Syndecan-4 is a maestro of gastric cancer cell invasion and communication that underscores poor survival.

Gastric cancer is a dominating cause of cancer-associated mortality with limited therapeutic options. Here, we show that syndecan-4 (SDC4), a transmembrane proteoglycan, is highly expressed in intestinal subtype gastric tumors and that this signature associates with patient poor survival. Further, we mechanistically demonstrate that SDC4 is a master regulator of gastric cancer cell motility and invasion. We also find that SDC4 decorated with heparan sulfate is efficiently sorted in extracellular vesicles (EVs). Interestingly, SDC4 in EVs regulates gastric cancer cell-derived EV organ distribution, uptake, and functional effects in recipient cells. Specifically, we show that SDC4 knockout disrupts the tropism of EVs for the common gastric cancer metastatic sites. Our findings set the basis for the molecular implications of SDC4 expression in gastric cancer cells and provide broader perspectives on the development of therapeutic strategies targeting the glycan-EV axis to limit tumor progression.

Ultrasound-guided hydrodilatation for adhesive capsulitis: capsule-preserving versus capsule-rupturing technique.

OBJECTIVE: To compare the clinical efficacy of capsule-rupturing versus capsule-preserving ultrasound-guided hydrodilatation in patients with shoulder adhesive capsulitis (AC). To determine potential factors affecting the outcome over a 6-month follow-up. MATERIALS AND METHODS: Within a 2-year period, 149 consecutive patients with AC were prospectively enrolled and allocated into (i) group-CR, including 39 patients receiving hydrodilatation of the glenohumeral joint (GHJ) with capsular rupture and (ii) group-CP, including 110 patients treated with GHJ hydrodilatation with capsular preservation. Demographics, affected shoulder, and AC grade were recorded. Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire and visual analog scale (VAS) were used for clinical assessment at baseline/1/3/6 months. Comparisons were performed with Mann-Whitney U test and Kolmogorov-Smirnov test. Linear regression was used to identify predictors of outcome. P value < 0.05 defined significance. RESULTS: DASH and VAS scores in both groups improved significantly compared to baseline (P < 0.001) and were significantly lower in the CP compared to CR group at all time-points following intervention (P < 0.001). Capsule rupture was a significant predictor of DASH score at all time-points (P < 0.001). DASH scores correlated to initial DASH score at all time-points (P < 0.001). DASH/VAS scores at 1 month were correlated to the AC grade (P = 0.025/0.02). CONCLUSION: GHJ hydrodilatation results in pain elimination and functional improvement till the mid-term in patients with AC, with improved outcome when adopting the capsule-preserving compared to the capsule-rupturing technique. Higher initial DASH score is predictive of impaired functionality in the mid-term.

Predicting residual neoplasia after a non-curative gastric ESD: validation and modification of the eCura system in the Western setting: the W-eCura score.

OBJECTIVE: To evaluate the risk factors for lymph node metastasis (LNM) after a non-curative (NC) gastric endoscopic submucosal dissection (ESD) and to validate and eventually refine the eCura scoring system in the Western setting. Also, to assess the rate and risk factors for parietal residual disease. DESIGN: Retrospective multicentre multinational study of prospectively collected registries from 19 Western centres. Patients who had been submitted to surgery or had at least one follow-up endoscopy were included. The eCura system was applied to assess its accuracy in the Western setting, and a modified version was created according to the results (W-eCura score). The discriminative capacities of the eCura and W-eCura scores to predict LNM were assessed and compared. RESULTS: A total of 314 NC gastric ESDs were analysed (72% high-risk resection (HRR); 28% local-risk resection). Among HRR patients submitted to surgery, 25% had parietal disease and 15% had LNM in the surgical specimen. The risk of LNM was significantly different across the eCura groups (areas under the receiver operating characteristic curve (AUC-ROC) of 0.900 (95% CI 0.852 to 0.949)). The AUC-ROC of the W-eCura for LNM (0.916, 95% CI 0.870 to 0.961; p=0.012) was significantly higher compared with the original eCura. Positive vertical margin, lymphatic invasion and younger age were associated with a higher risk of parietal residual lesion in the surgical specimen. CONCLUSION: The eCura scoring system may be applied in Western countries to stratify the risk of LNM after a gastric HRR. A new score is proposed that may further decrease the number of unnecessary surgeries.

Glycosyltransferases EXTL2 and EXTL3 cellular balance dictates heparan sulfate biosynthesis and shapes gastric cancer cell motility and invasion.

Heparan sulfate (HS) proteoglycans (HSPGs) are abundant glycoconjugates in cells' glycocalyx and extracellular matrix. By acting as scaffolds for protein-protein interactions, HSPGs modulate extracellular ligand gradients, cell signaling networks, and cell-extracellular matrix crosstalk. Aberrant expression of HSPGs and enzymes involved in HSPG biosynthesis and processing has been reported in tumors, with impact in cancer cell behavior and tumor microenvironment properties. However, the roles of specific glycosyltransferases in the deregulated biosynthesis of HSPGs are not fully understood. In this study, we established glycoengineered gastric cancer cell models lacking either exostosin-like glycosyltransferase 2 (EXTL2) or EXTL3 and revealed their regulatory roles in both HS and chondroitin sulfate (CS) biosynthesis and structural features. We showed that EXTL3 is key for initiating the synthesis of HS chains in detriment of CS biosynthesis, intervening in the fine-tuned balance of the HS/CS ratio in cells, while EXTL2 functions as a negative regulator of HS biosynthesis, with impact over the glycoproteome of gastric cancer cells. We demonstrated that KO of EXTL2 enhanced HS levels along with concomitant upregulation of Syndecan-4, which is a major cell surface carrier of HS. This aberrant HS expression profile promoted a more aggressive phenotype, characterized by higher cellular motility and invasion, and impaired activation of Ephrin type-A 4 cell surface receptor tyrosine kinase. Our findings uncover the biosynthetic roles of EXTL2 and EXTL3 in the regulation of cancer cell GAGosylation and proteoglycans expression and unravel the functional consequences of aberrant HS/CS balance in cellular malignant features.

Solar Energy Storage Using a Cu2 O-TiO2 Photocathode in a Lithium Battery.

A Cu2 O-TiO2 photoelectrode is pr+oposed for simultaneous solar light energy harvesting and storing of electrochemical energy in an adapted lithium coin cell. The p-type Cu2 O semiconductor layer is the light harvester component of the photoelectrode and the TiO2 film performs as the capacitive layer. The rationale of the energy scheme shows that the photocharges generated in the Cu2 O semiconductor induce lithiation/delithiation processes in the TiO2 film as a function of the applied bias voltage and light power. A photorechargeable lithium button cell drilled on one side recharges with visible white light in ≈9 h in open circuit. It provides an energy density of ≈150 mAh g-1 at 0.1 C discharge current in dark, and the overall efficiency is 0.29%. This work draws a new approach for the photoelectrode role to advance in monolithic rechargeable batteries.

ST3GalIV drives SLeX biosynthesis in gastrointestinal cancer cells and associates with cancer cell motility.

Expression of sialyl Lewis X (SLeX) is a well-documented event during malignant transformation of cancer cells, and largely associates with their invasive and metastatic properties. Glycoproteins and glycolipids are the main carriers of SLeX, whose biosynthesis is known to be performed by different glycosyltransferases, namely by the family of ß-galactoside-α2,3-sialyltransferases (ST3Gals). In this study, we sought to elucidate the role of ST3GalIV in the biosynthesis of SLeX and in malignant properties of gastrointestinal (GI) cancer cells. By immunofluorescent screening, we selected SLeX-positive GI cancer cell lines and silenced ST3GalIV expression via CRISPR/Cas9. Flow cytometry, immunofluorescence and western blot analysis showed that ST3GalIV KO efficiently impaired SLeX expression in most cancer cell lines, with the exception of the colon cancer cell line LS174T. The impact of ST3GalIV KO in the biosynthesis of SLeX isomer SLeA and non sialylated Lewis X and A were also evaluated and overall, ST3GalIV KO led to a decreased expression of SLeA and an increased expression in both LeX and LeA. In addition, the abrogation of SLeX on GI cancer cells led to a reduction in cell motility. Furthermore, ST3GalVI KO was performed in LS174T ST3GalIV KO cells, resulting in the complete abolishment of SLeX expression and consequent reduced motility capacity of those cells. Overall, these findings portray ST3GalIV as the main, but not the only, enzyme driving the biosynthesis of SLeX in GI cancer cells, with a functional impact on cancer cell motility.

Risk of residual neoplasia after a noncurative colorectal endoscopic submucosal dissection for malignant lesions: a multinational study.

BACKGROUND : Endoscopic submucosal dissection (ESD) in colorectal lesions is technically demanding and a significant rate of noncurative procedures is expected. We aimed to assess the rate of residual lesions after a noncurative ESD for colorectal cancer (CRC) and to establish predictive scores to be applied in the clinical setting. METHODS : Retrospective multicenter analysis of consecutive colorectal ESDs. Patients with noncurative ESDs performed for the treatment of CRC lesions submitted to complementary surgery or with at least one follow-up endoscopy were included. RESULTS : From 2255 colorectal ESDs, 381 (17 %) were noncurative, and 135 of these were performed in CRC lesions. A residual lesion was observed in 24 patients (18 %). Surgery was performed in 96 patients and 76 (79 %) had no residual lesion in the colorectal wall or in the lymph nodes. The residual lesion rate for sm1 cancers was 0 %, and for > sm1 cancers was also 0 % if no other risk factors were present. Independent risk factors for lymph node metastasis were poor differentiation and lymphatic permeation (NC-Lymph score). Risk factors for the presence of a residual lesion in the wall were piecemeal resection, poor differentiation, and positive/indeterminate vertical margin (NC-Wall score). CONCLUSIONS : Lymphatic permeation or poor differentiation warrant surgery owing to their high risk of lymph node metastasis, mainly in > sm1 cancers. In the remaining cases, en bloc and R0 resections resulted in a low risk of residual lesions in the wall. Our scores can be a useful tool for the management of patients who undergo noncurative colorectal ESDs.

Increases in maternal depressive symptoms during pregnancy and infant cortisol reactivity: Mediation by placental corticotropin-releasing hormone.

BACKGROUND: Maternal depressive symptoms in pregnancy may affect offspring health through prenatal programming of the hypothalamic-pituitary-adrenal (HPA) axis. The biological mechanisms that explain the associations between maternal prenatal depressive symptoms and offspring HPA axis regulation are not yet clear. This pre-registered investigation examines whether patterns of maternal depressive symptoms in pregnancy are associated with infant cortisol reactivity and whether this association is mediated by changes in placental corticotropin-releasing hormone (pCRH). METHOD: A sample of 174 pregnant women completed assessments in early, mid, and late pregnancy that included standardized measures of depressive symptoms and blood samples for pCRH. Infant cortisol reactivity was assessed at 1 and 6 months of age. RESULTS: Greater increases in maternal depressive symptoms in pregnancy were associated with higher cortisol infant cortisol reactivity at 1 and 6 months. Greater increases in maternal depressive symptoms in pregnancy were associated with greater increases in pCRH from early to late pregnancy which in turn were associated with higher infant cortisol reactivity. CONCLUSIONS: Increases in maternal depressive symptoms and pCRH over pregnancy may contribute to higher infant cortisol reactivity. These findings help to elucidate the prenatal biopsychosocial processes contributing to offspring HPA axis regulation early in development.

Ultrasound-Guided Hydrodistension for Adhesive Capsulitis: Is There Any Adjunct Effect of Immediate Post-Procedural Manipulation Over Instructed Physical Therapy?

OBJECTIVES: To compare the additive value of immediate post-procedural manipulation versus physiotherapy, following ultrasound (US)-guided hydrodistention of the glenohumeral joint (GHJ) in patients with adhesive capsulitis (AC) and define predictors of outcome. METHODS: Within a 19-month period, 161 consecutive patients with AC were prospectively enrolled and allocated to two groups according to treatment, based on patients' individual preferences: 1) group-I, US-guided hydrodistension plus immediate post-procedural manipulations and 2) group-II, US-guided hydrodistension plus supervised physiotherapy program. The Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire and a visual analog scale (VAS) were used for clinical assessment at baseline (immediately after treatment), 1, 3, and 6 months. Comparisons were performed with Mann-Whitney U test and Kolmogorov-Smirnov test. Linear regression was used to identify predictors of outcome. P value <.05 defined significance. RESULTS: GHJ hydrodistension with manipulation or physiotherapy was linked to clinical improvement at all follow-up time-points. DASH scores of group-I remained constantly lower than DASH scores of group-II at all time-points (P < .001). VAS scores were lower in group-I than group-II at 1 and 3 months (P < .001 and P = .0019, respectively). Both groups had improved to a similar degree with respect to pain at 6 months (P = .29). The performance of post-interventional manipulations was predictive of improved shoulder functionality (as assessed with DASH scores) at all time-points, while low-grade disease and milder symptoms at presentation were associated with improved short-term pain. CONCLUSIONS: Immediate post-procedural manipulations appeared to be superior to physiotherapy following GHJ hydrodistension for AC in terms of shoulder functionality during a 6-month follow-up period. Post-interventional manipulations, the stage of AC and lower DASH and VAS scores at presentations were predictive of improved outcome.

GECOP-MMC: phase IV randomized clinical trial to evaluate the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) with mytomicin-C after complete surgical cytoreduction in patients with colon cancer peritoneal metastases.

BACKGROUND: The French PRODIGE 7 trial, published on January 2021, has raised doubts about the specific survival benefit provided by HIPEC with oxaliplatin 460 mg/m2 (30 minutes) for the treatment of peritoneal metastases from colorectal cancer. However, several methodological flaws have been identified in PRODIGE 7, specially the HIPEC protocol or the choice of overall survival as the main endpoint, so its results have not been assumed as definitive, emphasizing the need for further research on HIPEC. It seems that the HIPEC protocol with high-dose mytomicin-C (35 mg/m2) is the preferred regime to evaluate in future clinical studies. METHODS: GECOP-MMC is a prospective, open-label, randomized, multicenter phase IV clinical trial that aims to evaluate the effectiveness of HIPEC with high-dose mytomicin-C in preventing the development of peritoneal recurrence in patients with limited peritoneal metastasis from colon cancer (not rectal), after complete surgical cytoreduction. This study will be performed in 31 Spanish HIPEC centres, starting in March 2022. Additional international recruiting centres are under consideration. Two hundred sixteen patients with PCI ≤ 20, in which complete cytoreduction (CCS 0) has been obtained, will be randomized intraoperatively to arm 1 (with HIPEC) or arm 2 (without HIPEC). We will stratified randomization by surgical PCI (1-10; 11-15; 16-20). Patients in both arms will be treated with personalized systemic chemotherapy. Primary endpoint is peritoneal recurrence-free survival at 3 years. An ancillary study will evaluate the correlation between surgical and pathological PCI, comparing their respective prognostic values. DISCUSSION: HIPEC with high-dose mytomicin-C, in patients with limited (PCI ≤ 20) and completely resected (CCS 0) peritoneal metastases, is assumed to reduce the expected risk of peritoneal recurrence from 50 to 30% at 3 years. TRIAL REGISTRATION: EudraCT number: 2019-004679-37; Clinicaltrials.gov: NCT05250648 (registration date 02/22/2022, ).

COVID-19 Outcomes Among the Hispanic Population of 27 Large US Cities, 2020-2021.

Objectives. To examine racial/ethnic disparities in COVID-19 outcomes between Hispanics and Whites across 27 US jurisdictions whose health departments are members of the Big Cities Health Coalition (BCHC). Methods. Using surveillance data from the BCHC COVID-19 dashboard as of mid-June 2021, we computed crude incidence, age-adjusted hospitalization and mortality, and full vaccination coverage rates for Hispanics and Whites by city. We estimated relative and absolute disparities cumulatively and for 2020 and 2021 and explored associations between city-level social vulnerability and the magnitude of disparities. Results. In most of the cities with available COVID-19 incidence data, rates among Hispanics were 2.2 to 6.7 times higher than those among Whites. In all cities, Hispanics had higher age-adjusted hospitalization (1.5-8.6 times as high) and mortality (1.4-6.2 times as high) rates. Hispanics had lower vaccination coverage in all but 1 city. Disparities in incidence and hospitalizations narrowed in 2021, whereas disparities in mortality remained similar. Disparities in incidence, hospitalization, mortality, and vaccination rates were wider in cities with lower social vulnerability. Conclusions. A deeper exploration of racial/ethnic disparities in COVID-19 outcomes is essential to understand and prevent disparities among marginalized communities. (Am J Public Health. 2022;112(7): 1034-1044. https://doi.org/10.2105/AJPH.2022.306809).

The PSMA8 subunit of the spermatoproteasome is essential for proper meiotic exit and mouse fertility.

The ubiquitin proteasome system regulates meiotic recombination in yeast through its association with the synaptonemal complex, a 'zipper'-like structure that holds homologous chromosome pairs in synapsis during meiotic prophase I. In mammals, the proteasome activator subunit PA200 targets acetylated histones for degradation during somatic DNA double strand break repair and during histone replacement during spermiogenesis. We investigated the role of the testis-specific proteasomal subunit α4s (PSMA8) during spermatogenesis, and found that PSMA8 was localized to and dependent on the central region of the synaptonemal complex. Accordingly, synapsis-deficient mice show delocalization of PSMA8. Moreover, though Psma8-deficient mice are proficient in meiotic homologous recombination, there are alterations in the proteostasis of several key meiotic players that, in addition to the known substrate acetylated histones, have been shown by a proteomic approach to interact with PSMA8, such as SYCP3, SYCP1, CDK1 and TRIP13. These alterations lead to an accumulation of spermatocytes in metaphase I and II which either enter massively into apoptosis or give rise to a low number of aberrant round spermatids that apoptose before histone replacement takes place.

The Landmark Series: Surgical Treatment of Colorectal Cancer Peritoneal Metastases.

BACKGROUND: Peritoneal metastases (PM) are a form of metastatic spread affecting approximately 5-15% of colon cancer patients. The attitude towards management of peritoneal metastases has evolved from therapeutic nihilism towards a more comprehensive and multidisciplinary approach, in large part due to the development of cytoreductive surgery (CRS), usually coupled with heated intraperitoneal chemotherapy (HIPEC), along with the constant improvement of systemic chemotherapy of colorectal cancer. Several landmark studies, including 5 randomized controlled trials have marked the development and refinement of surgical approaches to treating colorectal cancer peritoneal metastases. METHODS: This review article focuses on these landmark studies and their influence in 4 key areas: the evidence supporting surgical resection of peritoneal metastases, the identification and standardization of important prognostic variables influencing patient selection, the role of surgery and intraperitoneal chemotherapy in prevention of colorectal PM and the role of intraperitoneal chemotherapy as an adjuvant to surgical resection. RESULTS: These landmark studies indicate that surgical resection of colorectal PM should be considered as a therapeutic option in appropriately selected patients and when adequate surgical expertise is available. Standardized prognostic variables including the Peritoneal Cancer Index and the Completeness of Cytoreduction Score should be used for evaluating both indications and outcomes. CONCLUSIONS: Current evidence does not support the use of second look surgery with oxaliplatin HIPEC or prophylactic oxaliplatin HIPEC in patients with high risk colon cancer nor the use of oxaliplatin HIPEC with CRS of colorectal PM.

A Near-Zero Anastomotic Leak Rate in Cytoreductive Surgery with Heated Intraperitoneal Chemotherapy is Achievable.

Gastrointestinal complications are the main source of severe morbidity after cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC), mainly in the form of anastomotic leak. Reducing the rate of anastomotic leaks is of paramount importance and should be approached both through risk factor understanding and reduction, as well as optimization of surgical team performance. We performed a study that describes the details of a technical protocol for the creation of anastomoses after colorectal resections in CRS and HIPEC and the anastomotic outcomes associated with its systematic application in a high-volume peritoneal surface malignancy center. An extremely low, near-zero anastomotic leak rate (0.85% in colorectal anastomoses, 1% in ileo-colic anastomoses, and 0% in ileo-rectal anastomoses) was observed among 1172 patients. Extremely low, near-zero rates of anastomotic leak after colorectal resections in CRS and HIPEC could be achievable in high-volume peritoneal malignancy centers. The described techniques could be adopted and validated in other high-volume peritoneal malignancy centers.

Safe Anastomoses without Ostomies in Cytoreductive Surgery with Heated Intraperitoneal Chemotherapy: Technical Considerations and Modifications.

BACKGROUND: Gastrointestinal complications, predominantly anastomotic leak (AL), are the most frequent source of severe morbidity after cytoreductive surgery (CRS). OBJECTIVE: The aim of this study was to present the technical standards for colorectal anastomoses developed and systematically applied to all patients undergoing CRS in a high-volume tertiary center, and the associated AL rates. METHODS: This was a descriptive study reporting the technical characteristics of a standardized protocol for three types of colorectal anastomoses (colorectal, ileorectal, and ileocolic) in CRS with heated intraperitoneal chemotherapy (HIPEC), and a retrospective analysis of prospectively collected data on anastomotic outcomes. All patients (1172) undergoing CRS with HIPEC from September 2006 to September 2020 were included. The anastomotic complications were classified according to the International Study Group of Rectal Cancer Surgery (ISGRCS) classification. RESULTS: Overall, 1172 patients underwent 1300 procedures and 1359 gastrointestinal anastomoses. An ileocolic anastomosis was performed in 408 patients, colorectal anastomosis in 469 patients, and ileorectal anastomosis in 16 patients, none with diverting ileostomy; 345 other gastrointestinal reconstructions and 82 urinary reconstructions were performed in these patients. The AL rate was 1% (4/408) for the ileocolic anastomosis, 0.85% (4/469) for the colorectal anastomosis, and 0% (0/16) for the ileorectal anastomosis. One patient died postoperatively due to AL. CONCLUSIONS: Systematic application of standardized techniques adapted to ensure optimal tissue healing (stapled anastomoses avoiding overlap, accurate staple deployment, and hand-sewn reinforcement) are associated with a very high level of anastomotic safety in a large cohort of patients undergoing CRS and HIPEC.

Genome-wide association study of stage III/IV grade C periodontitis (former aggressive periodontitis) in a Spanish population.

AIM: To identify loci associated with stages III/IV, grade C periodontitis (PIII/IV-C) through a genome-wide association study (GWAS). MATERIALS AND METHODS: 441 Caucasian Spanish PIII/IV-C cases from the SEPA Network of Research Clinics and 1141 controls from the Banco Nacional de ADN were genotyped with "Axiom Spain Biobank Array," which contains 757836 markers, including rare and low-frequency Spanish variants. The analysis of the individual association and subsequently the gene-level analysis with Sequence Kernel Association Test (SKAT) were carried out adjusting for age, sex and PC1 covariates. Pathway Analysis was additionally performed with Ingenuity Pathway Analysis (IPA) software on the top associated genes. RESULTS: In the individual analyses, no genome-wide significant signals were detected. However, 8 SNPs of 8 loci reached suggestive evidence of association with PIII/IV-C, including FAT3 rs35709256, CSNK1G2 rs4807188, MYH13 rs2074872, CNTN2 rs116611488, ANTXR1 rs4854545, 8p23.2 rs78672540, ANGPT1 rs13439823 and PLEC rs11993287 (p < 5 × 10-6 ). SKAT analysis identified other interesting signals at CNTN2, FBXO44, AP1M2, RSPO4, KRI1, BPIFB1 and INMT, although their probability does not exceed the multiple-test correction. IPA indicated significant enrichment of pathways related to cAMP, IL-2, CD28, VDR/RXR and PI3K/Akt.  CONCLUSIONS: GWAS found no SNPs significantly associated with PIII/IV-C.

Ubiquitin-specific protease 26 (USP26) is not essential for mouse gametogenesis and fertility.

Ubiquitin-specific protease 26 (USP26) is a deubiquitylating enzyme belonging to the USPs family with a transcription pattern restricted to the male germline. Since protein ubiquitination is an essential regulatory mechanism during meiosis, many efforts have been focused on elucidating the function of USP26 and its relationship with fertility. During the last decade, several studies have reported the presence of different polymorphisms in USP26 in patients with non-obstructive azoospermia (NOA) or severe oligozoospermia suggesting that this gene may be associated with human infertility. However, other studies have revealed the presence of these and novel polymorphisms, including nonsense mutations, in men with normal spermatogenesis as well. Thus, the results remain controversial and its function is unknown. In the present study, we describe the in vivo functional analysis of mice lacking USP26. The phenotypic analysis of two different Usp26-null mutants showed no overt-phenotype with both males and females being fertile. Cytological analysis of spermatocytes showed no defects in synapsis, chromosome dynamics, DNA repair, or recombination. Histopathological analysis revealed a normal distribution and number of the different cell types in both male and female mice. Finally, normal counts were observed in fertility assessments. These results represent the first in vivo evidence showing that USP26 is not essential for mouse gametogenesis.

Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial.

BACKGROUND: Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia. METHODS: Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% fT>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia. RESULTS: The median (IQR) of meropenem AUC0-24 h in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC < 4 mg/L. CONCLUSIONS: An increase in the dose of meropenem administered by CI achieved a higher exposure in the plasma and ELF. The use of the highest licensed dose of 6 g/day may be necessary to achieve an optimal coverage in ELF for all susceptible isolates (MIC ≤ 2 mg/L) in patients with conserved renal function. An alternative therapy should be considered when the presence of microorganisms with a MIC greater than 2 mg/L is suspected. TRIAL REGISTRATION: The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT-no. 2016-002796-10). Registered on 27 December 2016.

Postpartum depressive symptoms in low-income Latinas: Cultural and contextual contributors.

OBJECTIVE: Using a conceptual model of postpartum depression risk in Latinas including both contextual and cultural stressors, we tested contributions to depressive symptom levels and trajectories over the course of 1 year following birth in a community sample of Latinas. METHOD: A multisite sample of low-income U.S.-born and foreign-born Latinas (n = 537; M age = 25.70) was interviewed on many topics including measures of stress and maternal health at 1, 6, and 12 months postpartum. Nested multilevel growth curve models were implemented to test associations of contextual stressors (poverty, domestic violence) with trajectories of depressive symptoms, adjusting for confounds. This model was compared to 1 that added cultural stress variables (everyday discrimination, foreign-born status, language preference, age at immigration) measured 1-month postpartum. RESULTS: The best fitting model provided evidence for the independent effects of cultural and contextual stressors. Discrimination (ß = .13 SE = .02, p = < .001) and domestic violence (ß = .39 SE = .09, p = < .001) predicted trajectories with higher levels of depressive symptoms 1 month postpartum, but not linear change in symptoms over the year. CONCLUSIONS: The present study provides evidence that discrimination, a cultural factor, and domestic violence, a contextual factor, each predict higher levels of early postpartum depressive symptoms. Interventions addressing discrimination and maternal safety are recommended. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Systemic pharmacokinetics and safety of high doses of nebulized colistimethate sodium in critically ill patients with hospital-acquired and ventilator-associated pneumonia.

OBJECTIVES: To assess the pharmacokinetics of formed colistin in plasma and the safety of two different high doses of colistimethate sodium administered via nebulization in critically ill surgical patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). PATIENTS AND METHODS: Formed colistin plasma concentrations were measured in critically ill surgical patients with pneumonia treated with two different doses of nebulized colistimethate sodium (3 MIU/8 h versus 5 MIU/8 h). Adverse events possibly related to nebulized colistimethate sodium were recorded. RESULTS: Twenty-seven patients (15 in the 3 MIU/8 h group and 12 in the 5 MIU/8 h group) were included. Colistin plasma concentrations were unquantifiable (<0.1 mg/L) in eight (53.3%) patients in the 3 MIU/8 h group and in seven patients (58.3%) in the 5 MIU/8 h group. Median (IQR) quantifiable colistin plasma concentrations before nebulization and at 1, 4 and 8 h were 0.17 (0.12-0.33), 0.20 (0.11-0.24), 0.17 (0.12-0.23) and 0.17 (0.11-0.32) mg/L, respectively, in the 3 MIU/8 h group and 0.20 (0.11-0.35), 0.24 (0.12-0.44), 0.24 (0.10-0.49) and 0.23 (0.11-0.44) mg/L, respectively, in the 5 MIU/8 h group, with no differences between the two groups at any time. Renal impairment during nebulized treatment was observed in three patients in each group, but was unlikely to be related to colistimethate sodium treatment. Nebulized colistimethate sodium therapy was well tolerated and no bronchospasms or neurotoxicity events were observed. CONCLUSIONS: In this limited observational case series of critically ill patients with HAP or VAP treated with high doses of nebulized colistimethate sodium, systemic exposure was minimal and the treatment was well tolerated.