Specificity of serological screening tests and reference laboratory tests to diagnose gambiense human African trypanosomiasis: a prospective clinical performance study.

BACKGROUND: Serological screening tests play a crucial role to diagnose gambiense human African trypanosomiasis (gHAT). Presently, they preselect individuals for microscopic confirmation, but in future "screen and treat" strategies they will identify individuals for treatment. Variability in reported specificities, the development of new rapid diagnostic tests (RDT) and the hypothesis that malaria infection may decrease RDT specificity led us to evaluate the specificity of 5 gHAT screening tests. METHODS: During active screening, venous blood samples from 1095 individuals from Côte d'Ivoire and Guinea were tested consecutively with commercial (CATT, HAT Sero-K-SeT, Abbott Bioline HAT 2.0) and prototype (DCN HAT RDT, HAT Sero-K-SeT 2.0) gHAT screening tests and with a malaria RDT. Individuals with ≥ 1 positive gHAT screening test underwent microscopy and further immunological (trypanolysis with T.b. gambiense LiTat 1.3, 1.5 and 1.6; indirect ELISA/T.b. gambiense; T.b. gambiense inhibition ELISA with T.b. gambiense LiTat 1.3 and 1.5 VSG) and molecular reference laboratory tests (PCR TBRN3, 18S and TgsGP; SHERLOCK 18S Tids, 7SL Zoon, and TgsGP; Trypanozoon S2-RT-qPCR 18S2, 177T, GPI-PLC and TgsGP in multiplex; RT-qPCR DT8, DT9 and TgsGP in multiplex). Microscopic trypanosome detection confirmed gHAT, while other individuals were considered gHAT free. Differences in fractions between groups were assessed by Chi square and differences in specificity between 2 tests on the same individuals by McNemar. RESULTS: One gHAT case was diagnosed. Overall test specificities (n = 1094) were: CATT 98.9% (95% CI: 98.1-99.4%); HAT Sero-K-SeT 86.7% (95% CI: 84.5-88.5%); Bioline HAT 2.0 82.1% (95% CI: 79.7-84.2%); DCN HAT RDT 78.2% (95% CI: 75.7-80.6%); and HAT Sero-K-SeT 2.0 78.4% (95% CI: 75.9-80.8%). In malaria positives, gHAT screening tests appeared less specific, but the difference was significant only in Guinea for Abbott Bioline HAT 2.0 (P = 0.03) and HAT Sero-K-Set 2.0 (P = 0.0006). The specificities of immunological and molecular laboratory tests in gHAT seropositives were 98.7-100% (n = 399) and 93.0-100% (n = 302), respectively. Among 44 reference laboratory test positives, only the confirmed gHAT patient and one screening test seropositive combined immunological and molecular reference laboratory test positivity. CONCLUSIONS: Although a minor effect of malaria cannot be excluded, gHAT RDT specificities are far below the 95% minimal specificity stipulated by the WHO target product profile for a simple diagnostic tool to identify individuals eligible for treatment. Unless specificity is improved, an RDT-based "screen and treat" strategy would result in massive overtreatment. In view of their inconsistent results, additional comparative evaluations of the diagnostic performance of reference laboratory tests are indicated for better identifying, among screening test positives, those at increased suspicion for gHAT. TRIAL REGISTRATION: The trial was retrospectively registered under NCT05466630 in clinicaltrials.gov on July 15 2022.

Dynamic compaction of cohesive granular materials: scaling behavior and bonding structures.

The compaction of cohesive granular materials is a common operation in powder-based manufacture of many products. However, the influence of particle-scale parameters such as bond strength on the packing structure and the general scaling of the compaction process are still poorly understood. We use particle dynamics simulations to analyze jammed configurations obtained by dynamic compaction of sticky particles under a fixed compressive pressure for a broad range of system parameter values. We show that relative porosity, representing the relative importance of porosity with respect to its minimum and maximum values, is a unique function of a modified cohesion number that combines adhesion force, confining pressure, and particle size, as well as contact stiffness, which is often assumed to be ineffective but is shown here to play an essential role in compaction. An asymmetric sigmoidal form based on two power laws provides an excellent fit to the data. The statistical properties of the bond network reveal self-balanced force structures and an exponential fall-off of the number of both tensile and compressive forces. Remarkably, the properties of the bond network depend on the cohesion number rather than the modified cohesion number, implying that similar bond network characteristics are compatible with a broad range of porosities mainly due to the effect of contact stiffness. We also discuss the origins of data points escaping the general scaling of porosity and show that they reflect either finite system size or rigid confining walls.

Dosimetry and pharmacokinetics of [177Lu]Lu-satoreotide tetraxetan in patients with progressive neuroendocrine tumours.

PURPOSE: To evaluate the dosimetry and pharmacokinetics of the novel radiolabelled somatostatin receptor antagonist [177Lu]Lu-satoreotide tetraxetan in patients with advanced neuroendocrine tumours (NETs). METHODS: This study was part of a phase I/II trial of [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three planned cycles (median activity/cycle: 4.5 GBq), in 40 patients with progressive NETs. Organ absorbed doses were monitored at each cycle using patient-specific dosimetry; the cumulative absorbed-dose limits were set at 23.0 Gy for the kidneys and 1.5 Gy for bone marrow. Absorbed dose coefficients (ADCs) were calculated using both patient-specific and model-based dosimetry for some patients. RESULTS: In all evaluated organs, maximum [177Lu]Lu-satoreotide tetraxetan uptake was observed at the first imaging timepoint (4 h after injection), followed by an exponential decrease. Kidneys were the main route of elimination, with a cumulative excretion of 57-66% within 48 h following the first treatment cycle. At the first treatment cycle, [177Lu]Lu-satoreotide tetraxetan showed a median terminal blood half-life of 127 h and median ADCs of [177Lu]Lu-satoreotide tetraxetan were 5.0 Gy/GBq in tumours, 0.1 Gy/GBq in the bone marrow, 0.9 Gy/GBq in kidneys, 0.2 Gy/GBq in the liver and 0.8 Gy/GBq in the spleen. Using image-based dosimetry, the bone marrow and kidneys received median cumulative absorbed doses of 1.1 and 10.8 Gy, respectively, after three cycles. CONCLUSION: [177Lu]Lu-satoreotide tetraxetan showed a favourable dosimetry profile, with high and prolonged tumour uptake, supporting its acceptable safety profile and promising efficacy. TRIAL REGISTRATION: NCT02592707. Registered October 30, 2015.

Trypanosoma brucei gambiense group 2 experimental in vivo life cycle: from procyclic to bloodstream form.

Trypanosoma brucei gambiense (Tbg) group 2 is a subgroup of trypanosomes able to infect humans and is found in West and Central Africa. Unlike other agents causing sleeping sickness, such as Tbg group 1 and Trypanosoma brucei rhodesiense, Tbg2 lacks the typical molecular markers associated with resistance to human serum. Only 36 strains of Tbg2 have been documented, and therefore, very limited research has been conducted despite their zoonotic nature. Some of these strains are only available in their procyclic form, which hinders human serum resistance assays and mechanistic studies. Furthermore, the understanding of Tbg2's potential to infect tsetse flies and mammalian hosts is limited. In this study, 165 Glossina palpalis gambiensis flies were experimentally infected with procyclic Tbg2 parasites. It was found that 35 days post-infection, 43 flies out of the 80 still alive were found to be Tbg2 PCR-positive in the saliva. These flies were able to infect 3 out of the 4 mice used for blood-feeding. Dissection revealed that only six flies in fact carried mature infections in their midguts and salivary glands. Importantly, a single fly with a mature infection was sufficient to infect a mammalian host. This Tbg2 transmission success confirms that Tbg2 strains can establish in tsetse flies and infect mammalian hosts. This study describes an effective in vivo protocol for transforming Tbg2 from procyclic to bloodstream form, reproducing the complete Tbg2 cycle from G. p. gambiensis to mice. These findings provide valuable insights into Tbg2's host infectivity, and will facilitate further research on mechanisms of human serum resistance.

Title: Cycle de vie expérimental in vivo de Trypanosoma brucei gambiense groupe 2 : de la forme procyclique à la forme sanguicole. Abstract: Trypanosoma brucei gambiense (Tbg) groupe 2 est un sous-groupe de trypanosomes capables d'infecter l'Homme, présent en Afrique de l'Ouest et en Afrique centrale. Contrairement aux autres agents responsables de la maladie du sommeil, tels que Tbg groupe 1 et Trypanosoma brucei rhodesiense, Tbg2 ne présente pas les marqueurs moléculaires habituellement associés à la résistance au sérum humain. Seules trente-six souches de Tbg2 ont été répertoriées, limitant considérablement les recherches sur ce sous-groupe malgré sa nature zoonotique. Certaines de ces souches ne sont disponibles que sous leur forme procyclique, ce qui freine la réalisation des tests de résistance au sérum humain et les études mécanistiques. De plus, la compréhension du potentiel de Tbg2 à infecter les glossines et les hôtes mammifères est limitée. Dans cette étude, 165 glossines Glossina palpalis gambiensis ont été infectées expérimentalement par des parasites Tbg2 sous leur forme procyclique. Trente-cinq jours après l'infection, 43 des 80 glossines encore en vie se sont révélées positives à Tbg2 en PCR sur leur salive. Ces glossines ont réussi à infecter trois des quatre souris utilisées pour leur repas de sang. La dissection des glossines a révélé que seules six d'entre elles étaient réellement porteuses d'infections matures dans leur intestin et leurs glandes salivaires. Il est important de noter qu'une seule glossine porteuse d'une infection mature a suffi pour infecter un hôte mammifère. Ce succès de transmission de Tbg2 confirme que les souches de Tbg2 peuvent s'établir dans les glossines et infecter des hôtes mammifères. Cette étude décrit un protocole in vivo pour transformer la forme procyclique de Tbg2 en forme sanguicole, en reproduisant le cycle complet de Tbg2 de G. p. gambiensis à la souris. Ces résultats fournissent des informations précieuses sur le potentiel infectieux de Tbg2 et faciliteront la recherche sur les mécanismes de résistance au sérum humain des souches.

Conducting active screening for human African trypanosomiasis with rapid diagnostic tests: The Guinean experience (2016-2021).

Strategies to detect Human African Trypanosomiasis (HAT) cases rely on serological screening of populations exposed to trypanosomes. In Guinea, mass medical screening surveys performed with the Card Agglutination Test for Trypanosomiasis have been progressively replaced by door-to-door approaches using Rapid Diagnostic Tests (RDTs) since 2016. However, RDTs availability represents a major concern and medical teams must often adapt, even in the absence of prior RDT performance evaluation. For the last 5 years, the Guinean HAT National Control Program had to combine three different RDTs according to their availability and price: the SD Bioline HAT (not available anymore), the HAT Sero-K-SeT (most expensive), and recently the Abbott Bioline HAT 2.0 (limited field evaluation). Here, we assess the performance of these RDTs, alone or in different combinations, through the analysis of both prospective and retrospective data. A parallel assessment showed a higher positivity rate of Abbott Bioline HAT 2.0 (6.0%, n = 2,250) as compared to HAT Sero-K-SeT (1.9%), with a combined positive predictive value (PPV) of 20.0%. However, an evaluation of Abbott Bioline HAT 2.0 alone revealed a low PPV of 3.9% (n = 6,930) which was surpassed when using Abbott Bioline HAT 2.0 in first line and HAT Sero-K-SeT as a secondary test before confirmation, with a combined PPV reaching 44.4%. A retrospective evaluation of all 3 RDTs was then conducted on 189 plasma samples from the HAT-NCP biobank, confirming the higher sensitivity (94.0% [85.6-97.7%]) and lower specificity (83.6% [76.0-89.1%]) of Abbott Bioline HAT 2.0 as compared to SD Bioline HAT (Se 64.2% [52.2-74.6%]-Sp 98.4% [94.2-99.5%]) and HAT Sero-K-SeT (Se 88.1% [78.2-93.8%]-Sp 98.4% [94.2-99.5%]). A comparison of Abbott Bioline HAT 2.0 and malaria-RDT positivity rates on 479 subjects living in HAT-free malaria-endemic areas further revealed that a significantly higher proportion of subjects positive in Abbott Bioline HAT 2.0 were also positive in malaria-RDT, suggesting a possible cross-reaction of Abbott Bioline HAT 2.0 with malaria-related biological factors in about 10% of malaria cases. This would explain, at least in part, the limited specificity of Abbott Bioline HAT 2.0. Overall, Abbott Bioline HAT 2.0 seems suitable as first line RDT in combination with a second HAT RDT to prevent confirmatory lab overload and loss of suspects during referral for confirmation. A state-of-the-art prospective comparative study is further required for comparing all current and future HAT RDTs to propose an optimal combination of RDTs for door-to-door active screening.

Deep transformer-based personalized dosimetry from SPECT/CT images: a hybrid approach for [177Lu]Lu-DOTATATE radiopharmaceutical therapy.

PURPOSE: Accurate dosimetry is critical for ensuring the safety and efficacy of radiopharmaceutical therapies. In current clinical dosimetry practice, MIRD formalisms are widely employed. However, with the rapid advancement of deep learning (DL) algorithms, there has been an increasing interest in leveraging the calculation speed and automation capabilities for different tasks. We aimed to develop a hybrid transformer-based deep learning (DL) model that incorporates a multiple voxel S-value (MSV) approach for voxel-level dosimetry in [177Lu]Lu-DOTATATE therapy. The goal was to enhance the performance of the model to achieve accuracy levels closely aligned with Monte Carlo (MC) simulations, considered as the standard of reference. We extended our analysis to include MIRD formalisms (SSV and MSV), thereby conducting a comprehensive dosimetry study. METHODS: We used a dataset consisting of 22 patients undergoing up to 4 cycles of [177Lu]Lu-DOTATATE therapy. MC simulations were used to generate reference absorbed dose maps. In addition, MIRD formalism approaches, namely, single S-value (SSV) and MSV techniques, were performed. A UNEt TRansformer (UNETR) DL architecture was trained using five-fold cross-validation to generate MC-based dose maps. Co-registered CT images were fed into the network as input, whereas the difference between MC and MSV (MC-MSV) was set as output. DL results are then integrated to MSV to revive the MC dose maps. Finally, the dose maps generated by MSV, SSV, and DL were quantitatively compared to the MC reference at both voxel level and organ level (organs at risk and lesions). RESULTS: The DL approach showed slightly better performance (voxel relative absolute error (RAE) = 5.28 ± 1.32) compared to MSV (voxel RAE = 5.54 ± 1.4) and outperformed SSV (voxel RAE = 7.8 ± 3.02). Gamma analysis pass rates were 99.0 ± 1.2%, 98.8 ± 1.3%, and 98.7 ± 1.52% for DL, MSV, and SSV approaches, respectively. The computational time for MC was the highest (~2 days for a single-bed SPECT study) compared to MSV, SSV, and DL, whereas the DL-based approach outperformed the other approaches in terms of time efficiency (3 s for a single-bed SPECT). Organ-wise analysis showed absolute percent errors of 1.44 ± 3.05%, 1.18 ± 2.65%, and 1.15 ± 2.5% for SSV, MSV, and DL approaches, respectively, in lesion-absorbed doses. CONCLUSION: A hybrid transformer-based deep learning model was developed for fast and accurate dose map generation, outperforming the MIRD approaches, specifically in heterogenous regions. The model achieved accuracy close to MC gold standard and has potential for clinical implementation for use on large-scale datasets.

Recyclability of Post-Consumer Polystyrene at Pilot Scale: Comparison of Mechanical and Solvent-Based Recycling Approaches.

Solvent-based and mechanical recycling technology approaches were compared with respect to each process's decontamination efficiency. Herein, post-consumer polystyrene (PS) feedstock was recycled by both technologies, yielding recycled PS resins (rPS). The process feedstock was subjected to four recycling cycles in succession to assess the technology perennity. The physico-chemical and mechanical properties of the rPS were then evaluated to discern the advantages and drawbacks of each recycling approach. The molecular weight of the mechanically recycled resin was found to decrease by 30% over the reprocessing cycles. In contrast, the solvent-base recycling technology yielded a similar molecular weight regarding the feedstock. This consistency in the rPS product is critical for consumer applications. Further qualitative and quantitative analyses on residual organic compounds and inorganic and particulate contaminants were investigated. It was found that the solvent-based technology is very efficient for purifying deeply contaminated feedstock in comparison to mechanical recycling, which is limited to well-cleaned and niche feedstocks.

A phase I/II study of the safety and efficacy of [177Lu]Lu-satoreotide tetraxetan in advanced somatostatin receptor-positive neuroendocrine tumours.

PURPOSE: We present the results of an open-label, phase I/II study evaluating the safety and efficacy of the novel somatostatin receptor (SSTR) antagonist [177Lu]Lu-satoreotide tetraxetan in 40 patients with previously treated, progressive neuroendocrine tumours (NETs), in which dosimetry was used to guide maximum administered activity. METHODS: This study was conducted in two parts. Part A consisted of 15 patients who completed three cycles of [177Lu]Lu-satoreotide tetraxetan at a fixed administered activity and peptide amount per cycle (4.5 GBq/300 µg). Part B, which included 25 patients who received one to five cycles of [177Lu]Lu-satoreotide tetraxetan, evaluated different administered activities (4.5 or 6.0 GBq/cycle) and peptide amounts (300, 700, or 1300 µg/cycle), limited to a cumulative absorbed radiation dose of 23 Gy to the kidneys and 1.5 Gy to the bone marrow. RESULTS: Median cumulative administered activity of [177Lu]Lu-satoreotide tetraxetan was 13.0 GBq over three cycles (13.1 GBq in part A and 12.9 GBq in part B). Overall, 17 (42.5%) patients experienced grade ≥ 3 treatment­related adverse events; the most common were lymphopenia, thrombocytopenia, and neutropenia. No grade 3/4 nephrotoxicity was observed. Two patients developed myeloid neoplasms considered treatment related by the investigator. Disease control rate for part A and part B was 94.7% (95% confidence interval [CI]: 82.3-99.4), and overall response rate was 21.1% (95% CI: 9.6-37.3). CONCLUSION: [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three cycles, has an acceptable safety profile with a promising clinical response in patients with progressive, SSTR-positive NETs. A 5-year long-term follow-up study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02592707. Registered October 30, 2015.

[Towards elimination of human African trypanosomiasis]. / Vers l'élimination de la maladie du sommeil.

Human African Trypanosomiasis (HAT) is caused by Trypanosoma brucei which is transmitted by the tsetse fly insect vector (Glossina spp). It is one of the 20 Neglected Tropical Diseases (NTD) listed by the WHO. These diseases affect the poorest and most vulnerable communities, for which the WHO has established a dedicated 2021-2030 roadmap. At the time of Alphonse Laveran, HAT devastated the African continent. In the 1960s, the disease was nearly under control, but it strongly re-emerged in the 1990s. A coordinated effort of all stakeholders, with national control programs as the main actors, a strong contribution of research and important donations by the private sector, allowed to decrease the HAT burden significantly. Since 2018, less than 1000 cases are detected annually. We here review new diagnostics, treatments and vector control tools that have been implemented jointly and successfully in several endemic countries.The next key challenge will be to sustain the gains. Newly emerging research questions include long-term carriage of trypanosomes and adaptation of tools to low prevalence contexts. Challenges out of the research area comprise the continued need of funding, maintenance of dedicated human resources, and the key question of access. Sustainable elimination as "interruption of transmission", which is the 2030 NTD roadmap target, can be reached, if these challenges are solved. We stress the importance of continuing to combine the efforts in the fight against the disease, because sustainable elimination of HAT is the best long-term prevention strategy against re-emergence. As such, HAT elimination can serve as an example for other infectious diseases.

Concordance of CT imaging and surgical lesions in penetrating abdominal trauma.

OBJECTIVE: The management of penetrating abdominal wounds has greatly benefited from the development of computed tomography (CT), particularly in stable patients. In this setting, the scanner is the reference examination. Our study aims to evaluate the performance of preoperative CT in the assessment of penetrating abdominal lesions. MATERIAL AND METHODS: Between January 1, 2015 and January 1, 2022, 81 patients were hospitalized following penetrating abdominal trauma at the Army Training Hospitals of Sainte-Anne and Laveran. Fifty-one stable patients who had an abdominopelvic CT scan and thereafter underwent abdominal surgery (laparotomy or laparoscopy) were included. Radiological and surgical data were collected from the electronic record and compared by a descriptive analysis (calculation of the sensitivity, specificity, positive and negative predictive value of the CT for the detection of lesions of the various organs) and by a correlation of the CT findings with surgical findings using Kripendorff's alpha coefficient. RESULTS: The cohort was largely male (n=45; 88%), with injuries by knife wound in 62.7% of cases (n=32) and gunshot in 35.3% (n=18) of cases. The median age was 36years (25-47). The median index of severity score (ISS) was 17 (10-26). Excellent agreement between predicted and actual findings was obtained for solid organs (α=0.801) with high sensitivity and specificity (81.8% and 96.6%, respectively). The largest discrepancies were observed for the hollow organs (α=26.2%, sensitivity of 53.3% and specificity of 76.2%) and the diaphragm (α=67.3%, sensitivity 75%, specificity 92.3%). Surgical exploration was non-therapeutic for five patients (9.8%). The failure rate for non-operative treatment was 10% (n=1). CONCLUSION: CT detection of solid organ lesions in patients with penetrating abdominal wounds is excellent. However, the detection of hollow organ and diaphragmatic wounds remains a challenge with a risk of over- and underdiagnosis. Laparoscopic exploration should be able to fill in the gaps in the CT findings.

The precursory phase of large earthquakes.

The existence of an observable precursory phase of slip on the fault before large earthquakes has been debated for decades. Although observations preceding several large earthquakes have been proposed as possible indicators of precursory slip, these observations do not directly precede earthquakes, are not seen before most events, and are also commonly observed without being followed by earthquakes. We conducted a global search for short-term precursory slip in GPS data. We summed the displacements measured by 3026 high-rate GPS time series-projected onto the directions expected from precursory slip at the hypocenter-during 48 hours before 90 (moment magnitude ≥7) earthquakes. Our approach reveals a ≈2-hour-long exponential acceleration of slip before the ruptures, suggesting that large earthquakes start with a precursory phase of slip, which improvements in measurement precision and density could more effectively detect and possibly monitor.

Does Atmospheric Corrosion Alter the Sound Quality of the Bronze Used for Manufacturing Bells?

Bells are made of bronze, an alloy of copper and tin. Art objects and musical instruments belong to tangible and intangible heritage. The effect of atmospheric alteration on their sound is not well documented. To address this question, alteration cycles of bronze specimens are performed in a chamber reproducing a realistic polluted coastal atmosphere. The corrosion layers are characterized by X-ray diffraction, electron microscopy and X-ray photoelectron spectrometry. The buried interface of the film (alloy-layer interface) is formed by a thin, adherent and micro-cracked layer, mainly composed of sulfates, copper oxide and chloride, on top of tin corrosion products. Near the atmosphere-film interface, less adherent irregular clusters of soot, calcite, gypsum and halite developed. Through these observations, an alteration scenario is proposed. To correlate the bronze corrosion effect on the bell sound, linear and nonlinear resonance experiments are performed on the corroded bronze specimens, where resonance parameters are monitored as a function of increasing driving force using a shaker. Results show that the corrosion effect on the acoustic properties can be monitored through the evolution of the acoustic nonlinear parameters (damping and resonance). These well-calibrated original experiments confirm the effect of corrosion on the acoustic properties of bronze.

Prevalence of blood and skin trypanosomes in domestic and wild fauna from two sleeping sickness foci in Southern Cameroon.

Although studies on African Trypanosomiases revealed a variety of trypanosome species in the blood of various animal taxa, animal reservoirs of Trypanosoma brucei gambiense and anatomical niches such as skin have been overlooked in most epidemiological settings. This study aims to update epidemiological data on trypanosome infections in animals from human African trypanosomiasis (HAT) foci of Cameroon. Blood and skin snips were collected from 291 domestic and wild animals. DNA was extracted from blood and skin snips and molecular approaches were used to identify different trypanosomes species. Immunohistochemical analyses were used to confirm trypanosome infections in skin snips. PCR revealed 137 animals (47.1%) with at least one trypanosome species in the blood and/or in the skin. Of these 137 animals, 90 (65.7%) and 32 (23.4%) had trypanosome infections respectively in the blood and skin. Fifteen (10.9%) animals had trypanosome infections in both blood and skin snip. Animals from the Campo HAT focus (55.0%) were significantly (X2 = 17.6; P< 0.0001) more infected than those (29.7%) from Bipindi. Trypanosomes of the subgenus Trypanozoon were present in 27.8% of animals while T. vivax, T. congolense forest type and savannah type were detected in 16.5%, 10.3% and 1.4% of animals respectively. Trypanosoma b. gambiense infections were detected in the blood of 7.6% (22/291) of animals. No T. b. gambiense infection was detected in skin. This study highlights the presence of several trypanosome species in the blood and skin of various wild and domestic animals. Skin appeared as an anatomical reservoir for trypanosomes in animals. Despite methodological limitations, pigs, sheep, goats and wild animals were confirmed as potential reservoirs of T. b. gambiense. These animal reservoirs must be considered for the designing of control strategies that will lead to sustainable elimination of HAT.

Health-related quality of life and pain outcomes with [177Lu]Lu-PSMA-617 plus standard of care versus standard of care in patients with metastatic castration-resistant prostate cancer (VISION): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: In VISION, the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy lutetium-177 [177Lu]Lu-PSMA-617 (vipivotide tetraxetan) improved radiographic progression-free survival and overall survival when added to protocol-permitted standard of care in patients with metastatic castration-resistant prostate cancer. Here, we report additional health-related quality of life (HRQOL), pain, and symptomatic skeletal event results. METHODS: This multicentre, open-label, randomised, phase 3 trial was conducted at 84 cancer centres in nine countries in North America and Europe. Eligible patients were aged 18 years or older; had progressive PSMA-positive metastatic castration-resistant prostate cancer; an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2; and had previously received of at least one androgen receptor pathway inhibitor and one or two taxane-containing regimens. Patients were randomly assigned (2:1) to receive either [177Lu]Lu-PSMA-617 plus protocol-permitted standard of care ([177Lu]Lu-PSMA-617 group) or standard of care alone (control group) using permuted blocks. Randomisation was stratified by baseline lactate dehydrogenase concentration, liver metastases, ECOG performance status, and androgen receptor pathway inhibitor inclusion in standard of care. Patients in the [177Lu]Lu-PSMA-617 group received intravenous infusions of 7·4 gigabecquerel (GBq; 200 millicurie [mCi]) [177Lu]Lu-PSMA-617 every 6 weeks for four cycles plus two optional additional cycles. Standard of care included approved hormonal treatments, bisphosphonates, and radiotherapy. The alternate primary endpoints were radiographic progression-free survival and overall survival, which have been reported. Here we report the key secondary endpoint of time to first symptomatic skeletal event, and other secondary endpoints of HRQOL assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-5L, and pain assessed with the Brief Pain Inventory-Short Form (BPI-SF). Patient-reported outcomes and symptomatic skeletal events were analysed in all patients who were randomly assigned after implementation of measures designed to reduce the dropout rate in the control group (on or after March 5, 2019), and safety was analysed according to treatment received in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, NCT03511664, and is active but not recruiting. FINDINGS: Between June 4, 2018, and Oct 23, 2019, 831 patients were enrolled, of whom 581 were randomly assigned to the [177Lu]Lu-PSMA-617 group (n=385) or control group (n=196) on or after March 5, 2019, and were included in analyses of HRQOL, pain, and time to first symptomatic skeletal event. The median age of patients was 71 years (IQR 65-75) in the [177Lu]Lu-PSMA-617 group and 72·0 years (66-76) in the control group. Median time to first symptomatic skeletal event or death was 11·5 months (95% CI 10·3-13·2) in the [177Lu]Lu-PSMA-617 group and 6·8 months (5·2-8·5) in the control group (hazard ratio [HR] 0·50, 95% CI 0·40-0·62). Time to worsening was delayed in the [177Lu]Lu-PSMA-617 group versus the control group for FACT-P score (HR 0·54, 0·45-0·66) and subdomains, BPI-SF pain intensity score (0·52, 0·42-0·63), and EQ-5D-5L utility score (0·65, 0·54-0·78). Grade 3 or 4 haematological adverse events included decreased haemoglobin (80 [15%] of 529 assessable patients who received [177Lu]Lu-PSMA-617 plus standard of care vs 13 [6%] of 205 who received standard of care only), lymphocyte concentrations (269 [51%] vs 39 [19%]), and platelet counts (49 [9%] vs five [2%]). Treatment-related adverse events leading to death occurred in five (1%) patients who received [177Lu]Lu-PSMA-617 plus standard of care (pancytopenia [n=2], bone marrow failure [n=1], subdural haematoma [n=1], and intracranial haemorrhage [n=1]) and no patients who received standard of care only. INTERPRETATION: [177Lu]Lu-PSMA-617 plus standard of care delayed time to worsening in HRQOL and time to skeletal events compared with standard of care alone. These findings support the use of [177Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer who received previous androgen receptor pathway inhibitor and taxane treatment. FUNDING: Advanced Accelerator Applications (Novartis).

"What is Wrong With You People That You are Happy Someone has Covid" Impoliteness in the Coronavirus Pandemic Era.

Whilst the coronavirus pandemic keeps threatening the world at large, little is yet known about the impoliteness implications of user-generated- Covid-related contents on social media such as Facebook. The aim of this study is to examine the comments made in response to Giuliani's Covid- 19 diagnosis, from an impoliteness perspective. A merely qualitative analysis of a dataset of 3,000 comments evenly collected from three different news outlets (i.e., BBC, CNN, Fox News), the findings reveal that the reactions to Giuliani's diagnosis are more focused on him being a politician, than him being a human being affected by the virus. The reactions attack his actions and the actions of others within his political party, which suggests that impoliteness has a strong dependence on previous actions and political engagement. Giuliani is seen by some users to be undeserving of compassion or empathy not just on the grounds of his active involvement in attempting to overturn the presidential election results, but also for his disregard toward mask wearing in public spheres. Not all the users, however, appreciate the attacks against Giuliani. Through metadiscursive comments, some users not just feel the need to treat Giuliani as a human being, but more importantly remind fellow users that Covid-19 should be a concern for all. What is particularly critical about these metacomments is that while the users advocate for civil interactions, they mostly do not condone Giuliani's actions. This so because these users understand what should be obligatory, permissible, or forbidden on the human level under the circumstances.

Differential Detection of Hepatic Metastases on 68 Ga-DOTATATE PET/CT and 177 Lu-DOTATATE SPECT/CT.

ABSTRACT: 68 Ga-DOTATATE PET/CT is indicated for selecting patients for peptide receptor radionuclide therapy (PRRT). Although highly sensitive, the detectability of smaller lesions, particularly in the liver, is lower. We present the case of a 58-year-old man with metastatic well-differentiated pancreatic neuroendocrine tumor whose MRI revealed progression of hepatic metastases. 68 Ga-DOTATATE PET/CT performed to determine eligibility for PRRT did not demonstrate DOTATATE-avid disease within the liver. 18 F-FDG PET/CT was also negative at the liver and the patient proceeded to 177 Lu-DOTATATE PRRT, where multi-time point posttherapy planar imaging and SPECT/CT showed intense uptake in the known liver metastases.

Use of imaging-based dosimetry for personalising radiopharmaceutical therapy of cancer.

Theranostics - i.e., the combination of molecular imaging and radiopharmaceutical therapy of cancer targeting a common biological feature - is a rapidly expanding field owing the recent successes of novel radiopharmaceutical therapies, such as 177Lu-based prostate-specific membrane antigen radioligand therapy of prostate cancer and peptide receptor radionuclide therapy of neuroendocrine tumours. Despite the ongoing technical developments in imaging-based dosimetry, the existence of tumour absorbed dose-efficacy and organ absorbed dose-toxicity relationships, as well as the high interpatient variability in absorbed doses per unit activity, radiopharmaceutical therapies are still mostly administered in a fixed-activity, one-size-fits-all fashion. This is at odds with the principles of radiation oncology, where the absorbed doses to tissues are prescribed and their delivery is carefully planned and controlled for each individual patient to maximise the clinical benefits. There is a growing body of clinical evidence that dosimetry-based radiopharmaceutical therapy allows to safely optimise tumour irradiation, which translates into improved clinical outcomes. In this narrative review, we will present the reported prospective clinical experience to date on the use of imaging-based dosimetry to personalise radiopharmaceutical therapies.

Impact of the dead-time correction method on quantitative 177Lu-SPECT (QSPECT) and dosimetry during radiopharmaceutical therapy.

BACKGROUND: Dead-time correction is required for accurate quantitative SPECT-based dosimetry in the context of personalised 177Lu radiopharmaceutical therapy. We aimed to evaluate the impact of applying dead-time correction on the reconstructed SPECT image versus on the acquisition projections before reconstruction. METHODS: Data from 16 SPECT/CT acquisitions of a decaying 177Lu-filled phantom (up to 20.75 GBq) and dual-timepoint SPECT/CT in 14 patients treated with personalised 177Lu peptide receptor radionuclide therapy were analysed. Dead time was determined based on the acquisition wide-spectrum count rate for each projection and averaged for the entire acquisition. Three dead-time correction methods (DTCMs) were used: the per-projection correction, where each projection was individually corrected before reconstruction (DTCM1, the standard of reference), and two per-volume methods using the average dead-time correction factor of the acquisition applied to all projections before reconstruction (DTCM2) or to the SPECT image after reconstruction (DTCM3). Relative differences in quantification were assessed for various volumes of interest (VOIs) on the phantom and patient SPECT images. In patients, the resulting dosimetry estimates for tissues of interest were also compared between DTCMs. RESULTS: Both per-volume DTCMs (DTCM2 and DTCM3) were found to be equivalent, with VOI count differences not exceeding 0.8%. When comparing the per-volume post-reconstruction DTCM3 versus the per-projection pre-reconstruction DTCM1, differences in VOI counts and absorbed dose estimates did not exceed 2%, with very few exceptions. The largest absorbed dose deviation was observed for a kidney at 3.5%. CONCLUSION: While per-projection dead-time correction appears ideal for QSPECT, post-reconstruction correction is an acceptable alternative that is more practical to implement in the clinics, and that results in minimal deviations in quantitative accuracy and dosimetry estimates, as compared to the per-projection correction.

Determination of CO2 solubility in semi-crystalline polylactic acid with consideration of rigid amorphous fraction.

Due to phase heterogeneity in semi-crystalline polymers, accurate determination of gas solubility has been a challenge. In this regard, PLA/CO2 was used as a case study to investigate the parameters governing formation of the rigid amorphous fraction (RAF) and its effect on the gas sorption behavior of the polymer. Six samples with different degrees of RAF were prepared through varying PLA tacticity and thermal history. Then, a gravimetric method involving a magnetic suspension balance and an in-house PVT visualization system was employed to experimentally determine the CO2 solubility at 70 °C under a pressure of 4.5 MPa. Furthermore, a theoretical CO2 solubility was calculated based on the Simha-Somcynski equation of state and was used in conjunction with the two-phase and three-phase models to describe the phase dependency of the gas solubility. The conventional two-phase model that considered the bulk amorphous phase consistently over-approximated the CO2 solubility compared to the measured data. On the other hand, the three-phase model that distinguished the rigid and the mobile amorphous phases well represented the experimental result. The analysis yielded CO2 solubility coefficients of 0.0375 ggas/gpoly for the RAF and 0.0817 ggas/gpoly for the mobile counterpart.