) and limits of agreement. Within a predefined error range of ±20% the amount of RIP-derived tidal volumes after CALIND was compared to corresponding amounts when gain factors of the first trial were applied on the following 4 trials (CALFIRST). ICC ranged within 0.96 and 0.98. The variability in gain factors (up to ± 24.06%) was reduced compensatively by their sum. Amounts of breaths within the predefined error range did not differ between CALIND and (CALFIRST) (P>0.32). The between-days variability of gain factors for a wearable RIP-device does not show impaired reliability in further derived tidal volumes., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background and Methods: By December 2013, it was estimated that close to 6 million men had been circumcised in the 14 priority countries for scaling up voluntary medical male circumcision (VMMC), the majority being adolescents (10-19 years). This article discusses why efforts to scale up VMMC should prioritize adolescent men, drawing from new evidence and experiences at the international, country, and service delivery levels. Furthermore, we review the extent to which VMMC programs have reached adolescents, addressed their specific needs, and can be linked to their sexual and reproductive health and other key services., Results and Discussion: In priority countries, adolescents represent 34%-55% of the target population to be circumcised, whereas program data from these countries show that adolescents represent between 35% and 74% of the circumcised men. VMMC for adolescents has several advantages: uptake of services among adolescents is culturally and socially more acceptable than for adults; there are fewer barriers regarding sexual abstinence during healing or female partner pressures; VMMC performed before the age of sexual debut has maximum long-term impact on reducing HIV risk at the individual level and consequently reduces the risk of transmission in the population. Offered as a comprehensive package, adolescent VMMC can potentially increase public health benefits and offers opportunities for addressing gender norms. Additional research is needed to assess whether current VMMC services address the specific needs of adolescent clients, to test adapted tools, and to assess linkages between VMMC and other adolescent-focused HIV, health, and social services.

Introduction: This analysis explores the association between elements of surgical efficiency in voluntary medical male circumcision (VMMC), quality of surgical technique, and the amount of time required to conduct VMMC procedures in actual field settings. Efficiency outcomes are defined in terms of the primary provider's time with the client (PPTC) and total elapsed operating time (TEOT)., Methods: Two serial cross-sectional surveys of VMMC sites were conducted in Kenya, Republic of South Africa, Tanzania and Zimbabwe in 2011 and 2012. Trained clinicians observed quality of surgical technique and timed 9 steps in the VMMC procedure. Four elements of efficiency (task-shifting, task-sharing [of suturing], rotation among multiple surgical beds, and use of electrocautery) and quality of surgical technique were assessed as explanatory variables. Mann Whitney and Kruskal Wallis tests were used in the bivariate analysis and linear regression models for the multivariate analyses to test the relationship between these five explanatory variables and two outcomes: PPTC and TEOT. The VMMC procedure TEOT and PPTC averaged 23-25 minutes and 6-15 minutes, respectively, across the four countries and two years. The data showed time savings from task-sharing in suturing and use of electrocautery in South Africa and Zimbabwe (where task-shifting is not authorized). After adjusting for confounders, results demonstrated that having a secondary provider complete suturing and use of electrocautery reduced PPTC. Factors related to TEOT varied by country and year, but task-sharing of suturing and/or electrocautery were significant in two countries. Quality of surgical technique was not significantly related to PPTC or TEOT, except for South Africa in 2012 where higher quality was associated with lower TEOT., Conclusions: SYMMACS data confirm the efficiency benefits of task-sharing of suturing and use of electrocautery for decreasing TEOT. Reduced TEOT and PPTC in high volume setting did not result in decreased quality of surgical care.

Background: Scaling up voluntary medical male circumcision (VMMC) to 80% of men aged 15-49 within five years could avert 3.4 million new HIV infections in Eastern and Southern Africa by 2025. Since 2009, Tanzania and Zimbabwe have rapidly expanded VMMC services through different delivery (fixed, outreach or mobile) and intensity (routine services, campaign) models. This review describes the modality and intensity of VMMC services and its influence on the number and age of clients., Methods and Findings: Program reviews were conducted using data from implementing partners in Tanzania (MCHIP) and Zimbabwe (PSI). Key informant interviews (N = 13 Tanzania; N = 8 Zimbabwe) were conducted; transcripts were analyzed using Nvivo. Routine VMMC service data for May 2009-December 2012 were analyzed and presented in frequency tables. A descriptive analysis and association was performed using the z-ratio for the significance of the difference. Key informants in both Tanzania and Zimbabwe believe VMMC scale-up can be achieved by using a mix of service delivery modality and intensity approaches. In Tanzania, the majority of clients served during campaigns (59%) were aged 10-14 years while the majority during routine service delivery (64%) were above 15 (p<0.0001). In Zimbabwe, significantly more VMMCs were done during campaigns (64%) than during routine service delivery (36%) (p<0.00001); the difference in the age of clients accessing services in campaign versus non-campaign settings was significant for age groups 10-24 (p<0.05), but not for older groups., Conclusions: In Tanzania and Zimbabwe, service delivery modalities and intensities affect client profiles in conjunction with other contextual factors such as implementing campaigns during school holidays in Zimbabwe and cultural preference for circumcision at a young age in Tanzania. Formative research needs to be an integral part of VMMC programs to guide the design of service delivery modalities in the face of, or lack of, strong social norms.

Background: Given the proven effectiveness of voluntary medical male circumcision (VMMC) in preventing the spread of HIV, Tanzania is scaling up VMMC as an HIV prevention strategy. This study will inform policymakers about the potential costs and benefits of scaling up VMMC services in Tanzania., Methodology: The analysis first assessed the unit costs of delivering VMMC at the facility level in three regions-Iringa, Kagera, and Mbeya-via three currently used VMMC service delivery models (routine, campaign, and mobile/island outreach). Subsequently, using these unit cost data estimates, the study used the Decision Makers' Program Planning Tool (DMPPT) to estimate the costs and impact of a scaled-up VMMC program., Results: Increasing VMMC could substantially reduce HIV infection. Scaling up adult VMMC to reach 87.9% coverage by 2015 would avert nearly 23,000 new adult HIV infections through 2015 and an additional 167,500 from 2016 through 2025-at an additional cost of US$253.7 million through 2015 and US$302.3 million from 2016 through 2025. Average cost per HIV infection averted would be US$11,300 during 2010-2015 and US$3,200 during 2010-2025. Scaling up VMMC in Tanzania will yield significant net benefits (benefits of treatment costs averted minus the cost of performing circumcisions) in the long run-around US$4,200 in net benefits for each infection averted., Conclusion: VMMC could have an immediate impact on HIV transmission, but the full impact on prevalence and deaths will only be apparent in the longer term because VMMC averts infections some years into the future among people who have been circumcised. Given the health and economic benefits of investing in VMMC, the scale-up of services should continue to be a central component of the national HIV prevention strategy in Tanzania.

Background: In 2009, the Government of Tanzania embarked on scaling up voluntary medical male circumcision (VMMC) services for HIV prevention in 8 priority regions, with the aim of serving 2.8 million boys and men ages 10-34 years by 2013. By mid-2012, more than 110,000 boys and men in Iringa and Njombe regions had received VMMC. The majority (85%) of these VMMC clients were under 19 years old (average age, 16 years). This study aimed to identify potential barriers and facilitators to VMMC among older men., Methods: We conducted 16 focus group discussions, stratified by sex and age, with 142 purposefully selected participants in 3 districts of Iringa and Njombe regions., Results: Both men and women generally had positive attitudes toward VMMC. Social and personal barriers to obtaining VMMC among adult men included shame associated with seeking services co-located with younger boys and perceived inappropriateness of VMMC after puberty, particularly after marriage and after having children. Additional barriers included concerns about partner infidelity during the post-surgical abstinence period, loss of income, and fear of pain associated with post-surgical erections. Facilitators included awareness of the HIV-prevention benefit and perceptions of cleanliness and enhanced attractiveness to women., Conclusions: While men and women in Iringa and Njombe regions in Tanzania generally view VMMC as a desirable procedure, program implementers need to address barriers to VMMC services among adult men. Selected service delivery sites in the Iringa and Njombe regions will be segregated by age to provide services that are "friendly" to adult men. Services will be complemented with behavior change communication initiatives to address concerns of older men, encourage women's support for circumcision and adherence to the post-surgical abstinence period, and change social norms that inhibit older men from seeking circumcision.

The metabolism of the novel designer drug 3-fluoromethcathinone (3-FMC), sold as "legal highs", was investigated in vitro via cryopreserved rabbit liver slices. The pharmacological properties and toxicological effects of 3-FMC and its metabolites are not known yet. It can be assumed that 3-FMC will cause effects similar to 4-methylmethcathinone (mephedrone) and methcathinone. For the metabolism studies, pretests were performed with rabbit liver slices incubated with kavain to evaluate optimal conditions. Finally, six known metabolites of kavain were revealed and therefore sufficient information about the suitability of the enzyme system of the rabbit liver slices was obtained. Under optimized conditions, 3-FMC was added to Krebs-Henseleit buffer, pH 7.4 containing NADPH and bicarbonate and incubated with a single rabbit liver slice at 37°C. The metabolism was monitored at 5, 30 and 180 min, respectively. The metabolites formed via the former cryopreserved rabbit liver slices were examined by LC/MS-TOF. Metabolites were identified by their exact masses and isotopic patterns. 3-Fluorocathinone, 3-fluorocathinone-imine, hydroxy-3-fluoromethcathinone and 3-fluoromethcathinone-diol were formed as the main metabolites.

Voluntary medical male circumcision (VMMC) reduces female-to-male HIV transmission by approximately 60%; modeling suggests that scaling up VMMC to 80% of men 15- to 49-years-old within five years would avert over 3.3 million new HIV infections in 14 high priority countries/regions in southern and eastern Africa by 2025 and would require 20.33 million circumcisions. However, the shortage of health professionals in these countries must be addressed to reach these proposed coverage levels. To identify human resource approaches that are being used to improve VMMC volume and efficiency, we looked at previous literature and conducted a program review. We identified surgical efficiencies, non-surgical efficiencies, task shifting, task sharing, temporary redeployment of public sector staff during VMMC campaign periods, expansion of the health workforce through recruitment of unemployed, recently retired, newly graduating, or on-leave health care workers, and the use of volunteer medical staff from other countries as approaches that address human resource constraints. Case studies from Kenya, Tanzania, and Swaziland illustrate several innovative responses to human resource challenges. Although the shortage of skilled personnel remains a major challenge to the rapid scale-up of VMMC in the 14 African priority countries/regions, health programs throughout the region may be able to replicate or adapt these approaches to scale up VMMC for public health impact.

Two isolation procedures for Δ9-tetrahydrocannabinolic acid A (THCA), the biogenetic precursor in the biosynthesis of the psychoactive Δ9-tetrahydrocannabinol (THC) in the cannabis plant, are presented. Two flash chromatography systems that can be used independently from each other were developed to separate THCA from other compounds of a crude cannabis extract. In both systems UV absorption at 209 and 270 nm was monitored. Purity was finally determined by HPLC-DAD, NMR and GC-MS analysis with a focus on the impurity THC. System 1 consisted of a normal phase silica column (120 g) as well as cyclohexane and acetone--both spiked with the modifier pyridine--as mobile phases. Gradient elution was performed over 15 min. After the chromatographic run the fractions containing THCA fractions were pooled, extracted with hydrochloric acid to eliminate pyridine and evaporated to dryness. Loading 1800 mg cannabis extract yielded 623 mg THCA with a purity of 99.8% and a THC concentration of 0.09%. System 2 was based on a reversed-phase C18 column (150 g) combined with 0.55% formic acid and methanol as mobile phases. A very flat gradient was set over 20 minutes. After pooling the THCA-containing fractions methanol was removed in a rotary evaporator. THCA was re-extracted from the remaining aqueous phase with methyl tert-butyl ether. The organic phase was finally evaporated under high vacuum conditions. Loading 300 mg cannabis extract yielded 51 mg THCA with a purity of 98.8% and a THC concentration of 0.67%., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: This paper proposes an approach to estimating the costs of demand creation for voluntary medical male circumcision (VMMC) scale-up in 13 countries of eastern and southern Africa. It addresses two key questions: (1) what are the elements of a standardized package for demand creation? And (2) what challenges exist and must be taken into account in estimating the costs of demand creation?, Methods and Findings: We conducted a key informant study on VMMC demand creation using purposive sampling to recruit seven people who provide technical assistance to government programs and manage budgets for VMMC demand creation. Key informants provided their views on the important elements of VMMC demand creation and the most effective funding allocations across different types of communication approaches (e.g., mass media, small media, outreach/mobilization). The key finding was the wide range of views, suggesting that a standard package of core demand creation elements would not be universally applicable. This underscored the importance of tailoring demand creation strategies and estimates to specific country contexts before estimating costs. The key informant interviews, supplemented by the researchers' field experience, identified these issues to be addressed in future costing exercises: variations in the cost of VMMC demand creation activities by country and program, decisions about the quality and comprehensiveness of programming, and lack of data on critical elements needed to "trigger the decision" among eligible men., Conclusions: Based on this study's findings, we propose a seven-step methodological approach to estimate the cost of VMMC scale-up in a priority country, based on our key assumptions. However, further work is needed to better understand core components of a demand creation package and how to cost them. Notwithstanding the methodological challenges, estimating the cost of demand creation remains an essential element in deriving estimates of the total costs for VMMC scale-up in eastern and southern Africa.

Singlet oxygen is reported to have the most potent damaging effect upon the photosynthetic machinery. Usually this reactive oxygen molecule acts in concert with other ROS types under stressful conditions. To understand the specific role of singlet oxygen we took advantage of the conditional flu mutant of Arabidopsis thaliana. In flu, the negative feedback loop is abolished, which blocks chlorophyll biosynthesis in the dark. Therefore high amounts of free protochlorophyllide accumulate during darkness. If flu gets subsequently illuminated, free protochlorophyllide acts as a photosensitiser leading almost exclusively to high amounts of (1)O2. Analysing the thylakoid protein pattern by using 2D PAGE and subsequent MALDI-TOF analysis, we could show, in addition to previous described effects on photosystem II, that singlet oxygen has a massive impact on the thylakoid ATP synthase, especially on its gamma subunit. Additionally, it could be shown that the activity of the ATP synthase is reduced upon singlet oxygen exposure and that the rate of non-photochemical quenching is affected in flu mutants exposed to (1)O2.

Delta9-tetrahydrocannabinolic acid A (Delta9-THCA-A) is the precursor of Delta9-tetrahydrocannabinol (Delta9-THC) in hemp plants. During smoking, the non-psychoactive Delta9-THCA-A is converted to Delta9-THC, the main psychoactive component of marihuana and hashish. Although the decarboxylation of Delta9-THCA-A to Delta9-THC was assumed to be complete--which means that no Delta9-THCA-A should be detectable in urine and blood serum of cannabis consumers--we found Delta9-THCA-A in the urine and blood serum samples collected from police controls of drivers suspected for driving under the influence of drugs (DUID). For LC-MS/MS analysis, urine and blood serum samples were prepared by solid-phase extraction. Analysis was performed with a phenylhexyl column using gradient elution with acetonitrile. For detection of Delta9-THCA-A, the mass spectrometer (MS) (SCIEX API 365 triple-quadrupole MS with TurboIonSpray source) was operated in the multiple reaction monitoring (MRM) mode using the following transitions: m/z357 --> 313, m/z357 --> 245 and m/z357 --> 191. Delta9-THCA-A could be detected in the urine and blood serum samples of several cannabis consumers in concentrations of up to 10.8 ng/ml in urine and 14.8 ng/ml in serum. The concentration of Delta9-THCA-A was below the Delta9-THC concentration in most serum samples, resulting in molar ratios of Delta9-THCA-A/Delta9-THC of approximately 5.0-18.6%. Only in one case, where a short elapsed time between the last intake and blood sampling is assumed, the molar ratio was 18.6% in the serum. This indicates differences in elimination kinetics, which need to be investigated in detail., (Copyright 2007 John Wiley & Sons, Ltd.)

Thalamic relay neurons have homogeneous, adult-like firing properties and similar morphology by 12 days postnatally (PN 12). Parafascicular (Pf) neurons have a different morphology compared with typical thalamic relay neurons, but the development of their electrophysiological properties is not well studied. Intracellular recordings in PN 12-50 Pf neurons revealed several heterogeneous firing patterns different from those in thalamic relay neurons. Two types of cells were identified: Type I cells displayed a fast afterhyperpolarization (AHP) followed by a large-amplitude, slow AHP; whereas Type II cells had only a fast AHP. These cell types had overlapping membrane properties but differences in excitability. Some properties of Pf neurons were adult-like by PN 12, but, unlike thalamic relay neurons, there were significant maturational changes thereafter, including decreased action potential (AP) duration, increased fast AHP amplitude and increased excitability. Pf neurons did not exhibit rhythmic bursting and generally lacked low-threshold spike (LTS) responses that characterize thalamic relay neurons. Pf neurons exhibited nonlinear I-V relationships, and only a third of the cells expressed the time and voltage-dependent hyperpolarization activated (Ih) current, which declined with age. These results indicate that the morphological differences between Pf neurons and typical thalamic relay neurons are paralleled by electrophysiological differences, and that Pf membrane properties change during postnatal development.

Background: The 7-valent pneumococcal (7vPn) conjugate vaccine is licensed for primary and booster vaccination according to the same immunization schedules as routinely recommended diphtheria-tetanus-pertussis-based childhood vaccines and can be coadministered during the same vaccination visit., Methods: An open, randomized study evaluated the immunogenicity and safety of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b (DTPa-HBV-IPV/Hib) vaccine and a 7vPn conjugate vaccine when coadministered at 2, 3 and 4 months and 12-23 months of age, compared with the administration of the hexavalent DTPa-HBV-IPV/Hib vaccine given alone. Serum antibody titers were measured before and 1 month after the primary course and before and 1 month after the booster dose. Solicited local and general adverse events were recorded for 4 days and unsolicited adverse events were recorded for 30 days after each vaccine dose., Results: A total of 345 subjects were enrolled for primary vaccination with the hexavalent vaccine (170 without and 175 with the 7vPn vaccine coadministered) and 266 returned for booster vaccination (122 without and 144 with coadministration of the 7vPn vaccine). After primary vaccination, antibody responses against the common antigens were similar in both groups, with seroprotection rates of 93.6-100% and with similar antibody decay before booster vaccination. The fourth dose induced a vigorous booster response, with seroprotection/vaccine response rates of 96.8-100%. Response to the 7vPn primary and booster vaccination was within previously reported ranges. Differences in reactogenicity resulted from higher incidences of symptoms after concomitant vaccination. Rectal temperature >39.5 degrees C was observed after 1.2% of the coadministered vaccine doses during primary vaccination and after 2.8% of the booster vaccine doses., Conclusion: Coadministration of the DTPa-HBV-IPV/Hib and 7vPn vaccines at separate injection sites during the same vaccination visit was effective and safe.

Kavain metabolism in humans was the target of this current investigation. In the present study a high-performance liquid chromatographic (HPLC-DAD) assay method for the simultaneous determination of kavain and its main metabolites (p-hydroxykavain, p-hydroxy-5,6-dehydrokavain and p-hydroxy-7,8-dihydrokavain) in serum and urine was developed and validated. The metabolites were mainly excreted in the form of their conjugates. All kavain metabolites were detectable in serum and urine, except for p-hydroxy-7,8-dihydrokavain, which was found in urine only. Confirmation of the results and identification of the metabolites were performed by LC-MS or LC-MS-MS. Kinetics of kavain and its metabolites in serum were investigated after administration of a single oral dose (800 mg kavain). Within 1 and 4 h after uptake, the serum concentrations ranged between 40 and 10 ng/ml for kavain, 300 and 125 ng/ml for p-hydroxykavain, 90 and 40 ng/ml for o-desmethyl-hydroxy-5,6-dehydrokavain, and 50 and 30 ng/ml for 5,6-dehydrokavain.

Gas chromatography with nitrogen/phosphorus sensitive detection (GC/PND) and electron impact mass spectrometry (GC/MS) with selected ion monitoring provides a simple, rapid and sensitive method for the determination of organophosphate pesticides (OPs). A selective single-step extraction of 23 different OPs in urine, blood, serum and food samples (baby food, soft drinks and instant soups suspected of contamination from a blackmailing scare) is described. The OPs were extracted with 1ml toluene (with and without addition of mevinphos as internal standard), using a 0.7ml aliquot of urine, blood or serum sample. Food samples (0.2g) were homogenised with water (0.5ml) before extraction. An amount of 1microl of the toluene phase (extraction supernatant) was analysed directly by GC/PND and GC/MS.The method was validated using spiked human serum. The OPs were mixed with serum containing 10mg/ml disodium ethane diamine tetraacetic acid disodium salt (EDTA disodium salt) and stored up to 10 days at 4 and -20 degrees C, respectively. The recovery rates of OPs in freshly spiked human plasma ranged between 50% (dimethoate) and 133% (dialifos). OPs in plasma proved to be stable at -20 degrees C. Their levels decreased only slightly after storage at 4 degrees C.

Like hydroxyl radicals, alkoxyl radicals have been implicated in the generation of cellular oxidative DNA damage under physiological conditions; however, their genotoxic potential has not yet been established. We have analyzed the DNA damage induced by a photochemical source of tert-butoxyl radicals, the water soluble peroxy ester [4-(tert-butyldioxycarbonyl)benzyl]triethylammonium chloride (BCBT), using various repair endonucleases as probes. The irradiation (UV(360)) of BCBT in the presence of bacteriophage PM2 DNA was found to generate a DNA damage profile that consisted mostly of base modifications sensitive to the repair endonuclease Fpg protein. Approximately 90% of the modifications were identified as 7,8-dihydro-8-oxoguanine (8-oxoGua) residues by HPLC/ECD analysis. Oxidative pyrimidine modifications (sensitive to endonuclease III), sites of base loss (AP sites) and single-strand breaks were only minor modifications. Experiments with various scavengers and quenchers indicated that the DNA damage by BCBT+UV(360) was caused by tert-butoxyl radicals as the ultimate reactive species. The mutagenicity associated with the induced damage was analyzed in the gpt gene of plasmid pSV2gpt, which was exposed to BCBT+UV(360) and subsequently transfected into Escherichia coli. The results were in agreement with the specific generation of 8-oxoGua. Nearly all point mutations (20 out of 21) were found to be GC-->TA transversions known to be characteristic for 8-oxoGua. In conclusion, alkoxyl radicals generated from BCBT+UV(360) induce 8-oxoGua in DNA with a higher selectivity than any other reactive oxygen species analyzed so far.

We have analyzed the recognition by various repair endonucleases of DNA base modifications induced by three oxidants, viz. [4-(tert-butyldioxycarbonyl)benzyl]triethylammonium chloride (BCBT), a photochemical source of tert-butoxyl radicals, disodium salt of 1,4-etheno-2,3-benzodioxin-1,4-dipropanoic acid (NDPO(2)), a chemical source of singlet oxygen, and riboflavin, a type-I photosensitizer. The base modifications induced by BCBT, which were previously shown to be mostly 7,8-dihydro-8-oxoguanine (8-oxoGua) residues, were recognized by Fpg and Ogg1 proteins, but not by endonuclease IIII, Ntg1 and Ntg2 proteins. In the case of singlet oxygen induced damage, 8-oxoGua accounted for only 35% of the base modifications recognized by Fpg protein. The remaining Fpg-sensitive modifications were not recognized by Ogg1 protein and relatively poor by endonuclease III, but they were relatively good substrates of Ntg1 and Ntg2. In the case of the damage induced by photoexcited riboflavin, the fraction of Fpg-sensitive base modifications identified as 8-oxoGua was only 23%. In contrast to the damage induced by singlet oxygen, the remaining lesions were not only recognized by Ntg1 and Ntg2 proteins and (relatively poor) by endonuclease III, but also by Ogg1 protein. The analysis of the mutations observed after transfection of modified plasmid pSV2gpt into Escherichia coli revealed that all agents induced near exclusively GC-->TA and GC-->CG transversions, the numbers of which were correlated with the numbers of 8-oxoGua residues and Ntg-sensitive modifications, respectively. In conclusion, both singlet oxygen and the type-I photosensitizer riboflavin induce predominantly oxidative guanine modifications other than 8-oxoGua, which most probably give rise to GC-->CG transversions and in which eukaryotic cells are substrates of Ntg1 and Ntg2 proteins.

The oxidative DNA damage induced by the polar photosensitizer Ro19-8022 in the presence of light was studied and correlated with the associated mutagenicity. Both in isolated DNA and AS52 Chinese hamster ovary cells, photoexcited Ro19-8022 gave rise to a DNA damage profile that was similar to that caused by singlet oxygen: base modifications sensitive to the repair endonuclease Fpg protein, which according to high-performance liquid chromatography (HPLC) analysis were predominantly 8-hydroxyguanine (8-oxoG) residues, were generated in much higher yield than single-strand breaks, sites of base loss (AP sites) and oxidative pyrimidine modifications sensitive to endonuclease III. Fifty percent of the Fpg-sensitive modifications were repaired within 2 h. Under conditions that induced 10 Fpg-sensitive modifications per 10(6) bp (six 8-oxoG residues per 10(6) bp), approximately 60 mutations per 10(6) cells were induced in the gpt locus of the AS52 cells. A rather similar mutation frequency was observed when a plasmid carrying the gpt gene was exposed to Ro19-8022 plus light under cell-free conditions and subsequently replicated in bacteria. Sequence analysis revealed that GC-->TA and GC-->CG transversions accounted for 90% of the base substitutions. A significant generation of micronuclei was detectable in AS52 cells exposed to the photosensitizer plus light as well.