Dynamic changes in polioviruses identified by environmental surveillance in Guangzhou, 2009-2021.

Polio cases can be missed by acute flaccid paralysis (AFP) case surveillance alone, emphasizing the importance of environmental surveillance (ES). In this study, to investigate the serotype distribution and epidemiological trends of poliovirus (PV), we characterized PV isolated from domestic sewage in Guangzhou City, Guangdong Province, China from 2009 to 2021. A total of 624 sewage samples were collected from the Liede Sewage Treatment Plant, and the positive rates of PV and non-polio enteroviruses were 66.67% (416/624) and 78.37% (489/624), respectively. After sewage sample treatment, each sewage sample was inoculated in six replicate tubes of three cell lines, and 3370 viruses were isolated during the 13-year surveillance period. Among these, 1086 isolates were identified as PV, including type 1 PV (21.36%), type 2 PV (29.19%), and type 3 PV (49.48%). Based on VP1 sequences, 1057 strains were identified as Sabin-like, 21 strains were high-mutant vaccines, and eight strains were vaccine-derived poliovirus (VDPV). The numbers and serotypes of PV isolates in sewage were influenced by the vaccine switch strategy. After type 2 OPV was removed from the trivalent oral PV (OPV) vaccine and a bivalent OPV (bOPV) was adopted in May 2016, the last type 2 PV strain was isolated from sewage, with no detection thereafter. Type 3 PV isolates increased significantly and became the dominant serotype. Before and after the second vaccine switch in January 2020, that is, from the first dose of IPV and second-fourth doses of bOPV to the first two doses of IPV and third-fourth doses of bOPV, there was also a statistical difference in PV positivity rates in sewage samples. Seven type 2 VDPVs and one type 3 VDPV were identified in sewage samples in 2009-2021, and phylogenetic analysis indicated that all VDPVs isolated from ES in Guangdong are newly discovered VDPVs, different from VDPV previously discovered in China, and were classified as ambiguous VDPV. It is noteworthy that no VDPV cases were reported in AFP case surveillance in the same period. In conclusion, continued PV ES in Guangzhou since April 2008 has been a useful supplement to AFP case surveillance, providing an important basis for evaluating the effectiveness of vaccine immunization strategies. ES improves early detection, prevention, and control; accordingly, this strategy can curb the circulation of VDPVs and provide a strong laboratory basis for maintaining a polio-free status.

Research about DoS Attack against ICPS.

This paper studies denial-of-services (DoS) attacks against industrial cyber-physical systems (ICPSs) for which we built a proper ICPS model and attack model. According to the impact of different attack rates on systems, instead of directly studying the time delay caused by the attacks some security zones are identified, which display how a DoS attack destroys the stable status of the ICPS. Research on security zone division is consistent with the fact that ICPSs' communication devices actually have some capacity for large network traffic. The research on DoS attacks' impacts on ICPSs by studying their operation conditions in different security zones is simplified further. Then, a detection method and a mimicry security switch strategy are proposed to defend against malicious DoS attacks and bring the ICPS under attack back to normal. Lastly, practical implementation experiments have been carried out to illustrate the effectiveness and efficiency of the method we propose.

Efficacy and tolerability of lamivudine plus dolutegravir as a switch strategy in a multicentre cohort of patients with suppressed HIV-1 replication.

OBJECTIVES: We evaluated the efficacy and tolerability of lamivudine + dolutegravir in a cohort of HIV-1 infected, treatment-experienced patients with undetectable HIV-RNA. METHODS: Time to treatment discontinuation (TD) and virological failure (VF) and their predictors were assessed in a multicenter cohort of HIV-1 infected patients, starting lamivudine + dolutegravir after reaching viral suppression. Secondary objective was the evaluation of changes in lipid profile, renal and immunological functions at week 48. RESULTS: We enrolled 206 patients (72.8% male, with 51 years median age), who mainly switched their antiretroviral therapy for simplification (32.5%) or drug toxicity (54.5%). The estimated probability of maintaining virological suppression at 48 and 96 weeks was 98.2% and 95.1%, respectively. VF was independently predicted by cumulative time on antiretroviral therapy. The estimated probability of remaining on lamivudine plus dolutegravir was 86.7% and 80.5% at week 48 and 96, respectively. A significant improvement in immunological function (CD4 count and CD4/CD8 ratio) was evidenced at week 48, as well as a decrease in total cholesterol/HDL ratio, triglycerides and estimated glomerular filtration rate. CONCLUSIONS: Lamivudine plus dolutegravir was effective in maintaining viral suppression in our cohort and led to an improvement in metabolic and immunologic functions.

Switching to Raltegravir From a Virologically Effective Boosted Protease Inhibitor Regimen: A Comparative Effectiveness Analysis From the French Hospital Database on HIV (FHDH-ANRS CO4).

BACKGROUND: In individuals with viral load (VL) suppression on a boosted protease inhibitor (PI) regimen, a switch to raltegravir (RAL) can be an option in case of comorbidities, but the SWITCHMRK trials challenged this strategy. Here, among individuals with VL suppression on a boosted PI, we compared outcomes between those who continued on the same regimen and those who switched to RAL. METHODS: In this cohort study from the French Hospital Database on HIV, each individual who switched to RAL was matched with up to 3 individuals who continued PI, were being followed up during the calendar period of the switch, and had the same duration of VL suppression (both ±6 months). The primary endpoint was a composite endpoint of hospitalization, or AIDS event or death, and secondary endpoints the immunovirologic responses. To control for measured confounders, the inverse probability treatment weighting (IPTW) method was applied to estimate hazards ratios between the 2 groups. RESULTS: We matched 282 RAL switchers with 838 nonswitchers. Although several variables differed significantly between the groups, including a higher prevalence of comorbidities in the RAL group, the IPTW method yielded standardized differences <10% for all variables. After IPTW, there was no difference in the risk of hospitalization or AIDS event or death between the 2 groups (13.6% and 10.5%, respectively; hazard ratio, 1.16 [95% confidence interval, .74-1.83]) and no difference in the likelihood of virologic failure or CD4 cell gain. CONCLUSIONS: In individuals with controlled VL on a boosted PI regimen who switched to RAL, none of the endpoints differed with nonswitchers after IPTW.

A Randomized Trial of Dolutegravir Plus Darunavir/Cobicistat as a Switch Strategy in HIV-1-Infected Patients With Resistance to at Least 2 Antiretroviral Classes.

Background: Suppressed patients with drug-resistant HIV-1 require effective and simple antiretroviral therapy to maintain treatment adherence and viral suppression. Methods: This randomized, open-label, noninferiority, multicenter pilot study involved HIV-infected adults who met the following criteria: confirmed HIV-1 RNA <50 copies/mL for ≥6 months preceding the study randomization, treatment with at least 3 antiretroviral drugs, and a history of drug resistance mutations against at least 2 antiretroviral classes but remaining fully susceptible to darunavir (DRV) and integrase inhibitors. Participants were randomized 1:1 to switch to dolutegravir (DTG; 50 mg once per day) plus DRV boosted with cobicistat (DRV/c; 800/150 mg once per day; 2D group) or continue with their baseline regimen (standard-of-care [SOC] group). The primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL at week 48 relative to time to loss of virologic response, with a noninferiority margin set at -12.5%. Virologic failure was defined as confirmed HIV-1 RNA ≥50 copies/mL or a single determination of HIV-1 RNA >50 copies/mL followed by antiretroviral therapy discontinuation. Results: Forty-five participants were assigned to the 2D group and 44 to the SOC group. Time to loss of virologic response showed no difference in the proportion maintaining HIV-1 RNA <50 copies/mL at week 48: 39 of 45 (86.7%; 95% CI, 73.21%-94.95%) in the 2D group vs 42 of 44 (95.4%; 95% CI, 84.53%-99.44%) in the SOC group (log-rank P = .159) with an estimated difference of -8.7 (95% CI, -22.72 to 5.14). Only 2 (4.5%) in the SOC group experienced virologic failure, and 3 participants from the 2D group experienced adverse events leading to treatment discontinuation. Conclusions: In suppressed patients with at least 2 resistant antiretroviral classes, noninferiority could not be demonstrated by fully active DRV/c plus DTG. Nevertheless, there were no unexpected adverse events or virologic failure. DRV/c plus DTG may be considered a once-daily therapy option only for well-selected patients. Clinical Trials Registration. ClinicalTrials.gov (NCT03683524).

Electrical brain activations in young children during a probabilistic reward-learning task are associated with behavioral strategy.

Both adults and children learn through feedback which events and choices in the environment are associated with higher probability of reward. This probability reward-learning ability is thought to be supported by the development of fronto-striatal reward circuits. Recent developmental studies have applied computational models of reward learning to investigate such learning in children. However, there has been limited development of task tools capable of measuring the cascade of neural reward-learning processes in children. Using a child-version of a probabilistic reward-learning task while recording event-related-potential (ERP) measures of electrical brain activity, this study examined key processes of reward learning in preadolescents (n=30), namely: (1) reward-feedback sensitivity, as measured by the early reward-related frontal ERP positivity, (2) rapid attentional shifting of processing toward favored visual stimuli, as measured by the N2pc component, and (3) longer-latency attention-related responses to reward feedback as a function of behavior strategies (i.e., Win-Stay-Lose-Shift), as measured by the central-parietal P300. Consistent with our prior work in adults, the behavioral findings indicate that preadolescents could learn stimulus-reward outcome associations, but at varying levels of performance. Neurally, poor preadolescent learners (those with slower learning rates) showed greater reward-related positivity amplitudes relative to good learners, suggesting greater reward sensitivity. We also found attention shifting towards to-be-chosen stimuli, as evidenced by the N2pc, but not to more highly rewarded stimuli. Lastly, we found an effect of behavioral learning strategies (i.e., Win-Stay-Lose-Shift) on the feedback-locked P300 over the parietal cortex. These findings provide novel insights into the key neural processes underlying reinforcement learning in preadolescents.

Successful switch (tOPV to bOPV) in India: Tribute to a resilient health system.

In accordance with the end game strategies for polio eradication a synchronized switch plan from tOPV to bOPV was implemented globally in 2016. The National Committee for Polio Eradication (NCCPE) validated the switch activities in India. An expert group of 104 academics conducted field visits in 25 states and 2 Union territories for independent verification (after an initial round of verification by the National Polio Surveillance Project [NPSP]). The objectives were to validate withdrawal and disposal of tOPV by screening cold chain points in public and private sector health facilities in both rural and urban areas; additionally, availability of bOPV and IPV was also documented. 34 filled tOPV and 5 empty vials were detected inside cold chain equipment and 17 outside. The disposal mechanism was found to be reasonably adequate. The key strategies -- 'throttling' of vaccine supplies well ahead of the switch date while preventing stock outs at various immunization points, simultaneously working with the regulators to delicense the tOPV on the switch date and helping manufacturers to calibrate vaccine production according to national timelines, and strong and persistent advocacy with professional associations to align with national bOPV and IPV policy facilitated successful accomplishment of the switch process. Effective implementation of the switch strategy in India also bears testimony to the resilience of the health system operating under diverse and heterogeneous governance.

Reducing return of disease activity in patients with relapsing multiple sclerosis transitioned from natalizumab to teriflunomide: 12-month interim results of teriflunomide therapy.

BACKGROUND: Natalizumab is an effective treatment for relapsing multiple sclerosis. Return of disease activity upon natalizumab discontinuance creates the need for follow-up therapeutic strategies. OBJECTIVE: To assess the efficacy of teriflunomide following natalizumab discontinuance in relapsing multiple sclerosis patients. METHODS: Clinically stable relapsing multiple sclerosis patients completing 12 or more consecutive months of natalizumab, testing positive for anti-John Cunningham virus antibody, started teriflunomide 14 mg/day, 28 ± 7 days after their final natalizumab infusion. Physical examination, Expanded Disability Status Scale, laboratory assessments, and brain magnetic resonance imaging were performed at screening and multiple follow-up visits. RESULTS: Fifty-five patients were enrolled in the study. The proportion of patients relapse-free was 0.94, restricted mean time to first gadolinium-enhancing lesion was 10.9 months and time to 3-month sustained disability worsening was 11.8 months. The mean number of new or enlarging T2 lesions per patient at 12 months was 0.42. Exploratory analyses revealed an annualized relapse rate of 0.08, and a proportion of patients with no evidence of disease activity of 0.68. Forty-seven patients (85.5%) reported adverse events, 95% of which were mild to moderate. CONCLUSIONS: Teriflunomide therapy initiated without natalizumab washout resulted in a low rate of return of disease activity. Clinicians may consider this a worthwhile strategy when transitioning clinically stable patients off natalizumab to another therapy.ClinicalTrials.gov Identifier: NCT01970410.

Impacts of water quality on the corrosion of cast iron pipes for water distribution and proposed source water switch strategy.

Switch of source water may induce "red water" episodes. This study investigated the impacts of water quality on iron release, dissolved oxygen consumption (ΔDO), corrosion scale evolution and bacterial community succession in cast iron pipes used for drinking water distribution at pilot scale, and proposed a source water switch strategy accordingly. Three sets of old cast iron pipe section (named BP, SP and GP) were excavated on site and assembled in a test base, which had historically transported blended water, surface water and groundwater, respectively. Results indicate that an increasing Cl- or SO42- concentration accelerated iron release, but alkalinity and calcium hardness exhibited an opposite tendency. Disinfectant shift from free chlorine to monochloramine slightly inhibited iron release, while the impact of peroxymonosulfate depended on the source water historically transported in the test pipes. The ΔDO was highly consistent with iron release in all three pipe systems. The mass ratio of magnetite to goethite in the corrosion scales of SP was higher than those of BP and GP and kept almost unchanged over the whole operation period. Siderite and calcite formation confirmed that an increasing alkalinity and hardness inhibited iron release. Iron-reducing bacteria decreased in the BP but increased in the SP and GP; meanwhile, sulfur-oxidizing, sulfate-reducing and iron oxidizing bacteria increased in all three pipe systems. To avoid the occurrence of "red water", a source water switch strategy was proposed based on the difference between local and foreign water qualities.

Dual antiretroviral therapy for HIV infection.

INTRODUCTION: For two decades, triple combinations of antiretrovirals have been the standard treatment for HIV infection. The challenges of such lifelong therapy include long-term side effects, high costs and reduced drug adherence. The recent advent of more potent and safer antiretrovirals has renewed the interest for simpler HIV regimens. Areas covered: We discuss the pros and cons of dual antiretroviral therapies in both drug-naïve and in treatment-experienced patients with viral suppression (switch strategy). Expert opinion: Some dual antiretroviral regimens are safe and efficacious, particularly as maintenance therapy. At this time, combinations of dolutegravir plus rilpivirine represent the best dual regimen. Longer follow-up and larger study populations are needed before supporting dolutegravir plus lamivudine. In contrast, dual therapy based on maraviroc is less effective. Although dual regimens with boosted protease inhibitors plus either lamivudine or raltegravir may be effective, they are penalized by metabolic side effects and risk for drug interactions. The newest dual regimens could save money, reduce toxicity and spare drug options for the future. For the first time in HIV therapeutics, less can be more. Dual therapy switching has set up a new paradigm in HIV treatment that uses induction-maintenance.

Atherogenic properties of LDL particles after switching from Truvada or Kivexa plus lopinavir/r to lamivudine plus lopinavir/r: OLE-MET substudy.

BACKGROUND: The objective of this study was to determine the impact of tenofovir or abacavir discontinuation on low-density lipoprotein (LDL) phenotype and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in HIV-infected patients treated with lopinavir/ritonavir plus 2 nucleos(t)ide reverse transcriptase inhibitors (NRTI). METHODS: Multicenter, open-label study. Patients were randomized to continue with lopinavir/ritonavir plus 2 NRTI (triple therapy) or to switch to lopinavir/ritonavir plus lamivudine (dual therapy). LDL phenotype (by gradient gel electrophoresis) and Lp-PLA2 (by 2-thio-PAF) were determined at baseline and week 48. RESULTS: Forty-four patients included (triple therapy n = 19, dual therapy n = 25): men 63.6%, age 41.5 years (25-61), Framingham score 4.9% (0.2-22). Tenofovir was part of the regimen in 28 (63.6%) patients. Dual therapy patients were younger (p = 0.013) and had lower baseline apolipoprotein A1 (p = 0.029). At week 48, there were no changes in standard lipid measurements, except ApoA1/Apo B, which increased in dual therapy (p = 0.038) with no differences between arms. At week 48, no change in LDL phenotype was found in either arm. No changes in total Lp-PLA2 activity or the relative distribution of LDL and HDL particles were found at week 48 in either arm. CONCLUSIONS: Discontinuing the third nucleos(t)ide, mainly tenofovir and abacavir, in a lopinavir/ritonavir-containing regimen was not associated with a deleterious effect on LDL phenotype nor in Lp-PLA2 activity.

A trial evaluating gradual- or immediate-switch strategies from risperidone, olanzapine, or aripiprazole to iloperidone in patients with schizophrenia.

In a 12-week randomized open-label trial, adults diagnosed with schizophrenia experiencing inadequate efficacy and/or poor tolerability on risperidone, olanzapine, or aripiprazole were randomized to switch to iloperidone either gradually (ie, down-titration of current therapy over the first 2weeks [to 50% on Day 1, 25% by Week 1, 0% by Week 2]) or immediately. All patients were titrated on iloperidone to 6mg BID by Day 4, then flexibly dosing between 6 and 12mg BID, as needed. The primary variable was the Integrated Clinical Global Impression of Change (I-CGI-C) and the primary analysis time point was Week 12. A total of 500 patients were randomized and received iloperidone (gradual switch, 240; immediate switch, 260), with 175, 155, and 170 patients switched from risperidone, olanzapine, and aripiprazole, respectively. I-CGI-C Results confirmed improved outcomes at Week 12, with scores that were similar between the gradual- and immediate-switch groups, respectively, for risperidone, 2.82 and 2.67 (95% CI: -0.229, 0.511); olanzapine, 2.87 and 3.03 (95% CI: -0.548, 0.235); and aripiprazole, 2.79 and 2.81 (95% CI: -0.405, 0.368). Incidence of adverse events (AEs) was similar in both switch groups, with the most frequently reported (≥10%) being dizziness, dry mouth, somnolence, and weight increase. In conclusion, switching to iloperidone by either a gradual or an immediate method did not reveal any clinically significant differences in ratings of overall efficacy and safety/tolerability outcomes, based on the I-CGI-C at 12weeks. Similar overall safety/AE profiles were observed regardless of the specific agent from which patients were switched.