Protective Role of NS1-Specific Antibodies in the Immune Response to Dengue Virus through Antibody-Dependent Cellular Cytotoxicity.

BACKGROUND: Dengue virus (DENV) non-structural protein 1 (NS1) has multiple functions within infected cells, on the cell surface, and in secreted form, and is highly immunogenic. Immunity from previous DENV infections is known to exert both positive and negative effects on subsequent DENV infections, but the contribution of NS1-specific antibodies to these effects is incompletely understood. METHODS: We investigated the functions of NS1-specific antibodies and their significance in DENV infection. We analyzed plasma samples collected in a prospective cohort study prior to symptomatic or subclinical secondary DENV infection. We measured binding to purified recombinant NS1 protein and to NS1-expressing CEM cells, antibody-mediated NK cell activation by plate-bound NS1 protein, and antibody-dependent cellular cytotoxicity (ADCC) of NS1-expressing target cells. RESULTS: We found that antibody responses to NS1 were highly serotype-cross-reactive and that subjects who experienced subclinical DENV infection had significantly higher antibody responses to NS1 in pre-infection plasma than subjects who experienced symptomatic infection. We observed strong positive correlations between antibody binding and NK activation. CONCLUSIONS: These findings demonstrate the involvement of NS1-specific antibodies in ADCC and provide evidence for a protective effect of NS1-specific antibodies in secondary DENV infection.

Efficacy and Safety of a Tetravalent Dengue Vaccine (TAK-003) in Children With Prior Japanese Encephalitis or Yellow Fever Vaccination.

BACKGROUND: We explored the impact of prior Yellow fever (YF) or Japanese encephalitis (JE) vaccination on the efficacy of Takeda's dengue vaccine candidate, TAK-003 (NCT02747927). METHODS: Children 4-16 years of age were randomized 2:1 to receive TAK-003 or placebo and were under active febrile surveillance. Symptomatic dengue was confirmed by serotype-specific RT-PCR. YF and JE vaccination history was recorded. RESULTS: Of the 20,071 children who received TAK-003 or placebo, 21.1% had a YF and 23.9% had a JE vaccination history at randomization. Fifty-seven months after vaccination, vaccine efficacy was 55.7% (95% CI, 39.7%-67.5%) in those with YF vaccination, 77.8% (70.8%-83.1%) for JE vaccination, and 53.5% (45.4%-60.4%) for no prior YF/JE vaccination. Regional differences in serotype distribution confound these results. The apparent higher vaccine efficacy in the JE vaccination subgroup could be largely explained by serotype-specific efficacy of TAK-003. Within 28 days of any vaccination, the proportions of participants with serious adverse events in the YF/JE prior vaccination population were comparable between the TAK-003 and placebo groups. CONCLUSIONS: The available data do not suggest a clinically relevant impact of prior JE or YF vaccination on TAK-003 performance. Overall, TAK-003 was well-tolerated and efficacious in different epidemiological settings.

Bridging frontiers: The role of a Global Breast Research Working Group.

Breast cancer remains a significant cause of death for women globally, despite advancements in detection and treatment, low- and middle-income countries face unique obstacles. Role of Research Working Group (RWG) can expedite research progress by fostering collaboration between scientists, clinicians, and stakeholders. Benefits of a Global RWG include pooling resources and expertise to develop new research ideas, addressing disparities, and building local research capacity, with the potential to improve breast cancer research and outcomes.

Anterolateral Thoracotomy: A Novel and Simple Technique to Improve the Closure Using the Self Locking Knot.

Thoracotomy is defined as an incision made by the surgeon in the chest wall in order to allow visibility of the thoracic cavity content. This can be used by surgeons to treat thoracic cavity content diseases including the heart, lungs, esophagus, and other organs. Thoracic incision closure remains an item with no consensus. Therefore, we present an easy way and give a little tip for closure using the slipknot that will allow the correct approach of ribs and the successful closure of the intercostal space.

Skimmed, Lactose-Free Milk Ingestion Postexercise: Rehydration Effectiveness and Gastrointestinal Disturbances Versus Water and a Sports Drink in Physically Active People.

Postexercise hydration is fundamental to replace fluid loss from sweat. This study evaluated rehydration and gastrointestinal (GI) symptoms for each of three beverages: water (W), sports drink (SD), and skimmed, lactose-free milk (SLM) after moderate-intensity cycling in the heat. Sixteen college students completed three exercise sessions each to lose ≈2% of their body mass. They drank 150% of body mass loss of the drink assigned in randomized order; net fluid balance, diuresis, and GI symptoms were measured and followed up for 3 hr after completion of fluid intake. SLM showed higher fluid retention (∼69%) versus W (∼40%; p < .001); SD (∼56%) was not different from SLM or W (p > .05). Net fluid balance was higher for SLM (-0.26 kg) and SD (-0.42 kg) than W (-0.67 kg) after 3 hr (p < .001), resulting from a significantly lower diuresis with SLM. Reported GI disturbances were mild and showed no difference among drinks (p > .05) despite ingestion of W (1,992 ± 425 ml), SD (1,999 ± 429 ml), and SLM (1,993 ± 426 ml) in 90 min. In conclusion, SLM was more effective than W for postexercise rehydration, showing greater fluid retention for the 3-hr follow-up and presenting with low-intensity GI symptoms similar to those with W and SD. These results confirm that SLM is an effective option for hydration after exercise in the heat.

Impact on infectious outcomes during laparoscopic cholecystectomy with the use of home-made vs commercial gallbladder retrieval bag: a retrospective comparative study in a high-volume center.

BACKGROUND: Laparoscopic cholecystectomy (LC) is one of the most commonly performed emergency procedures, with approximately 600,000 patients undergoing the procedure every year in the United States. Although LC is associated with fewer complications when compared with open cholecystectomy, the risk for infectious complications, including surgical site infection and intra-abdominal abscess, remains a significant source of postoperative morbidity. The goal of this study is to determine whether the gallbladder retrieval technique during LC affects risk of infectious complications. METHODS AND PROCEDURES: We conducted a retrospective comparative study in a minimally invasive surgery high-volume center in Bogota, Colombia. Patients who underwent LC in 2018 to 2020 were identified. The patients were divided into three groups. One group of LC performed using home-made gallbladder retrieval bag (HMGRB), and another group of LC performed using commercial gallbladder retrieval bag (CGRB). The primary outcomes were infectious complications of superficial site infection and intra-abdominal abscess. RESULTS: A total of 68 (7.58%) patients underwent LC using an HMGRB, and 828 (92.41%) using a CGRB. There was no significant difference in preoperative sepsis, or sex distribution between patient groups. Using t test, we found differences on age distribution among groups (p < 0.01), surgical times (p < 0.01), and length of stay (p = 0.01). When using Chi square, we found differences in Tokyo and Parkland Grading Scale severity (p < 0.01), use of postoperative antibiotics (p < 0.01), and drain use (p < 0.01). Nonetheless, there was no difference in the rate of superficial surgical site infection (p = 0.92). CONCLUSION: HMGRB are not associated with increased risk of postoperative intra-abdominal abscess or superficial surgical site infection in comparison with CGRB but imply longer surgical times and length of stay. The use of HMGRB is safe, feasible, and has lower cost during LC.

Applying the AHP to Conflict Resolution: A Russia-NATO Case Study.

In this paper, we apply the Analytic Hierarchy Process approach to conflict resolution in the context of the Russia-Ukraine conflict. We build models that illustrate the evaluation criteria, strategic and sub-criteria, and concessions for each party in this negotiation. Ratings are used to evaluate the degree to which concessions contribute or take away from successful resolution of the conflict. Afterwards, gain ratios are built to determine the benefit-cost scores so that concessions may be traded that result in equitable solutions. The approach presented here demonstrates for the first time why all concessions that parties to a conflict may offer might not trade all at once. A Max-Min optimization approach is used to maximize the gain to both parties of the conflict while minimizing the disparity in gain between the two.

Efficacy of a Dengue Vaccine Candidate (TAK-003) in Healthy Children and Adolescents 2 Years after Vaccination.

BACKGROUND: Takeda's dengue vaccine is under evaluation in an ongoing phase 3 efficacy study; we present a 2-year update. METHODS: Children (20 099, 4-16 years old) were randomized to receive 2 doses of TAK-003 or placebo 3 months apart and are under surveillance to detect dengue by serotype-specific RT-PCR. RESULTS: Cumulative efficacy against dengue approximately 27 months since first dose was 72.7% (95% confidence interval [CI], 67.1%-77.3%), including 67.0% (95% CI, 53.6%-76.5%) in dengue-naive and 89.2% (95% CI, 82.4%-93.3%) against hospitalized dengue. In the second year, decline in efficacy was observed (56.2%; 95% CI, 42.3%-66.8%) with the largest decline in 4-5 year olds (24.5%; 95% CI, -34.2% to 57.5%); efficacy was 60.6% (95% CI, 43.8%-72.4%) in 6-11 year and 71.2% (95% CI, 41.0%-85.9%) in 12-16 year age groups. As TAK-003 efficacy varies by serotype, changes in serotype dominance partially contributed to efficacy differences in year-by-year analysis. No related serious adverse events occurred during the second year. CONCLUSIONS: TAK-003 demonstrated continued benefit independent of baseline serostatus in reducing dengue with some decline in efficacy during the second year. Three-year data will be important to see if efficacy stabilizes or declines further.Clinical Trials Registration. NCT02747927.Takeda's tetravalent dengue vaccine (TAK-003) continued to demonstrate benefit in reducing dengue independent of baseline serostatus up to 2 years after completing vaccination with some decline in efficacy during the second year in 4-16 year olds in dengue-endemic countries.

Celiac disease seroprevalence in patients with infertility. A case-control study.

BACKGROUND: Although most patients with celiac disease (CD) have digestive manifestations, in some of them they may be of extraintestinal (atypical) nature, such as chronic anemia, ataxia, and fertility disorders. OBJECTIVE: To determine the prevalence of CD-related antibodies in Mexican women with fertility disorders. MATERIAL AND METHODS: Case-control study of women who attended evaluation for fertility disorders in a specialized center. h-tTG-IgA, gliadin IgA II and gliadin IgG II were quantified; titers > 30 IU were considered positive. RESULTS: One-hundred and seventy-one cases and 171 controls were included; 137 patients (80.1%) had infertility, and 34 (19.9%), sterility. Eight patients (4.6%, 95% CI = 2.3-8.9) had at least one positive marker for CD in comparison with one woman in the control group (0.5%, 95% CI = 0.01-3, p = 0.04, odds ratio = 8.3). Six of the eight patients had unexplained infertility. CONCLUSIONS: Up to 4.6% of women with infertility had at least one positive marker for CD. As in other parts of the world, screening for CD could be recommended in women with infertility, especially in those with unexplained infertility.

ANTECEDENTES: Aunque los pacientes con enfermedad celiaca (EC) tienen en su mayoría manifestaciones digestivas, algunos pueden presentarlas de índole extraintestinal (atípicas), como anemia crónica, ataxia y trastornos de la fertilidad. OBJETIVO: Determinar la prevalencia de anticuerpos relacionados con EC en mujeres mexicanas con trastornos de la fertilidad. MATERIAL Y MÉTODOS: Estudio de casos y controles de mujeres que acudieron a valoración por trastornos de la fertilidad en un centro especializado. Se cuantificó h-tTG IgA, gliadina IgA II y gliadina IgG II; los títulos > 30 UI fueron considerados como positivos. RESULTADOS: Se incluyeron 171 casos y 171 controles; 137 pacientes (80.1 %) tuvieron infertilidad y 34 (19.9 %), esterilidad. Ocho pacientes (4.6 %, IC 95 % = 2.3-8.9) tuvieron al menos un marcador positivo para EC comparadas con una mujer del grupo control (0.5 %, IC 95 % = 0.01-3, p = 0.04, razón de momios = 8.3). Seis de las ocho pacientes presentaron infertilidad inexplicable. CONCLUSIONES: Hasta 4.6 % de las mujeres con infertilidad presentó al menos un marcador positivo para EC. Al igual que en otras partes del mundo, podría recomendarse el escrutinio para EC en mujeres con infertilidad, en especial en quienes padecen infertilidad inexplicable.

Three-year Efficacy and Safety of Takeda's Dengue Vaccine Candidate (TAK-003).

BACKGROUND: Takeda's live attenuated tetravalent dengue vaccine candidate (TAK-003) is under evaluation in a long-term clinical trial across 8 dengue-endemic countries. Previously, we have reported its efficacy and safety in both seronegative and seropositive participants and that its performance varies by serotype, with some decline in efficacy from first to second year postvaccination. This exploratory analysis provides an update with cumulative and third-year data. METHODS: Healthy 4-16 year olds (n = 20099) were randomized 2:1 to receive TAK-003 or placebo (0, 3 month schedule). The protocol included baseline serostatus testing of all participants and detection of all symptomatic dengue throughout the trial with a serotype specific reverse transcriptase-polymerase chain reaction. RESULTS: Cumulative efficacy after 3 years was 62.0% (95% confidence interval, 56.6-66.7) against virologically confirmed dengue (VCD) and 83.6% (76.8-88.4) against hospitalized VCD. Efficacy was 54.3% (41.9-64.1) against VCD and 77.1% (58.6-87.3) against hospitalized VCD in baseline seronegatives, and 65.0% (58.9-70.1) against VCD and 86.0% (78.4-91.0) against hospitalized VCD in baseline seropositives. Efficacy against VCD during the third year declined to 44.7% (32.5-54.7), whereas efficacy against hospitalized VCD was sustained at 70.8% (49.6-83.0). Rates of serious adverse events were 2.9% in TAK-003 group and 3.5% in placebo group during the ongoing long-term follow-up (ie, second half of the 3 years following vaccination), but none were related. No important safety risks were identified. CONCLUSIONS: TAK-003 was efficacious against symptomatic dengue over 3 years. Efficacy declined over time but remained robust against hospitalized dengue. A booster dose evaluation is planned.

Temperature, detriment, or advantage for memory emergence: The case of ZnO.

Despite the widespread emergence of memory effects in solid systems, understanding the basic microscopic mechanisms that trigger them is still puzzling. We report how ingredients of solid state transport in polycrystalline systems, such as semiconductor oxides, become sufficient conditions for a memristive response that points to the natural emergence of memory, discernible under an adequate set of driving inputs. The experimental confirmation of these trends will be presented along with a compact analytical theoretical picture that allows discerning the relative contribution of the main building blocks of memory and the effect of temperature, in particular. These findings can be extended to a vast universe of materials and devices, providing a unified physical explanation for a wide class of resistive memories and pinpointing the optimal driving configurations for their operation.

Close-Range Thermography and Reflectance Spectroscopy Support In Vitro and In Vivo Characterization of Colletotrichum spp. Isolates from Mango Fruits.

Colletotrichum causing anthracnose in mango is known for its variable virulence that may have an effect on disease development and efficacy of management strategies. In this study, we characterized Colletotrichum spp. isolated from mango fruits under in vitro and in vivo conditions using close-range thermography and reflectance spectroscopy. Twenty-six isolates were phylogenetically characterized to ascertain species using the internal transcribed spacer sequence. Virulence, spectral (in vivo and in vitro), and thermographic responses (in vivo) of these isolates were analyzed. Isolates were grouped into the Colletotrichum gloeosporioides species complex and classified into eight morphotypes. Mycelial growth, conidia production, sporulation abundance, and area under disease progress curve (AUDPC) varied largely among isolates. Disease symptoms were observed 4 days after inoculation (dai), and, for most morphotypes, changes in tissue temperature were registered at 11 dai, with the greatest decrease at 14 dai with pathogen sporulation. In vitro and in vivo morphotypes shared changes in the spectrum range, and main variations were found in the number of informative spectral bands. In vivo average gross reflectance was higher in disease-inoculated tissue than in healthy uninoculated tissue. Morphotype responses varied depending on AUDPC values and postinoculation time. Discriminant analysis of the spectral response using principal component analysis and partial least squares regression explained 94 to 96.3 and 98 to 99.9% of the variance from in vitro and in vivo tests, respectively. Spectral markers were obtained for four distinct morphotype groups. We found three (550 to 650, 650.1 to 790, and 1,300 to 1,400 nm) and two (520 to 830 and 1,100 to 1,450 nm) regions with highly (P < 0.05) discriminant spectral bands for diseased fruits and morphotype characterization.

Does microwave and hydrogen peroxide disinfection reduce Candida albicans biofilm on polymethyl methacrylate denture surfaces?

STATEMENT OF PROBLEM: Whether the disinfection of polymethyl methacrylate (PMMA) dentures eliminates Candida albicans biofilm is unclear. PURPOSE: The purpose of this in vitro study was to determine the antimicrobial effect of immersion in hydrogen peroxide (H2O2) and subsequent application of microwaves on the formation of C albicans biofilm on the surface of polished and unpolished PMMA disks. MATERIAL AND METHODS: Polished and unpolished PMMA disks (n=40) were mounted in a Center for Disease Control (CDC) biofilm reactor by adding yeast-dextrose-peptone (YPD) broth inoculated with C albicans in a cell suspension for 24 hours. After this period, the PMMA disks (n=8) were disinfected with 5 different solutions: saline solution, 1% sodium hypochlorite (NaOCl), H2O2, H2O2 microwaved at 650 W for 3 minutes (H2O2/µw), and distilled water microwaved at 650 W for 3 minutes (H2O/µw). On the polished and unpolished surface of each disk, arbitrary fluorescence units (AFU) were quantified with the live/dead bacterial viability kit (Invitrogen) by using confocal laser scanning microscopy (CLSM) to evaluate 10 different areas of each surface; these were counted as the colony-forming units (CFUs). The mean values were compared by using the Mann-Whitney U test (α=.05). RESULTS: Polished surfaces disinfected with H2O2/µw obtained the lowest viable cells (9.76 AFU) and nonviable cells (12.46 AFU) compared with H2O/µw and H2O2. In the unpolished surface the lowest mean values of viable cells (14.64 AFU) and nonviable cells (12.46 AFU) were obtained for the PMMA disks disinfected with H2O/µw compared with H2O2/µw and H2O2. Both polished and unpolished disks showed significant difference (P<.05) compared with the group of PMMA disks immersed in saline solution. No CFUs were detected in the polished or unpolished PMMA disks immersed in H2O2/µw or in NaOCl. CONCLUSIONS: H2O2 alone did not eliminate the formation of the biofilm of C albicans; however, in combination with the use of the microwave at 650 W for 3 minutes, the biofilm formation of C albicans on polished surfaces was reduced. The number of AFUs of viable-nonviable cells and CFUs depended on whether the surfaces are polished or unpolished.

Deleterious oral habits related to vertical, transverse and sagittal dental malocclusion in pediatric patients.

BACKGROUND: Malocclusion is highly reported among mixed dentition cases. Therefore, we aimed to determine the relationship of dental malocclusions in the vertical, transverse, sagittal planes with deleterious habits in pediatric patients. METHODS: A cross-sectional analytical study was carried out on 155 children aged 6-12 years attended at the clinic of the School of Dentistry of Universidad Nacional Mayor de San Marcos in 2017. RESULTS: Among 155 evaluated patients, 45.3% had vertical malocclusion, 52.0% had sagittal malocclusion and 13.6% had transverse malocclusion. The most frequent type of malocclusion in the vertical plane was anterior deep bite (22.2%), in the transverse plane, the edge-to-edge bite (7.1%) and the anterior crossbite (6.5%) were less frequent. Finally, in the sagittal plane, Class II Div 1 (20%) and Class III (20.7%) were the most frequent. Among the most common deleterious habits, anteroposition (58.7%) and mixed breathing (51.0%) were observed in contrast to the habit of retroposition, lip sucking and mouth breathing, which were the least frequent. Considering age and sex, children who have an atypical swallowing habit are more likely to have malocclusion in all three planes of space. CONCLUSIONS: It is concluded that there is an association between the deleterious habits with the different types of malocclusions in the different planes of the space, being the atypical swallowing a habit that should be early diagnosed and treated interdisciplinary.

Non-structural protein 1-specific antibodies directed against Zika virus in humans mediate antibody-dependent cellular cytotoxicity.

There is growing interest in understanding antibody (Ab) function beyond neutralization. The non-structural protein 1 (NS1) of Zika virus (ZIKV) is an attractive candidate for an effective vaccine as Abs against NS1, unlike the envelope or premembrane, do not carry the risk of mediating antibody-dependent enhancement. Our aim was to evaluate whether ZIKV NS1 Abs elicited following natural infection in humans can mediate antibody-dependent cellular cytotoxicity (ADCC). We evaluated the isotype specificity of ZIKV-specific Abs in immune sera and supernatants from stimulated immune PBMC and found that Abs against ZIKV NS1 and virus-like particles were predominantly of the IgG1 isotype. Using a recently developed FluoroSpot assay, we found robust frequencies of NS1-specific Ab-secreting cells in PBMC of individuals who were naturally infected with ZIKV. We developed assays to measure both natural killer cell activation by flow cytometry and target cell lysis of ZIKV NS1-expressing cells using an image cytometry assay in the presence of ZIKV NS1 Abs. Our data indicate efficient opsonization of ZIKV NS1-expressing CEM-NKR cell lines using ZIKV-immune but not ZIKV-naïve sera, a prerequisite of ADCC. Furthermore, sera from immune donors were able to induce both NK cell degranulation and lysis of ZIKV NS1 CEM-NKR cells in vitro. Our data suggest that ADCC is a possible mechanism for ZIKV NS1 Abs to eliminate virally infected target cells.

Transplant trends in Mexico during the COVID-19 pandemic: Disparities within healthcare sectors.

Healthcare systems worldwide were challenged during the COVID-19 pandemic. In Mexico, the public hospitals that perform most transplants were adapted to provide care for COVID-19 patients. Using a nationwide database, we describe the first report of the impact of COVID-19 and related transplantation healthcare policies in a middle-income country by comparing statistics before and during the pandemic (pre-COVID: March 2019-February 2020 vs. COVID era: March 2020-February 2021) and by type of institution (public vs. private). The global reduction in transplantation was higher in public institutions compared with private institutions, 89% versus 62%, respectively, p < .001. When analyzing by organ, kidney transplantation decreased by 89% at public versus 57% at private, p < .001; cornea by 88% at public versus 64% at private, p < .001; liver by 88% at public versus 35% at private, p < .001; and heart by 88% in public versus 67% at private institutions, p = .4. The COVID-19 pandemic along with the implemented health policies were associated with a decrease in donations, waiting list additions, and a decrease in transplantation, particularly at public institutions, which care for the most vulnerable.

Efficacy of a tetravalent dengue vaccine in healthy children aged 4-16 years: a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: A substantial unmet need remains for safe and effective vaccines against dengue virus disease, particularly for individuals who are dengue-naive and those younger than 9 years. We aimed to assess the efficacy, safety, and immunogenicity of a live attenuated tetravalent dengue vaccine (TAK-003) in healthy children aged 4-16 years. METHODS: We present data up to 18 months post-vaccination from an ongoing phase 3, randomised, double-blind trial of TAK-003 in endemic regions of Asia and Latin America (26 medical and research centres across Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, and Thailand). Healthy children aged 4-16 years were randomly assigned 2:1 (stratified by age and region) to receive two doses of TAK-003 or two doses of placebo, 3 months apart. Investigators, participants and their parents or guardians, and sponsor representatives advising on trial conduct were masked to trial group assignments. Participants presenting with febrile illness were tested for virologically confirmed dengue (VCD) by serotype-specific RT-PCR. In timeframes beginning 30 days post-second dose, the primary endpoint (overall vaccine efficacy) was assessed in the first 11 months, and the secondary endpoints (efficacy by baseline serostatus, serotype, hospitalised dengue, and severe dengue) in the first 17 months. This study is registered with ClinicalTrials.gov, NCT02747927. FINDINGS: 20 099 participants were randomly assigned and vaccinated between Sept 7, 2016, and Aug 18, 2017; 19 021 (94·6%) were included in the per protocol analysis, and 20 071 (99·9%) in the safety set. The primary endpoint was achieved with an overall vaccine efficacy of 80·2% (95% CI 73·3 to 85·3; 61 cases of VCD in the TAK-003 group vs 149 cases of VCD in the placebo group). In the secondary endpoint assessment timeframe, an overall vaccine efficacy of 73·3% (95% CI 66·5 to 78·8) was observed. Analysis of secondary endpoints showed efficacies of 76·1% (95% CI 68·5 to 81·9) in individuals who were seropositive at baseline, 66·2% (49·1 to 77·5) in individuals who were seronegative at baseline, 90·4% (82·6 to 94·7) against hospitalised dengue, and 85·9% (31·9 to 97·1) against dengue haemorrhagic fever. Efficacy varied by individual serotypes (DENV 1, 69·8% [95% CI 54·8 to 79·9]; DENV 2, 95·1% [89·9 to 97·6]; DENV 3, 48·9% [27·2 to 64·1]; DENV 4, 51·0% [-69·4 to 85·8]). Cumulative rates of serious adverse events were similar in TAK-003 (4·0%) and placebo (4·8%) recipients, and were consistent with expected medical disorders in the study population. Infection was the most frequent reason leading to serious adverse events. 20 participants (<0·1% of the safety set) were withdrawn from the trial due to 21 adverse events by the end of part two; 14 of these participants received TAK-003 and six received placebo. INTERPRETATION: TAK-003 was well tolerated and efficacious against symptomatic dengue in children regardless of serostatus before immunisation. Vaccine efficacy varied by serotype, warranting continued follow-up to assess longer-term vaccine performance. FUNDING: Takeda Vaccines.

Energetic and structural effects of the Tanford transition on ligand recognition of bovine ß-lactoglobulin.

Bovine ß-lactoglobulin, an abundant protein in whey, is a promising nanocarrier for peroral administration of drug-like hydrophobic molecules, a process that involves transit through the different acidic conditions of the human digestive tract. Among the several pH-induced conformational rearrangements that this lipocalin undergoes, the Tanford transition is particularly relevant. This transition, which occurs with a midpoint around neutral pH, involves a conformational change of the E-F loop that regulates accessibility to the primary binding site. The effect of this transition on the ligand binding properties of this protein has scarcely been explored. In this study, we carried out an energetic and structural characterization of ß-lactoglobulin molecular recognition at pH values above and below the zone in which the Tanford transition occurs. The combined analysis of crystallographic, calorimetric, and molecular dynamics data sheds new light on the interplay between self-association, ligand binding, and the Tanford pre- and post-transition conformational states, revealing novel aspects underlying the molecular recognition mechanism of this enigmatic lipocalin.

Integrative overview of antibodies against SARS-CoV-2 and their possible applications in COVID-19 prophylaxis and treatment.

SARS-CoV-2 is a novel ß-coronavirus that caused the COVID-19 pandemic disease, which spread rapidly, infecting more than 134 million people, and killing almost 2.9 million thus far. Based on the urgent need for therapeutic and prophylactic strategies, the identification and characterization of antibodies has been accelerated, since they have been fundamental in treating other viral diseases. Here, we summarized in an integrative manner the present understanding of the immune response and physiopathology caused by SARS-CoV-2, including the activation of the humoral immune response in SARS-CoV-2 infection and therefore, the synthesis of antibodies. Furthermore, we also discussed about the antibodies that can be generated in COVID-19 convalescent sera and their associated clinical studies, including a detailed characterization of a variety of human antibodies and identification of antibodies from other sources, which have powerful neutralizing capacities. Accordingly, the development of effective treatments to mitigate COVID-19 is expected. Finally, we reviewed the challenges faced in producing potential therapeutic antibodies and nanobodies by cell factories at an industrial level while ensuring their quality, efficacy, and safety.

Frequency of Pathogenic Microorganisms in Removable Orthodontic Appliances and Oral Mucosa in Children.

OBJECTIVE: The aim of this study was to evaluate the frequency of Staphylococcus aureus, Pseudomonas aeruginosa, and Candida species in removable orthodontic appliances (ROA) and the support oral mucosa in children. STUDY DESIGN: The study participants comprised 55 patients aged 6-12 years requiring ROA. The samples of biofilm colonization from the support oral mucosa and the ROA were taken prior to the use of the ROA (T0) and 4 weeks (T1) after ROA placement. The biofilm samples were seeded on chromogenic culture plates and incubated for 24-48 h. RESULTS: The microbial species evaluated were not present in either the support oral mucosa nor in the ROA at T0. After 4 weeks, P. aeruginosa was found in the support oral mucosa with a frequency of 60%, Candida spp. with 30.9% and S. aureus with 89.09%; in the ROA, P. aeruginosa with 67.7%, Candida spp. with 32.7%, while S. aureus with 90.9%. In the ROA were found C. glabrata in 15 cases, C. albicans in 14 cases, C. tropicalis in two cases, and C. krusei in one case. In the oral mucosa there were 10 cases of C. glabrata, 14 cases of C. albicans, one case of C. tropicalis, and 0 cases of C. krusei. CONCLUSIONS: The frequency of S. aureus, P. aeruginosa, and Candida spp. increased after the orthodontic treatment in either the ROA and or in the support oral mucosa. There is a direct relation between the use of the ROA and the increase of periodontal-pathogenic microorganisms.