Defining novel causal SNPs and linked phenotypes at melanoma-associated loci.

A number of genomic regions have been associated with melanoma risk through genome-wide association studies; however, the causal variants underlying the majority of these associations remain unknown. Here, we sequenced either the full locus or the functional regions including exons of 19 melanoma-associated loci in 1959 British melanoma cases and 737 controls. Variant filtering followed by Fisher's exact test analyses identified 66 variants associated with melanoma risk. Sequential conditional logistic regression identified the distinct haplotypes on which variants reside, and massively parallel reporter assays provided biological insights into how these variants influence gene function. We performed further analyses to link variants to melanoma risk phenotypes and assessed their association with melanoma-specific survival. Our analyses replicate previously known associations in the melanocortin 1 receptor (MC1R) and tyrosinase (TYR) loci, while identifying novel potentially causal variants at the MTAP/CDKN2A and CASP8 loci. These results improve our understanding of the architecture of melanoma risk and outcome.

Structural and functional connectivity in hydrocephalus: a scoping review.

Optimizing the treatment of hydrocephalus remains a major challenge in adult and pediatric neurosurgery. Currently, clinical treatment relies heavily on anatomic imaging of ventricular size and clinical presentation. The emergence of functional and structural brain connectivity imaging has provided the basis for a new paradigm in the management of hydrocephalus. Here we review the pertinent advances in this field. Following PRISMA-ScR guidelines for scoping reviews, we searched PubMed for relevant literature from 1994 to April 2023 using hydrocephalus and MRI-related terms. Included articles reported original MRI data on human subjects with hydrocephalus, while excluding non-English or pre-1994 publications that didn't match the study framework. The review identified 44 studies that investigated functional and/or structural connectivity using various MRI techniques across different hydrocephalus populations. While there is significant heterogeneity in imaging technology and connectivity analysis, there is broad consensus in the literature that 1) hydrocephalus is associated with disruption of functional and structural connectivity, 2) this disruption in cerebral connectivity can be further associated with neurologic compromise 3) timely treatment of hydrocephalus restores both cerebral connectivity and neurologic compromise. The robustness and consistency of these findings vary as a function of patient age, hydrocephalus etiology, and the connectivity region of interest studied. Functional and structural brain connectivity imaging shows potential as an imaging biomarker that may facilitate optimization of hydrocephalus treatment. Future research should focus on standardizing regions of interest as well as identifying connectivity analysis most pertinent to clinical outcome.

Peri-operative night-time work of anaesthesiologists: A qualitative study of critical issues and proposals.

BACKGROUND: Qualitative data on the opinions of anaesthesiologists regarding the impact of peri-operative night-time working conditions on patient safety are lacking. OBJECTIVES: This study aimed to achieve in-depth understanding of anaesthesiologists' perceptions regarding the impact of night-time working conditions on peri-operative patient safety and actions that may be undertaken to mitigate perceived risks. DESIGN: Qualitative analysis of responses to two open-ended questions. SETTING: Online platform questionnaire promoted by the European Society of Anaesthesiology and Intensive Care (ESAIC). PARTICIPANTS: The survey sample consisted of an international cohort of anaesthesiologists. MAIN OUTCOME MEASURES: We identified and classified recurrent themes in the responses to questions addressing perceptions regarding (Q1) peri-operative night-time working conditions, which may affect patient safety and (Q2) potential solutions. RESULTS: We analysed 2112 and 2113 responses to Q1 and Q2, respectively. The most frequently reported themes in relation to Q1 were a perceived reduction in professional performance accompanied by concerns regarding the possible consequences of work with fatigue (27%), and poor working conditions at night-time (35%). The most frequently proposed solutions in response to Q2 were a reduction of working hours and avoidance of 24-h shifts (21%), an increase in human resources (14%) and performance of only urgent or emergency surgeries at night (14%). CONCLUSION: Overall, the surveyed anaesthesiologists believe that workload-to-staff imbalance and excessive working hours were potential bases for increased peri-operative risk for their patients, partly because of fatigue-related medical errors during night-time work. The performance of nonemergency elective surgical cases at night and lack of facilities were among the reported issues and potential targets for improvement measures. Further studies should investigate whether countermeasures can improve patient safety as well as the quality of life of anaesthesia professionals. Regulations to improve homogeneity, safety, and quality of anaesthesia practice at night seem to be urgently needed.

Role of Advanced Glycation End Products as New Biomarkers in Systemic Lupus Erythematosus.

Advanced glycation end-products (AGEs) may play a relevant role as inducers in the chronic inflammatory pathway present in immune-mediated diseases, such as systemic lupus erythematosus (SLE). AGEs concentrations have been associated, with discrepant results to date, with some parameters such as disease activity or accrual damage, suggesting their potential usefulness as biomarkers of the disease. Our objectives are to confirm differences in AGEs levels measured by cutaneous autofluorescence between SLE patients and healthy controls (HC) and to study their correlation with various disease parameters. Cross-sectional study, where AGEs levels were measured by skin autofluorescence, and SLE patients' data were compared with those of sex- and age-matched HC in a 1:3 proportion through a multiple linear regression model. Associations of AGEs levels with demographic and clinical data were analyzed through ANOVA tests. Both analyses were adjusted for confounders. AGEs levels in SLE patients were significantly higher than in HC (p < 0.001). We found statistically significant positive associations with SLE disease activity index (SLEDAI) and damage index (SDI), physician and patient global assessment, C-reactive protein, leukocyturia, complement C4, IL-6 and oral ulcers. We also found a negative statistically significant association with current positivity of anti-nuclear and anti-Ro60 antibodies. AGEs seem to have a contribution in LES pathophysiology, being associated with activity and damage and having a role as a new management and prognosis biomarker in this disease. The association with specific antibodies and disease manifestations may indicate a specific clinical phenotype related to higher or lower AGEs levels.

Handgrip strength and upper limb functional performance measures in people over 18 years old: Analysis of relationships and influencing factors.

BACKGROUND: Handgrip strength is a common, simple, and inexpensive method to measure muscle strength. On the other hand, the functional performance measurement involves a usual task which implies repeating elements between the individuals' interaction and the environment. This is fundamental for projecting their results to daily life situation. PURPOSE: To explore the relationship between grip strength and measures of functional performance of the upper limbs (ULs) in people over 18 years of age, and to determine the influence of sociodemographic and anthropometric variables on the relationship. STUDY DESIGN: A cross-sectional study was conducted under the analytical empirical approach, using linear associations between handgrip strength and functional performance measurement tests (correspondence analysis). METHODS: Three hundred sixty-two male and female individuals between 18 and 91 years of age from 4 Colombian cities participated. The grip strength of both ULs measured with a digital dynamometry was associated with the Box and Block Test (BBT, manual dexterity), Nine-Hole Peg Test (NHPT, daily living tasks), and Jebsen-Taylor Hand Function Test (JJT, ability to grasp, pick up, and place). Multiple linear regression analyzes were performed to assess possible explanatory factors of a sociodemographic and anthropometric order. RESULTS: A significant association was found between the grip strength of dominant and non-dominant ULs with all functional performance tests (ρ > 0.27 and p < .001), except for the writing and simulated feeding subtests of the JJT (ρ ≤ 0.16). An interactive effect of age was found in the relationship between grip strength and the 3 functional performance tests. CONCLUSIONS: These results support the association between grip strength with the NHPT, JJT, and BBT measures and the interactive effect of age on the performance of all tests.

Exchangeable Self-Assembled Lanthanide Antennas for PLIM Microscopy.

Lanthanides have unique photoluminescence (PL) emission properties, including very long PL lifetimes. This makes them ideal for biological imaging applications, especially using PL lifetime imaging microscopy (PLIM). PLIM is an inherently multidimensional technique with exceptional advantages for quantitative biological imaging. Unfortunately, due to the required prolonged acquisitions times, photobleaching of lanthanide PL emission currently constitutes one of the main drawbacks of PLIM. In this study, we report a small aqueous-soluble, lanthanide antenna, 8-methoxy-2-oxo-1,2,4,5-tetrahydrocyclopenta[de]quinoline-3-phosphonic acid, PAnt, specifically designed to dynamically interact with lanthanide ions, serving as exchangeable dye aimed at mitigating photobleaching in PLIM microscopy in cellulo. Thus, self-assembled lanthanide complexes that may be photobleached during image acquisition are continuously replenished by intact lanthanide antennas from a large reservoir. Remarkably, our self-assembled lanthanide complex clearly demonstrated a significant reduction of PL photobleaching when compared to well-established lanthanide cryptates, used for bioimaging. This concept of exchangeable lanthanide antennas opens new possibilities for quantitative PLIM bioimaging.

Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma that contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown. METHODS: We used a dual recombinase mouse model to delete Hif1α or Hif2α in α-smooth muscle actin-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF HIF2α expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, reverse transcription quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, an HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade. RESULTS: CAF-specific deletion of Hif2α, but not Hif1α, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = .0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models. CONCLUSIONS: Together, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.

The evolving landscape of COVID-19 and post-COVID condition in patients with chronic lymphocytic leukemia: A study by ERIC, the European research initiative on CLL.

In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high-count monoclonal B lymphocytosis) infected by SARS-CoV-2, including the development of post-COVID condition. Data from 1540 patients with CLL infected by SARS-CoV-2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS-CoV-2 variants emergence. Post-COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4-month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL-directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post-COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post-COVID. The median time to resolution of the post-COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS-CoV-2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post-COVID conditions, warranting further investigations.

The impact of early versus delayed cord clamping on hematological and cardiovascular changes in preterm newborns between 24 and 34 weeks' gestation: a randomized clinical trial.

PURPOSE: This study aimed to   investigate hematological and cardiac changes after early (ECC) versus delayed cord clamping (DCC) in preterm infants at 24-34 weeks of gestation. METHODS: Ninety-six healthy pregnant women were assigned randomly to the ECC (< 10 s postpartum, n = 49) or DCC (45-60 s postpartum, n = 47). Primary endpoint was evaluation of neonatal hemoglobin, hematocrit and bilirrubin levels within the first 7 days after birth. A postpartum blood test was performed in the mother and a neonatal echocardiography in the first week of life. RESULTS: We found differences in hematological parameters during the first week of life. On admission, the DCC group had higher hemoglobin levels than the ECC group (18.7 ± 3.0 vs. 16.8 ± 2.4, p < 0.0014) and higher hematocrit values (53.9 ± 8.0 vs. 48.8 ± 6.4, p < 0.0011). Around day 7 of life, hemoglobin levels were also higher in the DCC group compared with the ECC group (16.4 ± 3.8 vs 13.9 ± 2.5, p < 0.005), as was the hematocrit (49.3 ± 12.7 vs 41.2 ± 8.4, p < 0.0087). The need of transfusion was lower in the DCC compared to the ECC (8.5% vs 24.5%; OR: 0.29, 95% CI: 0.09-0.97, p < 0.036). The need for phototherapy was also higher in the DCC (80.9% vs 63.3%; OR: 0.23, 95% CI: 0.06-0.84, p < 0.026). No differences in cardiac parameters or maternal blood tests. CONCLUSION: DCC improved neonatal hematological parameters. No changes in cardiac function were found and maternal blood loss did not increase to require transfusion.

The burden of peri-operative work at night as perceived by anaesthesiologists: An international survey.

BACKGROUND: No international data are available on the night working conditions and workload of anaesthesiologists and their opinions about associated risks. OBJECTIVE: The aim of this international survey was to describe the peri-operative night working conditions of anaesthesiologists and their perception of the impact these conditions have on patient outcomes and their own quality of life. DESIGN: Cross-sectional survey. SETTING: Not applicable. PARTICIPANTS: Anaesthesiologists providing peri-operative care during night shifts responded to an online survey promoted by the European Society of Anaesthesiology and Intensive Care (ESAIC). INTERVENTIONS: None. MAIN OUTCOME MEASURE: Twenty-eight closed questions. RESULTS: Overall 5292 complete responses were analysed. Of these, 920 were from trainees. The median reported monthly number of night shifts was 4 [IQR 3-6]. An irregular weekly night shift schedule was most common (51%). Almost all the respondents (98%) declared that their centres have no relevant institutional programmes to monitor stress or fatigue. Most respondents (90%) had received no training or information regarding performance improvement methods for night work. Most respondents were of the opinion that sleep deprivation affects their professional performance (71%) and that their fatigue during night work may increase the peri-operative risk for their patients (74%). Furthermore, 81% of the respondents agreed or strongly agreed that night work represents an additional risk per se for patient safety, and 77% stated that their night work affects the quality of their daily life significantly or extremely. CONCLUSION: Anaesthesiologists commonly perform perioperative night work without appropriate training, education or support on this specific condition. They perceive current practice as adversely affecting their professional performance and the safety of their patients. They also report significant effects on their own quality of life. Adequate training and education for night work may ally some of these concerns and programmes to monitor workers' stress and fatigue should be mandated to assess whether these concerns are justified. TRIAL REGISTRATION: Not applicable.

A mechanistic spatio-temporal modeling of COVID-19 data.

Understanding the evolution of an epidemic is essential to implement timely and efficient preventive measures. The availability of epidemiological data at a fine spatio-temporal scale is both novel and highly useful in this regard. Indeed, having geocoded data at the case level opens the door to analyze the spread of the disease on an individual basis, allowing the detection of specific outbreaks or, in general, of some interactions between cases that are not observable if aggregated data are used. Point processes are the natural tool to perform such analyses. We analyze a spatio-temporal point pattern of Coronavirus disease 2019 (COVID-19) cases detected in Valencia (Spain) during the first 11 months (February 2020 to January 2021) of the pandemic. In particular, we propose a mechanistic spatio-temporal model for the first-order intensity function of the point process. This model includes separate estimates of the overall temporal and spatial intensities of the model and a spatio-temporal interaction term. For the latter, while similar studies have considered different forms of this term solely based on the physical distances between the events, we have also incorporated mobility data to better capture the characteristics of human populations. The results suggest that there has only been a mild level of spatio-temporal interaction between cases in the study area, which to a large extent corresponds to people living in the same residential location. Extending our proposed model to larger areas could help us gain knowledge on the propagation of COVID-19 across cities with high mobility levels.

Woodchip bioreactors for saline leachates denitrification can mitigate agricultural impacts in mediterranean areas: The Campo de Cartagena-Mar Menor environmental issue.

Leachates from intensive agriculture containing high nitrate have been identified as a major cause of the severe eutrophication crisis that impacts Mar Menor (SE Spain), the largest hypersaline coastal lagoon in the Mediterranean basin. A best management practice for removing NO3--N is denitrifying bioreactors. This is the first study to assess the efficiency of citrus woodchips bioreactors in treating agricultural leachates that flow to the Mar Menor via surface discharges. Denitrification capacity, woodchip degradation (by weight loss), formation of potentially harmful compounds, and greenhouse gas (GHG) emissions were assessed. Three bioreactors (6 m × 0.98 m x 1.2 m) filled with citrus woodchips (3 m3 d-1 per bioreactor) through which the untreated ditch water over 1.5 years. Bioreactors were operated at 8 h, 16 h, and 24 h hydraulic residence time respectively, in each bioreactor. The main characteristics of the ditch water were: pH ≈ 7.5-8.0, electrical conductivity ≈ 5-8 dS m-1, dissolved organic carbon ≈6-10 mg L-1, and NO3--N ≈ 22-45 mg L-1. Bioreactors were highly efficient in reducing NO3--N. The average RNO3 in effluents was for the complete experimental period 8 g N m-3 d-1, 10.9 g N m-3 d-1, and 12.6 g N m-3 d-1 for 8, 16 and 24 h residence time, respectively. Nitrate reduction efficiency was modulated by seasonal changes in temperature, with an increasing efficiency in warmer periods (maximum ≈ 85-90% for all hydraulic residence time) and decreasing in colder ones (minimum ≈ 12%, 23% and 41% for hydraulic residence time 8, 16 and 24 h respectively). Woodchips degradation was greatest during the first six months (average ≈ 29% weight loss) in the material above the water level, attributable to aerobic mineralization of the organic carbon, while weight loss was ≈11% in woodchip media continuously below the water level. Dissolved organic carbon, sulfide, ammonium, and soluble phosphorus concentrations in the effluents were mostly low, although some peaks in concentrations occurred. Design consideration must be taken to avoid environmental impacts due to the occasional presence of harmful compounds in the effluents.

Intradermally Administered Enterotoxigenic Escherichia coli Vaccine Candidate MecVax Induces Functional Serum Immunoglobulin G Antibodies against Seven Adhesins (CFA/I and CS1 through CS6) and Both Toxins (STa and LT).

There are no vaccines licensed for enterotoxigenic Escherichia coli (ETEC), a leading bacterial cause of children's diarrhea and travelers' diarrhea. MecVax, a multivalent E. coli vaccine candidate composed of two epitope- and structure-based polyvalent proteins (toxoid fusion 3xSTaN12S-mnLTR192G/L211A and colonization factor antigen [CFA]/I/II/IV multiepitope fusion antigen [MEFA]), is designed to induce broad antiadhesin and antitoxin antibodies against heterogeneous ETEC pathovars. When administered intraperitoneally or intramuscularly, MecVax was shown to induce antibodies against seven ETEC adhesins (CFA/I and CS1 to CS6) produced by ETEC pathovars that cause over 60% of ETEC-associated diarrheal cases and moderate-to-severe cases and both toxins (heat-labile toxin [LT] and heat-stable toxin [STa]) expressed by all ETEC strains. To further characterize the immunogenicity of this protein-based injectable subunit vaccine candidate and to explore other parenteral administration routes for the product, in this study we immunized mice intradermally (i.d.) with MecVax and measured antigen-specific antibody responses and further antibody functional activities against the adhesins and toxins targeted by the vaccine. Data showed that mice immunized i.d. with MecVax developed robust anti-CFA/I, CS1, CS2, CS3, CS4, CS5, CS6, LT and anti-STa IgG responses. Furthermore, antibodies derived from MecVax administered via the i.d. route inhibited the adherence of ETEC or E. coli strains expressing any of the seven target adhesins (CFA/I and CS1 to CS6) and neutralized the enterotoxicity of LT and STa. These results confirmed broad immunogenicity of MecVax and suggested that this multivalent ETEC subunit vaccine candidate can be effectively delivered via the i.d. route. IMPORTANCE ETEC is a leading bacterial cause of diarrhea in children living in developing countries and international travelers. Developing an effective vaccine for ETEC diarrhea has been hampered because of the challenges of virulence heterogeneity and the difficulties of inducing neutralizing antibodies against the key toxin STa. MecVax, a subunit vaccine candidate carrying two polyvalent protein antigens, for the first time induces functional antibodies against the most important ETEC adhesins, which are associated with a majority of diarrheal cases and moderate-to-severe cases, and also against the enterotoxicity of LT and more importantly STa, which plays a key role in children's diarrhea and travelers' diarrhea, potentially leading to the development of a truly effective ETEC vaccine. Data from this study may also indicate that this ETEC subunit vaccine can be administered effectively via the i.d. route, expanding clinical administration options for this vaccine product.

Feasibility of administering human pancreatic cancer chemotherapy in a spontaneous pancreatic cancer mouse model.

BACKGROUND: Both modified FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel chemotherapy regimens have been shown to improve clinical outcomes in patients with pancreatic cancer, and are often used interchangeably as the standard of care. Preclinical studies often do not use these regimens, since administering these multiagent approaches can be difficult. In this study, we assessed the feasibility of administering these two chemotherapy regimens in spontaneous pancreatic tumors using KPC mice with the ultimate goal of advancing preclinical studies. METHODS: KPC mice were created by breeding KrasLSL-G12D/+ to Trp53fl/fl;Ptf1αCre/+, resulting in KrasLSL-G12D/+;p53fl/+;Ptf1αCre/+ mice. At 14 weeks of age, mice were palpated for spontaneous tumor growth that was verified using ultrasounds. Mice with tumors under 15 mm in diameter were used. The mice were assigned to one of seven treatment regimens: 1 cycle of mFFX (FFX X1), 2 cycles of mFFX (FFX X2), 1 cycle of mFFXwith 40 Gy SBRT (FFX SBRT), 1 cycle of gemcitabine/nab-paclitaxel (GEM/AB X1), 2 cycles of gemcitabine/nab-paclitaxel (GEM/AB X2), 2 cycles of gemcitabine/nab-paclitaxel with 40 Gy SBRT (GEM/AB SBRT), or saline only (control). RESULTS: In total, 92 mice were included. The median OS in the FFX X2 group was slightly longer that the median OS in the FFX X1 group (15 days vs 11 days, P = 0.003). Mice in the GEM/AB X2 group had longer OS when compared to mice in the GEM/AB X1 group (33.5 vs 13 days, P = 0.001). Mice treated with chemotherapy survived longer than untreated control animals (median OS: 6.5 days, P < 0.001). Moreover, in mice treated with chemotherapy, mice that received 2 cycles of GEM/AB X2 had the longest survival, while the FFX X1 group had the poorest OS (P < 0.001). The addition of chemotherapy was associated with reduced number of myeloid and lymphoid cell types, except for CD4 + cells whose levels were largely unaltered only in tumors treated with gemcitabine/nab-paclitaxel. Lastly, chemotherapy followed by consolidative SBRT trended towards increased local control and survival. CONCLUSIONS: We demonstrate the utility and feasibility of clinically relevant mFOLFIRINOX and gemcitabine/nab-paclitaxel in preclinical models of pancreatic cancer.

Micropatterned functional interfaces on elastic substrates fabricated by fixing out of plane deformations.

We report on the preparation of micropatterned functional surfaces produced by inducing an out-of-plane deformation on elastic substrates and fixing these by creating a rigid oxidized top layer. Specifically, the elastic substrate used was Polydimethylsiloxane (PDMS) and the rigid layer on top was created by ozonation of this material. We evidenced that the surface pattern formed is directly dependent on the pressure applied, the mechanical properties of the elastic substrate and on the dimensions and shape of the mask employed to define the exposed and non-exposed areas. In addition to the pattern formed, another interesting aspect is related to the ozone diffusion within the material. Softer PDMS enables more efficient diffusion and produced a thicker oxidized layer in comparison to rigid PDMS. Finally, a simulation was carried out using the distribution of Von Misses stresses of a solid plate to understand the conditions in which the applied force resulted in the rupture of the rigid oxidized layer under a permanent deformation.

Treatment of asymptomatic bacteriuria in the first 2 months after kidney transplant: A controlled clinical trial.

BACKGROUND: The incidence of urinary tract infections (UTIs) in the first 2 months postrenal transplantation (pRT) is very high. We evaluate the efficacy of asymptomatic bacteriuria (AB) screening and treatment on the incidence of UTI in the first 2 months pRT METHODS: We conducted a randomized controlled clinical trial. A urine culture was obtained in all patients on the day of the bladder catheter removal, on week three, and before removal of the ureteral catheter. The intervention group received treatment for AB. The control group did not receive treatment. The primary outcomes were the cumulative incidence of UTI and/or graft pyelonephritis and the time to the first episode of UTI and/or graft pyelonephritis RESULTS: Eighty patients were randomized, 40 in each group, and the median follow-up was 63 days (IQR 54-70). The average age was 29.8 years and 33.7% (n = 27) were women. The incidences of UTI (n = 10, 25 % vs. n = 4, 10%, p = .07) and pyelonephritis (n = 6, 15% vs. n = 1, 2.5%, p = .04) were greater in the intervention group, as also shown in the survival analysis: UTI (HR2.8, 95% CI 0.8-9.1, p = .07) and pyelonephritis (HR 6.5, 95% CI 0.8-54.7, p = .08), respectively. The most commonly isolated bacterium was Escherichia coli (n = 28, 59.5%), and over half were E. coli with extended-spectrum beta-lactamases (n = 15). A major limitation was not obtaining the calculated sample size due to a delay in patient recruitment resulting from the COVID-19 pandemic CONCLUSION: Treatment of AB in the first 2 months pRT does not decrease the incidence of UTI or graft pyelonephritis and may actually increase their frequency. Routine treatment of AB during the first months after renal transplantation should not be a standard procedure.

Preclinical Characterization of Immunogenicity and Efficacy against Diarrhea from MecVax, a Multivalent Enterotoxigenic E. coli Vaccine Candidate.

There are no vaccines licensed for enterotoxigenic Escherichia coli (ETEC), a leading cause of diarrhea for children in developing countries and international travelers. Virulence heterogeneity among strains and difficulties identifying safe antigens for protective antibodies against STa, a potent but poorly immunogenic heat-stable toxin which plays a key role in ETEC diarrhea, are challenges in ETEC vaccine development. To overcome these challenges, we applied a toxoid fusion strategy and a novel epitope- and structure-based multiepitope fusion antigen (MEFA) vaccinology platform to construct two chimeric multivalent proteins, toxoid fusion 3xSTaN12S-mnLTR192G/L211A and adhesin CFA/I/II/IV MEFA, and demonstrated that the proteins induced protective antibodies against STa and heat-labile toxin (LT) produced by all ETEC strains or the seven most important ETEC adhesins (CFA/I and CS1 to CS6) expressed by the ETEC strains causing 60 to 70% of diarrheal cases and moderate to severe cases. Combining two proteins, we prepared a protein-based multivalent ETEC vaccine, MecVax. MecVax was broadly immunogenic; mice and pigs intramuscularly immunized with MecVax developed no apparent adverse effects but had robust antibody responses to the target toxins and adhesins. Importantly, MecVax-induced antibodies were broadly protective, demonstrated by significant adherence inhibition against E. coli bacteria producing any of the seven adhesins and neutralization of STa and cholera toxin (CT) enterotoxicity. Moreover, MecVax protected against watery diarrhea and provided over 70% and 90% protection against any diarrhea from an STa-positive or an LT-positive ETEC strain in a pig challenge model. These results indicated that MecVax induces broadly protective antibodies and prevents diarrhea preclinically, signifying that MecVax is potentially an effective injectable vaccine for ETEC. IMPORTANCE Enterotoxigenic Escherichia coli (ETEC) bacteria are a top cause of children's diarrhea and travelers' diarrhea and are responsible for over 220 million diarrheal cases and more than 100,000 deaths annually. A safe and effective ETEC vaccine can significantly improve public health, particularly in developing countries. Data from this preclinical study showed that MecVax induces broadly protective antiadhesin and antitoxin antibodies, becoming the first ETEC vaccine candidate to induce protective antibodies inhibiting adherence of the seven most important ETEC adhesins and neutralizing the enterotoxicity of not only LT but also STa toxin. More importantly, MecVax is shown to protect against clinical diarrhea from STa-positive or LT-positive ETEC infection in a pig challenge model, recording protection from antibodies induced by the protein-based, injectable, subunit vaccine MecVax against ETEC diarrhea and perhaps the possibility of intramuscularly administered protein vaccines for protection against intestinal mucosal infection.

Frailty Worsens Antidepressant Treatment Outcomes in Late Life Depression.

OBJECTIVE: To investigate the relationship between frailty and treatment response to antidepressant medications in adults with late life depression (LLD). METHODS: Data were evaluated from 100 individuals over age 60 years (34 men, 66 women) with a depressive diagnosis, who were assessed for frailty at baseline (characteristics include gait speed, grip strength, activity levels, fatigue, and weight loss) and enrolled in an 8-week trial of antidepressant medication followed by 10 months of open-treatment. RESULTS: Frail individuals (n = 49 with ≥3 deficits in frailty characteristics) did not differ at baseline from the non/intermediate frail (n = 51 with 0-2 deficits) on demographic, medical comorbidity, cognitive, or depression variables. On average, frail individuals experienced 2.82 fewer Hamilton Rating Scale for Depression (HRSD) points of improvement (t = 2.12, df 89, p = 0.037) than the non/intermediate frail over acute treatment, with this difference persisting over 10 months of open-treatment. Weak grip strength and low physical activity levels were each associated with decreased HRSD improvement, and lower response and remission rates over the course of the study. Despite their poorer outcomes, frail individuals received more antidepressant medication trials than the non/intermediate frail. CONCLUSION: Adults with LLD and frailty have an attenuated response to antidepressant medication and a greater degree of disability compared to non/intermediate frail individuals. This disability and attenuated response remain even after receiving a greater number of antidepressant medication trials. Future research must focus on understanding the specific pathophysiology associated with the frail-depressed phenotype to permit the design and implementation of precision medicine interventions for this high-risk population.

Association of White Matter Integrity With Executive Function and Antidepressant Treatment Outcome in Patients With Late-Life Depression.

OBJECTIVE: While patients with late-life depression (LLD) often exhibit microstructural white matter alterations that can be identified with diffusion tensor imaging (DTI), there is a dearth of information concerning the links between DTI findings and specific cognitive performance, as well as between DTI measures and antidepressant treatment outcomes. DESIGN: Neuroimaging and cognitive tests were conducted at baseline in 71 older adults participating in a larger, 8-week duration antidepressant randomized controlled trial. Correlations between DTI measures of white matter integrity evaluated with tract-based spatial statistics, baseline neurocognitive performance, and prospective antidepressant treatment outcome were evaluated. RESULTS: Fractional anisotropy (FA), an index of white matter integrity, was significantly positively associated with better cognitive function as measured by the Initiation/Perseveration subscale of the Dementia Rating Scale in the bilateral superior longitudinal fasciculus (SLF), bilateral SLF-temporal, and right corticospinal tract (CST). An exploratory analysis limited to these tracts revealed that increased FA in the right CST, right SLF, and right SLF-temporal tracts was correlated with a greater decrease in depressive symptoms. Increased FA in the right CST predicted a greater chance of remission, while increased FA in the right CST and the right SLF predicted a greater chance of treatment response. CONCLUSION: In late-life depression LLD subjects, white matter integrity was positively associated with executive function in white matter tracts which act as key connecting structures underlying the cognitive control network. These tracts may play a role as a positive prognostic factor in antidepressant treatment outcome.

The COVID-19 Pandemic as a Traumatic Stressor: Mental Health Responses of Older Adults With Chronic PTSD.

OBJECTIVE: Individuals with post-traumatic stress disorder (PTSD) who experience additional traumas or stressful life events may undergo symptomatic worsening, but no data exist on whether exposure to the COVID-19 pandemic in a high infection area worsens mental health among older adults with chronic PTSD. METHODS: Seventy-six older adults (N = 46 with PTSD and N = 30 trauma-exposed comparison subjects [TE]) for whom prepandemic data were available were interviewed between April 1 and May 8, 2020 to quantify depressive (Hamilton Rating Scale for Depression [HRSD]) and PTSD symptom (Post-traumatic Stress Disorder Checklist [PCL-5]) levels. Group differences in baseline characteristics as well as pre-post pandemic symptom levels were examined, and participant characteristics were assessed as moderators of symptom change. RESULTS: Compared to TEs, individuals with PTSD more often reported living alone and experiencing a physical illness (χ2 = 5.1, df = 1, p = 0.02). PCL-5 scores among individuals with PTSD decreased during the COVID-19 pandemic by 7.1 points (t(69) = -3.5, p = 0.0008), whereas the TE group did not change significantly. Overall no significant differences in HRSD were found between groups, but a race or ethnicity variable was found to moderate HRSD symptom change. Non-black or Hispanic individuals with PTSD experienced significantly increased HRSD scores during the pandemic compared to black or Hispanic PTSD participants. CONCLUSION: The findings are indicative of complexity in the responses of older individuals with PTSD to further stressful life events as well as possibly unique aspects to the COVID-19 pandemic as a stressor. Sources of resilience may exist based on experience with prior traumas as well as increasing age promoting more adaptive coping styles.