Combined Decompression of Pudendal and Inferior Cluneal Nerves for Entrapment Neuralgias Using Transperitoneal Robotic Laparoscopy: Feasibility and Our Four-Step Technique.

OBJECTIVE: To demonstrate the feasibility of a combined decompression of pudendal and inferior cluneal nerves for entrapment syndrome using a transperitoneal robotic laparoscopy. DESIGN: Demonstration of our 4-step technique with narrated video footage. SETTING: Pudendal and inferior cluneal neuralgias caused by an entrapment syndrome are both responsible for perineal pain [1]. Although more precise data are lacking, these 2 neuralgias are frequently associated. Failure of surgical pudendal nerve decompression in the early 2000 has driven to discover the entity of a potential entrapment syndrome of the posterior cutaneous nerve of the tight and its inferior cluneal branches between the ischium bone and the sacrotuberous ligament [2]. The corresponding neuralgia is responsible for a neuropathic pain to a more posterior part of the perineum and the thigh, without any neurovegetative symptom. In case of failure of medical treatment, surgery can be proposed using an invasive open transgluteal approach as a standard treatment [3-5]. INTERVENTIONS: Transperitoneal robotic laparoscopy for a mini-invasive releasing of both pudendal and inferior cluneal nerves, following a 4-step technique: 1. Opening of the peritoneum between the external iliac vessels and the umbilical ligament 2. Dissection of the internal iliac and pudendal arteries up to the pudendal nerve 3. Section of the sacrospinous ligament and release of the pudendal nerve 4. Section of the sacrotuberous ligament and release of the inferior cluneal nerve CONCLUSION: Previously, pudendal and inferior cluneal neuralgias have been managed with an invasive open transgluteal surgery. Here, we demonstrate the feasibility of a mini-invasive transperitoneal robotic laparoscopy, with a standardized 4-step surgical technique. VIDEO ABSTRACT.

Combined Cystoscopic-Abdominal Versus Abdominal-Only Route for Complete Excision of Large Deep Endometriosis Nodules Infiltrating the Supratrigonal Area of the Bladder: A Comparative Study.

STUDY OBJECTIVE: Surgical excision of large deep endometriosis nodules infiltrating the bladder may be challenging, particularly when the nodule limits are close to the trigone and ureteral orifice. Bladder nodules have classically been approached abdominally. However, combining a cystoscopic with an abdominal approach may help to better identify the mucosal borders of the lesion to ensure complete excision without unnecessary resection of healthy bladder. This study aimed to compare classical excision of large bladder nodules by abdominal route with a combined cystoscopic-abdominal approach. DESIGN: Retrospective comparative study on data prospectively recorded in a database. Patients were managed from September 2009 to June 2022. SETTING: Two tertiary referral endometriosis centers. PATIENTS: A total of 175 patients with deep endometriosis infiltrating the bladder more than 2 cm undergoing surgical excision of bladder nodules. INTERVENTIONS: Excision of bladder nodules by either abdominal or combined cystoscopic-abdominal approaches. MEASUREMENTS AND MAIN RESULTS: A total of 141 women (80.6%) were managed by abdominal route and 34 women (19.4%) underwent a combined cystoscopic-abdominal approach. In 99.4% of patients, the approach was minimally invasive. Patients with nodules requiring the combined approach had a lower American Fertility Society revised score and endometriosis stage and less associated digestive tract nodules, but larger bladder nodules. They were less frequently associated with colorectal resection and preventive stoma. Operative time was comparable. The rate of early postoperative complications was comparable (8.8% vs 22%), as were the rates of ureteral fistula (2.2% vs 2.9%), bladder fistula (2.2% vs 0), and vesicovaginal fistula (0.7% vs 2.9%). CONCLUSION: In our opinion, the combined cystoscopic-abdominal approach is useful in patients with large bladder nodules with limits close to the trigone and ureteral orifice. These large deep bladder nodules seemed paradoxically associated to less nodules on the digestive tract, resulting in an overall comparable total operative time and complication rate.

Estimating the programmatic cost of targeted mass drug administration for malaria in Myanmar.

BACKGROUND: Mass drug administration (MDA) has received growing interest to accelerate the elimination of multi-drug resistant malaria in the Greater Mekong Subregion. Targeted MDA, sometimes referred to as focal MDA, is the practice of delivering MDA to high incidence subpopulations only, rather than the entire population. The potential effectiveness of delivering targeted MDA was demonstrated in a recent intervention in Kayin State, Myanmar. Policymakers and funders need to know what resources are required if MDA, targeted or otherwise, is to be included in elimination packages beyond existing malaria interventions. This study aims to estimate the programmatic cost and the unit cost of targeted MDA in Kayin State, Myanmar. METHODS: We used financial data from a malaria elimination initiative, conducted in Kayin State, to estimate the programmatic costs of the targeted MDA component using a micro-costing approach. Three activities (community engagement, identification of villages for targeted MDA, and conducting mass treatment in target villages) were evaluated. We then estimated the programmatic costs of implementing targeted MDA to support P. falciparum malaria elimination in Kayin State. A costing tool was developed to aid future analyses. RESULTS: The cost of delivering targeted MDA within an integrated malaria elimination initiative in eastern Kayin State was approximately US$ 910,000. The cost per person reached, distributed among those in targeted and non-targeted villages, for the MDA component was US$ 2.5. CONCLUSION: This cost analysis can assist policymakers in determining the resources required to clear malaria parasite reservoirs. The analysis demonstrated the value of using financial data from research activities to predict programmatic implementation costs of targeting MDA to different numbers of target villages.

Algorithm in the Diagnosis of Febrile Illness Using Pathogen-specific Rapid Diagnostic Tests.

BACKGROUND: In the absence of proper guidelines and algorithms, available rapid diagnostic tests (RDTs) for common acute undifferentiated febrile illnesses are often used inappropriately. METHODS: Using prevalence data of 5 common febrile illnesses from India and Cambodia, and performance characteristics (sensitivity and specificity) of relevant pathogen-specific RDTs, we used a mathematical model to predict the probability of correct identification of each disease when diagnostic testing occurs either simultaneously or sequentially in various algorithms. We developed a web-based application of the model so as to visualize and compare output diagnostic algorithms when different disease prevalence and test performance characteristics are introduced. RESULTS: Diagnostic algorithms with appropriate sequential testing predicted correct identification of etiology in 74% and 89% of patients in India and Cambodia, respectively, compared with 46% and 49% with simultaneous testing. The optimally performing sequential diagnostic algorithms differed in India and Cambodia due to varying disease prevalence. CONCLUSIONS: Simultaneous testing is not appropriate for the diagnosis of acute undifferentiated febrile illnesses with presently available tests, which should deter the unsupervised use of multiplex diagnostic tests. The implementation of adaptive algorithms can predict better diagnosis and add value to the available RDTs. The web application of the model can serve as a tool to identify the optimal diagnostic algorithm in different epidemiological settings, while taking into account the local epidemiological variables and accuracy of available tests.

Towards malaria elimination in Savannakhet, Lao PDR: mathematical modelling driven strategy design.

BACKGROUND: The number of Plasmodium falciparum malaria cases around the world has decreased substantially over the last 15 years, but with the spread of resistance against anti-malarial drugs and insecticides, this decline may not continue. There is an urgent need to consider alternative, accelerated strategies to eliminate malaria in countries like Lao PDR, where there are a few remaining endemic areas. A deterministic compartmental modelling tool was used to develop an integrated strategy for P. falciparum elimination in the Savannakhet province of Lao PDR. The model was designed to include key aspects of malaria transmission and integrated control measures, along with a user-friendly interface. RESULTS: Universal coverage was the foundation of the integrated strategy, which took the form of the deployment of community health workers who provided universal access to early diagnosis, treatment and long-lasting insecticidal nets. Acceleration was included as the deployment of three monthly rounds of mass drug administration targeted towards high prevalence villages, with the addition of three monthly doses of the RTS,S vaccine delivered en masse to the same high prevalence sub-population. A booster dose of vaccine was added 1 year later. The surveillance-as-intervention component of the package involved the screening and treatment of individuals entering the simulated population. CONCLUSIONS: In this modelling approach, the sequential introduction of a series of five available interventions in an integrated strategy was predicted to be sufficient to stop malaria transmission within a 3-year period. These interventions comprised universal access to early diagnosis and adequate treatment, improved access to long-lasting insecticidal nets, three monthly rounds of mass drug administration together with RTS,S vaccination followed by a booster dose of vaccine, and screening and treatment of imported cases.

Prognostic interest in discriminating muscularis mucosa invasion (T1a vs T1b) in nonmuscle invasive bladder carcinoma: French national multicenter study with central pathology review.

PURPOSE: Predictive factors of T1 nonmuscle invasive bladder cancer evolution that could guide treatment decision making are lacking. We assessed the prognostic value of muscularis mucosa invasion in nonmuscle invasive bladder cancer. MATERIALS AND METHODS: In a national multicenter study patients with primary T1 nonmuscle invasive bladder cancer were recruited from 6 French hospitals. All patients had undergone transurethral resection of bladder tumor. All T1 tumors were substaged according to muscularis mucosa invasion as T1a-no invasion beyond the muscularis mucosa or T1b-invasion beyond the muscularis mucosa with muscle preservation. Subsequent central pathology review was then done by a single referent uropathologist. Muscularis mucosa invasion was tested as a prognostic factor for survival on univariate and multivariate analysis. RESULTS: A total of 587 patients were enrolled in the study, including 388 (66%) with T1a and 199 (34%) with T1b tumors. Median followup after transurethral resection of bladder tumor was 35 months (IQR 14-54). There was no significant difference between groups T1a and T1b except high tumor grade in T1b cases (p <0.0001). After central review, initial pathological substaging was confirmed in 84% of cases. On multivariate analysis muscularis mucosa invasion (T1b substage) was significantly associated with recurrence-free (p = 0.03), progression-free (p = 0.0002) and cancer specific (p = 0.02) survival. The main study limitation was absent systematic subsequent transurethral resection of bladder tumor. CONCLUSIONS: Muscularis mucosa invasion appears to be highly predictive of T1 nonmuscle invasive bladder cancer behavior. Consequently, systematic T1a vs T1b discrimination should be highly advocated by urologists and pathologists. We believe that it could aid in crucial decision making when choosing between conservative management and radical cystectomy remains a moot point.

Benefits of active oxygenation during hypothermic machine perfusion of kidneys in a preclinical model of deceased after cardiac death donors.

BACKGROUND: Deceased after cardiac death donors (DCDs) represent a valuable source of organs; however, preventing poor outcome is difficult, even with the use of machine perfusion (MP). It is of paramount importance to improve this method. We proposed to evaluate the benefits of active oxygenation during kidney graft hypothermic MP using a novel perfusion machine: Kidney Assist (KA). METHODS: We used a pig model of DCD transplantation in Large White pigs. Cold preservation was performed by conventional non-oxygenated MP (KAnoO2) or oxygenated MP (KA). RESULTS: In the first 2 wk post-transplant, KA grafts displayed a lower serum creatinine peak and a faster return to normal levels compared with KAnoO2 animals, translating into a smaller area under the curve. Urinary neutrophil gelatinase-associated lipocalin levels and serum aspartate amino transferase levels were lower in KA animals compared with the non-oxygenated group. These correlated with better chronic function. Longer follow-up of the animals (3 mo) permitted evaluation of chronic outcome lesions. Interstitial fibrosis was reduced in the KA group, and these kidneys also displayed significantly lower levels of vimentin staining. Further histologic investigation also showed a trend toward decreased chronic inflammation in kidneys preserved with oxygen. CONCLUSIONS: This new MP system is efficient in preserving DCD kidneys, greatly enhancing the capacity of the graft to withstand preservation stress and improving outcome. Oxygen delivery during preservation is thus valuable for highly damaged organs and offers an important therapeutic tool for transplant teams faced with decreased quality of donor organs.

A Clinically Oriented antimicrobial Resistance surveillance Network (ACORN): pilot implementation in three countries in Southeast Asia, 2019-2020.

Background: Case-based surveillance of antimicrobial resistance (AMR) provides more actionable data than isolate- or sample-based surveillance. We developed A Clinically Oriented antimicrobial Resistance surveillance Network (ACORN) as a lightweight but comprehensive platform, in which we combine clinical data collection with diagnostic stewardship, microbiological data collection and visualisation of the linked clinical-microbiology dataset. Data are compatible with WHO GLASS surveillance and can be stratified by syndrome and other metadata. Summary metrics can be visualised and fed back directly for clinical decision-making and to inform local treatment guidelines and national policy. Methods: An ACORN pilot was implemented in three hospitals in Southeast Asia (1 paediatric, 2 general) to collect clinical and microbiological data from patients with community- or hospital-acquired pneumonia, sepsis, or meningitis. The implementation package included tools to capture site and laboratory capacity information, guidelines on diagnostic stewardship, and a web-based data visualisation and analysis platform. Results: Between December 2019 and October 2020, 2294 patients were enrolled with 2464 discrete infection episodes (1786 community-acquired, 518 healthcare-associated and 160 hospital-acquired). Overall, 28-day mortality was 8.7%. Third generation cephalosporin resistance was identified in 54.2% (39/72) of E. coli and 38.7% (12/31) of K. pneumoniae isolates . Almost a quarter of S. aureus isolates were methicillin resistant (23.0%, 14/61). 290/2464 episodes could be linked to a pathogen, highlighting the level of enrolment required to achieve an acceptable volume of isolate data. However, the combination with clinical metadata allowed for more nuanced interpretation and immediate feedback of results. Conclusions: ACORN was technically feasible to implement and acceptable at site level. With minor changes from lessons learned during the pilot ACORN is now being scaled up and implemented in 15 hospitals in 9 low- and middle-income countries to generate sufficient case-based data to determine incidence, outcomes, and susceptibility of target pathogens among patients with infectious syndromes.

Prevalence and seroprevalence of Plasmodium infection in Myanmar reveals highly heterogeneous transmission and a large hidden reservoir of infection.

Malaria incidence in Myanmar has significantly reduced over recent years, however, completeness and timeliness of incidence data remain a challenge. The first ever nationwide malaria infection and seroprevalence survey was conducted in Myanmar in 2015 to better understand malaria epidemiology and highlight gaps in Annual Parasite Index (API) data. The survey was a cross-sectional two-stage stratified cluster-randomised household survey conducted from July-October 2015. Blood samples were collected from household members for ultra-sensitive PCR and serology testing for P. falciparum and P. vivax. Data was gathered on demography and a priori risk factors of participants. Data was analysed nationally and within each of four domains defined by API data. Prevalence and seroprevalence of malaria were 0.74% and 16.01% nationwide, respectively. Prevalent infection was primarily asymptomatic P. vivax, while P. falciparum was predominant in serology. There was large heterogeneity between villages and by domain. At the township level, API showed moderate correlation with P. falciparum seroprevalence. Risk factors for infection included socioeconomic status, domain, and household ownership of nets. Three K13 P. falciparum mutants were found in highly prevalent villages. There results highlight high heterogeneity of both P. falciparum and P. vivax transmission between villages, accentuated by a large hidden reservoir of asymptomatic P. vivax infection not captured by incidence data, and representing challenges for malaria elimination. Village-level surveillance and stratification to guide interventions to suit local context and targeting of transmission foci with evidence of drug resistance would aid elimination efforts.

Expression of estrogen related proteins in hormone refractory prostate cancer: association with tumor progression.

PURPOSE: Despite increasing evidence that estrogen signaling has a key role in prostate cancer development and progression, few studies have focused on the estrogen pathway in the transition from hormone sensitive to hormone refractory tumors. We investigated the expression of proteins related to androgen and estrogen metabolism in paired prostate cancer samples collected before androgen deprivation therapy and after hormonal relapse. MATERIALS AND METHODS: The study included 55 patients treated for prostate cancer only with androgen deprivation therapy and in whom tissue was available before treatment induction and after recurrence. Immunohistochemistry was performed using tissue microarray with antibodies directed against androgen receptor, phosphorylated androgen receptor, estrogen receptor α, estrogen receptor ß, 5α-reductase 1 and 2, aromatase, BCAR1 and the proliferation marker Ki67. RESULTS: Compared to hormone sensitive samples, tissues collected after hormonal relapse were characterized by increased expression of Ki67, androgen receptor, phosphorylated androgen receptor (p <0.001) and BCAR (p = 0.03), and by lower staining for 5α-reductase 2 (p = 0.002), estrogen receptor ß (p = 0.016) and aromatase (p <0.001). Shorter time to hormonal relapse was associated with high expression of aromatase and BCAR1 on diagnostic biopsy, together with low staining for estrogen receptor α in stromal cells. Overall survival was significantly shorter when tissues collected after relapse showed a high proliferation index and low estrogen receptor α expression. CONCLUSIONS: Results revealed dysregulation of proteins involved in androgen pathways, and in estrogen synthesis and signaling during the development of hormone refractory prostate cancer.

Modelling the COVID-19 pandemic in context: an international participatory approach.

The SARS-CoV-2 pandemic has had an unprecedented impact on multiple levels of society. Not only has the pandemic completely overwhelmed some health systems but it has also changed how scientific evidence is shared and increased the pace at which such evidence is published and consumed, by scientists, policymakers and the wider public. More significantly, the pandemic has created tremendous challenges for decision-makers, who have had to implement highly disruptive containment measures with very little empirical scientific evidence to support their decision-making process. Given this lack of data, predictive mathematical models have played an increasingly prominent role. In high-income countries, there is a long-standing history of established research groups advising policymakers, whereas a general lack of translational capacity has meant that mathematical models frequently remain inaccessible to policymakers in low-income and middle-income countries. Here, we describe a participatory approach to modelling that aims to circumvent this gap. Our approach involved the creation of an international group of infectious disease modellers and other public health experts, which culminated in the establishment of the COVID-19 Modelling (CoMo) Consortium. Here, we describe how the consortium was formed, the way it functions, the mathematical model used and, crucially, the high degree of engagement fostered between CoMo Consortium members and their respective local policymakers and ministries of health.

ACORN (A Clinically-Oriented Antimicrobial Resistance Surveillance Network): a pilot protocol for case based antimicrobial resistance surveillance.

Background: Antimicrobial resistance (AMR) / drug resistant infections (DRIs) are a major global health priority. Surveillance data is critical to inform infection treatment guidelines, monitor trends, and to assess interventions. However, most existing AMR / DRI surveillance systems are passive and pathogen-based with many potential biases. Addition of clinical and patient outcome data would provide considerable added value to pathogen-based surveillance. Methods: The aim of the ACORN project is to develop an efficient clinically-oriented AMR surveillance system, implemented alongside routine clinical care in hospitals in low- and middle-income country settings. In an initial pilot phase, clinical and microbiology data will be collected from patients presenting with clinically suspected meningitis, pneumonia, or sepsis. Community-acquired infections will be identified by daily review of new admissions, and hospital-acquired infections will be enrolled during weekly point prevalence surveys, on surveillance wards. Clinical variables will be collected at enrolment, hospital discharge, and at day 28 post-enrolment using an electronic questionnaire on a mobile device. These data will be merged with laboratory data onsite using a flexible automated computer script. Specific target pathogens will be Streptococcus pneumoniae, Staphylococcus aureus, Salmonella spp ., Klebsiella pneumoniae, Escherichia coli, and Acinetobacter baumannii. A bespoke browser-based app will provide sites with fully interactive data visualisation, analysis, and reporting tools. Discussion: ACORN will generate data on the burden of DRI which can be used to inform local treatment guidelines / national policy and serve as indicators to measure the impact of interventions. Following development, testing and iteration of the surveillance tools during an initial six-month pilot phase, a wider rollout is planned.

Differential expression of the semaphorin 3A pathway in prostatic cancer.

AIMS: To analyse the expression pattern of the semaphorin 3A (Sema3A) pathway, including the receptor neuropilin 1 (NRP1) and its ligands the 'antitumoral' Sema3A and the 'protumoral' vascular endothelial growth factor (VEGF)in prostatic cancer. METHODS AND RESULTS: tissues were obtained from 120 patients treated by prostatectomy for clinically localized prostatic cancer, and 31 hormone-refractory prostatic cancer (HRPC) samples. Immunohistochemistry was performed on tissue microarrays using antibodies directed against Sema3A, NRP1 and VEGF. Moreover, real-time reverse transcriptase-polymerase chain reaction was performed on frozen prostatic tissue, including normal prostate, clinically localized tumours and HPRC. Sema3A immunoreactivity of the membrane of cancer cells was closely associated with NRP1 expression in clinically localized prostatic cancer, but not in HRPC. In clinically localized cancer, Sema3A expression correlated with lower preoperative prostate-specific antigen (PSA) and pathological stage; NRP1 reactivity was associated with lower PSA and Gleason score, and VEGF reactivity with higher PSA and Gleason score. HRPC displayed higher expression of NRP1 compared with clinically localized cancer, and lower Sema3A immunoreactivity. CONCLUSIONS: These results support the hypothesis that dysregulation of the Sema3A pathway plays a key role in prostatic cancer progression, and suggest a loss of the inhibitory Sema3A autocrine loop in HRPC.

Percentage of positive biopsy cores at the onset of hormone therapy for prostate cancer: prognostic significance.

INTRODUCTION: The percentage of positive prostate biopsy cores (%PBC) has been shown to be a prognostic factor in localized prostate cancer. We hypothesized that it would predict time to hormonal independence and survival in prostate cancer patients treated with androgen deprivation therapy (ADT). PATIENTS AND METHODS: We used clinical data from 403 men treated with ADT between 1980 and 1999 and focused on a subgroup of 220 patients treated with GnRH analogue. %PBC was defined as the number of positive biopsy cores multiplied by 100 and divided by the total number of biopsy cores. RESULTS: Median %PBC was 83.3% (16.7-100%). Mean follow-up was 57.4 months. Survival at 5 years in men with 83.3% PBC or less was 62.3, 89.1 and 82.6% for recurrence-free, specific and overall survival, respectively, significantly better than that of men with a %PBC of more than 83.3% (32.2, 74.7 and 67.7%, respectively; p < 0.004). Among the factors available in the pretreatment setting, namely age, clinical stage, PSA, Gleason score, bone scan and %PBC, the latter was independently associated with survival in multivariate analysis. CONCLUSIONS: %PBC may improve the ability to predict time to hormonal resistance and survival in patients treated with ADT for prostate cancer. This finding warrants further investigation.

An interactive application for malaria elimination transmission and costing in the Asia-Pacific.

Leaders in the Asia-Pacific have endorsed an ambitious target to eliminate malaria in the region by 2030. The emergence and spread of artemisinin drug resistance in the Greater Mekong Subregion makes elimination urgent and strategic for the global goal of malaria eradication. Mathematical modelling is a useful tool for assessing and comparing different elimination strategies and scenarios to inform policymakers. Mathematical models are especially relevant in this context because of the wide heterogeneity of regional, country and local settings, which means that different strategies are needed to eliminate malaria. However, models and their predictions can be seen as highly technical, limiting their use for decision making. Simplified applications of models are needed to allow policy makers to benefit from these valuable tools. This paper describes a method for communicating complex model results with a user-friendly and intuitive framework. Using open-source technologies, we designed and developed an interactive application to disseminate the modelling results for malaria elimination. The design was iteratively improved while the application was being piloted and extensively tested by a diverse range of researchers and decision makers. This application allows several target audiences to explore, navigate and visualise complex datasets and models generated in the context of malaria elimination. It allows widespread access, use of and interpretation of models, generated at great effort and expense as well as enabling them to remain relevant for a longer period of time. It has long been acknowledged that scientific results need to be repackaged for larger audiences. We demonstrate that modellers can include applications as part of the dissemination strategy of their findings. We highlight that there is a need for additional research in order to provide guidelines and direction for designing and developing effective applications for disseminating models.

Malaria elimination transmission and costing in the Asia-Pacific: Developing an investment case.

Background: The Asia-Pacific region has made significant progress against malaria, reducing cases and deaths by over 50% between 2010 and 2015. These gains have been facilitated in part, by strong political and financial commitment of governments and donors. However, funding gaps and persistent health system challenges threaten further progress. Achieving the regional goal of malaria elimination by 2030 will require an intensification of efforts and a plan for sustainable financing. This article presents an investment case for malaria elimination to facilitate these efforts. Methods: A transmission model was developed to project rates of decline of Plasmodium falciparum and Plasmodium vivax malaria and the output was used to determine the cost of the interventions that would be needed for elimination by 2030. In total, 80 scenarios were modelled under various assumptions of resistance and intervention coverage. The mortality and morbidity averted were estimated and health benefits were monetized by calculating the averted cost to the health system, individual households, and society. The full-income approach was used to estimate the economic impact of lost productivity due to premature death and illness, and a return on investment was computed. Results: The study estimated that malaria elimination in the region by 2030 could be achieved at a cost of USD 29.02 billion (range: USD 23.65-36.23 billion) between 2017 and 2030. Elimination would save over 400,000 lives and avert 123 million malaria cases, translating to almost USD 90 billion in economic benefits. Discontinuing vector control interventions and reducing treatment coverage rates to 50% will result in an additional 845 million cases, 3.5 million deaths, and excess costs of USD 7 billion. Malaria elimination provides a 6:1 return on investment. Conclusion: This investment case provides compelling evidence for the benefits of continued prioritization of funding for malaria and can be used to develop an advocacy strategy.

Individual Comparison of Cholesterol Metabolism in Normal and Tumour Areas in Radical Prostatectomy Specimens from Patients with Prostate Cancer: Results of the CHOMECAP Study.

BACKGROUND: Deregulation of cholesterol metabolism represents a hallmark of prostate cancer (PCa) and promotes its development. OBJECTIVE: To compare cholesterol metabolism on individual paired normal and tumour prostate tissues obtained from patients with PCa. DESIGN, SETTING, AND PARTICIPANTS: Between 2008 and 2012, normal and tumour paired tissue samples were collected from radical prostatectomy specimens from a cohort of 69 patients treated for localised PCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Tumour and normal tissues were subjected to gene analysis, sterol measurement, and immunohistochemistry. The Wilcoxon paired test and Spearman test were applied for comparison and correlation analyses, respectively. Principal component analysis was also carried out to investigate relationships between quantitative variables. RESULTS AND LIMITATIONS: Overall, cholesterol concentrations were not significantly different between tissue pairs. However, tumour samples were significantly associated with downregulated de novo cholesterol synthesis, but exhibited 54.7% overexpression of SCARB1 that could increase high-density lipoprotein uptake in PCa. Tumour tissues showed different trafficking of available cholesterol, with significantly lower ACAT1, and an altered efflux via APOE. Furthermore, cholesterol metabolism in tumour tissues was characterised by higher accumulation of 7α-hydroxycholesterol (OHC), 7ßOHC, and 7-ketosterol, and a lower level of 27OHC. CONCLUSIONS: Focusing on individually paired prostate tissues, our results highlighted several differences between normal and tumour samples linked to a metabolic shift in cholesterol flux. PCa samples exhibited a specific tissue signature characterised by higher SCARB1 expression, higher accumulation of OHC species, and clear downregulation of de novo cholesterol synthesis. PATIENT SUMMARY: Comparing normal and tumour tissues from the same prostates, our study identified a set of alterations in prostate cancer samples in terms of their use of cholesterol. These included higher cholesterol uptake, accumulation of oxidised cholesterol derivatives, and autonomous cellular production of cholesterol. Together, these data provide promising clinical targets to fight prostate cancer.

Plasmodium Infections in Anopheles Mosquitoes in Ubon Ratchathani Province, Northeastern Thailand During a Malaria Outbreak.

An unprecedented malaria outbreak occurred in Ubon Ratchathani Province, northeastern Thailand, in 2014. The province showed the highest number of malaria cases of all Thai provinces. Five entomological surveys were conducted at 8 sentinel sites from September 2013 to September 2015 to address the role of different Anopheles species in malaria transmission. Mosquito collections were conducted using human landing catches and cow bait. A total of 10,369 Anopheles mosquitoes were collected and 2,240 were morphologically identified as potential malaria vectors, including An. dirus (n = 78), An. minimus (n = 18), An. sawadwongporni (n = 4), An. barbirostris s.l. (n = 819), An. philippinensis (n = 612), An. nivipes (n = 676), An. annularis (n = 42), An. aconitus (n = 7), and An. rampae (n = 142). Real-time polymerase chain reaction was used to screen for the presence of Plasmodium spp. in salivary glands. The proportion of primary vectors of surveyed villages was very low (<1%), and no Plasmodium-infected specimens were detected among in the 2,240 Anopheles mosquitoes tested. The absence of positive Plasmodium samples during malaria outbreaks suggests that malaria transmission most likely occurred outside the villages, particularly in the deep-forested hilly areas that provided suitable habitats for competent malaria vectors. These results emphasize the need to develop vector control related to village community activities to reduce malaria transmission along Thailand border areas.

Enumerating the economic cost of antimicrobial resistance per antibiotic consumed to inform the evaluation of interventions affecting their use.

Background: Antimicrobial resistance (AMR) poses a colossal threat to global health and incurs high economic costs to society. Economic evaluations of antimicrobials and interventions such as diagnostics and vaccines that affect their consumption rarely include the costs of AMR, resulting in sub-optimal policy recommendations. We estimate the economic cost of AMR per antibiotic consumed, stratified by drug class and national income level. Methods: The model is comprised of three components: correlation coefficients between human antibiotic consumption and subsequent resistance; the economic costs of AMR for five key pathogens; and consumption data for antibiotic classes driving resistance in these organisms. These were used to calculate the economic cost of AMR per antibiotic consumed for different drug classes, using data from Thailand and the United States (US) to represent low/middle and high-income countries. Results: The correlation coefficients between consumption of antibiotics that drive resistance in S. aureus, E. coli, K. pneumoniae, A. baumanii, and P. aeruginosa and resistance rates were 0.37, 0.27, 0.35, 0.45, and 0.52, respectively. The total economic cost of AMR due to resistance in these five pathogens was $0.5 billion and $2.9 billion in Thailand and the US, respectively. The cost of AMR associated with the consumption of one standard unit (SU) of antibiotics ranged from $0.1 for macrolides to $0.7 for quinolones, cephalosporins and broad-spectrum penicillins in the Thai context. In the US context, the cost of AMR per SU of antibiotic consumed ranged from $0.1 for carbapenems to $0.6 for quinolones, cephalosporins and broad spectrum penicillins. Conclusion: The economic costs of AMR per antibiotic consumed were considerable, often exceeding their purchase cost. Differences between Thailand and the US were apparent, corresponding with variation in the overall burden of AMR and relative prevalence of different pathogens. Notwithstanding their limitations, use of these estimates in economic evaluations can make better-informed policy recommendations regarding interventions that affect antimicrobial consumption and those aimed specifically at reducing the burden of AMR.

[Prognostic significance of "sawtooth" PSA and "stepwise" PSA]. / PSA "en dents de scie" et PSA "en escalier": quelles implications pronostiques?

OBJECTIVE: To evaluate the risk of diagnosing prostate cancer on repeated biopsies in patients with fluctuating PSA values compared to patients with stable or regularly increasing PSA values. MATERIAL: Retrospective study conducted on the 2000-2003 databases of 2 French teaching hospitals. Selected patients had a first negative prostatic biopsy, then at least one other series of prostatic biopsies. "Sawtooth" PSA was defined by a PSA value less than that of the previous assay. Other cases were described as "stepwise" PSA. RESULTS: 191 patients were included: 79 in the "sawtooth" group and 112 in the "stepwise" group. Prostate cancer was diagnosed in 53 patients (27.7%), on the second prostatic biopsy 39 cases. Prostate cancer was detected in 17 (21.5%) of the 79 patients of the "sawtooth" group. This proportion was not significantly different (p = 0.14) from that observed in patients of the "stepwise" group: 36/112 (32.1%). No significant difference in terms of age, stage, Gleason score and initial PSA was observed between patients with a diagnosis of prostate cancer in the "sawtooth" and "stepwise" groups. CONCLUSION: In our study, the risk of diagnosing prostate cancer on repeated prostatic biopsies was not greater in patients with "stepwise" PSA compared to patients with "sawtooth" PSA.