Category: Nevin Manimala

Proc Natl Acad Sci U S A. 2021 Nov 9;118(45):e2113527118. doi: 10.1073/pnas.2113527118.

ABSTRACT

Here, we study the dynamical expression of endogenously labeled Hes1, a transcriptional repressor implicated in controlling cell proliferation, to understand how cell-cycle length heterogeneity is generated in estrogen receptor (ER)⁺ breast cancer cells. We find that Hes1 shows oscillatory expression with ∼25 h periodicity and during each cell cycle has a variable peak in G1, a trough around G1-S transition, and a less variable second peak in G2/M. Compared to other subpopulations, the cell cycle in CD44^HighCD24^Low cancer stem cells is longest and most variable. Most cells divide around the peak of the Hes1 expression wave, but preceding mitoses in slow dividing CD44^HighCD24^Low cells appear phase-shifted, resulting in a late-onset Hes1 peak in G1. The position, duration, and shape of this peak, rather than the Hes1 expression levels, are good predictors of cell-cycle length. Diminishing Hes1 oscillations by enforcing sustained expression slows down the cell cycle, impairs proliferation, abolishes the dynamic expression of p21, and increases the percentage of CD44^HighCD24^Low cells. Reciprocally, blocking the cell cycle causes an elongation of Hes1 periodicity, suggesting a bidirectional interaction of the Hes1 oscillator and the cell cycle. We propose that Hes1 oscillations are functionally important for the efficient progression of the cell cycle and that the position of mitosis in relation to the Hes1 wave underlies cell-cycle length heterogeneity in cancer cell subpopulations.

PMID:34725165 | DOI:10.1073/pnas.2113527118

Hosp Pediatr. 2021 Nov 1:hpeds.2021-005903. doi: 10.1542/hpeds.2021-005903. Online ahead of print.

ABSTRACT

BACKGROUND: Social determinants of health (SDOH) contribute to racial disparities in asthma outcomes. Community health worker (CHW) programs represent a promising way to screen for SDOH and connect patients to resources, but the impact of CHW programs in the inpatient pediatric setting has been examined in few studies. In this study, we aimed to evaluate a CHW program for children hospitalized with asthma in a predominantly Hispanic community by examining rates of SDOH and social resource navigation.

METHODS: This pilot study involved a CHW intervention to improve pediatric asthma care. Patients were included if they were hospitalized with asthma over an 18-month period and enrolled in the CHW program during their hospitalization. In an intake interview, CHWs screened caregivers for SDOH and provided tailored social resource navigation. Descriptive statistics were used to assess rates of social risk factors and social resource navigation.

RESULTS: Eighty patients underwent SDOH screening. The majority of patients were Hispanic (81.3%, n = 65). Half of caregivers reported food or housing insecurity over the past 12 months (50.0%, n = 40), and most reported inadequate housing conditions (63.8%, n = 51). CHWs coordinated social resources for the majority of families (98.8%, n = 79), with the most common being food resources (42.5%, n = 34), housing resources (82.5%, n = 66), and appointment navigation (41.3%, n = 33).

CONCLUSIONS: CHWs identified a high burden of unmet social needs and provided associated social resource navigation in a largely Hispanic pediatric population hospitalized for asthma. CHW programs have potential to improve asthma outcomes by linking high-risk patients with social resources.

PMID:34725201 | DOI:10.1542/hpeds.2021-005903

Proc Natl Acad Sci U S A. 2021 Nov 9;118(45):e2111863118. doi: 10.1073/pnas.2111863118.

ABSTRACT

Although amyloid plaques composed of fibrillar amyloid-β (Aβ) assemblies are a diagnostic hallmark of Alzheimer’s disease (AD), quantities of amyloid similar to those in AD patients are observed in brain tissue of some nondemented elderly individuals. The relationship between amyloid deposition and neurodegeneration in AD has, therefore, been unclear. Here, we use solid-state NMR to investigate whether molecular structures of Aβ fibrils from brain tissue of nondemented elderly individuals with high amyloid loads differ from structures of Aβ fibrils from AD tissue. Two-dimensional solid-state NMR spectra of isotopically labeled Aβ fibrils, prepared by seeded growth from frontal lobe tissue extracts, are similar in the two cases but with statistically significant differences in intensity distributions of cross-peak signals. Differences in solid-state NMR data are greater for 42-residue amyloid-β (Aβ42) fibrils than for 40-residue amyloid-β (Aβ40) fibrils. These data suggest that similar sets of fibril polymorphs develop in nondemented elderly individuals and AD patients but with different relative populations on average.

PMID:34725161 | DOI:10.1073/pnas.2111863118

BMJ Open. 2021 Nov 1;11(11):e054777. doi: 10.1136/bmjopen-2021-054777.

ABSTRACT

INTRODUCTION: Major depressive disorder (MDD or depression) is prevalent among adults aged 65 years and older. The effectiveness and safety of interventions used to treat depression is often assessed through randomised controlled trials (RCTs). However, heterogeneity in the selection, measurement and reporting of outcomes in RCTs renders comparisons between trial results, interpretability and generalisability of findings challenging. There is presently no core outcome set (COS) for use in RCTs that assess interventions for older adults with MDD. We will conduct a methodological review of the literature for outcomes reported in trials for adults 65 years and older with depression to assess the heterogeneity of outcome measures.

METHODS AND ANALYSIS: RCTs evaluating pharmacotherapy, psychotherapy, or any other treatment intervention for older adults with MDD published in the last 10 years will be located using electronic database searches (MEDLINE, Embase, PsycINFO and the Cochrane Central Register of Controlled Trials). Reviewers will conduct title and abstract screening, full-text screening and data extraction of trials eligible for inclusion independently and in duplicate. Outcomes will be synthesised and mapped to core outcome-domain frameworks. We will summarise characteristics associated with trials and outcomes.

ETHICS AND DISSEMINATION: We hope that findings from our methodological review will reduce variability in outcome selection, measurement and reporting and facilitate the development of a COS for older adults with MDD. Our review will also inform evidence synthesis efforts in identifying the best treatment practices for this clinical population. Ethics approval is not required, as this study is a literature review.

PROSPERO REGISTRATION NUMBER: CRD42021244753.

PMID:34725082 | DOI:10.1136/bmjopen-2021-054777

Proc Natl Acad Sci U S A. 2021 Nov 9;118(45):e2108551118. doi: 10.1073/pnas.2108551118.

ABSTRACT

Fluids in natural systems, like the cytoplasm of a cell, often contain thousands of molecular species that are organized into multiple coexisting phases that enable diverse and specific functions. How interactions between numerous molecular species encode for various emergent phases is not well understood. Here, we leverage approaches from random-matrix theory and statistical physics to describe the emergent phase behavior of fluid mixtures with many species whose interactions are drawn randomly from an underlying distribution. Through numerical simulation and stability analyses, we show that these mixtures exhibit staged phase-separation kinetics and are characterized by multiple coexisting phases at steady state with distinct compositions. Random-matrix theory predicts the number of coexisting phases, validated by simulations with diverse component numbers and interaction parameters. Surprisingly, this model predicts an upper bound on the number of phases, derived from dynamical considerations, that is much lower than the limit from the Gibbs phase rule, which is obtained from equilibrium thermodynamic constraints. We design ensembles that encode either linear or nonmonotonic scaling relationships between the number of components and coexisting phases, which we validate through simulation and theory. Finally, inspired by parallels in biological systems, we show that including nonequilibrium turnover of components through chemical reactions can tunably modulate the number of coexisting phases at steady state without changing overall fluid composition. Together, our study provides a model framework that describes the emergent dynamical and steady-state phase behavior of liquid-like mixtures with many interacting constituents.

PMID:34725154 | DOI:10.1073/pnas.2108551118

AJNR Am J Neuroradiol. 2021 Nov 1. doi: 10.3174/ajnr.A7324. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Compared with BRAF p. V600E wild-type pleomorphic xanthoastrocytoma, BRAF p. V600E-mutant pleomorphic xanthoastrocytoma showed a higher survival rate. In this study, we focused on finding preoperative MR imaging differences between BRAF p. V600E mutant and wild-type in pleomorphic xanthoastrocytoma and anaplastic pleomorphic xanthoastrocytoma.

MATERIALS AND METHODS: Twenty-three patients with pathologically confirmed pleomorphic xanthoastrocytoma or anaplastic pleomorphic xanthoastrocytoma in our hospital were retrospectively analyzed from January 2015 to December 2020. They were divided into a BRAF p. V600E-mutant group (including 6 pleomorphic xanthoastrocytomas and 5 anaplastic pleomorphic xanthoastrocytomas) and a wild-type group (including 8 pleomorphic xanthoastrocytomas and 4 anaplastic pleomorphic xanthoastrocytomas). The preoperative MR imaging characteristics of these groups were statistically compared.

RESULTS: The wild-type pleomorphic xanthoastrocytoma group presented with more aggressive conventional and advanced MR imaging features than the mutant pleomorphic xanthoastrocytoma group, including greater mean maximum tumor diameter (3.1 [SD, 0.9] cm versus 1.7 [SD, 0.4 ] cm, P < .05), more frequent heterogeneous contrast enhancement of solid portions (100% versus 0%, P < .001), more obvious peritumoral edema (mean, [2.1 SD, 0.7] cm versus 0.6 [SD, 0.2] cm, P < .01), and lower mean minimum relative ADC (896 [SD, 86] versus 988 [SD, 73], P < .05) and mean relative ADC (1060 [SD, 159] versus 1248 [SD, 116], P < .05) on DWI. However, there was no significant difference in either conventional or advanced MR imaging features between the wild-type anaplastic pleomorphic xanthoastrocytoma group and the mutant anaplastic pleomorphic xanthoastrocytoma group.

CONCLUSIONS: Neurosurgeons should carefully interpret MR images before an operation and select appropriate surgical strategies according to genotype prediction.

PMID:34725042 | DOI:10.3174/ajnr.A7324

BMJ Open. 2021 Nov 1;11(11):e049884. doi: 10.1136/bmjopen-2021-049884.

ABSTRACT

INTRODUCTION: Activity-based therapy (ABT) is an important aspect of rehabilitation following traumatic spinal cord injury (SCI). Unfortunately, it has never been adapted to acute care despite compelling preclinical evidence showing that it is safe and effective for promoting neurological recovery when started within days after SCI. This article provides the protocol for a study that will determine the feasibility and explore potential benefits of early ABT in the form of in-bed leg cycling initiated within 48 hours after the end of spinal surgery for SCI.

METHODS AND ANALYSIS: PROMPT-SCI (protocol for rapid onset of mobilisation in patients with traumatic SCI) is a single-site single-arm proof-of-concept trial. Forty-five patients aged 18 years or older with a severe traumatic SCI (American Spinal Injury Association Impairment Scale grade A, B or C) from C0 to L2 undergoing spinal surgery within 48 hours of the injury will be included. Participants will receive daily 30 min continuous sessions of in-bed leg cycling for 14 consecutive days, initiated within 48 hours of the end of spinal surgery. The feasibility outcomes are: (1) absence of serious adverse events associated with cycling, (2) completion of 1 full session within 48 hours of spinal surgery for 90% of participants and (3) completion of 11 sessions for 80% of participants. Patient outcomes 6 weeks and 6 months after the injury will be measured using neurofunctional assessments, quality of life questionnaires and inpatient length of stay. Feasibility and patient outcomes will be analysed with descriptive statistics. Patient outcomes will also be compared with a matched historical cohort that has not undergone in-bed cycling using McNemar and Student’s t-tests for binary and continuous outcomes, respectively.

ETHICS AND DISSEMINATION: PROMPT-SCI is approved by the Research Ethics Board of the CIUSSS NIM. Recruitment began in April 2021. Dissemination strategies include publications in scientific journals and presentations at conferences.

TRIAL REGISTRATION NUMBER: NCT04699474.

PMID:34725077 | DOI:10.1136/bmjopen-2021-049884

Rev Gastroenterol Peru. 2021 Apr-Jun;41(2):94-102.

ABSTRACT

INTRODUCTION: Bile duct stones constitutes 20% of symptomatic gallbladder disease and difficult stones are one third of this. Endoscopic papillary large balloon dilation (EPLBD) with or without prior endoscopic sphincterotomy (EST) produces excellent outcomes for the treatment of complex or difficult common bile duct (CBD) stones, alone or combined with previous therapeutic options as mechanical lithotripsy (ML) and temporary or definitive stenting.

OBJECTIVES: Show success rate, complications and adverse events. Show that higher success rates are obtained combining ERCP techniques with no increase in complications.

MATERIALS AND METHODS: We evaluated the safety and therapeutic outcomes of EPLBD with vs. without EST and other combinations for the removal of difficult bile duct stones. We described our procedures for a decade and compare them with the previous decade without balloon dilation. Of 865 patients and procedures, 223 (25.78%) had difficult stones. Treatments where EPLBD with EST (n=183), EPLBD alone group (n=40). Additional modalities where required in 15.25% (n=34). These two groups were compared with respect to overall procedure-related adverse events, overall stone removal success rate, number of sessions required for complete stone removal, need for mechanical lithotripsy, temporal or definite stenting and total procedure time. Results Safety removal of stones was achieved in one session on 84.75% of cases with EPLBD. The incidence of adverse events was not significantly different between the groups (EPLBD alone vs. EPLBD with EST: overall adverse events 12.5% vs. 10.38% (including pain); pancreatitis 2.7% vs. 2.5%, p=0.62). Overall success similar, initial success similar, and the need for additional techniques were also similar between groups. Median total procedure time tended to be greater in the EPLBD alone group (20.5 minutes) than in the EPLBD with EST group. Conclusion DPBGD in ERCP allows bile duct stone extraction rates close to 99.65% (90% in previous decade) according to other reports of literature. Adverse events of EPLBD alone or with EST are similar between them and with classic ERCP without statistical difference and similar to other world series.

PMID:34724690

Anesth Analg. 2021 Sep 13. doi: 10.1213/ANE.0000000000005745. Online ahead of print.

ABSTRACT

At the outbreak of World War II (WWII), anesthesiology was struggling to establish itself as a medical specialty. The battlefield abruptly exposed this young specialty to the formidable challenge of mass casualties, with an urgent need to provide proper fluid resuscitation, airway management, mechanical ventilation, and analgesia to thousands. But while Europe was suffering under the Nazi boot, anesthesia was preparing to rise to the challenge posed by the impending war. While war brings death and destruction, it also opens the way to medical advances. The aim of this study is to measure the evolution of anesthesia owing to WWII. We conducted a retrospective observational bibliometric study involving a quantitative and statistical analysis of publications. The following 7 journals were selected to cover European and North American anesthesia-related publications: Anesthesia & Analgesia, the British Journal of Anaesthesia, Anesthesiology, Schmerz-Narkose-Anaesthesie, Surgery, La Presse Médicale, and The Military Surgeon (later Military Medicine). Attention was focused on journal volumes published between 1920 and 1965. After reviewing the literature, we selected 12 keywords representing important advances in anesthesiology since 1920: “anesthesia,” “balanced anesthesia,” “barbiturates,” “d-tubocurarine,” “endotracheal intubation,” “ether,” “lidocaine,” “morphine,” “spinal anesthesia,” “thiopental,” “transfusion,” and “trichloroethylene.” Titles of original articles from all selected journals editions between 1920 and 1965 were screened for the occurrence of 1 of the 12 keywords. A total of 26,132 original article titles were screened for the occurrence of the keywords. A total of 1815 keywords were found. Whereas Anesthesia & Analgesia had the highest keyword occurrence (493 citations), Schmerz-Narkose-Anaesthesie had the lowest (38 citations). The number of publications of the 12 keywords was significantly higher in the postwar than in the prewar period (65% and 35%, respectively; P < .001). Not surprisingly, the anesthesiology journals have a higher occurrence of keywords than those journals covering other specialties. The overall occurrence of keywords also showed peaks during other major conflicts, namely the Spanish Civil War (1936-1939), the Korean War (1950-1953), and the Vietnam War (1955-1975). For the first time, this study demonstrates statistically the impact of WWII on the progress of anesthesiology. It also offers an objective record of the chronology of the major advances in anesthesiology before and after the conflict. While the war arguably helped to enhance anesthesiology as a specialty, in return anesthesiology helped to heal the wounds of war.

PMID:34724677 | DOI:10.1213/ANE.0000000000005745

Anesth Analg. 2021 Sep 13. doi: 10.1213/ANE.0000000000005753. Online ahead of print.

ABSTRACT

BACKGROUND: Utilization of extracorporeal membrane oxygenation (ECMO) for adult critically ill patients is increasing, but data in obstetric cohorts are scant. This study analyzed ECMO utilization and maternal outcomes in obstetric patients in the United States.

METHODS: Data were abstracted from the 1999-2014 National Inpatient Sample (NIS), a 20% US national representative sample. ECMO hospitalizations (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 39.65) in patients ≥15 years of age were categorized into obstetric ECMO and nonobstetric ECMO. Obstetric patients included 4 categories: (1) loss or termination of pregnancy, (2) delivery (term or preterm), (3) postdelivery hospitalization, and (4) pregnancy without an obstetrical outcome. Possible underlying causes for obstetric ECMO were identified by analysis of ICD-9-CM codes in individual records. In-hospital death was abstracted from the NIS, and ECMO complications were identified using ICD-9-CM algorithms. Statistical significance in time-effect was assessed using weighted regression models.

RESULTS: During the 16-year study period, 20,454 adult ECMO cases were identified, of which 331 occurred in obstetric patients (1.6%; 95% confidence interval [CI], 1.4-1.8). Obstetric ECMO utilization rate was 4.7 per million obstetric discharges (95% CI, 4.2-5.2). The top 3 possible indications were sepsis (22.1%), cardiomyopathy (16.6%), and aspiration pneumonia (9.7%). Obstetric ECMO utilization rate increased significantly during the study period from 1.1 per million obstetric discharges in 1999-2002 (95% CI, 0.6-1.7) to 11.2 in 2011-2014 (95% CI, 9.6-12.9), corresponding to a 144.7% increase per 4-year period (95% CI, 115.3-178.1). Compared with nonobstetric ECMO, obstetric ECMO was associated with decreased in-hospital all-cause mortality (adjusted odds ratio [aOR] 0.78; 95% CI, 0.66-0.93). In-hospital all-cause mortality for obstetric ECMO decreased from 73.7% in 1999-2002 (95% CI, 48.8-90.8) to 31.9% in 2011-2014 (95% CI, 25.2-39.1), corresponding to a 26.1% decrease per 4-year period (95% CI, 10.1-39.3). Compared with nonobstetric ECMO, obstetric ECMO was associated with significantly increased risk of both venous thromboembolism without associated pulmonary embolism (aOR 1.83; 95% CI, 1.06-3.15) and of nontraumatic hemoperitoneum (aOR 4.32; 95% CI, 2.41-7.74).

CONCLUSIONS: During the study period, obstetric ECMO utilization has increased significantly and maternal prognosis improved.

PMID:34724684 | DOI:10.1213/ANE.0000000000005753