A multi-omics systems vaccinology resource to develop and test computational models of immunity.

Systems vaccinology studies have identified factors affecting individual vaccine responses, but comparing these findings is challenging due to varying study designs. To address this lack of reproducibility, we established a community resource for comparing Bordetella pertussis booster responses and to host annual contests for predicting patients' vaccination outcomes. We report here on our experiences with the "dry-run" prediction contest. We found that, among 20+ models adopted from the literature, the most successful model predicting vaccination outcome was based on age alone. This confirms our concerns about the reproducibility of conclusions between different vaccinology studies. Further, we found that, for newly trained models, handling of baseline information on the target variables was crucial. Overall, multiple co-inertia analysis gave the best results of the tested modeling approaches. Our goal is to engage community in these prediction challenges by making data and models available and opening a public contest in August 2024.

Somatic Copy Number Alterations in Colorectal Cancer Lead to a Differentially Expressed ceRNA Network (ceRNet).

Colorectal cancer (CRC) represents the second deadliest malignancy worldwide. Around 75% of CRC patients exhibit high levels of chromosome instability that result in the accumulation of somatic copy number alterations. These alterations are associated with the amplification of oncogenes and deletion of tumor-ppressor genes and contribute to the tumoral phenotype in different malignancies. Even though this relationship is well known, much remains to be investigated regarding the effect of said alterations in long non-coding RNAs (lncRNAs) and, in turn, the impact these alterations have on the tumor phenotype. The present study aimed to evaluate the role of differentially expressed lncRNAs coded in regions with copy number alterations in colorectal cancer patient samples. We downloaded RNA-seq files of the Colorectal Adenocarcinoma Project from the The Cancer Genome Atlas (TCGA) repository (285 sequenced tumor tissues and 41 non-tumor tissues), evaluated differential expression, and mapped them over genome sequencing data with regions presenting copy number alterations. We obtained 78 differentially expressed (LFC > 1|< -1, padj < 0.05) lncRNAs, 410 miRNAs, and 5028 mRNAs and constructed a competing endogenous RNA (ceRNA) network, predicting significant lncRNA-miRNA-mRNA interactions. Said network consisted of 30 lncRNAs, 19 miRNAs, and 77 mRNAs. To understand the role that our ceRNA network played, we performed KEGG and GO analysis and found several oncogenic and anti-oncogenic processes enriched by the molecular players in our network. Finally, to evaluate the clinical relevance of the lncRNA expression, we performed survival analysis and found that C5orf64, HOTAIR, and RRN3P3 correlated with overall patient survival. Our results showed that lncRNAs coded in regions affected by SCNAs form a complex gene regulatory network in CCR.

A systems vaccinology resource to develop and test computational models of immunity.

Computational models that predict an individual's response to a vaccine offer the potential for mechanistic insights and personalized vaccination strategies. These models are increasingly derived from systems vaccinology studies that generate immune profiles from human cohorts pre- and post-vaccination. Most of these studies involve relatively small cohorts and profile the response to a single vaccine. The ability to assess the performance of the resulting models would be improved by comparing their performance on independent datasets, as has been done with great success in other areas of biology such as protein structure predictions. To transfer this approach to system vaccinology studies, we established a prototype platform that focuses on the evaluation of Computational Models of Immunity to Pertussis Booster vaccinations (CMI-PB). A community resource, CMI-PB generates experimental data for the explicit purpose of model evaluation, which is performed through a series of annual data releases and associated contests. We here report on our experience with the first such 'dry run' for a contest where the goal was to predict individual immune responses based on pre-vaccination multi-omic profiles. Over 30 models adopted from the literature were tested, but only one was predictive, and was based on age alone. The performance of new models built using CMI-PB training data was much better, but varied significantly based on the choice of pre-vaccination features used and the model building strategy. This suggests that previously published models developed for other vaccines do not generalize well to Pertussis Booster vaccination. Overall, these results reinforced the need for comparative analysis across models and datasets that CMI-PB aims to achieve. We are seeking wider community engagement for our first public prediction contest, which will open in early 2024.

Coronavirus Immunotherapeutic Consortium Database.

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has seen multiple anti-SARS-CoV-2 antibodies being generated globally. It is difficult, however, to assemble a useful compendium of these biological properties if they are derived from experimental measurements performed at different sites under different experimental conditions. The Coronavirus Immunotherapeutic Consortium (COVIC) circumvents these issues by experimentally testing blinded antibodies side by side for several functional activities. To collect these data in a consistent fashion and make it publicly available, we established the COVIC database (COVIC-DB, https://covicdb.lji.org/). This database enables systematic analysis and interpretation of this large-scale dataset by providing a comprehensive view of various features such as affinity, neutralization, in vivo protection and effector functions for each antibody. Interactive graphs enable direct comparisons of antibodies based on select functional properties. We demonstrate how the COVIC-DB can be utilized to examine relationships among antibody features, thereby guiding the design of therapeutic antibody cocktails. Database URL  https://covicdb.lji.org/.

Anticoagulación En Pacientes Con Injuria Traumática Cerebral: Revisión Narrativa / Anticoagulation In Patients With Traumatic Brain Injury: Narrative Review

RESUMEN Los pacientes que reciben anticoagulación y que presentan lesiones traumáticas craneales están en riesgo aumentado de presentar fenómenos hemorrágicos a nivel intracraneal. La mortalidad en esta clase de pacientes es elevada lo que los convierte en una población que amerita un cuidadoso abordaje y seguimiento. Usualmente los pacientes que observamos en servicios de urgencia son traumas craneales leves pero la evolución del paciente anticoagulado en algunos casos es impredecible. Actualmente, han sido publicados diversos estudios con relación a anticoagulación y lesión traumática cerebral. Presentamos una concisa revisión de la literatura enfocada a médicos neurólogos y neurocirujanos.

Abstract Patients receiving anticoagulation and those with traumatic cranial lesions are at increased risk of hemorrhagic phenomena at the intracranial level. Mortality in this class of patients is high, which makes them a population that deserves a careful approach and follow-up. Usually the patients we observe in emergency services are mild cranial traumas but the evolution of the anticoagulated patient in some cases is unpredictable. Currently, several studies have been published in relation to anticoagulation and traumatic brain injury. We present a concise review of the literature focused on neurologists and neurosurgeons.

A shift from the osteocutaneous fibula flap to the prelaminated osteomucosal fibula flap for maxillary reconstruction.

BACKGROUND: Reconstruction of the maxilla with the fibula free flap is a popular and well-described technique. The ideal intraoral lining would be mucosa, which is moist, thin, and non-hair-bearing. Prelamination of the fibula with buccal mucosa replaces like tissue with like tissue, obviates the need for a skin paddle, and facilitates placement of osseointegrated implants in a single stage. For central maxillary defects, the authors have shifted from using an osteocutaneous to a prelaminated free fibula flap. In this article, the authors report their experience using the prelaminated osteomucosal fibula for maxillary reconstruction. METHODS: From 2003 to 2011, 24 patients underwent reconstruction of a central maxillary defect using a free fibula flap. The first 10 patients had osteoseptocutaneous flaps, and the other 14 patients had prelaminated flaps. Data collected included patient age, cause of defect, type and number of operations, complications at both the donor and recipient sites, and placement of osseointegrated implants. RESULTS: The majority of patients in the series (n = 21) had central maxillary defects caused by loss of the premaxilla during early repair of bilateral cleft lip-cleft palate. There was one flap failure in the nonprelaminated flap group and one in the prelaminated group. Repeated debulking to thin the skin paddle was required in all of the patients with osteocutaneous flaps. CONCLUSIONS: Prelamination delivers like tissue to the recipient site, obviates the need for debulking, and may reduce donor-site wound problems. To the authors' knowledge, this is the largest series of prelaminated fibulas for maxillary reconstruction in the literature. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The antipsychotic thioridazine shows promising therapeutic activity in a mouse model of multidrug-resistant tuberculosis.

Multidrug- and extensively drug-resistant tuberculosis have emerged as grave threats to public health worldwide. Very few active drugs are available or likely to become available soon. To address these problems we revisited a classical observation, the applicability of phenothiazines as antimicrobial drugs. Within this pharmacological class we selected thioridazine, which is most efficacious and least toxic, when used as an antipsychotic drug. We tested thioridazine monotherapy in the Balb/c mouse model for its activity to treat both susceptible and multidrug-resistant tuberculosis by a two months daily oral administration of 32 and 70 mg/kg. In addition, we tested its additive value when combined with a standard first-line regimen for susceptible tuberculosis. Thioridazine treatment resulted in a significant reduction of colony-forming-units of the susceptible (-4.4 log CFU, p<0.05) and multidrug-resistant tuberculosis bacilli (-2.4 log CFU, p<0.009) in the lung both at one and two months after infection, compared to controls. Moreover, when thioridazine was added to a regimen containing rifampicin, isoniazid and pyrazinamide for susceptible tuberculosis, a significant synergistic effect was achieved (-6.2 vs -5.9 log CFU, p<0.01). Thioridazine may represent an effective compound for treatment of susceptible and multidrug-resistant tuberculosis. The phenothiazines and their targets represent interesting novel opportunities in the search for antituberculosis drugs.

Specific bacterial genotypes of Mycobacterium tuberculosis cause extensive dissemination and brain infection in an experimental model.

Meningeal tuberculosis is a severe type of extrapulmonary disease, which is thought to begin with respiratory infection, followed by hematogenous dissemination and brain infection. Host genetic susceptibility factors and specific mycobacterial substrains could be involved in its development. From an epidemiological study in Colombia, we selected three Mycobacterium tuberculosis clinical strains isolated from the cerebrospinal fluid (CSF) of patients with meningeal tuberculosis, and used them to infect BALB/c mice through the intratracheal route. These strains showed a distinctive spoligotype pattern. The course of infection in terms of strain virulence (mice survival, bacillary loads in lungs), bacilli dissemination and extrapulmonary infection (bacilli loads in blood, brain, liver, kidney and spleen), and immune responses (cytokine expression determined by real time PCR in brain and lung) was studied and compared with that induced by the laboratory strain H37Rv and other five clinical strains isolated from patients with pulmonary TB. All the clinical isolates from meningeal TB patients disseminated extensively through the hematogenous route infecting the brain, producing inflammation in the cerebral parenchyma and meninges, whereas H37Rv and clinical isolates from pulmonary TB patients showed very limited efficiency to infect the brain. Thus, it seems that mycobacterial strains with a distinctive genotype are able to disseminate extensively after the respiratory infection and infect the brain.

Factors that deregulate the protective immune response in tuberculosis.

Tuberculosis (TB) is a chronic infectious disease which essentially affects the lungs and produces profound abnormalities on the immune system. Although most people infected by the tubercle bacillus (90%) do not develop the disease during their lifetime, when there are alterations in the immune system, such as co-infection with HIV, malnutrition, or diabetes, the risk of developing active disease increases considerably. Interestingly, during the course of active disease, even in the absence of immunosuppressive conditions, there is a profound and prolonged suppression of Mycobacterium tuberculosis-specific protective immune responses. Several immune factors can contribute to downregulate the protective immunity, permitting disease progression. In general, many of these factors are potent anti-inflammatory molecules that are probably overproduced with the intention to protect against tissue damage, but the consequence of this response is a decline in protective immunity facilitating bacilli growth and disease progression. Here the most significant participants in protective immunity are reviewed, in particular the factors that deregulate protective immunity in TB. Their manipulation as novel forms of immunotherapy are also briefly commented.

Prophylactic effect of administration of human gamma globulins in a mouse model of tuberculosis.

The protective effect of human gamma globulins on Mycobacterium tuberculosis infection was evaluated in a mouse model of intratracheal infection. Animals receiving human gamma globulins intranasally, 2h before intratracheal challenge showed a significant decrease in lung bacilli load compared to non-treated animals in different time intervals of up to 2 months after challenge. The same effect was obtained when M. tuberculosis was pre-incubated with the gamma globulin before challenge. The protective effect of the gamma-globulin formulation was abolished after pre-incubation with M. tuberculosis. These results suggest a potential role of specific antibodies in the defence against mycobacterial infections.

Orally administered Mycobacterium vaccae modulates expression of immunoregulatory molecules in BALB/c mice with pulmonary tuberculosis.

The environmental saprophyte Mycobacterium vaccae induces a Th1 response and cytotoxic T cells that recognize M. tuberculosis, and by subcutaneous injection, it is therapeutic for pulmonary tuberculosis (TB) induced by high-dose challenge in BALB/c mice. However, M. vaccae also drives regulatory T cells that inhibit Th2 responses, and this is seen in allergy models, not only following subcutaneous injection but also after oral administration. An oral immunotherapeutic for TB would be clinically useful, so we investigated M. vaccae given orally by gavage at 28-day intervals in the TB model. We used two different protocols: starting the oral M. vaccae either 1 day before or 32 days after infection with M. tuberculosis. Throughout the infection (until 120 days), we monitored outcome (CFU), molecules involved in the development of immunoregulation (Foxp3, hemoxygenase 1, idoleamine 2,3-dioxygenase, and transforming growth factor beta [TGF-beta]), and indicators of cytokine balance (tumor necrosis factor, inducible nitric oxide synthase, interleukin-4 [IL-4], and IL-4delta2; an inhibitory splice variant of IL-4 associated with improved outcome in human TB). Oral M. vaccae had a significant effect on CFU and led to increased expression of Th1 markers and of IL-4delta2, while suppressing IL-4, Foxp3, and TGF-beta. When administered 1 day before infection, oral M. vaccae induced a striking peak of expression of hemoxygenase 1. In conclusion, we show novel information about the expression in TB of murine IL-4delta2 and molecules involved in immunoregulation and show that these can be modulated by oral administration of a saprophytic mycobacterium. A clinical trial of oral M. vaccae in extensively drug-resistant TB might be justified.

Hepatic artery reconstruction with inferior mesenteric vein graft in pediatric living donor liver transplantation.

We report a transplant of the left lateral liver segments with two arteries for a pediatric recipient from a live donor. A six-month-old female patient was diagnosed with liver cirrhosis secondary to biliary atresia and scheduled for LDLT (father as donor). Left lateral hepatectomy was performed at the donor site. The dissection of the left HA, which divided immediately after its origin, showed two branches for segments II and III. The artery for segment III was anastomosed to the recipient HA. The artery for segment II was too short for direct anastomosis with the gastroduodenal artery. After an unsuccessful attempt to use of the recipient's saphenous vein, the recipient's IMV was used as an interposition graft. No post-operative complications were observed. The outcome of this case demonstrates that left lateral segments with two arteries can be successfully used if proper surgical techniques are applied. From this experience we can recommend the IMV as an alternative to the saphenous vein for an interposition graft.

[Retrospective study between open vs. laparoscopic funduplication in gastroesophageal reflux disease]. / Estudio retrospectivo entre funduplicatura abierta vs. laparoscópica en enfermedad por reflujo gastroesofágico.

INTRODUCTION: Nissen funduplication is each time more frequently used for gastroesophageal reflux disease (GERD) treatment. Surgical technique has changed from open to laparoscopic. OBJECTIVE: To analyze in comparative form the results of open and laparoscopic Nissen procedure. MATERIAL AND METHODS: In a period of five years, Nissen funduplication was practiced to 144 patients with confirmed GERD (50 open and 94 laparoscopic). All the patients were follow-up in Outpatient Consultation of the hospital for a minimum period of a year, evaluating in comparative form results and complications of the intervention. Retrospective revision of the files was made. RESULTS: Surgical time average in open surgeries was of 2.6 hours, and laparoscopic 2.57 hours (p = ns). Splenectomy in a patient operated in open form was an only complication. Postoperating complications in four patients (5%) laparoscopic and in 10 (20%) open (p 0.002). Hospital stay in these last ones was of 7.6 days and in laparoscopic 4.7 days (p < 0.0001). A year after the intervention, 19 patients (38%) open surgeries presented suggestive symptoms of reflux or had proton pump inhibitors (PPIs). Of these, in 5 (10%) recurrence of the GERD by some method was confirmed requiring reoperation two of them. In five peptic acid gastro/duodenal disease was confirmed and the rest had drugs without specific indication, demonstrating suitable morphology of the SEGD intervention. In the laparoscopic group, there were 26 symptomatic patients or who had PPIs a year after the intervention (27%). In seven (7%) reflux recurrence was confirmed, becoming necessary the reintervention in two. Another gastric/duodenal pathology in 13 was documented and six had drugs without specific indication. CONCLUSIONS: Nissen operation allows reflux control in 90% of the patients. Laparoscopic intervention requires a smaller hospital stay and is associated to less frequency of complications. The accomplishment of all technical steps of Nissen surgery, open or laparoscopic, is indispensable for good results.

A study of piglets born by spontaneous parturition under uncontrolled conditions: could this be a naturalistic model for the study of intrapartum asphyxia?

In order to evaluate how spontaneously born piglets could be a suitable model for the study of intrapartum hypoxia, 230 newborn piglets were studied. Out them, 8.3% (n = 19) died intrapartum, 21.7% (n = 50) were born with moderate-to-severe intrapartum hypoxia, and 70% (n = 161) were born with mild or no evidence of intrapartum distress. Piglets born without any evidence of intrapartum asphyxia weighed approximately 240 g lower than those born with intrapartum hypoxia and intrapartum-dead piglets (P<0.0001). The viability score was approximately 3 units lower and the latency to contact the udder was two times longer in the piglets surviving intrapartum hypoxia than in controls (P <0.0001). In comparison with the control group, metabolic acidosis was most severe among intrapartum-dead piglets followed by piglets surviving intrapartum asphyxia (P =0.002). According to a multiple linear regression analysis, pCO2 and lactate blood levels, and birth weight were identified as explanatory variables of viability score (r: 0.78; P <0.001). Viability score, K+ and lactate blood levels, and birth weight were identified as explanatory variables of latency to contact the udder (r: 0.80; P <0.001). In conclusion, the spontaneously-born asphyxiated piglet could be considered as a naturalistic model for the study of intrapartum asphyxia. Histopathologic and more rigorous functional and behavioral evaluations are still required to further characterize the model. (www.actabiomedica.it)

[Hemodynamic study of the patient with hemorrhagic portal hypertension: importance of the left renal vein in patients with a distal splenorenal shunt (Warren)]. / Estudio hemodinámico del paciente con hipertensión portal hemorrágica: importancia de la vena renal izquierda en los pacientes con derivación esplenorrenal distal (Warren).

INTRODUCTION: There is no information in the literature about surgical outcome of the distal splenorenal shunt (Warren shunt) in those patients with anomalous flow in the left renal vein to the inferior vena cava. OBJECTIVE: The purpose of this manuscript was to evaluate the incidence of thrombosis in the Warren shunt in those patients with anomalous flow in the left renal vein to the inferior vena cava. METHODS: We performed a prospective, descriptive and longitudinal study in those patients who performed a surgical procedure to the treatment of hemorrhagic portal hypertension in a tertiary referral center in Mexico City during a one year period (2002-2003). Before the surgical procedure an arterial and venous angiographic study was done including celiac axis, superior mesenteric artery and splenic artery. The patients were scheduled in the outpatient office the first, third, sixth month and the year after the surgical procedure. We looked in them for gastrointestinal bleeding secondary to portal hypertension. In those patients with Warren shunt an angiographic study was done during the first month after the surgical procedure. RESULTS: Twenty eight patients were included, 17 of them women (60.7%). Median patient age was 48 years old. In 20 patients a Warren shunt were done and in eigth patients a devascularization operation were done. The anomalous flow of the left renal vein was identified in nine patients (28.7%). In seven of them a Warren shunt were done and in two of them a devascularization operation were done. We didn't find gastrointestinal bleeding or thrombosis of the Warren shunt in any of these patients. CONCLUSION: In those cases of patients with anomalous flow in the left renal vein a Warren shunt can be performed. In this study we didn't find thrombosis of the shunt or gastrointestinal bleeding. In this way a surgical decompression of the portal system can be done preventing bleeding episodes.

Bile duct growing factor: an alternate technique for reconstruction of thin bile ducts after iatrogenic injury.

A variant of bilioenteric anastomosis, laterolateral hepatojejunostomy, is described in which the opened anterior aspect of the common hepatic duct and left hepatic duct is anastomosed to a Roux jejunal limb. This technique is specially designed for thin, injured bile ducts in which a conventional anastomosis is difficult due to the small diameter of the ducts. A wide anastomosis is obtained, leaving the posterior wall as a conduit for bile, ensuring an adequate anastomotic diameter.

Bile duct injuries related to misplacement of "T tubes".

INTRODUCTION: T tubes can be placed in the bile ducts either open or laparoscopically for several reasons such as: extraction of stones, biliary reconstruction after liver transplant and in end-to-end anastomosis in iatrogenic injuries. Inadequate placement of the T tube, long term stay and technical difficulties that can affect the outcome, can lead to an injury that usually requires a biliodigestive reconstruction. METHODS: In a 15-year period (1990-2005) a total of 343 patients have been referred to our university hospital for biliary reconstruction. Files of those patients in which the injury was due to misplacement of a T tube or associated with a long-term stay were reviewed. We evaluated the type of injury, technique used for the reconstruction, longterm staying of the T tubes (1-6 months), hospital in stay, long term outcomes as well as associated comorbidities. RESULTS: In 42 cases a biliary injury related to a T tube was identified (13%). All the injuries were classified as Strasberg E, with demonstration of a fistula (internal or external); 18 to the duodenum, 5 to the jejunum-ileum and 3 to the colon. A hepatojejunostomy was done to all patients; the duodenum and small gut fistulas were closed and in the 3 cases with colonic injury a right hemicolectomy was performed. The postoperative evolution was adequate without major complications but with a longer hospital stay. In 39 of the 42 patients (92%), good postoperative results were obtained. Only one case required a new surgery (22 months after the first one), due to recidivant cholangitis. CONCLUSION: Inadequate placement of the T tubes and long-term stay can produce complex biliary injuries with associated comorbidities such as fistulas to the adjacent viscera. Placement of T tubes need a careful surgical technique and their indication must be carefully assessed.

Molgramostim (GM-CSF) associated with antibiotic treatment in nontraumatic abdominal sepsis: a randomized, double-blind, placebo-controlled clinical trial.

HYPOTHESIS: The addition of molgramostim (recombinant human granulocyte-macrophage colony-stimulating factor) to antibiotic therapy for nontraumatic and generalized abdominal sepsis is effective and has a significant impact on length of hospitalization, direct medical costs, and mortality. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. SETTING: Tertiary referral center. PATIENTS: Fifty-eight patients with abdominal sepsis. INTERVENTIONS: Patients were allocated to receive, in addition to ceftriaxone sodium, amikacin sulfate, and metronidazole, molgramostim in a daily dosage of 3 microg/kg for 4 days (group 1) or placebo (group 2). Antibiotics were administered for at least 5 days and discontinued after clinical improvement had occurred and white blood cell count had been normal for 48 hours. MAIN OUTCOME MEASURES: Time to improvement, duration of antibiotic therapy, hospital stay, complications, mortality, and adverse reactions to drugs. RESULTS: Median time to improvement was 2 days in group 1 and 4 days in group 2 (P<.005). Median length of hospitalization was 9 and 13 days, respectively (P<.001), and median duration of antibiotic therapy was 9 and 13 days, respectively (P<.001). Numbers of infectious complications in the 2 groups were, respectively, 6 and 16 (P = .02); of residual abscesses, 3 and 5; and of deaths, 2 and 2. Costs per patient were 12,333 dollars and 16,081 dollars (US dollars), respectively. CONCLUSION: Addition of molgramostim to antibiotic therapy reduces the rate of infectious complications, the length of hospitalization, and costs in patients with nontraumatic abdominal sepsis.