Efficacy of osimertinib plus bevacizumab in glioblastoma patients with simultaneous EGFR amplification and EGFRvIII mutation.

BACKGROUND: Amplification of EGFR and its active mutant EGFRvIII are common in glioblastoma (GB). While EGFR and EGFRvIII play critical roles in pathogenesis, targeted therapy with EGFR-tyrosine kinase inhibitors or antibodies has shown limited efficacy. To improve the likelihood of effectiveness, we targeted adult patients with recurrent GB enriched for simultaneous EGFR amplification and EGFRvIII mutation, with osimertinib/bevacizumab at doses described for non-small cell lung cancer. METHODS: We retrospectively explored whether previously described EGFRvIII mutation in association with EGFR gene amplification could predict response to osimertinib/bevacizumab combination in a subset of 15 patients treated at recurrence. The resistance pattern in a subgroup of subjects is described using a commercial next-generation sequencing panel in liquid biopsy. RESULTS: There were ten males (66.7%), and the median patient's age was 56 years (range 38-70 years). After their initial diagnosis, 12 patients underwent partial (26.7%) or total resection (53.3%). Subsequently, all cases received IMRT and concurrent and adjuvant temozolomide (TMZ; the median number of cycles 9, range 6-12). The median follow-up after recurrence was 17.1 months (95% CI 12.3-22.6). All patients received osimertinib/bevacizumab as a second-line intervention with a median progression-free survival (PFS) of 5.1 months (95% CI 2.8-7.3) and overall survival of 9.0 months (95% CI 3.9-14.0). The PFS6 was 46.7%, and the overall response rate was 13.3%. After exposure to the osimertinib/bevacizumab combination, the main secondary alterations were MET amplification, STAT3, IGF1R, PTEN, and PDGFR. CONCLUSIONS: While the osimertinib/bevacizumab combination was marginally effective in most GB patients with simultaneous EGFR amplification plus EGFRvIII mutation, a subgroup experienced a long-lasting meaningful benefit. The findings of this brief cohort justify the continuation of the research in a clinical trial. The pattern of resistance after exposure to osimertinib/bevacizumab includes known mechanisms in the regulation of EGFR, findings that contribute to the understanding and targeting in a stepwise rational this pathway.

Chromatic aberration compensation in numerical reconstruction of digital holograms by Fresnel-Bluestein propagation.

In this Letter, we present a method for chromatic compensation in numerical reconstruction of digitally recorded holograms based on Fresnel-Bluestein propagation. The proposed technique is applied to correct the chromatic aberration that arises in the reconstruction of RGB holograms of both millimeter- and micrometer-sized objects. The results show the feasibility of this strategy to remove the wavelength dependence of the size of the numerically propagated wavefields.

Outcome Evaluation of a Policy-Mandated Lifestyle and Environmental Modification Program in a National Job Training Center.

Excess weight gain is common when adolescents become young adults, but there are no obesity prevention or weight management interventions that have been tested for emerging adults who follow non-traditional post-secondary paths, such as enrolling in job training programs. We evaluated Healthy Eating & Active Lifestyles (HEALs), a policy-mandated lifestyle education/environmental modification program, at a job training center for low-income 16-24 year olds. We examined average change in body mass index (BMI) z-score from baseline to 6 months for emerging adults (aged 16-24 years) in pre-HEALs implementation (n = 125) and post-HEALs implementation (n = 126) cohorts living at the job training center, by baseline weight status. In both cohorts, average BMI z-score significantly increased from baseline to 6 months for students with BMI < 25. Average BMI z-score significantly decreased for the overweight (BMI 25 to <30; -0.11, p = .03) and obese (BMI ≥ 30; -0.11, p = .001) students only within the post-HEALs cohort; changes within the pre-HEALs cohort and between cohorts were not significant. HEALs may promote positive weight-related trends for overweight/obese students, but prevention efforts for non-overweight/obese students need to be improved.

Interference of Monovalent, Bivalent, and Trivalent Oral Poliovirus Vaccines on Monovalent Rotavirus Vaccine Immunogenicity in Rural Bangladesh.

BACKGROUND: Trivalent oral poliovirus vaccine (OPV) is known to interfere with monovalent rotavirus vaccine (RV1) immunogenicity. The interference caused by bivalent and monovalent OPV formulations, which will be increasingly used globally in coming years, has not been examined. We conducted a post hoc analysis to assess the effect of coadministration of different OPV formulations on RV1 immunogenicity. METHODS: Healthy infants in Matlab, Bangladesh, were randomized to receive 3 doses of monovalent OPV type 1 or bivalent OPV types 1 and 3 at either 6, 8, and 10 or 6, 10, and 14 weeks of age or trivalent OPV at 6, 10, and 14 weeks of age. All infants received 2 doses of RV1 at about 6 and 10 weeks of age. Concomitant administration was defined as RV1 and OPV given on the same day; staggered administration as RV1 and OPV given ≥1 day apart. Rotavirus seroconversion was defined as a 4-fold rise in immunoglobulin A titer from before the first RV1 dose to ≥3 weeks after the second RV1 dose. RESULTS: There were no significant differences in baseline RV1 immunogenicity among the 409 infants included in the final analysis. Infants who received RV1 and OPV concomitantly, regardless of OPV formulation, were less likely to seroconvert (47%; 95% confidence interval, 39%-54%) than those who received both vaccines staggered ≥1 day (63%; 57%-70%; P < .001). For staggered administration, we found no evidence that the interval between RV1 and OPV administration affected RV1 immunogenicity. CONCLUSIONS: Coadministration of monovalent, bivalent, or trivalent OPV seems to lower RV1 immunogenicity. CLINICAL TRIALS REGISTRATION: NCT01633216.

Prevaccination Rotavirus Serum IgG and IgA Are Associated With Lower Immunogenicity of Live, Oral Human Rotavirus Vaccine in South African Infants.

BACKGROUND: Live oral rotavirus (RV) vaccines have shown modest efficacy among children in African countries for reasons that are not completely understood. We examined the possible inhibitory effect of preexisting antirotavirus antibodies on immunogenicity of monovalent RV vaccine (RV1). METHODS: Mother-infant pairs were enrolled at presentation for their routine immunization visit in Soweto, South Africa, when infants were aged 5-8 weeks. Infant serum samples were obtained before the first and second doses of RV1 and 1 month after the second dose. Maternal serum and breast milk samples were obtained prior to administration of each dose of RV1 to infants. RV-specific immunoglobulin G (IgG), IgA, and neutralizing activity in sera of infants and serum or breast milk samples of mothers were measured using enzyme-linked immunosorbent assays or a microneutralization test. RESULTS: Of the 107 serum pairs from infants who were seronegative for RV IgA at enrollment, we observed a strong positive association between IgG titers in pre-dose 1 sera of infants and mothers and significant negative associations between IgG titers in pre-dose 1 sera of infants and seroconversion to RV1 post-dose 1. Similarly, mothers whose infants' IgA seroconverted after RV1 had significantly lower pre-dose 1 IgG titers in sera than those whose infants did not seroconvert. CONCLUSIONS: High levels of preexisting serum IgG, including transplacentally acquired maternal IgG, appeared to have an inhibitory effect on the immunogenicity of RV1 among infants and may, in part, contribute to lower efficacy of RV vaccines in this and other low-income settings.

Multiple norovirus infections in a birth cohort in a Peruvian Periurban community.

BACKGROUND: Human noroviruses are among the most common enteropathogens globally, and are a leading cause of infant diarrhea in developing countries. However, data measuring the impact of norovirus at the community level are sparse. METHODS: We followed a birth cohort of children to estimate norovirus infection and diarrhea incidence in a Peruvian community. Stool samples from diarrheal episodes and randomly selected nondiarrheal samples were tested by polymerase chain reaction for norovirus genogroup and genotype. Excretion duration and rotavirus coinfection were evaluated in a subset of episodes. RESULTS: Two hundred twenty and 189 children were followed to 1 and 2 years of age, respectively. By 1 year, 80% (95% confidence interval [CI], 75%-85%) experienced at least 1 norovirus infection and by 2 years, 71% (95% CI, 65%-77%) had at least 1 episode of norovirus-associated diarrhea. Genogroup II (GII) infections were 3 times more frequent than genogroup 1 (GI) infections. Eighteen genotypes were found; GII genotype 4 accounted for 41%. Median excretion duration was 34.5 days for GII vs 8.5 days for GI infection (P = .0006). Repeat infections by the same genogroup were common, but repeat infections by the same genotype were rare. Mean length-for-age z score at 12 months was lower among children with prior norovirus infection compared to uninfected children (coefficient: -0.33 [95% CI, -.65 to -.01]; P = .04); the effect persisted at 24 months. CONCLUSIONS: Norovirus infection occurs early in life and children experience serial infections with multiple genotypes, suggesting genotype-specific immunity. An effective vaccine would have a substantial impact on morbidity, but may need to target multiple genotypes.

Effect of breastfeeding on immunogenicity of oral live-attenuated human rotavirus vaccine: a randomized trial in HIV-uninfected infants in Soweto, South Africa.

OBJECTIVE: To investigate the effect of abstention from breastfeeding, for an hour before and after each vaccination, on the immune responses of infants to two doses of rotavirus vaccine. METHODS: In Soweto, South Africa, mother-infant pairs who were uninfected with human immunodeficiency virus (HIV) were enrolled as they presented for the "6-week" immunizations of the infants. Each infant was randomly assigned to Group 1 - in which breastfeeding was deferred for at least 1 h before and after each dose of rotavirus vaccine - or Group 2 - in which unrestricted breastfeeding was encouraged. Enzyme-linked immunosorbent assays were used to evaluate the titres of rotavirus-specific IgA in samples of serum collected from each infant immediately before each vaccine dose and 1 month after the second dose. Among the infants, a fourfold or greater increase in titres of rotavirus-specific IgA following vaccination was considered indicative of seroconversion. FINDINGS: The evaluable infants in Group 1 (n=98) were similar to those in Group 2 (n=106) in their baseline demographic characteristics and their pre-vaccination titres of anti-rotavirus IgA. After the second vaccine doses, geometric mean titres of anti-rotavirus IgA in the sera of Group-1 infants were similar to those in the sera of Group-2 infants (P=0.685) and the frequency of seroconversion in the Group-1 infants was similar to that in the Group-2 infants (P=0.485). CONCLUSION: Among HIV-uninfected South African infants, abstention from breastfeeding for at least 1 h before and after each vaccination dose had no significant effect on the infants' immune response to a rotavirus vaccine.

Clinical Characteristics and Treatment of Irritable Bowel Syndrome in a Colombian Population: A Cross-Sectional Study.

BACKGROUND: Irritable bowel syndrome (IBS) is a functional disorder that leads to abdominal pain; its diagnosis is based on Rome IV criteria (recurrent abdominal pain at least 1 day per week in the last 3 months with more than two of the following: related to defecation, associated with a change in stool frequency and/or with a change in stool appearance). OBJECTIVE: To characterize an outpatient population diagnosed with IBS in Colombia during 2017-2018. METHODS: A cross-sectional study based on a review of clinical records of patients with a primary diagnosis of IBS. A representative sample of 380 individuals was recruited from a population of 38,182 people with a new diagnosis of IBS from a drug-claim database. Sociodemographic, clinical (symptoms, type of IBS, alarm features, etc.), treatment (pharmacological or not), and follow-up variables (for those with additional medical care at 3-12 months) were analyzed. The diagnosis and treatment used in the consultation were compared with clinical guidelines. RESULTS: Most of the 380 patients were women (n = 238; 62.6%), and the mean age was 40.1 ± 15.0 years. None of the physicians recorded the Rome IV criteria in the medical records. Unclassified IBS was the most prevalent subtype (n = 311; 81.8%), and the main symptom was abdominal pain (n = 327; 86.1%). Only 73 patients (19.2%) had follow-up data. The most frequently used drugs were aluminum hydroxide (n = 203; 53.4%) and hyoscine N-butyl bromide (n = 200; 52.6%). Regarding drugs included in the clinical practice guidelines, 19 people received loperamide (5.0%), 3 received trimebutine (0.8%), and 1 received sertraline (0.3%). CONCLUSIONS: The patients were diagnosed without clearly established criteria, and they were treated symptomatically with little follow-up.

Cavia porcellus as a model for experimental infection by Trypanosoma cruzi.

The guinea pig (Cavia porcellus) is a natural reservoir for Trypanosoma cruzi but has seldom been used as an experimental infection model. We developed a guinea pig infection model for acute and chronic Chagas disease. Seventy-two guinea pigs were inoculated intradermally with 10(4) trypomastigotes of T. cruzi strain Y (experimental group); 18 guinea pigs were used as control group. Eight animals from the experimental group and two from the control group were sacrificed 5, 15, 20, 25, 40, 55, 115, 165, and 365 days after inoculation. During the acute phase (15 to 55 days), we observed parasitemia (with a peak on day 20) and positive IgM and IgG Western blots with anti-shed acute-phase antigen bands. The cardiac tissue showed vasculitis, necrosis (on days 40 to 55), moderate to severe inflammation, and abundant amastigote nests. Smaller numbers of amastigote nests were also present in kidney, brain, and other organs. In the early chronic phase (115 to 165 days), parasitemia disappeared and anti-T. cruzi IgG antibodies were still detectable. In cardiac tissue, the number of amastigote nests and the grade of inflammation decreased. In the chronic phase (365 days), the cardiac tissue showed vasculitis and fibrosis; detectable parasite DNA was associated with higher grades of inflammation. The experimental T. cruzi infection model in guinea pigs shows kinetics and pathologic changes similar to those of the human disease.

Prognostic significance of telomerase reverse transcriptase promoter gen mutations in high grade meningiomas / Importancia pronóstica de las mutaciones del gen promotor de la transcriptasa inversa de la telomerasa en los meningiomas de alto grado

Introduction: Mutations in the promoter region of telomerase reverse transcriptase occur frequently in meningiomas. Objective: To estimate the prognostic importance of telomerase reverse transcriptase mutations in Colombian patients with grades II and III meningioma. Materials and methods: This was a multicenter retrospective cohort study of patients diagnosed with refractory or recurrent WHO grades II and III meningiomas, recruited between 2011 and 2018, and treated with systemic therapy (sunitinib, everolimus ± octreotide, and bevacizumab). Mutation status of the telomerase reverse transcriptase promoter was established by PCR. Results: Forty patients were included, of which telomerase reverse transcriptase mutations were found in 21 (52.5%), being C228T and C250T the most frequent variants with 87.5 % and 14.3 %, respectively. These were more frequent among patients with anaplastic meningiomas (p=0.18), with more than 2 recurrences (p=0.04); and in patients with parasagittal region and anterior fossa lesions (p=0.05). Subjects characterized as having punctual mutations were more frequently administered with everolimus, sunitinib and bevacizumab drug series (p=0.06). Overall survival was 23.7 months (CI95% 13.1-34.2) and 43.4 months (CI95% 37.5-49.3; p=0.0001) between subjects with and without mutations, respectively. Multivariate analysis showed that the number of recurrences and the presence of telomerase reverse transcriptase mutations were tthe only variables that negatively affected overall survival. Conclusions: Mutations in telomerase reverse transcriptase allows the identification of high-risk patients and could be useful in the selection of the best medical treatment.

Introducción. En los meningiomas, ocurren con frecuencia mutaciones en la región promotora de la transcriptasa inversa de la telomerasa. Objetivo. Estimar la importancia pronóstica de las mutaciones de la transcriptasa inversa de la telomerasa en pacientes colombianos con meningiomas de grados II y III. Materiales y métodos. Es un estudio de cohorte, retrospectivo y multicéntrico, que incluyó pacientes con diagnóstico de meningioma persistente o recidivante, de grados II y III, según la clasificación de la OMS, reclutados entre el 2011 y el 2018, con tratamiento sistémico (sunitinib, everolimus con octreótido o sin él, y bevacizumab). El estado de la mutación del promotor de la transcriptasa inversa de la telomerasa se determinó por medio de la PCR. Resultados. Se incluyeron 40 pacientes, en 21 (52,5 %) de los cuales se encontraron mutaciones en la transcriptasa inversa de la telomerasa, siendo las variantes más frecuentes la C228T (87,5 %) y la C250T (14,3 %). Estas fueron más frecuentes entre los pacientes con meningiomas anaplásicos (p=0,18), en aquellos con más de dos recurrencias (p=0,04), y en los que presentaron lesiones en la región parasagital y la fosa anterior (p=0,05). Los sujetos caracterizados por tener alteraciones puntuales fueron tratados con mayor frecuencia con la serie de medicamentos everolimus, sunitinib y bevacizumab (p=0,06). Tras el inicio del tratamiento médico, la supervivencia global fue de 23,7 meses (IC95% 13,1-34,2) en los pacientes con mutaciones y, de 43,4 meses (IC95% 37,5-49,3), entre aquellos sin mutaciones (p=0,0001). Los resultados del análisis multivariado demostraron que, únicamente, el número de recurrencias y la presencia de mutaciones en el gen de la transcriptasa inversa de la telomerasa, fueron factores que afectaron negativamente la supervivencia global. Conclusiones. Las mutaciones en el gen promotor de la transcriptasa inversa de la telomerasa permiten identificar los pacientes con alto riesgo, cuya detección podría ser de utilidad para seleccionar el mejor esquema terapéutico.

Salomón Hakim, MD (1922-2011): A honeymoon with Neurosurgery.

Salomón Hakim (1922-2011) was a Colombian neurosurgeon and brain scientist This biography examines the social and cultural background through which he emerged as an inquisitive and multi-dimensional surgeon-scientist, and his lifelong contributions to the specialty of neurosurgery. With empirical knowledge in applied medical physics, electronics, electricity and chemistry, he understood the paradoxical phenomenon of symptomatic hydrocephalus with normal cerebrospinal fluid pressure. This ultimately led Hakim to describe in exquisite detail the physics of the cranial cavity and brain hydrodynamics. His name is intertwined with the identification of the entity of a syndrome which had not previously been addressed in the medical literature: Normal Pressure Hydrocephalus (Hakim's syndrome). Additionally, he designed and built various models of valved shunting devices to treat the condition (eg the Hakim programmable valve). Through his selflessness and cogent work, Hakim left a legacy and intellectual heritage that has allowed many colleagues worldwide to save thousands of lives who would be otherwise condemned to oblivion.

Ventriculo-atrial shunt. Comparison of an ultrasound-guided peel-away technique versus conventional technique in the management of normal pressure hydrocephalus: A retrospective cohort.

BACKGROUND: Normal pressure hydrocephalus (NPH) is a common neurodegenerative syndrome among the elderly characterized by ventriculomegaly and the classic triad of symmetric gait disturbance, cognitive decline and urinary incontinence. To date, the only effective treatment is a cerebrospinal fluid shunting procedure that can either be ventriculo-atrial, ventriculo-peritoneal, or lumbo-peritoneal shunt. The conventional ventriculo-atrial shunt uses venodissection, whereas the peel-away is a percutaneous ultrasound (US)-guided technique that shows some advantages over conventional technique. We sought to compare perioperative complication rates, mean operating time and clinical outcomes for both techniques in NPH patients at our institution. METHODS: A retrospective cohort-type analytical study was conducted, using clinical record data of patients diagnosed with NPH and treated at our center from January 2009 to September 2019. Parameters to be compared include: Perioperative complication rates, intraoperative bleeding, mortality, and mean operating time. Perioperative complication rates are those device-related such as shunt infection, dysfunction, and those associated with the procedure. Complications are further classified in immediate (occurring during the first inpatient stay), early (within the first 30 days of surgery), and late (after day 30 of surgery). RESULTS: A total of 123 patients underwent ventriculo-atrial shunt. Eighty-two patients (67%) underwent conventional venodissection technique and 41 patients (33%) underwent a peel-away technique. Immediate complications were 3 (3.6%) and 0 for conventional and peel-away groups, respectively. Early complications were 0 and 1 (2.4%) for conventional and peel-away groups, respectively. Late complications were 5 (6.1%) and 2 (4.9%) for conventional and peel-away groups, respectively. Mean operating time was lower in the peel-away group (P = 0.0000) and mortality was 0 for both groups. CONCLUSION: Ventriculo-atrial shunt is an effective procedure for patients with NPH. When comparing the conventional venodissection technique with a percutaneous US-guided peel-away technique, the latter offers advantages such as shorter operating time and lower perioperative complication rates.

[Early-onset type 2 diabetes mellitus. The experience from a third level medical institution]. / Diabetes tipo 2 de inicio temprano. Experiencia en una institución de tercer nivel de atención médica.

OBJECTIVE: Describe the clinical, metabolic and psychosocial characteristics observed among patients with early onset type 2 diabetes (T2DM). METHODS: We included 80 consecutive patients with early onset T2DM. All had a medical record, completed a battery of questionnaires and had blood and urine tests. RESULTS: Mean age was 49 +/- 12 years, 57.5% were women, 76.2% had a family history of diabetes and 68.8% a personal history of obesity. Diabetes was diagnosed at the mean age of 32 +/- 6 years with a mean duration of 17 +/- 11 years. Most patients (66.2%) were on poor glycemic control (Alc > 9.0%) and 30% were depressed. Insulin was commonly needed (80% of the patients) and started on average 9 years after diagnosis Significant diabetes related complications were common (71.3% of patients). A longer diabetes duration was the variable most significantly associated with developing complications (p < 0.00001). CONCLUSIONS: Patients with early onset T2DM constitute 27.8% of the total number of diabetic patients attending our clinic; they are characterized by a stronger family history of diabetes, a personal history of obesity and co-morbidities associated with metabolic syndrome. Longer disease course and poor glycemic control contribute to a high prevalence of diabetes related complications and high rates of mortality.

Metagenomic sequencing generates the whole genomes of porcine rotavirus A, C, and H from the United States.

The genus Rotavirus comprises eight species, designated A to H, and two recently identified tentative species I in dogs and J in bats. Species Rotavirus A, B, C and H (RVA, RVB, RVC and RVH) have been detected in humans and animals. While human and animal RVA are well characterized and defined, complete porcine genome sequences in the GenBank are limited compared to human strains. Here, we used a metagenomic approach to sequence the 11 segments of RVA, RVC and RVH strains from piglets in the United States (US) and explore the evolutionary relations of these RV species. Metagenomics identified Astroviridae, Picornaviridae, Caliciviridae, Coronoviridae in samples MN9.65 and OK5.68 while Picobirnaviridae and Arteriviridae were only identified in sample OK5.68. Whole genome sequencing and phylogenetic analyses identified multiple genotypes with the RVA of strain MN9.65 and OK5.68, with the genome constellation of G5/G9-P[7]/P[13]-I5/I5- R1/R1-C1-M1-A8-N1-T7-E1/E1-H1 and G5/G9-P[6]/P[7]-I5-R1/R1-C1-M1-A8-N1-T1/T7-E1/E1-H1, respectively. The RVA strains had a complex evolutionary relationship with other mammalian strains. The RVC strain OK5.68 had a genome constellation of G9-P[6]-I1-R1-C5-M6-A5-N1-T1-E1-H1, and shared an evolutionary relationship with porcine strains from the US. The RVH strains MN9.65 and OK5.68 had the genome constellation of G5-P1-I1-R1-C1-M1-A5-N1-T1-E4-H1 and G5-P1-I1-R1-C1-M1-A5-N1-T1-E1-H1, indicating multiple RVH genome constellations are circulating in the US. These findings allow us to understand the complexity of the enteric virome, develop improved screening methods for RVC and RVH strains, facilitate expanded rotavirus surveillance in pigs, and increase our understanding of the origin and evolution of rotavirus species.

Cerebrospinal fluid closing pressure-guided tap test for the diagnosis of idiopathic normal pressure hydrocephalus: A descriptive cross-sectional study.

BACKGROUND: Tap test improves symptoms of idiopathic normal pressure hydrocephalus (iNPH); hence, it is widely used as a diagnostic procedure. However, it has a low sensitivity and there is no consensus on the parameters that should be used nor the volume to be extracted. We propose draining cerebrospinal fluid (CSF) during tap test until a closing pressure of 0 cm H2O is reached as a standard practice. We use this method with all our patients at our clinic. METHODS: This is a descriptive cross-sectional study where all patients with presumptive diagnosis of iNPH from January 2014 to December 2019 were included in the study. We used a univariate descriptive analysis and stratified analysis to compare the opening pressure and the volume of CSF extracted during the lumbar puncture, between patients in whom a diagnosis of iNPH was confirmed and those in which it was discarded. RESULTS: A total of 92 patients were included in the study. The mean age at the time of presentation was 79.4 years and 63 patients were male. The diagnosis of iNPH was confirmed in 73.9% patients. The mean opening pressure was 14.4 cm H2O mean volume of CSF extracted was 43.4 mL. CONCLUSION: CSF extraction guided by a closing pressure of 0 cm H2O instead of tap test with a fixed volume of CSF alone may be an effective method of optimizing iNPH symptomatic improvement and diagnosis.

Evolution of P[8], P[4], and P[6] VP8* genes of human rotaviruses globally reported during 1974 and 2017: possible implications for rotavirus vaccines in development.

Non-replicating parenteral rotavirus (RV) vaccine candidates are in development in an attempt to overcome the lower efficacy and effectiveness of oral RV vaccines in low-income countries. One of the leading candidates is a truncated recombinant VP8* protein, expressed in Escherichia coli from original sequences of the prototype RV genotypes P[8], P[4], or P[6] isolated before 1983. Since VP8* is highly variable, it was considered useful to examine the evolutionary changes of RV strains reported worldwide over time in relation to the three P2-VP8 vaccine strains. Here, we retrieved from the GenBank 6,366 RV VP8* gene sequences of P[8], P[4], or P[6] strains isolated between 1974 and 2017, in 77 countries, and compared them with those of the three P2-VP8 vaccine strains: Wa (USA, 1974, G1P[8]), DS-1 (USA, 1976, G2P[4]), and 1076 (Sweden, 1983, G2P[6]). Phylogenetic analysis showed that 94.9% (4,328/4,560), 99.8% (1,141/1,143), and 100% (663/663) of the P[8], P[4], and P[6] strains, respectively, reported globally between 1974 and 2018 belong to non-vaccine lineages. These P[8], P[4], and P[6] RV strains have a mean of 9%, 5%, and 6% amino acid difference from the corresponding vaccine strains. Additionally, in the USA, the mean percentage difference between all the P[8] RV strains and the original Wa strain increased over time: 4% (during 1974-1980), 5% (1988-1991), and 9% (2005-2013). Our analysis substantiated high evolutionary changes in VP8* of the P[8], P[4], and P[6] major RV strains and their increasing variations from the candidate subunit vaccine strains over time. These findings may have implications for the development of new RV vaccines.

Decreased performance of live attenuated, oral rotavirus vaccines in low-income settings: causes and contributing factors.

INTRODUCTION: Numerous studies have shown that the oral rotavirus vaccines are less effective in infants born in low income countries compared to those born in developed countries. Identifying the specific factors in developing countries that decrease and/or compromise the protection that rotavirus vaccines offer, could lead to a path for designing new strategies for the vaccines' improvement. AREAS COVERED: We accessed PubMed to identify rotavirus vaccine performance studies (i.e., efficacy, effectiveness and immunogenicity) and correlated performance with several risk factors. Here, we review the factors that might contribute to the low vaccine efficacy, including passive transfer of maternal rotavirus antibodies, rotavirus seasonality, oral polio vaccine (OPV) administered concurrently, microbiome composition and concomitant enteric pathogens, malnutrition, environmental enteropathy, HIV, and histo blood group antigens. EXPERT COMMENTARY: We highlight two major factors that compromise rotavirus vaccines' efficacy: the passive transfer of rotavirus IgG antibodies to infants and the  co-administration of rotavirus vaccines with OPV. We also identify other potential risk factors that require further research because the data about their interference with the efficacy of rotavirus vaccines are inconclusive and at times conflicting.

Effect of Antibiotic-Mediated Microbiome Modulation on Rotavirus Vaccine Immunogenicity: A Human, Randomized-Control Proof-of-Concept Trial.

Rotavirus vaccines (RVV) protect against childhood gastroenteritis caused by rotavirus (RV) but have decreased effectiveness in low- and middle-income settings. This proof-of-concept, randomized-controlled, open-label trial tested if microbiome modulation can improve RVV immunogenicity. Healthy adults were randomized and administered broad-spectrum (oral vancomycin, ciprofloxacin, metronidazole), narrow-spectrum (vancomycin), or no antibiotics and then vaccinated with RVV, 21 per group per protocol. Baseline anti-RV IgA was high in all subjects. Although antibiotics did not alter absolute anti-RV IgA titers, RVV immunogenicity was boosted at 7 days in the narrow-spectrum group. Further, antibiotics increased fecal shedding of RV while also rapidly altering gut bacterial beta diversity. Beta diversity associated with RVV immunogenicity boosting at day 7 and specific bacterial taxa that distinguish RVV boosters and RV shedders were identified. Despite the negative primary endpoint, this study demonstrates that microbiota modification alters the immune response to RVV and supports further exploration of microbiome manipulation to improve RVV immunogenicity.

Epilepsia y quemados: Descripción de casos

La epilepsia es uno de los trastornos neurológicos más frecuentes a nivel mundial y afecta a más de 70 millones de personas en todo el mundo, las quemaduras son eventos traumáticos que representan un importante problema de salud pública. Método: Se realizó un estudio descriptivo de corte transversal, se incluyeron pacientes con quemaduras secundarias a eventos convulsivos, en un hospital de Bogotá, Colombia entre agosto de 2019 y diciembre de 2020, con el objetivo de describir la frecuencia y características de las quemaduras secundarias a un evento convulsivo en esta población. Resultados: La mayoría de los casos se presentó en mujeres solteras (65%) con una edad promedio de 44 años provenientes en su mayoría de zona urbana (70%), con ocupación principal ama de casa (45%), el principal desencadenante de la crisis epiléptica fue la mala adherencia al tratamiento (70%), el 95% de los pacientes no tuvo un control previo por neurología y el área corporal más afectada fue las extremidades superiores (brazos) en el 55%, la estancia hospitalaria promedio fue de 20 días en Unidad de Cuidados Intensivos. Conclusión: La epilepsia es una enfermedad prevalente, una baja adherencia a la medicación y un inadecuado seguimiento neurológico pueden llevar a problemas graves como las quemaduras, con la consecuente afectación de la calidad de vida de los pacientes y estancias en UCI prolongadas, así como secuelas importantes que imposibiliten la reincorporación laboral de la persona, convirtiéndose en un problema de salud pública.

Epilepsy is one of the most common neurological disorders worldwide, affecting more than 70 million people worldwide; on the other hand, burns are traumatic events that represent an important public health problem. Considering the relationship that has been documented between epilepsy and burns, a descriptive cross-sectional study was carried out in the burn unit of a tertiary care hospital in the city of Bogotá, Colombia. 78 medical records were reviewed, 20 correspond to patients burned during a convulsive episode, most of the cases occurred in single women (65%) with an average age of 44 years, mostly from urban areas (70%), with main occupation housewife (45%), the main trigger of the epileptic crisis was poor adherence to treatment (70%), 95% of the patients did not have a previous control by neurology and the body area most affected was the upper limbs (arms) in 55%, the average hospital stay was 20 days in the Intensive Care Unit. Epilepsy is a disease with poor adherence to medication and inadequate neurological follow-up that may be related to the presence of convulsive episodes, which can lead to serious problems such as burns, with the consequent impact on the quality of life of patients. as well as important consequences that make it impossible for the person to return to work, becoming a public health problem.

Innate Immune Factors in Mothers' Breast Milk and Their Lack of Association With Rotavirus Vaccine Immunogenicity in Nicaraguan Infants.

To better understand underlying causes of lower rotavirus vaccine effectiveness in low-middle income countries (LMICs), we measured innate antiviral factors in Nicaraguan mothers' milk and immune response to the first dose of the pentavalent rotavirus vaccine in corresponding infants. No relationship was found between concentrations of innate factors and rotavirus vaccine response.