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This paper introduces a new learning-based approach for approximately solving the Kidney-Exchange Problem (KEP), an NP-hard problem on graphs. The KEP consists of, given a pool of kidney donors and patients waiting for kidney donations, optimally selecting a set of donations to optimize the quantity and quality of transplants performed while respecting a set of constraints about the arrangement of these donations. The proposed technique consists of two major steps: the first is a Graph Neural Network (GNN) trained without supervision; the second is a deterministic non-learned search heuristic that uses the output of the GNN to find a valid solution. To allow for comparisons, we also implemented and tested an exact solution method using integer programming, two greedy search heuristics without the machine learning module, and the GNN alone without a heuristic. We analyze and compare the methods and conclude that the learning-based two-stage approach is the best solution quality, outputting approximate solutions on average 1.1 times more valuable than the ones from the deterministic heuristic alone.

Malaria affects millions of people worldwide and hundreds of thousands of people each year in Brazil. The mosquito Anopheles aquasalis is an important vector of Plasmodium vivax, the main human malaria parasite in the Americas. Reactive oxygen species (ROS) have been shown to have a role in insect innate immune responses as a potent pathogen-killing agent. We investigated the mechanisms of free radicals modulation after A. aquasalis infection with P. vivax. ROS metabolism was evaluated in the vector by studying expression and activity of three key detoxification enzymes, one catalase and two superoxide dismutases (SOD3A and SOD3B). Also, the involvement of free radicals in the mosquito immunity was measured by silencing the catalase gene followed by infection of A. aquasalis with P. vivax. Catalase, SOD3A and SOD3B expression in whole A. aquasalis were at the same levels of controls at 24 h and upregulated 36 h after ingestion of blood containing P. vivax. However, in the insect isolated midgut, the mRNA for these enzymes was not regulated by P. vivax infection, while catalase activity was reduced 24 h after the infectious meal. RNAi-mediated silencing of catalase reduced enzyme activity in the midgut, resulted in increased P. vivax infection and prevalence, and decreased bacterial load in the mosquito midgut. Our findings suggest that the interactions between A. aquasalis and P. vivax do not follow the model of ROS-induced parasite killing. It appears that P. vivax manipulates the mosquito detoxification system in order to allow its own development. This can be an indirect effect of fewer competitive bacteria present in the mosquito midgut caused by the increase of ROS after catalase silencing. These findings provide novel information on unique aspects of the main malaria parasite in the Americas interaction with one of its natural vectors.

ObjectivesTo assess the efficacy of golimumab in combination with methotrexate (MTX) versus MTX monotherapy in psoriatic arthritis (PsA) dactylitis.MethodsMulticentre, investigator-initiated, randomised, double-blind, placebo-controlled, parallel-design phase 3b trial in 11 Portuguese rheumatology centres. Patients with PsA along with active dactylitis and naive to MTX and biologic disease-modifying antirheumatic drugs (bDMARDs) were randomly assigned to golimumab or placebo, both in combination with MTX. The primary endpoint was Dactylitis Severity Score (DSS) change from baseline to week 24. Key secondary endpoints included DSS and Leeds Dactylitis Index (LDI) response, and changes from baseline in the LDI and MRI dactylitis score. Analysis was by intention-to-treat for the primary endpoint.ResultsTwenty-one patients received golimumab plus MTX and 23 MTX monotherapy for 24 weeks. One patient from each arm discontinued. Patient inclusion was halted at 50% planned recruitment due to a favourable interim analysis. Median baseline DSS was 6 in both arms. By week 24, patients treated with golimumab plus MTX exhibited significantly greater improvements in DSS relative to MTX monotherapy (median change of 5 vs 2 points, respectively; p=0.026). In the golimumab plus MTX arm, significantly higher proportions of patients achieved at least 50% or 70% improvement in DSS and 20%, 50% or 70% improvement in LDI in comparison to MTX monotherapy.ConclusionsThe combination of golimumab and MTX as first-line bDMARD therapy is superior to MTX monotherapy for the treatment of PsA dactylitis.Trial registration number NCT02065713

PurposeThe aim of this paper is to identify some specificities of production planning and control (PPC) activities in the one-of-a-kind-production (OKP) process through an extensive literature review. Relevant aspects related to systems and PPC activities in the context of OKP environment are discussed, and six opportunities for future research are highlighted.Design/methodology/approachThe following research is based on a review of 53 articles published in peer-reviewed journals over the past three decades. After an initial descriptive analysis based on bibliometric indicators, a cluster analysis of 15 most cited articles was carried out using multivariate data analysis techniques and in-depth analysis.FindingsThe results reveal some specificities inherent to the clusters featured in the research, including aspects of planning, control and systems for OKP process. This cluster addresses information regarding next-generation manufacturing systems, scheduling and design science, computer simulation and project approach. On the other hand, the authors point out six topics for future research regarding contemporary issues associated with PPC in the context of OKP.Originality/valueThis paper fills an important gap regarding OKP production planning and control practices. The results provide a theoretical overview of different PPC practices suitable for the OKP environment. Furthermore, it can provide insights for scientific developments in order to manage the complexity inherent in the OKP process.

The antibacterial, antifungal, and anti-inflammatory properties of refined wood vinegar make it a promising product for ruminant nutrition. This study aimed to evaluate the effect of increasing oral doses (0, 10, 20, 30, and 40 mL d−1) of wood vinegar (WV) on the intake, apparent digestibility, ingestive behavior, water balance, ruminal parameters, serum biochemistry, nitrogen balance, and physiology of sheep fed with high levels of concentrate. We used five castrated male sheep, 1/2 Dorper × 1/2 Santa Inês, with an average age of 36 months and an average weight of 59.34±5.73 kg, in a Latin-square design. The animals were provided a total mixed ration formulated at a roughage-to-concentrate ratio of 20:80, which was offered twice daily following the delivery of half the daily dose of WV. There was no effect (P>0.05) of WV on dry-matter intake. Increasing WV levels linearly increased (P<0.05) the neutral-detergent fiber intake and apparent digestibility of crude protein in the sheep's diet. Feeding time was increased (P<0.05) by increasing the supply of WV to the sheep; pH values decreased (P<0.05), and ruminal ammonia nitrogen increased (P<0.05) with an increasing dose of WV. The increase in the WV supplied did not influence the water absorbed and nitrogen retained by the lambs (P>0.05). The supply of WV to lambs altered the concentrations of total protein, globulin, urea, and gamma-glutamyltransferase (P<0.05). It may be advisable to offer up to 40 mL d−1 of WV to sheep fed high-concentrate diets.

Abstract Background Sodium glucose co-transporter 2 inhibitors (SGLT2i) and mineralocorticoid receptor antagonists (MRA) reduce heart failure (HF) events in patients with heart failure and mildly reduced or preserved ejection fraction (HFmr/pEF). The randomized comparison of SGLT2i/MRA combination versus SGLT2i or MRA alone requires further testing in HFmr/pEF. Aims To compare the efficacy (NT-proBNP change as primary outcome) and safety (potassium, creatinine, and blood pressure changes) of dapagliflozin/spironolactone combination versus dapagliflozin alone (primary comparison) and spironolactone alone (exploratory comparison). Methods SOGALDI-PEF (SOdium-Glucose cotransporter 2 inhibitor, ALDosterone AntagonIst, or both for heart failure with preserved ejection fraction; NCT05676684), a proof-of-concept investigator-initiated two-centre randomized cross-over trial comparing three arms (dapagliflozin, spironolactone, or both) for three periods of 12 weeks each intercalated by a wash-out period of 4 weeks. After two independent trials demonstrating efficacy of SGLT2i in HFmr/pEF, a mid-trial protocol amendment dropped the spironolactone alone sequence and reduced the wash-out period to 1 week. A sample size of 108 patients was estimated to provide 80% power, at a 0.05 alfa level, to detect a 0.15 LogNT-proBNP difference between the spironolactone/dapagliflozin combination and dapagliflozin alone sequence. Results SOGALDI-PEF included 108 patients with a median age of 76 years, 57% women, 42% with atrial fibrillation, 46% with type 2 diabetes, 33% having an eGFR below 60 mL/min/1.73m2, and 93% having an ejection fraction ≥ 50%. The median serum potassium was 4.3 mmol/L, and the median NT-proBNP was 764 pg/mL. Most patients were treated with renin–angiotensin blockers (68%), beta-blockers (70%) and loop diuretics (69%). Compared to other HFmr/pEF trials, SOGALDI-PEF patients were older, were more frequently women, had a high prevalence of atrial fibrillation, and had more often a preserved ejection fraction. Conclusions SOGALDI-PEF will be the first trial in HFmr/pEF to test the combination of dapagliflozin/spironolactone vs dapagliflozin alone in a randomized manner. SOGALDI-PEF will provide information on the potential efficacy and safety of concomitant administration of spironolactone with dapagliflozin vs dapagliflozin alone in an elderly population with HFmr/pEF.

The E3 ubiquitin ligase Smurf1 catalyzes the ubiquitination and proteasomal degradation of several protein substrates related to inflammatory responses and antiviral signaling. This study investigated the role of Smurf1 in modulating inflammation induced by Betacoronavirus infection. Bone marrow-derived macrophages (BMDMs) from C57BL/6 (wild-type) or Smurf1-deficient (Smurf1−/−) mice were infected with MHV-A59 to evaluate the inflammatory response in vitro. Smurf1 was found to be required to downregulate the macrophage production of pro-inflammatory mediators, including TNF, and CXCL1; to control viral release from infected cells; and to increase cell viability. To assess the impact of Smurf 1 in vivo, we evaluated the infection of mice with MHV-A59 through the intranasal route. Smurf1−/− mice infected with a lethal inoculum of MHV-A59 succumbed earlier to infection. Intranasal inoculation with a 10-fold lower dose of MHV-A59 resulted in hematological parameter alterations in Smurf1−/− mice suggestive of exacerbated systemic inflammation. In the lung parenchyma, Smurf1 expression was essential to promote viral clearance, downregulating IFN-β mRNA and controlling the inflammatory profile of macrophages and neutrophils. Conversely, Smurf1 did not affect IFN-β mRNA regulation in the liver, but it was required to increase TNF and iNOS expression in neutrophils and decrease TNF expression in macrophages. In addition, Smurf1−/− mice exhibited augmented liver injuries, accompanied by high serum levels of alanine aminotransferase (ALT). These findings suggest that Smurf1 plays a critical role in regulating the inflammatory response in macrophages and attenuating systemic inflammation during Betacoronavirus infection.

To compare visual outcomes and performance between bilateral implantation of a diffractive trifocal intraocular lens (IOL) Acrysof PanOptix TFNT00 and blended implantation of two different near add power bifocal IOLs: Acrysof Restor SV25T0 in dominant eye and Acrysof Restor SN6AD1 in the nondominant eye. This prospective, nonrandomized, consecutive and comparative study assessed 20 patients (40 eyes) who had bilateral cataract surgery performed using the IOLs described. Patients were divided into groups, bilateral trifocal implant and blended implant. Evaluation included measurement of binocular uncorrected and corrected distance visual acuity at 4 m (UDVA, CDVA) and uncorrected intermediate (60 cm) and near (at 40 cm) visual acuity; contrast sensitivity (CS) and visual defocus curve. Postoperative CDVA comparison showed no statistical significance between groups. UDVA was significantly better in the trifocal groups. Under photopic conditions, the trifocal group had better CS in higher frequencies with and without glare. The binocular defocus curve demonstrated a trifocal behavior in both groups, with the bilateral trifocal group exhibiting better performance for intermediate vision. Both lens combinations were able to provide good near, intermediate and distance vision, with the trifocal group showing significantly better performance at intermediate distances and better CS under photopic conditions.

BackgroundLung congestion is frequent in heart failure (HF) and is associated with symptoms and poor prognosis. Lung ultrasound (LUS) identification of B-lines may help refining congestion assessment on top of usual care. Three small trials comparing LUS-guided therapy to usual care in HF suggested that LUS-guided therapy could reduce urgent HF visits. However, to our knowledge, the usefulness of LUS in influencing loop diuretic dose adjustment in ambulatory chronic HF has not been studied.AimsTo study whether to show or not LUS results to the HF assistant physician would change loop diuretic adjustments in “stable” chronic ambulatory HF patients.MethodsProspective randomised single-blinded trial comparing two strategies: (1) open 8-zone LUS with B-line results available to clinicians, or (2) blind LUS. The primary outcome was change in loop diuretic dose (up- or down-titration).ResultsA total of 139 patients entered the trial, 70 were randomised to blind LUS and 69 to open LUS. The median (percentile25-75) age was 72 (63–82) years, 82 (62%) were men, and the median LVEF was 39 (31–51) %. Randomisation groups were well balanced. Furosemide dose changes (up- and down-titration) were more frequent among patients in whom LUS results were open to the assistant physician: 13 (18.6%) in blind LUS vs. 22 (31.9%) in open LUS, OR 2.55, 95%CI 1.07–6.06. Furosemide dose changes (up- and down-titration) were more frequent and correlated significantly with the number of B-lines when LUS results were open (Rho = 0.30, P = 0.014), but not when LUS results were blinded (Rho = 0.19, P = 0.13). Compared to blind LUS, when LUS results were open, clinicians were more likely to up-titrate furosemide dose if the result “presence of pulmonary congestion” was identified and more likely to decrease furosemide dose in the case of an “absence of pulmonary congestion” result. The risk of HF events or cardiovascular death did not differ by randomisation group: 8 (11.4%) in blind LUS vs. 8 (11.6%) in open LUS.ConclusionsShowing the results of LUS B-lines to assistant physicians allowed more frequent loop diuretic changes (both up- and down-titration), which suggests that LUS may be used to tailor diuretic therapy to each patient congestion status.

Introduction Tenofovir‐based oral pre‐exposure prophylaxis (PrEP) is pivotal for HIV prevention in Latin America. Monitoring PrEP adherence is crucial for maximizing its impact and identifying individuals who may benefit from additional support. We evaluated the performance of indirect adherence measures and factors associated with PrEP non‐adherence in Brazil, Mexico and Peru. Methods ImPrEP was a prospective, multicentre, PrEP implementation study which enrolled 9509 persons from 6 February 2018 to 30 June 2021. For this analysis, we included men who have sex with men (MSM) aged 18–24 years and transgender women aged 18+ years with at least one dried blood spot (DBS) sample collected. Adherence was assessed objectively (tenofovir diphosphate [TFV‐DP] levels in DBS) and indirectly (medication possession rate [MPR] and self‐report). We estimated area under the curve (AUC) to evaluate the performance of each indirect adherence measure, and the optimal cut‐off points for discriminating protective TFV‐DP levels based on the Youden index. We used generalized estimating equations to identify factors associated with PrEP non‐adherence (TFV‐DP<900 fmol/punch). Results We included 2096 participants (1692 young MSM and 404 transgender women) with 4257 DBS samples. Overall, 62.3% DBS samples showed protective TFV‐DP levels, which declined over time (68.8% at week 4 to 33.8% at week 124). Both MPR and self‐report demonstrated moderate concordance (AUC: 0.74) with no difference between them (p = 0.79). Optimal cut‐offs were 97.6% for MPR and 93.3% for self‐report; self‐report showed higher sensitivity (84.6%), while MPR had higher specificity (62.9%). Among young adults, PrEP non‐adherence was higher among transgender women, participants with lower education and from Peru. Among transgender women, PrEP non‐adherence was higher among those with younger age, lower education, and from Peru and Mexico. Self‐reported sexual behaviours conveying elevated HIV exposure were associated with lower PrEP non‐adherence. Conclusions MPR and self‐report are pragmatic and clinically useful adherence monitoring tools for PrEP programmes in Latin America. Social determinants of health, particularly education, emerged as major drivers of PrEP non‐adherence among transgender women and young MSM. To maximize impact, PrEP programmes must prioritize person‐centred interventions that address stigma within health services, remove barriers to sustained engagement, strengthen health literacy and include long‐acting PrEP modalities.