PET/CT imaging of differentiated and medullary thyroid carcinoma using the novel SSTR-targeting peptide [18F]SiTATE - first clinical experiences.

PURPOSE: The novel 18F-labeled somatostatin receptor (SSTR)-directed radiotracer [18F]SiTATE demonstrated promising results for the imaging of various SSTR-expressing tumor types. Although thyroid carcinomas (TC) express SSTR, data on [18F]SiTATE PET/CT imaging in TC are lacking. This study explores the use of [18F]SiTATE PET/CT in a patient cohort with histologically proven TC. METHODS: As part of a prospective observational study at a single tertiary cancer center, 21 patients with TC (10 medullary (MTC) and 11 differentiated (DTC)) who underwent at least one [18F]SiTATE PET/CT were included (37 scans in total). Mean SUVmax and SUVmean of tumoral lesions, mean total-tumor-volume (TTV), and whole-body (WB)-SUVmax and WB-SUVmean on PET with their standard deviations (SDs) were determined. PET parameters were correlated to clinical parameters including tumor marker levels (thyroglobulin for DTC, calcitonin for MTC). RESULTS: 89 lesions were included in the analysis. Metastases were localized in the bone, lymph nodes, lung, soft tissue, and thyroid bed. Osseous (31 lesions; SUVmax 8.6 ± 8.0; SUVmean 5.8 ± 5.4) and nodal (37 lesions; SUVmax 8.7 ± 7.8; SUVmean 5.7 ± 5.4) metastases showed the highest uptake. The MTC disease burden on PET significantly correlated with the calcitonin tumor marker level (e.g., TTV: r = 0.771, r2 = 0.594, p = 0.002). For DTC, no such correlation was present. CONCLUSION: Our data demonstrate high feasibility of [18F]SiTATE PET/CT in a small cohort of patients with MTC and DTC. The use of [18F]SiTATE may overcome logistical disadvantages of 68Ga-based tracers and facilitate SSTR-targeted PET/CT imaging of thyroid carcinoma.

Diagnostic value of an interpretable machine learning model based on clinical ultrasound features for follicular thyroid carcinoma.

Background: Follicular thyroid carcinoma (FTC) and follicular thyroid adenoma (FTA) present diagnostic challenges due to overlapping clinical and ultrasound features. Improving the diagnosis of FTC can enhance patient prognosis and effectiveness in clinical management. This study seeks to develop a predictive model for FTC based on ultrasound features using machine learning (ML) algorithms and assess its diagnostic effectiveness. Methods: Patients diagnosed with FTA or FTC based on surgical pathology between January 2009 and February 2023 at Zhejiang Provincial Cancer Hospital and Zhejiang Provincial People's Hospital were retrospectively included. A total of 562 patients from Zhejiang Provincial Cancer Hospital comprised the training set, and 218 patients from Zhejiang Provincial People's Hospital constituted the validation set. Subsequently, clinical parameters and ultrasound characteristics of the patients were collected. The diagnostic parameters were analyzed using the least absolute shrinkage and selection operator and multivariate logistic regression screening methods. Next, a comparative analysis was performed using seven ML models. The area under the receiver operating characteristic (ROC) curve (AUC), accuracy, sensitivity, specificity, positive predicted value (PPV), negative predicted value (NPV), precision, recall, and comprehensive evaluation index (F-score) were calculated to compare the diagnostic efficacy among the seven models and determine the optimal model. Further, the optimal model was validated, and the SHapley Additive ExPlanations (SHAP) approach was applied to explain the significance of the model variables. Finally, an individualized risk assessment was conducted. Results: Age, echogenicity, thyroglobulin antibody (TGAb), echotexture, composition, triiodothyronine (T3), thyroglobulin (TG), margin, thyroid-stimulating hormone (TSH), calcification, and halo thickness >2 mm were influential factors for diagnosing FTC. The XGBoost model was identified as the optimal model after a comprehensive evaluation. The AUC of this model in the validation set was 0.969 [95% confidence interval (CI), 0.946-0.992], while its precision sensitivity, specificity, and accuracy were 0.791, 0.930, 0.913 and 0.917, respectively. Conclusions: XGBoost model based on ultrasound features was constructed and interpreted using the SHAP method, providing evidence for the diagnosis of FTC and guidance for the personalized treatment of patients.

The effect of total thyroidectomy and radioactive iodine on long-term survival in unilateral T3/T4 follicular thyroid carcinoma: insights from a propensity-matched retrospective analysis.

Background: Follicular thyroid carcinoma (FTC) is the second most common thyroid malignancy and is particularly aggressive in advanced stages such as T3 and T4. This retrospective study aimed to evaluate the long-term survival outcomes of total thyroidectomy (TT) and radioactive iodine therapy (RAIT) in unilateral T3 or T4 FTC using propensity score-matched analysis. Methods: Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we identified patients diagnosed with T3 or T4 FTC and categorized them into two cohorts, namely those who were treated with TT and those who were not (non-TT). The non-TT group was further analyzed to determine the impact of RAIT on survival. Propensity score matching (PSM) was applied to adjust for confounding variables. Survival analysis, including Kaplan-Meier survival curves and landmark analysis, evaluated the effects on overall survival (OS) and cancer-specific survival (CSS). Results: A total of 2,957 patients were included, with 2,271 (76.8%) undergoing TT and 686 (23.2%) receiving alternative treatments. Before and after PSM, there were no significant differences in OS and CSS between the two groups. Post-PSM landmark analysis revealed that beyond 90 months, the TT group had superior CSS compared with the non-TT group (P=0.06). Cox multivariate regression identified follicular adenocarcinoma trabecular [hazard ratio (HR) =4.7041; 95% confidence interval (CI): 1.1218-19.727] and minimally invasive follicular carcinoma (HR =2.0202; 95% CI: 1.2140-3.362) as independent risk factors affecting prognosis. In the second part of the study, 671 patients were analyzed, namely 197 (29.4%) who received RAIT and 474 (70.6%) who did not. Landmark analysis indicated that after 30 months, the RAIT group had superior CSS compared with the non-RAIT group (P<0.05). Conclusions: TT does not improve the survival rates of patients with stage T3/T4 FTC. For those patients who have not undergone TT, RAIT proves beneficial for CSS; however, further in-depth studies are required.

Evaluation of pharmacokinetics of Tenofovir Alafenamide (TAF) and Tenofovir Disoproxil (TDF) in pregnant and postpartum women in South Africa: PrEP-PP PK study.

BACKGROUND: There are few data on tenofovir-diphosphate (TFV-DP) concentrations in pregnant and postpartum women on Tenofovir Disoproxil Fumarate-Emtricitabine (TDF-FTC) or Tenofovir Alafenamide-Emtricitabine (TAF-FTC). METHODS: Eligible pregnant women were randomized to TDF-FTC or TAF-FTC and followed for 16 weeks (8-weeks pregnant, 8-weeks postpartum) with weekly collection of dried blood spot (DBS) and 4-weekly peripheral blood mononuclear cells (PBMC). PrEP dosing was observed daily via asynchronous videos sent via cell phone. We report geometric means (GM) and their ratios (GMR) with 95% confidence intervals (CIs) for TFV-DP in PBMC and DBS from pregnancy and postpartum. RESULTS: We enrolled N = 39 participants (n = 19 TDF-FTC, n = 20 TAF-FTC): median age was 28 years (IQR:25-34); median gestational age was 24-weeks (IQR:21-28). For TDF-FTC, TFV-DP DBS concentrations at 8-weeks did not differ significantly between pregnancy (GM: 675; 95%CI:537-849) and postpartum (GM: 583; 95%CI:471-722; GMR-TDF = 1.16; 95%CI:0.74-1.80). For TAF-FTC, TFV-DP DBS concentrations at 8-weeks were 44% higher in postpartum (GM: 1199; 95%CI:929-1549) versus pregnancy (GM: 832; 95%CI:751-922; GMR-TAF = 1.44; 95% CI: 1.01-2.06). In PBMC analysis of TDF-FTC, 8-week median TFV-DP (pmol/10^6 cell) was 71 (IQR 44-112) in pregnancy and 73 (IQR 50-102) in postpartum (GMR = 1.04; 95%CI:0.44-2.44). In TAF-FTC, median PBMC at 8-weeks was 580 (IQR:341-985) in pregnancy and 666 (IQR:396-1123) in postpartum (GMR = 1.15; 95%CI:0.30-2.49). CONCLUSION: TFV-DP concentrations were overall lower during pregnancy than postpartum for TAF-FTC. We found high concentrations of TFV-DP in PBMC in pregnancy and postpartum on TAF-FTC, suggesting PrEP efficacy is maintained. Efficacy and safety studies are warranted to evaluate TAF-FTC for PrEP in pregnant and postpartum women.

A randomised control trial of BIC/F/TAF vs DRV/c/F/TAF in context of HIV test-and-treat, BicTnT.

BACKGROUND: Head-to-head data for bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF; B) and darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/F/TAF; D) are lacking in the context of rapid antiretroviral therapy (ART) initiation. This study, BIC-T&T, evaluates the efficacy and tolerability of B vs D in a UK test-and-treat setting. SETTING: BIC-T&T was a randomised, open-label, multi-centre, study in which participants initiated ART within 14 days after confirmed HIV-1 diagnosis before baseline laboratory. METHODS: The primary endpoint is the virological response (HIV RNA < 50copies/mL) at week 12 by time-weighted average change in log10 HIV RNA recorded in viral load assays from treatment initiation to week 12, using two-sample Wilcoxon rank-sum test. RESULTS: 36 participants were randomised: 94% were male, 53% white; mean (SD) age was 35 years (11.8). Baseline mean (±SD) log10 HIV-RNA was 4.79 (± 0.87) log10 copies/mL and CD4 505 (±253) cells/mm3. The mean (±SD) time from confirmed HIV diagnosis to ART initiation was 7.9 (± 3.7) days. The time-weighted mean decrease in log10 HIV RNA from treatment initiation to week 12 was significantly greater in B in comparison to D (3.1 vs. 2.6 log10 copies/mL, p < 0.001). Both regimens demonstrated good tolerability with infrequent laboratory abnormalities and no grade 3 or 4 adverse events. CONCLUSION: In this first head-to-head study in the context of ART initiation, HIV RNA decline from baseline to week 12 was significantly more rapid for BIC/F/TAF compared with DRV/c/F/TAF.

Synchronous papillary and follicular thyroid carcinomas: the first retrospective cohort study and literature review.

Background: Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) contribute to more than 95% of thyroid malignancies. However, synchronous PTC and FTC are less common; it is most commonly discovered incidentally as synchronous malignancies during operation, which adds difficulties to intraoperative decision-making and postoperative treatment. Therefore, we analyzed the clinicopathological characteristics and prognosis of patients with PTC and FTC in our center. Methods: We conducted a search of single PTC, single FTC, and synchronous PTC/FTC patients who received initial surgery treatment at Fudan University Shanghai Cancer Center from 2006 to 2018 and collected paraffin-embedded samples of synchronous patients. Clinicopathological characteristics were collected from the electronic medical record system. Follow-up was performed through telephone contact or medical records. Exome sequencing was performed by ThyroLead panel. Results: Total of 42 synchronous PTC/FTC patients, 244 single FTC patients, and 2,959 single PTC patients were included. It showed a similarity between the clinicopathological features of synchronous thyroid cancer patients and single PTC patients, with a greater proportion of females, higher probabilities of lymph node metastasis, and higher rate of concurrence of Hashimoto's disease. The disease-free survival (DFS) curve indicated a worse prognosis of the synchronous group and single PTC group compared to the single FTC group, who had a propensity for neck lymph node recurrence; however, logistic multivariate regression analysis did not find any factor related to recurrence in the synchronous group. After re-checking pathology, DNA extraction, and quality control, genetic alteration information of 62 samples including primary tumors and metastatic lymph nodes from 35 synchronous cancer patients was displayed. In total, 81 mutations and 1 fusion gene were identified, including mutations related to outcomes and targeted therapy. Besides, some rare mutations in thyroid cancer were found in these patients. Conclusions: To conclude, synchronous PTC/FTC tend to be incidentally discovered during or after operation, behaving more like single PTC. The prognosis of synchronous patients is worse than that of single FTC patients and supplemental cervical lymph node dissection, total thyroidectomy, and postoperative radioiodine therapy should be taken into consideration after diagnosis. The next-generation sequencing (NGS) showed a unique molecular feature of synchronous patients with some rare mutations.

Seeding recurrence of follicular thyroid carcinoma after transoral endoscopic thyroidectomy vestibular approach: a case report.

Background: While track recurrence of thyroid cancer following endoscopic and robotic transaxillary surgeries has been reported previously, no such cases have been reported for transoral endoscopic thyroidectomy vestibular approach (TOETVA). This case report describes the first documented case of recurrence of thyroid cancer along the surgical track after TOETVA. Case Description: The patient underwent right lobectomy via TOETVA for a 4 cm follicular thyroid carcinoma (FTC) initially diagnosed as benign follicular nodule on preoperative gun biopsy. The thyroid capsule partially ruptured within the surgical field during surgery. Ultrasonography and computed tomography conducted 27 months after surgery revealed seeding recurrence in the postsurgical thyroid bed, and subcutaneous layers of the right lower lip, submental area, and mid to right upper neck levels I, IIA, and VI. Two-stage re-operation was done to perform completion thyroidectomy, lymph node dissection, and excision of recurrent nodules, which were pathologically confirmed as metastatic FTC. The patient underwent two treatments of radioactive iodine therapy, and post-therapeutic whole-body scintigraphy and computed tomography showed no residual disease. Conclusions: Careful monitoring after TOETVA is essential due to the rare but potential risk of seeding recurrence, especially when the thyroid gland ruptures during surgery. Surgeons should be aware of this atypical complication and be prepared to recommend surgical and/or medical strategies to manage any local seeding of thyroid tissue that may occur.

Spatial Transcriptomics in a Case of Follicular Thyroid Carcinoma Reveals Clone-Specific Dysregulation of Genes Regulating Extracellular Matrix in the Invading Front.

Follicular thyroid carcinoma (FTC) is recognized by its ability to invade the tumor capsule and blood vessels, although the exact molecular signals orchestrating this phenotype remain elusive. In this study, the spatial transcriptional landscape of an FTC is detailed with comparisons between the invasive front and histologically indolent central core tumor areas. The Visium spatial gene expression platform allowed us to interrogate and visualize the whole transcriptome in 2D across formalin-fixated paraffin-embedded (FFPE) tissue sections. Four different 6 × 6 mm areas of an FTC were scrutinized, including regions with capsular and vascular invasion, capsule-near area without invasion, and a central core area of the tumor. Following successful capturing and sequencing, several expressional clusters were identified with regional variation. Most notably, invasive tumor cell clusters were significantly over-expressing genes associated with pathways interacting with the extracellular matrix (ECM) remodeling and epithelial-to-mesenchymal transition (EMT). Subsets of these genes (POSTN and DPYSL3) were additionally validated using immunohistochemistry in an independent cohort of follicular thyroid tumors showing a clear gradient pattern from the core to the periphery of the tumor. Moreover, the reconstruction of the evolutionary tree identified the invasive clones as late events in follicular thyroid tumorigenesis. To our knowledge, this is one of the first 2D global transcriptional mappings of FTC using this platform to date. Invasive FTC clones develop in a stepwise fashion and display significant dysregulation of genes associated with the ECM and EMT - thus highlighting important molecular crosstalk for further investigations.

A facile synthesis of precursor for the σ-1 receptor PET radioligand [18 F]FTC-146 and its radiofluorination.

The σ-1 receptor is a non-opioid transmembrane protein involved in various human pathologies including neurodegenerative diseases, inflammation, and cancer. The previously published ligand [18 F]FTC-146 is among the most promising tools for σ-1 molecular imaging by positron emission tomography (PET), with a potential for application in clinical diagnostics and research. However, the published six- or four-step synthesis of the tosyl ester precursor for its radiosynthesis is complicated and time-consuming. Herein, we present a simple one-step precursor synthesis followed by a one-step fluorine-18 labeling procedure that streamlines the preparation of [18 F]FTC-146. Instead of a tosyl-based precursor, we developed a one-step synthesis of the precursor analog AM-16 containing a chloride leaving group for the SN 2 reaction with 18 F-fluoride. 18 F-fluorination of AM-16 led to a moderate decay-corrected radiochemical yield (RCY = 7.5%) with molar activity (Am ) of 45.9 GBq/µmol. Further optimization of this procedure should enable routine radiopharmaceutical production of this promising PET tracer.

Nearly optimal fault-tolerant constrained tracking for multi-axis servo system via practical terminal sliding mode and adaptive dynamic programming.

In this paper, a nearly optimal tracking control is proposed for n-links robotic manipulators subject to parameter uncertainties, time-profile failures, and input saturation constraints. Firstly, the practical terminal sliding-mode (PTSM) manifold with a linear additional term is proposed to combine the system states related to joint rotation, such that the controlled states quickly fall into a tiny neighborhood of the equilibrium once they reach the PTSM manifold. Secondly, a nearly optimal sliding-mode reaching law is designed by using the adaptive dynamic programming (ADP) technique. Benefiting from a non-quadratic positive defined mapping of the proposed performance index, which relates to the derivative of the sliding-mode function, reduced-order system dynamics can be constrained to a desired region. For the bounded actuator fault caused by various inducements such as the power supply fluctuation and the wear of parts, a radial basis function neural network (RBFNN) is introduced to compensate for this, and the input saturation constraints of the controlled plant are also compensated at the same time. Innovatively, the node weights of RBFNN are updated by the critic network of the ADP framework, such that the integrity of the proposed control strategy is improved. Simulations verify the main conclusions.

Effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide in HIV late presenters.

OBJECTIVES: The efficacy of BIC/FTC/TAF in HIV late presenters initiating antiretroviral therapy (ART) has not been sufficiently evaluated. METHODS: The aim of this study was to assess the effectiveness and tolerability of BIC/FTC/TAF compared to other first-line antiretroviral regimens in treatment-naïve adult individuals from the CoRIS Cohort starting ART with CD4 counts <200 cells/mm3 and/or AIDS-defining conditions between January 1st 2019 and November 30th 2020. Logistic regression models were used to estimate odds ratios (ORs) of association between initial regimen and achievement of viral suppression (VS) (primary objective), defined as HIV RNA <50 cop/mL, and immunological recovery (IR) (secondary objective), defined as CD4 count >200 cells/mm3, at weeks 24 and 48 after initiation of ART. RESULTS: We evaluated 314 individuals (84.7% men, median age 40 years). Of them, 158 initiated with BIC/FTC/TAF. At inclusion, 117 had an AIDS-defining condition. In multivariable analyses, individuals with AIDS-defining conditions initiating ART with BIC/FTC/TAF achieved higher rates of VS at 24 weeks than other regimens (aOR: 0.2; 95% CI: 0.06-0.64) and, at 48 weeks, than DTG/ABC/3TC (aOR: 0.06; 95% CI: 0.01-0.76) and DTG + TDF/3TC (aOR: 0.2; 95% CI: 0.47-0.9). No other differences in VS or IR were observed. At 24 and 48 weeks after ART initiation, treatment discontinuations were lower with BIC/FTC/TAF than with other regimens (3.2% and 7.6% vs. 24.4% and 37.8%, respectively; P < 0.005). CONCLUSION: Our results suggest that BIC/FTC/TAF could be a preferred regimen as initial therapy in HIV late presenters because of its high effectiveness and good tolerability.

Rapid ART initiation with bictegravir/emtricitabine/tenofovir alafenamide in individuals presenting with advanced HIV disease (Rainbow study).

BACKGROUND: A rapid ART initiation approach can be beneficial in people with advanced HIV disease, in consideration of their high morbidity and mortality. The aim of our study was to evaluate the feasibility, efficacy and safety of rapid ART start with BIC/FTC/TAF in this setting. METHODS: Pilot, single-centre, single-arm, prospective, phase IV clinical trial conducted in a tertiary Italian hospital. Thirty ART-naïve people presenting with advanced HIV-1 diagnosis (defined as the presence of an AIDS-defining event and/or CD4 cell count <200 µL), were enrolled. Main exclusion criteria were active tuberculosis, cryptococcosis and pregnant/breastfeeding women. BIC/FTC/TAF was started within 7 days from HIV diagnosis. The primary endpoint was clinical or virologic failure (VF). Immunological parameters, safety, feasibility, neurocognitive performances and patient-reported outcomes were assessed as well. RESULTS: Over the study period, 40 (34%) of 116 patients diagnosed with HIV infection at INMI Spallanzani had advanced disease, of whom 30 (26%) were enrolled. The proportion of participants with HIV-RNA <50 cp/mL was 9/30 (30%) at week (w) 4, 19/30 (63%) at w12, 24/30 (80%) at w24, 23/30 (77%) at w36 and 27/30 (90%) at w48. Two unconfirmed VF occurred. No ART discontinuation due to toxicity or VF was observed. No ART modification was performed based on the review of genotype and no mutations for the study drugs were detected. Mean CD4 cells count changed by 133 cells/µL at BL to 309 cells/µL at w 48 and 83% of participants had a CD4 > 200 cells/µL at w 48. Two participants developed IRIS and one was diagnosed with disseminated TB and needed an ART switch. INTERPRETATIONS: Our results support the feasibility, efficacy and safety of BIC/FTC/TAF as a rapid ART strategy in patients with advanced HIV disease.

Bictegravir/Emtricitabine/Tenofovir Alafenamide in a Multicentre Cohort: Real-Life Experience From Spain.

BACKGROUND: The evaluation of bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) in clinical trials has shown high rates of virological suppression but information about its use in real-life settings is scarce. OBJECTIVE: To evaluate the effectiveness, safety, durability, and predictive variables of therapeutic failure of BIC/FTC/TAF in a real-life cohort. METHODS: This observational, retrospective, multicentered cohort study included treatment-naive (TN) and treatment-experienced (TE) adult patients living with HIV (PLWH) who started treatment with BIC/FTC/TAF from January 1, 2019, to January 31, 2022. Treatment effectiveness (based on intention-to-treat [ITT], modified ITT [mITT], and on-treatment [OT]), tolerability, and safety were evaluated in all patients who started BIC/FTC/TAF antiretroviral therapy. RESULTS: We included a total of 505 PLWH of whom 79 (16.6%) were TN and 426 (83.4%) were TE. Patients were followed up for a median (interquartile range [IQR]) of 19.6 (9.6-27.3) months, and 76% and 56% of PLWH reached month 6 and month 12 of treatment, respectively. Rates of TN PLWH with HIV-RNA <50 copies/mL in the OT, mITT, and ITT groups were 94%, 80%, and 62%, respectively, after 12 months of BIC/FTC/TAF treatment. Rates of TE PLWH with HIV-RNA <50 copies/mL were 91%, 88%, and 75% at month 12. The multivariate analysis revealed that neither age, sex, CD4 cell count <200 cells/µL, or viral load >100 000 copies/mL were associated with therapeutic failure. CONCLUSION AND RELEVANCE: Our real-life data showed that BIC/FTC/TAF is effective and safe for use in the treatment of both TN and TE patients in clinical practice.

Unmasking the Silent Invader: A Rare Case of Follicular Thyroid Carcinoma With Skull Metastasis and an Uncommon KRAS Q61R Mutation.

Follicular thyroid carcinoma (FTC) is a noteworthy subtype of thyroid cancer known for its tendency to metastasize through the bloodstream, usually to the lungs and bones. This case report examines an exceptionally rare instance involving an 81-year-old female presenting with an unusual metastatic scalp lesion. Remarkably, this aggressive metastasis originated from a thyroid lesion as small as 0.7 cm. Lab findings, including suppressed TSH and elevated T3 levels, revealed subclinical hyperthyroidism, adding another layer of rarity to this FTC case. Molecular profiling identified a rare KRAS Q61R mutation, providing potential insight into the case's aggressive behavior and underscoring the importance of genetic assessment in FTC. This report emphasizes the critical role of comprehensive diagnostic evaluations, including histopathological assessments, in properly diagnosing and managing FTC, especially when clinical presentations defy conventional paradigms.

Biktarvy for the treatment of HIV infection: Progress and prospects.

Bictegravir (BIC), a second-generation integrase strand-transfer inhibitor (INSTI) with high resilience to INSTI-resistance mutations, is integrated as a key component of Biktarvy® - a fixed-dose once-daily triple-drug regimen of bictegravir (BIC), emtricitabine (FTC) plus tenofovir alafenamide (TAF). Based on the accumulated evidence from HIV clinical trials and real-world studies, the clinical effectiveness of BIC + FTC + TAF has been proven non-inferior to other fixed-dose once-daily combinations such as dolutegravir + FTC + TAF and dolutegravir + abacavir + lamivudine. Biktarvy also shows limited drug-drug interactions and a high barrier to drug resistance. According to recent HIV guidelines, BIC + FTC + TAF is recommended as initial and long-term therapy for the treatment of HIV infection. For the pre-exposure prophylaxis, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) remains advisable, but BIC may be possibly added to TDF or TAF. In the development of a long-acting once-monthly regimen, the novel nano-formulation of BIC + FTC + TAF could be possibly developed in the future.

Damage Model of Steel Fiber-Reinforced Coal Gangue Concrete under Freeze-Thaw Cycles Based on Weibull Distribution.

In order to improve the utilization rate of coal gangue and expand the application range of coal gangue concrete (CGC), a certain proportion of steel fiber was added to the concrete, and the freeze-thaw cycles (FTCs) and flexural tests were used to explore the effects of different mass replacement rates of coal gangue (0%, 25%, 50%, 75%, and 100%) and different proportions of the volumetric blending of the steel fiber (0%, 0.8%, 1.0%, and 1.2%) on the frost resistance of steel fiber-reinforced CGC (SCGC). The governing laws of mass loss rate, relative dynamic elastic modulus and load-midspan deflection curve were obtained on the base of the analysis of testing results. The damage mechanisms of the SCGC under the FTCs were analyzed using the results of scanning electron microscopy (SEM). Based on the Lemaitre's strain equivalence principle and Krajcinovic's vector damage theory, a damage evolution model of the SCGC under the FTCs was established by introducing the damage variable of the SCGC satisfying Weibull distribution. The results show an increasing mass loss rate of the SCGC and a decreasing relative dynamic elastic modulus with an increasing mass replacement rate of coal gangue. The proper content of the steel fiber can reduce the mass loss rate of concrete by 10~40% and the relative loss rate of dynamic elastic modulus of concrete by 2~8%, thus significantly improving the ductility and toughness of the concrete. The established damage evolution model is well validated by the experimental results, which further help to improve the modelling accuracy. This study provides key experimental data and a theoretical basis for a wider range of proper utilization of coal gangue in cold regions.

HIV Pre-Exposure Prophylaxis, Blood Donor Deferral, Occult Infection, and Risk of HIV Transmission by Transfusion: A Fine Balance Between Evidence-Based Donor Selection Criteria and Transfusion Safety.

Pre- and postexposure prophylaxis for human immunodeficiency virus (HIV) are key to reducing the transmission of this virus. Furthermore, low-toxicity, long-acting formulations provide additional clinical benefits, in particular easier adherence to treatment and prevention. However, breakthrough HIV infections can occur despite the use of pre-exposure prophylaxis (PrEP), mainly due to suboptimal adherence or multi-drug resistant HIV strains. Albeit rare, PrEP breakthrough infections have also been reported in fully adherent patients. Should such breakthrough infection occur in an eligible blood donor, PrEP might suppress viremia and delay antibody seroconversion, thereby masking the infection and increasing the risk of transfusion transmission. This possibility has raised concerns in the blood transfusion community but remains little documented. Therefore, a literature search was performed to assess the state of knowledge on the risk of PrEP breakthrough infection, with a particular focus on the risk of HIV entering the blood supply. Evidently, PrEP breakthrough infections are rare, although the risk is not zero. Moreover, a fraction of individuals - including blood donors - do not disclose PrEP use according to various surveys and measurements of HIV PrEP analytes. Additionally, viremia and seroconversion may remain undetectable or close to the limit of detection for a long time after cessation of PrEP, particularly with long-acting antiretrovirals. Therefore, current recommendations to defer donors for at least 3 months after the last dose of oral PrEP or 2 years for long-acting PrEP appear justified, as they safeguard the blood supply and public trust toward the system. These recommendations help to safeguard blood safety and public trust in the blood supply.

Immune Reconstitution and Safe Metabolic Profile after the Switch to Bictegravir/Emtricitabine/Tenofovir Alafenamide Fumarate among Virologically Controlled PLWH: A 96 Week Update from the BICTEL Cohort.

BACKGROUND: Bictegravir/emtricitabine/tenofovir alafenamide fumarate (BIC/FTC/TAF) is a recommended once-daily single-tablet regimen for the treatment of people living with HIV (PLWH). We aimed to assess efficacy, safety, and tolerability of BIC/FTC/TAF among PLWH, with a specific focus on people older than 55 years. METHODS: We recruited an observational retrospective real-life cohort, including all PLWH who underwent a therapeutic switch to BIC/FTC/TAF, independently from the previous treatment regimen (the BICTEL cohort). Longitudinal nonparametric analyses and linear models were built. RESULTS: After 96 weeks of follow-up, 164 PLWH were included, with 106 older than 55. Both the intention-to-treat and the per-protocol analysis showed low rates of virologic failure, independent of the pre-switch anchor drug. At week 96, a significant increase in CD4+ T cell count and in CD4+/CD8+ ratio was observed, inversely correlated with baseline immune status. Fasting serum lipid profile, total body weight, BMI, and hepatic function were not affected by the switch, without new onset of metabolic syndrome or weight gain. Compared to baseline, we observed a renal function worsening which is worthy of further follow-up. CONCLUSION: BIC/FTC/TAF is an effective, safe, and well-tolerated switching strategy for PLWH, especially among those older than 55.

Cable failure tolerant control and planning in a planar reconfigurable cable driven parallel robot.

The addition of geometric reconfigurability in a cable driven parallel robot (CDPR) introduces kinematic redundancies which can be exploited for manipulating structural and mechanical properties of the robot through redundancy resolution. In the event of a cable failure, a reconfigurable CDPR (rCDPR) can also realign its geometric arrangement to overcome the effects of cable failure and recover the original expected trajectory and complete the trajectory tracking task. In this paper we discuss a fault tolerant control (FTC) framework that relies on an Interactive Multiple Model (IMM) adaptive estimation filter for simultaneous fault detection and diagnosis (FDD) and task recovery. The redundancy resolution scheme for the kinematically redundant CDPR takes into account singularity avoidance, manipulability and wrench quality maximization during trajectory tracking. We further introduce a trajectory tracking methodology that enables the automatic task recovery algorithm to consistently return to the point of failure. This is particularly useful for applications where the planned trajectory is of greater importance than the goal positions, such as painting, welding or 3D printing applications. The proposed control framework is validated in simulation on a planar rCDPR with elastic cables and parameter uncertainties to introduce modeled and unmodeled dynamics in the system as it tracks a complete trajectory despite the occurrence of multiple cable failures. As cables fail one by one, the robot topology changes from an over-constrained to a fully constrained and then an under-constrained CDPR. The framework is applied with a constant-velocity kinematic feedforward controller which has the advantage of generating steady-state inputs despite dynamic oscillations during cable failures, as well as a Linear Quadratic Regulator (LQR) feedback controller to locally dampen these oscillations.

Advances with the discovery and development of novel sigma 1 receptor antagonists for the management of pain.

INTRODUCTION: Interest in sigma-1 receptors (S1Rs) has significantly increased in the last 25 years and more recently for their role in pain modulation. S1Rs are novel chaperone proteins that modulate several cellular processes and can modulate the activity of many ion channels and receptors. They are heavily localized in pain pathways, leading to the development of S1R antagonists for pain modulation. Although the exact mechanism by which S1R antagonists act is unclear, there has been marked advances in the preclinical and clinical development of S1R antagonists. AREAS COVERED: This review covers the brief history of S1Rs and the research leading to the development of S1R antagonists in clinical trials for chronic pain. Focus is given to E-52862 and [18F]FTC-146 (aka CM-304) as their clinical development has broken ground for S1R antagonists- with both being first-in-class ligands for treatment and diagnostic imaging, respectively. EXPERT OPINION: S1R antagonists represent a unique intracellular target for pain modulation, due to the receptor's chaperone activity in modulating various proteins in pain pathways. The research on S1R has grown exponentially in the last 20 years, and as more is understood about the basic science of the receptor, the drug development in this field will also flourish.