Key Contributions by the Swiss Tropical and Public Health Institute Towards New and Better Drugs for Tropical Diseases

Thanks to its expertise in clinical research, epidemiology, infectious diseases, microbiology, parasitology, public health, translational research and tropical medicine, coupled with deeply rooted partnerships with institutions in low- and middle-income countries (LMICs), the Swiss Tropical and Public Health Institute (Swiss TPH) has been a key contributor in many drug research and development consortia involving academia, pharma and product development partnerships. Our know-how of the maintenance of parasites and their life-cycles in the laboratory, plus our strong ties to research centres and disease control programme managers in LMICs with access to field sites and laboratories, have enabled systems for drug efficacy testing in vitro and in vivo, clinical research, and modelling to support the experimental approaches. Thus, Swiss TPH has made fundamental contributions towards the development of new drugs – and the better use of old drugs – for neglected tropical diseases and infectious diseases of poverty, such as Buruli ulcer, Chagas disease, food-borne trematodiasis (e.g. clonorchiasis, fascioliasis and opisthorchiasis), human African trypanosomiasis, leishmaniasis, malaria, schistosomiasis, soil-transmitted helminthiasis and tuberculosis. In this article, we show case the success stories of molecules to which Swiss TPH has made a substantial contribution regarding their use as anti-infective compounds with the ultimate aim to improve people’s health and well-being

Superior virologic and treatment outcomes when viral load is measured at 3 months compared to 6 months on antiretroviral therapy.

INTRODUCTION: Routine viral load (VL) monitoring is utilized to assess antiretroviral therapy (ART) adherence and virologic failure, and it is currently scaled-up in many resource-constrained settings. The first routine VL is recommended as late as six months after ART initiation for early detection of sub-optimal adherence. We aimed to assess the optimal timing of first VL measurement after initiation of ART. METHODS: This was a retrospective, cohort analysis of routine monitoring data of adults enrolled at three primary care clinics in Khayelitsha, Cape Town, between January 2002 and March 2009. Primary outcomes were virologic failure and switch to second-line ART comparing patients in whom first VL done was at three months (VL3M) and six months (VL6M) after ART initiation. Adjusted hazard ratios (aHR) were estimated using Cox proportional hazard models. RESULTS: In total, 6264 patients were included for the time to virologic failure and 6269 for the time to switch to second-line ART analysis. Patients in the VL3M group had a 22% risk reduction of virologic failure (aHR 0.78, 95% CI 0.64-0.95; p=0.016) and a 27% risk reduction of switch to second-line ART (aHR 0.73, 95% CI 0.58-0.92; p=0.008) when compared to patients in the VL6M group. For each additional month of delay of the first VL measurement (up to nine months), the risk of virologic failure increased by 9% (aHR 1.09, 95% CI 1.02-1.15; p=0.008) and switch to second-line ART by 13% (aHR 1.13, 95% CI 1.05-1.21; p<0.001). CONCLUSIONS: A first VL at three months rather than six months with targeted adherence interventions for patients with high VL may improve long-term virologic suppression and reduce switches to costly second-line ART. ART programmes should consider the first VL measurement at three months after ART initiation

Multimessenger Search for Sources of Gravitational Waves and High-Energy Neutrinos: Results for Initial LIGO-Virgo and IceCube

We report the results of a multimessenger search for coincident signals from the LIGO and Virgo gravitational-wave observatories and the partially completed IceCube high-energy neutrino detector, including periods of joint operation between 2007-2010. These include parts of the 2005-2007 run and the 2009-2010 run for LIGO-Virgo, and IceCube's observation periods with 22, 59 and 79 strings. We find no significant coincident events, and use the search results to derive upper limits on the rate of joint sources for a range of source emission parameters. For the optimistic assumption of gravitational-wave emission energy of $10^{-2}$\,M$_\odot$c$^2$ at $\sim 150$\,Hz with $\sim 60$\,ms duration, and high-energy neutrino emission of $10^{51}$\,erg comparable to the isotropic gamma-ray energy of gamma-ray bursts, we limit the source rate below $1.6 \times 10^{-2}$\,Mpc$^{-3}$yr$^{-1}$. We also examine how combining information from gravitational waves and neutrinos will aid discovery in the advanced gravitational-wave detector era

Digital telephony and network integration

What is "digital telephony"? To the authors, the term digital telephony denotes the technology used to provide a completely digital telecommunication system from end-to-end. This implies the use of digital technology from one end instru­ ment through transmission facilities and switching centers to another end instru­ ment. Digital telephony has become possible only because of the recent and on­ going surge of semiconductor developments, allowing microminiaturization and high reliability along with reduced costs. This book deals with both the future and the present. Thus, the first chapter is entitled, "A Network in Transition." As baselines, Chapters 2 and 11 provide the reader with the present status of teler-hone technology in terms of voice digiti­ zation as well as switching principles. The book is an outgrowth of the authors' consulting and teaching experience in the field since the early 1980s. The book has been written to provide both the engineering student and the practicing engineer a working knowledge of the prin­ ciples of present and future telecommunication systems based upon the use of the public switched network. Problems or discussion questions have been included at the ends of the chapters to facilitate the book's use as a senior-level or first­ year graduate-level course text. Numerous clients and associates of the authors as well as hundreds of others have provided useful information and examples for the text, and the authors wish to thank all those who have so contributed either directly or indirectly

Ferrocenyl, Ruthenocenyl, and Benzyl Oxamniquine derivatives with cross-species activity against Schistosoma mansoni and Schistosoma haematobium

Schistosomiasis is a parasitic disease that affects more than 250 million people annually, mostly children in poor, tropical, rural areas. Only one treatment (praziquantel) is available, putting control efforts at risk should resistance occur. In pursuit of treatment alternatives, we derivatized an old antischistosomal agent, oxamniquine (OXA). Four organometallic derivatives of OXA were synthesized and tested against Schistosoma mansoni in vitro and in vivo. Of these, a ferrocenyl derivative, 1, killed larval and adult worms 24 h postexposure in vitro, in contrast to OXA, which lacks in vitro activity against adult worms. A dose of 200 mg/kg of 1 completely eliminated the worm burden in mice. Subsequently, a ruthenocenyl (5) and a benzyl derivative (6) of OXA were synthesized to probe the importance of the ferrocenyl group in 1. Compounds 1, 5, and 6 were lethal to both S. mansoni and S. haematobium adults in vitro. In vivo, at 100 mg/kg, all three compounds revealed S. mansoni worm burden reductions of 76 to 93%, commensurate with OXA. Our findings present three compounds with activity against S. mansoni in vitro, comparable activity in vivo, and high activity against S. haematobium in vitro. These compounds may possess a different binding mode or mode of action compared to OXA and present excellent starting points for further SAR studies

Ferrocenyl Derivatives of the Anthelmintic Praziquantel: Design, Synthesis, and Biological Evaluation

The design, synthesis, and biological evaluation of 18 ferrocenyl derivatives (<b>4A</b>–<b>12A</b> and <b>4B</b>–<b>12B</b>) of the most well-known drug against schistosomiasis, namely praziquantel (PZQ), are reported. These compounds, which have been all isolated as racemates, were unambiguously characterized by ¹H and ¹³C NMR spectroscopy, mass spectrometry, and elemental analysis as well as by X-ray crystallography for <b>4A</b>, <b>5A</b>, and <b>7A</b>. Cytotoxicity studies revealed that the complexes were moderately toxic toward a cervical cancer cell line (HeLa) and, importantly, significantly less active toward a noncancerous cell line (MRC-5). The <i>in vitro</i> anthelmintic activity of the 18 ferrocenyl PZQ derivatives was tested against adult <i>Schistosoma mansoni</i>, and values in the micromolar range (26–68 μM) were determined for the four most active compounds. It was also demonstrated using two compounds of the series as models (<b>8A</b> and <b>8B</b>) that the complexes were stable when incubated for 24 h at 37 °C in human plasma

Ferrocenyl Derivatives of the Anthelmintic Praziquantel: Design, Synthesis, and Biological Evaluation

The design, synthesis, and biological evaluation of 18 ferrocenyl derivatives (<b>4A</b>–<b>12A</b> and <b>4B</b>–<b>12B</b>) of the most well-known drug against schistosomiasis, namely praziquantel (PZQ), are reported. These compounds, which have been all isolated as racemates, were unambiguously characterized by ¹H and ¹³C NMR spectroscopy, mass spectrometry, and elemental analysis as well as by X-ray crystallography for <b>4A</b>, <b>5A</b>, and <b>7A</b>. Cytotoxicity studies revealed that the complexes were moderately toxic toward a cervical cancer cell line (HeLa) and, importantly, significantly less active toward a noncancerous cell line (MRC-5). The <i>in vitro</i> anthelmintic activity of the 18 ferrocenyl PZQ derivatives was tested against adult <i>Schistosoma mansoni</i>, and values in the micromolar range (26–68 μM) were determined for the four most active compounds. It was also demonstrated using two compounds of the series as models (<b>8A</b> and <b>8B</b>) that the complexes were stable when incubated for 24 h at 37 °C in human plasma

Ferrocenyl Derivatives of the Anthelmintic Praziquantel: Design, Synthesis, and Biological Evaluation

The design, synthesis, and biological evaluation of 18 ferrocenyl derivatives (<b>4A</b>–<b>12A</b> and <b>4B</b>–<b>12B</b>) of the most well-known drug against schistosomiasis, namely praziquantel (PZQ), are reported. These compounds, which have been all isolated as racemates, were unambiguously characterized by ¹H and ¹³C NMR spectroscopy, mass spectrometry, and elemental analysis as well as by X-ray crystallography for <b>4A</b>, <b>5A</b>, and <b>7A</b>. Cytotoxicity studies revealed that the complexes were moderately toxic toward a cervical cancer cell line (HeLa) and, importantly, significantly less active toward a noncancerous cell line (MRC-5). The <i>in vitro</i> anthelmintic activity of the 18 ferrocenyl PZQ derivatives was tested against adult <i>Schistosoma mansoni</i>, and values in the micromolar range (26–68 μM) were determined for the four most active compounds. It was also demonstrated using two compounds of the series as models (<b>8A</b> and <b>8B</b>) that the complexes were stable when incubated for 24 h at 37 °C in human plasma

Risk factors for severe outcomes for COVID-19 patients hospitalised in Switzerland during the first pandemic wave, February to August 2020: prospective observational cohort study.

BACKGROUND As clinical signs of COVID-19 differ widely among individuals, from mild to severe, the definition of risk groups has important consequences for recommendations to the public, control measures and patient management, and needs to be reviewed regularly. AIM The aim of this study was to explore risk factors for in-hospital mortality and intensive care unit (ICU) admission for hospitalised COVID-19 patients during the first epidemic wave in Switzerland, as an example of a country that coped well during the first wave of the pandemic. METHODS This study included all (n = 3590) adult polymerase chain reaction (PCR)-confirmed hospitalised patients in 17 hospitals from the hospital-based surveillance of COVID-19 (CH-Sur) by 1 September 2020. We calculated univariable and multivariable (adjusted) (1) proportional hazards (Fine and Gray) survival regression models and (2) logistic regression models for in-hospital mortality and admission to ICU, to evaluate the most common comorbidities as potential risk factors. RESULTS AND DISCUSSION We found that old age was the strongest factor for in-hospital mortality after having adjusted for gender and the considered comorbidities (hazard ratio [HR] 2.46, 95% confidence interval [CI] 2.33&minus;2.59 and HR 5.6 95% CI 5.23&minus;6 for ages 65 and 80 years, respectively). In addition, male gender remained an important risk factor in the multivariable models (HR 1.47, 95% CI 1.41&minus;1.53). Of all comorbidities, renal disease, oncological pathologies, chronic respiratory disease, cardiovascular disease (but not hypertension) and dementia were also risk factors for in-hospital mortality. With respect to ICU admission risk, the pattern was different, as patients with higher chances of survival might have been admitted more often to ICU. Male gender (OR 1.91, 95% CI 1.58&minus;2.31), hypertension (OR&nbsp; 1.3, 95% CI 1.07&minus;1.59) and age 55&ndash;79 years (OR 1.15, 95% CI 1.06&minus;1.26) are risk factors for ICU admission. Patients aged 80+ years, as well as patients with dementia or with liver disease were admitted less often to ICU. CONCLUSION We conclude that increasing age is the most important risk factor for in-hospital mortality of hospitalised COVID-19 patients in Switzerland, along with male gender and followed by the presence of comorbidities such as renal diseases, chronic respiratory or cardiovascular disease, oncological malignancies and dementia. Male gender, hypertension and age between 55 and 79 years are, however, risk factors for ICU admission. Mortality and ICU admission need to be considered as separate outcomes when investigating risk factors for pandemic control measures and for hospital resources planning