Impact of extended lung protection during mechanical ventilation on lung recovery in patients with COVID-19 ARDS: a phase II randomized controlled trial.

BACKGROUND: Protective ventilation seems crucial during early Acute Respiratory Distress Syndrome (ARDS), but the optimal duration of lung protection remains undefined. High driving pressures (ΔP) and excessive patient ventilatory drive may hinder lung recovery, resulting in self-inflicted lung injury. The hidden nature of the ΔP generated by patient effort complicates the situation further. Our study aimed to assess the feasibility of an extended lung protection strategy that includes a stepwise protocol to control the patient ventilatory drive, assessing its impact on lung recovery. METHODS: We conducted a single-center randomized study on patients with moderate/severe COVID-19-ARDS with low respiratory system compliance (CRS < 0.6 (mL/Kg)/cmH2O). The intervention group received a ventilation strategy guided by Electrical Impedance Tomography aimed at minimizing ΔP and patient ventilatory drive. The control group received the ARDSNet low-PEEP strategy. The primary outcome was the modified lung injury score (mLIS), a composite measure that integrated daily measurements of CRS, along with oxygen requirements, oxygenation, and X-rays up to day 28. The mLIS score was also hierarchically adjusted for survival and extubation rates. RESULTS: The study ended prematurely after three consecutive months without patient enrollment, attributed to the pandemic subsiding. The intention-to-treat analysis included 76 patients, with 37 randomized to the intervention group. The average mLIS score up to 28 days was not different between groups (P = 0.95, primary outcome). However, the intervention group showed a faster improvement in the mLIS (1.4 vs. 7.2 days to reach 63% of maximum improvement; P < 0.001), driven by oxygenation and sustained improvement of X-ray (P = 0.001). The intervention group demonstrated a sustained increase in CRS up to day 28 (P = 0.009) and also experienced a shorter time from randomization to room-air breathing (P = 0.02). Survival at 28 days and time until liberation from the ventilator were not different between groups. CONCLUSIONS: The implementation of an individualized PEEP strategy alongside extended lung protection appears viable. Promising secondary outcomes suggested a faster lung recovery, endorsing further examination of this strategy in a larger trial. Clinical trial registration This trial was registered with ClinicalTrials.gov (number NCT04497454) on August 04, 2020.

Functional impact of bilateral vestibular loss and the unexplained complaint of oscillopsia.

Introduction: The vestibulo-ocular reflex (VOR) stabilizes vision during head movements. VOR disorders lead to symptoms such as imbalance, dizziness, and oscillopsia. Despite similar VOR dysfunction, patients display diverse complaints. This study analyses saccades, balance, and spatial orientation in chronic peripheral and central VOR disorders, specifically examining the impact of oscillopsia. Methods: Participants involved 15 patients with peripheral bilateral vestibular loss (pBVL), 21 patients with clinically and genetically confirmed Machado-Joseph disease (MJD) who also have bilateral vestibular deficit, and 22 healthy controls. All pBVL and MJD participants were tested at least 9 months after the onset of symptoms and underwent a detailed clinical neuro-otological evaluation at the Dizziness and Eye Movements Clinic of the Meir Medical Center. Results: Among the 15 patients with pBVL and 21 patients with MJD, only 5 patients with pBVL complained of chronic oscillopsia while none of the patients with MJD reported this complaint. Comparison between groups exhibited significant differences in vestibular, eye movements, balance, and spatial orientation. When comparing oscillopsia with no-oscillopsia subjects, significant differences were found in the dynamic visual acuity test, the saccade latency of eye movements, and the triangle completion test. Discussion: Even though there is a significant VOR gain impairment in MJD with some subjects having less VOR gain than pBVL with reported oscillopsia, no individuals with MJD reported experiencing oscillopsia. This study further supports that subjects experiencing oscillopsia present a real impairment to stabilize the image on the retina, whereas those without oscillopsia may utilize saccade strategies to cope with it and may also rely on visual information for spatial orientation. Finding objective differences will help to understand the causes of the oscillopsia experience and develop coping strategies to overcome it.

Enantioselective synthesis of ß-aryl-γ-lactam derivatives via Heck-Matsuda desymmetrization of N-protected 2,5-dihydro-1H-pyrroles.

We report herein an enantioselective palladium-catalyzed Heck-Matsuda reaction for the desymmetrization of N-protected 2,5-dihydro-1H-pyrroles with aryldiazonium salts, using the chiral N,N-ligand (S)-PyraBox. This strategy has allowed straightforward access to a diversity of 4-aryl-γ-lactams via Heck arylation followed by a sequential Jones oxidation. The overall method displays a broad scope and good enantioselectivity, favoring the (R) enantiomer. The applicability of the protocol is highlighted by the efficient enantioselective syntheses of the selective phosphodiesterase-4-inhibitor rolipram and the commercial drug baclofen as hydrochloride.

Heteropolyacids@Silica Heterogeneous Catalysts to Produce Solketal from Glycerol Acetalization.

The composites of heteropolyacids (H3PW12, H3PMo12) incorporated into amine-functionalized silica materials were used for the first time as heterogeneous catalysts in the valorization of glycerol (a major waste from the biodiesel industry) through acetalization reaction with acetone. The polyoxotungstate catalyst H3PW12@AptesSBA-15 exhibited higher catalytic efficiency than the phosphomolybdate, achieving 97% conversion and 97% of solketal selectivity, after 60 min at 25 °C, or 91% glycerol conversion and the same selectivity, after 5 min, performing the reaction at 60 °C. A correlation between catalytic performance and catalyst acidity is presented here. Furthermore, the stability of the solid catalyst was investigated and discussed.

Treatment Interruptions and Mortality among Puerto Rican Women with Gynecologic Cancers in Puerto Rico after Hurricanes Irma and María: A Retrospective Cohort Study.

OBJECTIVE: Cancer patients are among the most vulnerable populations during and after a disaster. We evaluated the impact of treatment interruption on the survival of women with gynecologic cancer in Puerto Rico following hurricanes Irma and María. METHODS: Retrospective cohort study among a clinic-based sample of women diagnosed between January 2016-September 2017 (n=112). Women were followed up from their diagnosis until December 2019, to assess vital status. Kaplan-Meier survival curves and Cox proportional hazards models were performed. RESULTS: Mean age was 56 (±12.3) years; corpus uteri (58.9%) was the most common gynecologic cancer. Predominant treatments were surgery (91.1%) and chemotherapy (44.6%). Overall, 75.9% were receiving treatment before the hurricanes, 16.1% experienced treatment interruptions and 8.9% died during the follow-up period. Factors associated with treatment interruption in bivariate analysis included younger age (≤55 years), having regional/distant disease, and receiving >1 cancer treatment (p<0.05). Crude analysis revealed an increased risk of death among women with treatment interruption (HR: 3.88, 95% CI=1.09-13.77), persisting after adjusting for age and cancer stage (HR: 2.49, 95% CI= 0.69-9.01). CONCLUSIONS: Findings underscore the detrimental impact of treatment interruption on cancer survival in the aftermath of hurricanes, emphasizing the need for emergency response plans for this vulnerable population.

Investigation of the Effects of Labware Contamination on Mass Spectrometry-Based Human Serum Lipidome Analysis.

Polypropylene microcentrifuge tubes (MCTs) are increasingly used in lipidome sample preparation. In the absence of a comprehensive study evaluating ramifications of plasticware utilization in mass spectrometry-based lipidomic analyses, we conducted a systematic analysis to elucidate potential negative effects ascribable to labware contamination in serum lipidomics. During serum lipid extractions, tested glassware introduced 24 labware contaminants. In contrast, Eppendorf polypropylene MCTs contributed 485 contaminant features, many of which could be erroneously putatively identified as lipids via their m/z values. Eppendorf MCTs contamination engendered severe ion-suppression of 40 low abundance serum lipids, while generating mild to modest lipid ion-suppression across a multitude of higher abundance coeluting lipids. Less compatible polypropylene MCTs from an alternative manufacturer introduced a staggering 2,949 contaminant m/z values, severely affecting 75 coeluting serum lipids and causing more frequent and pronounced ion-suppression instances. Furthermore, by performing serum extractions with varied initial volumes, it was ascertained that labware-induced lipid ion-suppression is a dynamic phenomenon, contingent on both lipid and labware contaminant concentrations where low-abundance lipids are disproportionately impacted by coelutes of suppressive contaminants. In addition to lipid ion-suppression, the identification and quantification of 7 fatty acid endogenous serum lipids were compromised by the leaching of structurally identical surfactants from MCTs. MCTs artificially introduced 10 additional primary amides extraneous to serum samples. Utmost caution is imperative in interpreting data concerning primary amides and fatty acids when employing plastic labware. Through this investigation, we aspire to elevate awareness regarding the pernicious impact of labware contamination on lipidome analysis.

TIMP-1 is an activator of MHC-I expression in myeloid dendritic cells with implications for tumor immunogenicity.

Immune checkpoint therapies (ICT) for advanced solid tumors mark a new milestone in cancer therapy. Yet their efficacy is often limited by poor immunogenicity, attributed to inadequate priming and generation of antitumor T cells by dendritic cells (DCs). Identifying biomarkers to enhance DC functions in such tumors is thus crucial. Tissue Inhibitor of Metalloproteinases-1 (TIMP-1), recognized for its influence on immune cells, has an underexplored relationship with DCs. Our research reveals a correlation between high TIMP1 levels in metastatic melanoma and increased CD8 + T cell infiltration and survival. Network studies indicate a functional connection with HLA genes. Spatial transcriptomic analysis of a national melanoma cohort revealed that TIMP1 expression in immune compartments associates with an HLA-A/MHC-I peptide loading signature in lymph nodes. Primary human and bone-marrow-derived DCs secrete TIMP-1, which notably increases MHC-I expression in classical type 1 dendritic cells (cDC1), especially under melanoma antigen exposure. TIMP-1 affects the immunoproteasome/TAP complex, as seen by upregulated PSMB8 and TAP-1 levels of myeloid DCs. This study uncovers the role of TIMP-1 in DC-mediated immunogenicity with insights into CD8 + T cell activation, providing a foundation for mechanistic exploration and highlighting its potential as a new target for combinatorial immunotherapy to enhance ICT effectiveness.

Risk Factors for Pediatric Critical COVID-19: A Systematic Review and Meta-Analysis.

BACKGROUND: Risk stratification is a cornerstone of the Pediatric Infectious Diseases Society COVID-19 treatment guidance. This systematic review and meta-analysis aimed to define the clinical characteristics and comorbidities associated with critical COVID-19 in children and adolescents. METHODS: Two independent reviewers screened the literature (Medline and EMBASE) for studies published through August 31, 2023, that reported outcome data on patients aged ≤21 years with COVID-19. Critical disease was defined as an invasive mechanical ventilation requirement, intensive care unit admission, or death. Random effects models were used to estimate pooled odds ratios (OR) with 95% confidence intervals (CI), and heterogeneity was explored through subgroup analyses. RESULTS: Among 10,178 articles, 136 studies met the inclusion criteria for review. Data from 70 studies, which collectively examined 172,165 children and adolescents with COVID-19, were pooled for meta-analysis. In previously healthy children, the absolute risk of critical disease from COVID-19 was 4% (95% CI, 1%-10%). Compared with no comorbidities, the pooled OR for critical disease was 3.95 (95% CI, 2.78-5.63) for the presence of one comorbidity and 9.51 (95% CI, 5.62-16.06) for ≥2 comorbidities. Key risk factors included cardiovascular and neurological disorders, chronic pulmonary conditions (excluding asthma), diabetes, obesity, and immunocompromise, all with statistically significant ORs >2.00. CONCLUSIONS: While the absolute risk for critical COVID-19 in children and adolescents without underlying health conditions is relatively low, the presence of one or more comorbidities was associated with markedly increased risk. These findings support the importance of risk stratification in tailoring pediatric COVID-19 management.

Uncommon Twist: Femoral Neck Stress Fracture in a High-Performance Athlete With an Incidental Diagnosis of Femoroacetabular Impingement.

Femoral neck stress fractures (FNSFs) are rare but significant injuries, often leading to delayed diagnosis due to nonspecific symptomatology. This case report presents a 30-year-old professional surfer who experienced acute groin pain during a half marathon, ultimately diagnosed with a left intertrochanteric line femur stress fracture and with femoroacetabular impingement (FAI) in the opposite hip. Despite being physically fit, his presentation challenges the prevailing notion that FNSFs predominantly occur in military personnel or the elderly. The patient underwent surgical left hip osteosynthesis without complications. This case highlights the importance of early suspicion of FNSFs in young, active individuals and emphasizes the need for comprehensive evaluation to prevent complications like osteonecrosis and malunion. It underscores the value of a broad differential diagnosis and timely intervention in optimizing outcomes, especially in the context of rising high-impact sports participation.

Comparative Outcomes of Minimally Invasive Versus Open Pancreatoduodenectomy in Distal Cholangiocarcinoma: A Systematic Review and Meta-Analysis.

Pancreatoduodenectomy, the primary surgical strategy for managing cholangiocarcinoma, is executed via two distinct methodologies, namely minimally invasive pancreatoduodenectomy (MIPD) and open pancreatoduodenectomy (OPD). The selection between these surgical options is critical, as it directly influences patient outcomes, encompassing both short-term recovery metrics and long-term survival rates. Despite the clinical significance of these procedures, there exists a notable void in the literature regarding a comprehensive comparison of MIPD and OPD, particularly in assessing their respective efficacies and complications. This lack of detailed comparative analysis has left a gap in evidence-based guidance for clinicians faced with the decision of choosing the most appropriate surgical approach for their patients. The absence of robust data comparing the two techniques underscores the necessity for a meta-analysis that rigorously examines and contrasts the outcomes associated with MIPD and OPD. By drawing upon a wide array of international studies, this research aims to shed light on the advantages and potential drawbacks of each method, thereby providing a more informed basis for surgical decision-making in the treatment of cholangiocarcinoma.

Interactive effects of parental support and psychological control on children's emotion regulation.

Parents engage in a variety of behaviors that have important impacts on children's psychosocial functioning, including their ability to effectively regulate emotions. Parental support includes behaviors that convey warmth, love, and acceptance, whereas parental psychological control includes shaming, guilt induction, and love withdrawal. Although the unique effects of these parenting behaviors are most often examined in the literature, it is possible that they may interact with one another to influence child outcomes. The goal of the present study was to examine whether parental psychological control moderated the effect of parental support on children's emotion (dys)regulation over a 6-month period. Participants included 284 third- through fifth-grade students (51.8% boys; 51.1% Hispanic/Latinx) as well as their homeroom teachers. Children completed self-report measures of parental support, psychological control, and emotion (dys)regulation during the fall and spring semesters of an academic year. Teachers also completed measures of emotion (dys)regulation at each time point. Results indicated that parental psychological control moderated the association between parental support and self-reported emotion regulation over time. Specifically, parental support predicted increases in emotion regulation over time among youth reporting lower levels of psychological control; at higher levels, however, parental support was not associated with emotion regulation. Furthermore, psychological control uniquely predicted increases in child-reported emotion dysregulation, whereas parental support predicted decreases in teacher-reported emotion dysregulation. Findings from this study suggest that psychological control may serve as an important target for future parenting interventions. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

MANUSCRIPT Local Crowd, Local Probe: Strengths and Drawbacks of Azidohomoalanine as a Site-Specific Crowding Probe.

Every residue on a protein can be characterized by its interaction with water, in lack or in excess, as water is the matrix of biological systems. Infrared spectroscopy and the implementation of local azidohomoalanine (AHA) probes allow us to move beyond an ensemble or surface-driven conceptualization of water behavior and toward a granular, site-specific picture. In this paper, we examined the role of crowding in modulating both global and local behavior on the ß-hairpin, TrpZip2 using a combination of Fourier-transform infrared spectroscopy (FTIR) spectroscopy, two-dimensional infrared (2D IR) spectroscopy, and molecular dynamics simulations. We found that, at the amino acid level, crowding drove dehydration of both sheet and turn peptide sites as well as free AHA. However, the subpicosecond dynamics showed highly individualized responses based on the local environment. Interestingly, while steady-state FTIR measurements revealed similar responses at the amino-acid level to hard versus soft crowding (dehydration), we found that PEG and glucose had opposite stabilizing and destabilizing effects on the protein secondary structure, emphasizing an important distinction in understanding the impact of crowding on protein structure as well as the role of crowding across length scales.

The Pattern of GH Action in the Mouse Brain.

GH acts in numerous organs expressing the GH receptor (GHR), including the brain. However, the mechanisms behind the brain's permeability to GH and how this hormone accesses different brain regions remain unclear. It is well-known that an acute GH administration induces phosphorylation of the signal transducer and activator of transcription 5 (pSTAT5) in the mouse brain. Thus, the pattern of pSTAT5 immunoreactive cells was analyzed at different time points after IP or intracerebroventricular GH injections. After a systemic GH injection, the first cells expressing pSTAT5 were those near circumventricular organs, such as arcuate nucleus neurons adjacent to the median eminence. Both systemic and central GH injections induced a medial-to-lateral pattern of pSTAT5 immunoreactivity over time because GH-responsive cells were initially observed in periventricular areas and were progressively detected in lateral brain structures. Very few choroid plexus cells exhibited GH-induced pSTAT5. Additionally, Ghr mRNA was poorly expressed in the mouse choroid plexus. In contrast, some tanycytes lining the floor of the third ventricle expressed Ghr mRNA and exhibited GH-induced pSTAT5. The transport of radiolabeled GH into the hypothalamus did not differ between wild-type and dwarf Ghr knockout mice, indicating that GH transport into the mouse brain is GHR independent. Also, single-photon emission computed tomography confirmed that radiolabeled GH rapidly reaches the ventral part of the tuberal hypothalamus. In conclusion, our study provides novel and valuable information about the pattern and mechanisms behind GH transport into the mouse brain.

Quantitative correlation of ENPP1 pathogenic variants with disease phenotype.

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) codes for a type 2 transmembrane glycoprotein which hydrolyzes extracellular phosphoanhydrides into bio-active molecules that regulate, inter alia, ectopic mineralization, bone formation, vascular endothelial proliferation, and the innate immune response. The clinical phenotypes produced by ENPP1 deficiency are disparate, ranging from life-threatening arterial calcifications to cutaneous hypopigmentation. To investigate associations between disease phenotype and enzyme activity we quantified the enzyme velocities of 29 unique ENPP1 pathogenic variants in 41 patients enrolled in an NIH study along with 33 other variants reported in literature. We correlated the relative enzyme velocities with the presenting clinical diagnoses, performing the catalytic velocity measurements simultaneously in triplicate using a high-throughput assay to reduce experimental variation. We found that ENPP1 variants associated with autosomal dominant phenotypes reduced enzyme velocities by 50 % or more, whereas variants associated with insulin resistance had non-significant effects on enzyme velocity. In Cole disease the catalytic velocities of ENPP1 variants associated with AD forms trended to lower values than those associated with autosomal recessive forms - 8-32 % vs. 33 % of WT, respectively. Additionally, ENPP1 variants leading to life-threatening vascular calcifications in GACI patients had widely variable enzyme activities, ranging from no significant differences compared to WT to the complete abolishment of enzyme velocity. Finally, disease severity in GACI did not correlate with the mean enzyme velocity of the variants present in affected compound heterozygotes but did correlate with the more severely damaging variant. In summary, correlation of ENPP1 enzyme velocity with disease phenotypes demonstrate that enzyme velocities below 50 % of WT levels are likely to occur in the context of autosomal dominant disease (due to a monoallelic variant), and that disease severity in GACI infants correlates with the more severely damaging ENPP1 variant in compound heterozygotes, not the mean velocity of the pathogenic variants present.

Nanoencapsulation of extracts and isolated compounds of plant origin and their cytotoxic effects on breast and cervical cancer treatments: Advantages and new challenges.

This review analyzes the current progress in loaded nanoparticles (NPs) of plant extracts or isolated antineoplastic compounds used in breast and cervical cancer treatments. Also, it provides a comprehensive overview of the contributions made by traditional medicine and nanomedicine to the research of two of the most prevalent types of cancer in women worldwide: breast and cervical cancer. Searches were conducted in electronic databases to gather relevant information related to the biological activity of the NPs, which were meticulously reviewed. Nanomedicine has advanced to incorporate plant compounds including their crude extracts, in the preparation of NPs. The most used method is green synthesis, whose most outstanding advantages, is the reduced preparation time, and the variety of results that can be obtained depending on the reaction times, pH, temperature, and concentration of both the bio-reducing agent and the compound or plant extract. Most of the studies focus on evaluating crude extracts with high polarity, such as aqueous, alcoholic, and hydroalcoholic extracts. In conclusion, exploring the use of organic compounds is considered an area of opportunity for further research and future perspectives. Most of the analyzed studies were conducted using in vitro assays, highlighting the relatively recent nature of this field. It is expected that future research will involve more in vivo assays, particularly focusing on isolated cell lines representing the most difficult-to-treat types of cancer, such as triple-negative breast cancer like MDA-MB-231. Notably the MCF-7 cell line is one of the most used, while limited studies were found concerning cervical cancer.

Age and Sex Differences in the Contribution of Mean Arterial Pressure to Pulse Pressure Before Middle Age.

INTRODUCTION: A lower ability to buffer pulse pressure (PP) in the face of increasing mean arterial pressure (MAP) may underlie the disproportionate increase in systolic blood pressure (SBP) in women from young adulthood through middle-aged relative to men. AIM: To evaluate the contribution of MAP to the change in PP and pressure wave contour in men and women from young adulthood to middle age. METHODS: Central pressure waveform was obtained from radial artery applanation tonometry in 312 hypertensive patients between 16 to 49 years (134 women, mean age 35 ± 9 years), 185 of whom were on antihypertensive treatment. RESULTS: Higher MAP levels (≥ 100 mmHg) were significantly associated with higher brachial and central SBP (P < 0.001), PP (P < 0.001), incident wave (P = 0.005), AP (P < 0.001), and PWV (P < 0.001) compared to lower MAP levels. The relationship between MAP and brachial PP (P < 0.001), central PP (P < 0.001), incident wave (P < 0.001), and AP (P < 0.01), but not PWV, strengthens with age. The age-related increase in the contribution of MAP to brachial PP (P < 0.001), central PP (P < 0.001), and incident wave (P < 0.001) was more prominent in women than in men beginning in the fourth decade. In multiple regression analyses, MAP remained a significantly stronger predictor of central PP and incident wave in women than in men, independent of age, heart rate, and antihypertensive treatment. In turn, age remained a significantly stronger predictor of central PP and incident wave in women than in men, independent of MAP, heart rate, and antihypertensive treatment. CONCLUSIONS: Women of reproductive age showed a steeper increase in PP with increasing MAP, despite comparable increases in arterial stiffness in both sexes. The difference was driven by a greater contribution of MAP to the forward component of the pressure wave in women.

Mapping twist-tuned multiband topology in bilayer WSe2.

Semiconductor moiré superlattices have been shown to host a wide array of interaction-driven ground states. However, twisted homobilayers have been difficult to study in the limit of large moiré wavelengths, where interactions are most dominant. In this study, we conducted local electronic compressibility measurements of twisted bilayer WSe2 (tWSe2) at small twist angles. We demonstrated multiple topological bands that host a series of Chern insulators at zero magnetic field near a "magic angle" around 1.23°. Using a locally applied electric field, we induced a topological quantum-phase transition at one hole per moiré unit cell. Our work establishes the topological phase diagram of a generalized Kane-Mele-Hubbard model in tWSe2, demonstrating a tunable platform for strongly correlated topological phases.

Bilateral vestibulopathy as the initial presentation of CANVAS.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a slowly progressing autosomal recessive ataxic disorder linked to an abnormal biallelic intronic (most commonly) AAGGG repeat expansion in the replication factor complex subunit 1 (RFC1). While the clinical diagnosis is relatively straightforward when the three components of the disorder are present, it becomes challenging when only one of the triad (cerebellar ataxia, neuropathy or vestibular areflexia) manifests. Isolated cases of Bilateral Vestibulopathy (BVP) or vestibular areflexia that later developed the other components of CANVAS have not been documented. We report four cases of patients with chronic imbalance and BVP that, after several years, developed cerebellar and neuropathic deficits with positive genetic testing for RFC1. Our report supports the concept that CANVAS should be considered in every patient with BVP of unknown etiology, even without the presence of the other triad components. This is especially important given that about 50% of cases in many BVP series are diagnosed as idiopathic, some of which may be undiagnosed CANVAS.