bluuebunny/crossref_metadata_2025 huggingface dataset:
Accelerating integration of tobacco use treatment in the context of lung cancer screening: Relevance and application of implementation science to achieving policy and practice
Authors: Shelley Donna , Wang Vivian Hsing-Chun , Taylor Kathryn , Williams Randi , Toll Benjamin , Rojewski Alana , Foley Kristie L , Rigotti Nancy , Ostroff Jamie S
Published: October 2022

Based on the findings from the National Lung Screening Trial, the U.S. Preventive Services Task Force recommends annual low dose computed tomography (LDCT) lung cancer screening (LCS) among high-risk adults. Approximately 54% of individuals seeking LCS report current cigarette smoking. Effective smoking cessation interventions, offered at the time of LCS, enhances the health benefits of screening that are attributable to reductions in lung cancer overall and tobacco-related mortality. Considering these data, the Centers for Medicare & Medicaid Services’ (CMS) 2015 decision to cover LCS with LDCT required that radiology imaging facilities make tobacco cessation interventions available for people who smoke. In February 2022, CMS reversed their 2015 coverage requirement for delivering tobacco use treatment at the time of LDCT; CMS retained the requirement for counseling during the shared decision-making visit prior to the exam. The policy change does not diminish the importance of offering high-quality tobacco cessation services in conjunction with routine LDCT for LCS. However, LCS programs face a range of barriers to implementing tobacco use treatment in their settings. As a result, implementation has lagged. Closing the “evidence to practice” gap is the focus of implementation science, a field that offers a set of rigorous methods and a systematic approach to identifying and overcoming contextual barriers to implementing evidence-based guidelines in a range of clinical settings. In this paper, we describe how implementation science frameworks and methods can be used to help guide LCS programs in their efforts to integrate tobacco use treatment and discuss policy changes needed to further facilitate the delivery of TUT as an essential component of the LCS process.
Optimum dose of oral folic acid supplementation in transfusion-dependent thalassemia: a randomized controlled trial
Authors: Agrawal Titiksha , Dewan Pooja , Gomber Sunil , Agarwal Rachna , Sharma Sangeeta , Kotru Mrinalini
Published: October 2022

Aim and objectives

We compared the effect of different doses of oral folic acid (FA) supplementation (5 mg/day vs. 2.5 mg/day vs. 5 mg/week) on the proportion of children with folate excess (serum folate >20 ng/ml) and plasma homocysteine (Hcys) excess (>15 µmol/l) in transfusion-dependent thalassemia (TDT).

Materials and methods

Children with TDT aged 5–18 years received oral FA in doses of 5 mg/day (Group 1), 2.5 mg/day (Group 2) and 5 mg/week (Group 3) for 9 months, after a wash-off period of 8 weeks. Folate levels (Serum and RBC) and plasma Hcys levels were measured after the therapy.

Results

Ninety children were randomized to receive one of the three interventions (30 per group). After wash-off period, the median serum folate levels were significantly lower and five children developed folate deficiency; the median [interquartile range (IQR)] serum folate levels (ng/dl) were comparable in the three groups [Group 1: 6.5 (3.3–14.2), Group 2: 5.1 (2.6–10.5) and Group 3: 4.8 (3.4–10.0)]. After 9 months of intervention, the median (IQR) serum folate levels (ng/ml) were comparable in all participants [Group 1: 18.0 (6.5–28), Group 2: 13.5 (6.4–24.5) and Group 3: 9.7 (5.3–22.5); p = 0.11]. Proportion of children with serum folate excess was 40%, 26.7% and 26.7% in Group 1, Group 2 and Group 3 (p = 0.48). Proportion of children with RBC folate excess was 92%, 86.7% and 86.7% in Group 1, Group 2 and Group 3 (p = 0.79). Hyperhomocysteinemia was seen in eight children with no significant difference between median Hcys levels in the groups (p = 0.75).

Conclusion

Folic acid supplementation is recommended in TDT with 5 mg weekly dose being adequate.
Improving the Well-Being of Adolescent Girls in Developing Countries
Authors: Bergstrom Katy , Özler Berk
Published: October 2022

This paper conducts a large, narrative review of interventions that might plausibly (a) increase educational attainment, (b) delay childbearing, and/or (c) delay marriage for adolescent girls in low- and middle-income countries (LMICs). Using 108 interventions from 78 studies, predominantly in LMICs, the paper summarizes the performance of 15 categories of interventions in improving these outcomes. Transfer programs emerge as broadly effective in increasing educational attainment but their effects on delaying fertility and marriage remain mixed and dependent on context. Construction of schools in underserved areas and the provision of information on returns to schooling and academic performance also increase schooling. No category of interventions is found to be categorically effective in delaying pregnancies and reducing child marriages among adolescent girls. While targeted provision of sexual and reproductive health services, including vouchers and subsidies for family planning, and increasing job opportunities for women seem promising, more research is needed to evaluate the longer-term effects of such interventions. We propose that future studies should aim to measure short-term outcomes that can form good surrogates for long-term welfare gains and should collect detailed cost information.
Reconceptualizing the Juvenile Bunion
Authors: Zide Jacob R. , Hardin Caitlin , Shivers Claire , Tulchin-Francis Kirsten , Jo Chan-Hee , Riccio Anthony I.
Published: October 2022

Background:

The operative management of the juvenile bunion has not enjoyed the same level of success as its adult counterpart leading to the concern that we do not fully understand what differentiates these 2 deformities. This study aims to (1) characterize the radiographic and pedobarographic features commonly encountered in the juvenile bunion and (2) determine which of these radiographic or pedobarographic parameters correlate with patient-reported outcome (PRO) scores at the time of presentation.

Methods:

An IRB-approved retrospective analysis of prospectively enrolled patients between 10 and 18 years of age with bunion deformities was performed at a single pediatric institution over a 4-year period. Standardized weight-bearing radiographs were used to determine hallux valgus angle (HVA), intermetatarsal angle, sesamoid position (SP), distal metatarsal articular angle (DMAA), and other radiographic parameters. Pedobarographic analysis was used to determine peak pressure, contact area, contact time, and pressure-time integral within 11 plantar regions. Foot-specific PRO measures were administered at the initial presentation.

Results:

Thirty-two patients (57 feet) met the inclusion criteria of which56/57 feet (98.2%) had an elevated DMAA (average 21.4degrees±8.9 degrees), and 51/57 (89.4%) had a congruent joint. The DMAA correlated positively with the HVA (r=0.734 P<0.001), intermetatarsal angle (r=0.439 P=0.001), and SP (r=0.627 P<0.001). Pedobarographic analysis (available in 15/32 patients) demonstrated that the HVA correlated with increased second metatarsal head peak pressure (r=0.667 P=0.011) and pressure-time integral (r=0.604 P=0.002), which in turn was strongly correlated with worse PROs. Conversely, increased first metatarsal head contact area correlated with improved PROs. Analysis of radiographic measurements demonstrated that HVA and lateralized SP correlated significantly with worse PRO scores.

Conclusions:

Nearly all juvenile bunions have an elevated DMAA and a congruent joint. There is a clear correlation between the severity of radiographic and pedobarographic deformity and worse PRO scores at the time of presentation. We believe that the presence of elevated DMAA is the defining factor that differentiates the juvenile bunion from the deformity typically seen in adults.

Level of Evidence:

III.
Comparing the Clinical Frailty Scale and an International Classification of Diseases-10 Modified Frailty Index in Predicting Long-Term Survival in Critically Ill Patients
Authors: Subramaniam Ashwin , Ueno Ryo , Tiruvoipati Ravindranath , Darvall Jai , Srikanth Velandai , Bailey Michael , Pilcher David , Bellomo Rinaldo
Published: October 2022

IMPORTANCE:

The Clinical Frailty Scale (CFS) is the most used frailty measure in intensive care unit (ICU) patients. Recently, the modified frailty index (mFI), derived from 11 comorbidities has also been used. It is unclear to what degree the mFI is a true measure of frailty rather than comorbidity. Furthermore, the mFI cannot be freely obtained outside of specific proprietary databases.

OBJECTIVE:

To compare the performance of CFS and a recently developed International Classification of Diseases-10 (ICD-10) mFI (ICD-10mFI) as frailty-based predictors of long-term survival for up to 1 year.

DESIGN:

A retrospective multicentric observational study.

SETTING AND PARTICIPANTS:

All adult (≥16 yr) critically ill patients with documented CFS scores admitted to sixteen Australian ICUs in the state of Victoria between April 1, 2017 to June 30, 2018 were included. We used probabilistic methods to match de-identified ICU admission episodes listed in the Australia and New Zealand Intensive Care Society Adult Patient Database with the Victorian Admission Episode Dataset and the Victorian Death Index via the Victorian Data Linkage Centre.

MAIN OUTCOMES AND MEASURES:

The primary outcome was the longest available survival following ICU admission. We compared CFS and ICD-10mFI as primary outcome predictors, after adjusting for key confounders.

RESULTS:

The CFS and ICD-10mFI were compared in 7,001 ICU patients. The proportion of patients categorized as frail was greater with the CFS than with the ICD-10mFI (18.9% [n = 1,323] vs. 8.8% [n = 616]; p < 0.001). The median (IQR) follow-up time was 165 (82–276) days. The CFS predicted long-term survival up to 6 months after adjusting for confounders (hazard ratio [HR] = 1.26, 95% CI, 1.21–1.31), whereas ICD-10mFI did not (HR = 1.04, 95% CI, 0.98–1.10). The ICD-10mFI weakly correlated with the CFS (Spearman’s rho = 0.22) but had a poor agreement (kappa = 0.06). The ICD-10mFI more strongly correlated with the Charlson comorbidity index (Spearman’s rho 0.30) than CFS (Spearman’s rho = 0.25) (p < 0.001).

CONCLUSIONS:

CFS, but not ICD-10mFI, predicted long-term survival in ICU patients. ICD-10mFI correlated with co-morbidities more than CFS. These findings suggest that CFS and ICD-10mFI are not equivalent.

RELEVANCE:

CFS and ICD-10mFI are not equivalent in screening for frailty in critically ill patients and therefore ICD-10mFI in its current form should not be used.
An Analytical Study of Primus Stove Burns: A Catastrophic and Costly but Preventable Tragedy
Authors: Soltany Amjad , Al Aissami Salman , Al Aissami Maen
Published: October 2022

Background:

Burns are still considered to be an enormous public issue. Syrian burn centers have to deal, especially during the current war, with burns caused by manually processed petroleum derivatives, and particularly‚ primus stove injuries. This kind of burn is severe and devastating. Prevention is key in management. This is one of the leading studies to include this high number of cases in relative medical literature.

Methods:

This retrospective descriptive cross-sectional study was conducted at Al-Mouwasat University Hospital, from June 2021 to October 2021. Inclusion criteria included admitted patients with a clear history of kerosene primus stove burn, either gender, and any age. Exclusion criteria included no clear history of a primus stove burn, injuries with causes other than primus stove, and outpatients. Data were recorded in Microsoft Excel sheets, and analyzed using IBM SPSS Statistics 26 software.

Results:

In total, 135 burn patients were included. Of the total number of 135 patients, 65 (48%) patients were admitted with primus stove burns, with 70 (52%) non-primus stove injury patients. Of the 65 patients, 25 were men and 40 were women (38% and 62% respectively). The mean percentage of total body surface area was 45%. Average hospital stay was 30.5 days, whereas 16 of 65 (25%) primus stove admissions died.

Conclusions:

Primus stove injuries are catastrophic and costly, but preventable. This study provides a detailed analytic and epidemiological approach to these injuries, hoping to shed light on the severity of such cases‚ and stresses the importance of prevention, which is always better than cure.
NEW ARTIFICIAL INTELLIGENCE ANALYSIS FOR PREDICTION OF LONG-TERM VISUAL IMPROVEMENT AFTER EPIRETINAL MEMBRANE SURGERY
Authors: Crincoli Emanuele , Savastano Maria Cristina , Savastano Alfonso , Caporossi Tomaso , Bacherini Daniela , Miere Alexandra , Gambini Gloria , De Vico Umberto , Baldascino Antonio , Minnella Angelo Maria , Scupola Andrea , DAmico Guglielmo , Molle Fernando , Bernardinelli Patrizio , De Filippis Alessandro , Kilian Raphael , Rizzo Clara , Ripa Matteo , Ferrara Silvia , Scampoli Alessandra , Brando Davide , Molle Andrea , Souied Eric H. , Rizzo Stanislao
Published: October 2022

Purpose:

To predict improvement of best-corrected visual acuity (BCVA) 1 year after pars plana vitrectomy for epiretinal membrane (ERM) using artificial intelligence methods on optical coherence tomography B-scan images.

Methods:

Four hundred and eleven (411) patients with Stage II ERM were divided in a group improvement (IM) (≥15 ETDRS letters of VA recovery) and a group no improvement (N-IM) (<15 letters) according to 1-year VA improvement after 25-G pars plana vitrectomy with internal limiting membrane peeling. Primary outcome was the creation of a deep learning classifier (DLC) based on optical coherence tomography B-scan images for prediction. Secondary outcome was assessment of the influence of various clinical and imaging predictors on BCVA improvement. Inception-ResNet-V2 was trained using standard augmentation techniques. Testing was performed on an external data set. For secondary outcome, B-scan acquisitions were analyzed by graders both before and after fibrillary change processing enhancement.

Results:

The overall performance of the DLC showed a sensitivity of 87.3% and a specificity of 86.2%. Regression analysis showed a difference in preoperative images prevalence of ectopic inner foveal layer, foveal detachment, ellipsoid zone interruption, cotton wool sign, unprocessed fibrillary changes (odds ratio = 2.75 [confidence interval: 2.49–2.96]), and processed fibrillary changes (odds ratio = 5.42 [confidence interval: 4.81–6.08]), whereas preoperative BCVA and central macular thickness did not differ between groups.

Conclusion:

The DLC showed high performances in predicting 1-year visual outcome in ERM surgery patients. Fibrillary changes should also be considered as relevant predictors.
The role of AMP-activated protein kinase in GVHD-causing T cells
Authors: Ramgopal Archana , Sun Lee-Kai , Byersdorfer Craig A.
Published: October 2022

Allogeneic stem cell transplantation is a curative therapy for multiple hematologic disorders. However, this life-saving procedure is often complicated by acute graft-versus-host disease (GVHD), where donor T cells attack tissues in the recipient’s skin, liver, and gastrointestinal tract. Previous research has demonstrated that GVHD-causing T cells undergo significant metabolic reprogramming during disease pathogenesis, with an increased reliance on oxidative metabolism. This dependence makes metabolic modulation a potential approach to treat and/or prevent GVHD. Here, we provide an overview on the metabolic changes adopted by allogeneic T cells during disease initiation, highlighting the role played by AMP-activated protein kinase (AMPK) and identifying ways in which these insights might be leveraged to therapeutic advantage clinically.
Incidence and Severity of Kawasaki Disease Among Vietnamese Children
Authors: Doan Nguyen-Huong , Sivilay Nipha , Shimizu Chisato , Nguyen Hai , Bainto Emelia , Nguyen Quyen , Tremoulet Adriana H. , Burns Jane C.
Published: October 2022

Background:

Kawasaki disease (KD) disproportionately affects children of Asian descent. San Diego is home to a large Vietnamese population but no previous study has addressed the outcome of KD in this group.

Methods:

We performed a retrospective review of Vietnamese patients seen at Rady Children’s Hospital San Diego from 2001 to 2019. Non-Vietnamese Asian and non-Asian KD patients were matched (2:1) based on date of onset and age with Vietnamese patients. Demographic, clinical, and echocardiographic data were compared. Interviews with cardiologists at the Children’s Hospital 1 in Ho Chi Minh City, Vietnam, explored local practices in the diagnosis and management of KD patients. KD publications in Vietnamese were translated and summarized.

Results:

Of 978 KD patients for whom both parents had the same ethnicity, 20 were Vietnamese (2.1%), 168 (17%) were non-Vietnamese Asian, and 789 (81%) were non-Asian. Vietnamese and non-Vietnamese Asians had an earlier median day of diagnosis at day 6 (interquartile range [IQR] 5–6) and 5.5 (IQR 4–6.75), respectively, compared with non-Asians (day 7, IQR 5–8.75, P = 0.02). Prominent cervical lymphadenopathy at diagnosis was more common in both Vietnamese and non-Vietnamese Asians (20% and 40%, respectively) compared with non-Asians (12.5%, P = 0.01). Importantly, Vietnamese KD patients had a higher rate of coronary artery aneurysms (60% vs. 27.5%) compared to non-Asians (P = 0.024). Vietnamese literature review and structured interviews suggested a high incidence and severity of KD in Vietnamese children.

Conclusions:

Physicians should be aware that Vietnamese children may be disproportionately affected by KD and have worse coronary artery outcomes.
Chronic Q Fever as Recurrent Osteoarticular Infection in Children: Case Report and Literature Review
Authors: Hernández-Rupérez María Belén , Seoane-Reula Elena , Villa Ángel , Lancharro Ángel , Marín Arriaza Mercedes , Saavedra-Lozano Jesús
Published: October 2022

Q fever osteomyelitis has been rarely reported in children. This infection has an unclear pathophysiology and the optimal therapy is unknown. We report a 2-year-old girl with Coxiella burnetti recurrent multifocal osteomyelitis: femur, metatarsal, cuneiform, and calcaneus. We highlight the complicated diagnosis and management of this case and the importance of considering Q fever in children with chronic-recurrent multifocal osteomyelitis.
EHR-Integrated Clinical Pathways Promote Education, Confidence, and Save Time for Primary Care Providers
Authors: Macke Laura B. , Sieja Amber , Suresh Krithika , Schilling Lisa M.
Published: October 2022

Computerized clinical decision support tools are increasingly necessary and widespread in primary care due to rapidly evolving evidence and shifting clinical guidelines. Clinical pathways are a subtype of clinical decision support tool which aim to link evidence to practice and which require evaluation of benefits and barriers to use to inform user-centered design. The objective was to describe the use and perceived benefits and barriers to evidence-based, disease-specific electronic health record pathways for clinical decision support. Primary care providers at a large integrated health system were surveyed about their use of clinical pathways using an online questionnaire distributed via email in November 2021. Descriptive statistics were estimated and differences in the characteristics and responses by pathway use were assessed using chi-square or Fisher exact tests. The survey response rate was 26% (153/593). There were differences in the response rates between providers by practice type (42% academic versus 54% community; P < 0.001). No difference was found in the demographics of those that used the pathways versus those that did not according to role, age, or length of time in practice. Providers in the academic practice were more likely than those in community practices to have used the pathways. Among providers who used the pathways, 98% agree they have evidence-based information, 98% agree they allow them to take better care of patients, 88% agree they guide clinical-decisions, and 85% agree they save time. The main barrier for those who had used pathways was that they forget about them. Among those who had not used pathways, 35% were unaware that pathways existed. This analysis demonstrates that primary care providers who adopt clinical pathways perceive benefits in several domains. The largest barriers to adoption were that users forgot about pathways or were unaware of them. Future work should focus on dissemination and education, improving tool accessibility, and content optimization to balance complexity with efficiency.
Impact of ICU strain on outcomes
Authors: Duggal Abhijit , Mathews Kusum S.
Published: October 2022

Purpose of review

Acute surge events result in health capacity strain, which can result in deviations from normal care, activation of contingencies and decisions related to resource allocation. This review discusses the impact of health capacity strain on patient centered outcomes

Recent findings

This manuscript discusses the lack of validated metrics for ICU strain capacity and a need for understanding the complex interrelationships of strain with patient outcomes. Recent work through the coronavirus disease 2019 pandemic has shown that acute surge events are associated with significant increase in hospital mortality. Though causal data on the differential impact of surge actions and resource availability on patient outcomes remains limited the overall signal consistently highlights the link between ICU strain and critical care outcomes in both normal and surge conditions.

An understanding of ICU strain is fundamental to the appropriate clinical care for critically ill patients. Accounting for stain on outcomes in critically ill patients allows for minimization of variation in care and an ability of a given healthcare system to provide equitable, and quality care even in surge scenarios.
Quality, safety, and implementation science in acute kidney care
Authors: Rewa Oleksa G. , Kashani Kianoush
Published: October 2022

Purpose of review

Quality and safety are important themes in acute kidney care (AKC). There have been many recent initiatives highlighting these aspects. However, for these to become part of clinical practice, a rigorous implementation science methodology must be followed. This review will present these practices and will highlight recent initiatives in acute kidney injury (AKI), kidney replacement therapy (KRT) and recovery from AKI.

Recent findings

The 22nd Acute Disease Quality Initiative (ADQI) focused on achieving a framework for improving AKI care. This has led to various quality improvement (QI) initiatives that have been implemented following a robust implementation science methodology. In AKI, QI initiatives have been focused on implementing care bundles and early detection systems for patients at risk or with AKI. KRT initiatives have focused on measuring and reporting key performance indicators (KPIs), and providing targeted feedback and education to improve delivery of KRT. Finally, it has been recognized that post-AKI care is vitally important, and ongoing work has been focused on implementing pathways to ensure continuing kidney-focused care.

Quality and safety continue to be important focuses in AKC. Although recent work have focused on initiatives to improve these themes, additional work is necessary to further develop these items as we strive to improve the care to patients with AKI.
The 2016 Presidential Election and Prenatal Care Utilization Among Foreign-born Hispanic Pregnant People
Authors: Young Anna Marie Pacheco , Catalano Ralph , Gemmill Alison
Published: October 2022

Background:

Few studies have evaluated the relationship between adequate and timely prenatal care among immigrant pregnant people and the recent political climate, including the 2016 election and associated campaigns.

Objectives:

We examine whether the 2016 presidential election was associated with changes in prenatal care utilization among US foreign-born Hispanic pregnant people.

Research Design:

Interrupted time series.

Subjects:

All foreign-born Hispanic and US-born non-Hispanic White people delivering singleton infants from 2008 to 2017 who resided in the 23 states that fully implemented the 2003 version of the birth certificate before January 2008 (n=12,397,503).

Measures:

We examine the relationship between the presidential election and changes in the odds of inadequate or late/no prenatal care among immigrant Hispanic pregnant people, as well as trends in prenatal care utilization before the election.

Results:

Our results show no unexpected changes in receipt of inadequate prenatal care, and late/no prenatal care, among the 7 monthly conception cohorts exposed to the election before the third trimester. However, we detected increases in the odds of both inadequate care and late/no prenatal care among foreign-born Hispanic pregnant people in June 2015 and January 2016, respectively. These upward level shifts persisted through the remainder of our time series ending with the cohort conceived around December 2016.

Conclusions:

The worsening shifts in prenatal care utilization we observe may serve as a bellwether for worsening outcomes among immigrant women and their families. Research is therefore urgently needed to investigate the determinants and consequences of these concerning trends.
Depression in transplantation
Authors: Zimbrean Paula C.
Published: October 2022

Purpose of review

To review and summarize the literature published between 1 January 2020 and 30 June 2022, on the prevalence, risk factors and impact of depression in transplant population.

Recent findings

Depression is common in transplantation candidates and recipients, with a prevalence up to 85.8% in kidney recipients. Multiple studies have indicated after transplantation depression correlates with increased mortality and with higher healthcare utilization. Social risk factors for posttransplant depression include financial difficulties and unemployment, while less is understood about the biological substrate of depression in this population. There is evidence that dynamic psychotherapy is effective for depression in organ transplant recipients, while cognitive behavioral therapy or supportive therapy did not lead to improvement of depression in transplant recipients. For living organ donors, the rates of depression are similar to the general population, with financial factors and the clinical status of the recipient playing a significant role.

Depression is a common finding in transplant population. More research is needed to understand the biological substrate and risk factors and to develop effective treatment interventions.
Racial Discrimination in Patient Care—Preserving Relationships With Integrity
Authors: Fahey Donna M.
Published: October 2022

The following case study describes what is known as the health care system's open secret of allowing a patient or family to refuse care from a clinician of another race. This article explores the ethical tension between autonomy, nonmaleficence, justice, and duty to treat as it relates to racism and the potential harm to clinicians, health care teams, and organizations. When racism is experienced within the clinical setting, clinician knowledge, organizational training, and moral character are essential for identifying and addressing it effectively. Racial discrimination and related mistreatment are not part of a responsive and proactive moral community. This article explores creative solutions that preserve patient-clinician relationships without sacrificing personal integrity when racism is encountered.
FOXP1 and FOXO3a Are Prognostic Markers in Gallbladder Squamous Cell/Adenosquamous Carcinomas and Adenocarcinomas
Authors: Jiao Jingjing , Liu Ziru , Li Xiong , Li Daiqiang , Zou Qiong , Yuan Yuan
Published: October 2022

The pathologic characteristics of squamous cell/adenosquamous carcinomas (SC/ASC) have not been well clarified. As a rare subtype of gallbladder cancer (GBC), no biological markers for diagnosis and prognosis are available. This research evaluated the expression of FOXP1 and FOXO3a in 69 SC/ASC, and 146 adenocarcinoma (AC) samples were analyzed via immunohistochemistry. SC/ASCs were associated with higher rates of lymph node metastasis, invasion, and patients older than 45 years comparing to ACs. FOXP1 and FOXO3a positivity rates were significantly lower in SC/ASC and AC samples from patients with large tumor size, a high TNM stage, lymph node metastasis, invasion, and no history of tumor resection (biopsy only). Positive FOXP1 expression levels were significantly decreased in cases of poorly differentiated AC. The univariate Kaplan-Meier analysis revealed that negative FOXP1 and FOXO3a expression, poor differentiation, large tumor size, high TNM stage, lymph node metastasis, invasion, and an inability to undergo curative resection were all closely associated with decreased overall survival in SC/ASC and AC patients. The multivariate cox regression analysis showed that negative FOXP1 and FOXO3a expression levels were independent predictors of poor prognosis in SC/ASC and AC patients. Our results indicate that negative FOXP1 and FOXO3a expression are closely associated with the pathogenesis, clinicopathologic properties, and prognosis of GBC patients. FOXP1 and FOXO3a may thus be biomarkers of GBC carcinogenesis, progression, and prognosis.
Droplet Digital PCR (ddPCR) as a Novel Technology in Detecting CTNNB1 Mutations in Desmoid Fibromatosis
Authors: Gandhi Jatin , Kao Erica , Wu Yu , Mantilla Jose G. , Ricciotti Robert W. , Bandhlish Anshu , Liu Yajuan J. , Chen Eleanor Y.
Published: October 2022

Desmoid fibromatosis (DF) is a locally aggressive soft tissue neoplasm with frequent recurrences. DF is characterized by alterations in the Wnt/β-catenin pathway, with the majority showing sporadic mutations in CTNNB1, whereas others have germline mutations in APC. Immunohistochemical staining for β-catenin is often difficult to interpret and can be negative in up to 30% of cases. Prior studies have shown that some DFs lacking nuclear expression of β-catenin may carry activating CTNNB1 mutations. Droplet digital polymerase chain reaction (ddPCR) has been used effectively in detecting mutations in formalin-fixed, paraffin-embedded (FFPE) samples of various cancer types. In this study, we assess the diagnostic utility of ddPCR to detect CTNNB1 mutations in DF with β-catenin expression on immunohistochemistry (IHC), as well as in diagnostically challenging cases. Of the 28 DFs with nuclear β-catenin expression by IHC, 24 cases showed a CTNNB1 mutation by ddPCR using primers against the most common point mutations in CTNNB1. The most frequent mutation was T41A (n=14; 50%), followed by S45F (n=8; 33%) and S45P (n=3;12%). We identified 8 additional (myo)fibroblastic lesions of uncertain classification, which were negative for nuclear β-catenin expression by IHC. We detected CTNNB1 mutations in 3 unknown lesions, including S45F (n=2) and S45P (n=1). ddPCR is a sensitive, rapid and cost-efficient methodology to detect common CTNNB1 mutations in DF, especially in diagnostically challenging cases.
The IASLC Proposed Grading System Accurately Predicts Prognosis and Mediastinal Nodal Metastasis in Patients With Clinical Stage I Lung Adenocarcinoma
Authors: Xu Long , Su Hang , Hou Likun , Wang Fang , Xie Huikang , She Yunlang , Gao Jiani , Zhao Shengnan , Dai Chenyang , Xie Dong , Zhu Yuming , Wu Chunyan , Zhao Deping , Chen Chang ,   and on behalf of the Surgical Thoracic Alliance of Rising Star Group
Published: October 2022

The International Association for the Study of Lung Cancer (IASLC) recently proposed a new grading system for lung adenocarcinoma (LUAD). We aimed to validate the prognostic performance of the grading system and explore its role in guiding the strategy of lymph node (LN) dissection. We retrospectively reviewed 1029 patients with clinical stage I LUAD who underwent surgery between 2011 and 2013. The association between mediastinal nodal metastasis and grading system was evaluated. To investigate the value of the grading system in guiding LN dissection strategies, 3 pathologists evaluated the feasibility of identifying the grading system using frozen section (FS). The differences in prognosis between all neighboring grades were highly significant based on the grading system (P<0.001). Notably, almost no grade 1 LUAD (1.4%) had pN2 disease, whereas higher rates were found in grade 2 LUAD (9.6%) and grade 3 LUAD (18.3%) (P<0.001). Multivariate logistic regression analysis revealed that higher tumor grade was an independent predictor of mediastinal nodal metastasis (P=0.002). Moreover, limited mediastinal LN dissection had equivalent prognosis in grade 1 LUAD, but significantly worse prognosis in grade 2 and grade 3 LUAD than systematic mediastinal LN dissection. The overall accuracy of using intraoperative FS to identify the IASLC grading system was 85.4% (κ=0.765) with substantial agreement. The IASLC grading system could accurately stratify prognosis and predict mediastinal nodal metastasis in patients with clinical stage I LUAD. FS was feasible for identifying the IASLC grading system.
Video-Recorded In Situ Simulation Before Moving to the New Combined Neonatal/Pediatric Intensive Care Facility: An Observational Study
Authors: Krammer Theresa , Kessler Lisa , Aspalter Gerhard , Kuster Lucas , Fussenegger Barbara , Aichner Heidi , Simma Burkhard
Published: October 2022

OBJECTIVES:

Moving an ICU to a new location is a challenge. The objective of this study was to use in situ simulation to identify potential problems and solutions with the new environment before commencing patient care.

DESIGN:

Planned, observational video-recorded simulation study using four scenarios: delivery room management of term-neonate; delivery room management of extremely low-birth-weight infant; management and transfer of an infant with respiratory syncytial virus bronchiolitis and apnea; and management and transfer of an adolescent with septic shock.

SETTING:

Academic tertiary neonatal and combined neonatal ICU/PICU.

PARTICIPANTS:

Sixteen volunteers (eight physicians, eight nurses).

INTERVENTIONS:

Standardized briefing introduction, with before versus after survey of thoughts about each scenario, and after 8 weeks, debriefing at least 60 minutes and additional video recording.

MEASUREMENTS AND MAIN RESULTS:

A total of 91 potential problem areas were identified and included issues related to technical aspects (n = 29), infrastructure (n = 27), administration (n = 19), and structure (n = 16). Fifty-three (58%) of these potential issues could be resolved before the move, including: 15 of 29 technical, 15 of 27 infrastructure, nine of 19 administration, and 14 of 16 structural. The video analysis revealed an additional 13 problem areas (six technical, three infrastructure, two administration, and two structural). Participants felt more confident 8 weeks after the simulations (χ2 = 12.125; p < 0.002). All 16 participants confirmed the usefulness of the in situ simulation, the majority wanted further introductions to the new ward (n = 13) and noted a positive impact of the changes on the new ward (n = 12).

CONCLUSIONS:

In situ simulation before moving into a new facility identifies numerousness potential problem areas. Survey shows that providers feel better prepared and are more confident. Video recording reveals additional difficulties not addressed in conventional verbal debriefing.
Do Treg Speed Up with CARs? Chimeric Antigen Receptor Treg Engineered to Induce Transplant Tolerance
Authors: Kaljanac Marcell , Abken Hinrich
Published: October 2022

Adoptive transfer of regulatory T cells (Treg) can induce transplant tolerance in preclinical models by suppressing alloantigen-directed inflammatory responses; clinical translation was so far hampered by the low abundance of Treg with allo-specificity in the peripheral blood. In this situation, ex vivo engineering of Treg with a T-cell receptor (TCR) or chimeric antigen receptor (CAR) provides a cell population with predefined specificity that can be amplified and administered to the patient. In contrast to TCR-engineered Treg, CAR Treg can be redirected toward a broad panel of targets in an HLA-unrestricted fashion‚ making these cells attractive to provide antigen-specific tolerance toward the transplanted organ. In preclinical models, CAR Treg accumulate and amplify at the targeted transplant, maintain their differentiated phenotype, and execute immune repression more vigorously than polyclonal Treg. With that, CAR Treg are providing hope in establishing allospecific, localized immune tolerance in the long term‚ and the first clinical trials administering CAR Treg for the treatment of transplant rejection are initiated. Here, we review the current platforms for developing and manufacturing alloantigen-specific CAR Treg and discuss the therapeutic potential and current hurdles in translating CAR Treg into clinical exploration.
Normothermic Regional Perfusion in Pediatric Controlled Donation After Circulatory Death Can Lead to Optimal Organ Utilization and Posttransplant Outcomes
Authors: Miñambres Eduardo , Estébanez Belen , Ballesteros Maria Ángeles , Coll Elisabeth , Flores-Cabeza Eva Mercedes , Mosteiro Fernando , Lara Ramón , Domínguez-Gil Beatriz
Published: October 2022

Background.

The benefits of normothermic regional perfusion (NRP) in posttransplant outcomes after controlled donation after the determination of death by circulatory criteria (cDCD) has been shown in different international adult experiences. However, there is no information on the use of NRP in pediatric cDCD donors.

Methods.

This is a multicenter, retrospective, observational cohort study describing the pediatric (<18 y) cDCD procedures performed in Spain, using either abdominal NRP or thoracoabdominal NRP and the outcomes of recipients of the obtained organs.

Results.

Thirteen pediatric cDCD donors (age range, 2–17 y) subject to abdominal NRP or thoracoabdominal NRP were included. A total of 46 grafts (24 kidneys, 11 livers, 8 lungs, 2 hearts, and 1 pancreas) were finally transplanted (3.5 grafts per donor). The mean functional warm ischemic time was 15 min (SD 6 min)‚ and the median duration of NRP was 87 min (interquartile range, 69–101 min). One-year noncensored for death kidney graft survival was 91.3%. The incidence of delayed graft function was 13%. One-year‚ noncensored-for-death liver graft survival was 90.9%. All lung and pancreas recipients had an excellent evolution. One heart recipient died due to a septic shock.

Conclusions.

This is the largest experience of pediatric cDCD using NRP as graft preservation method. Although our study has several limitations, such as its retrospective nature and the small sample size, its reveals that NRP may increase the utilization of cDCD pediatric organs and offer optimal recipients’ outcomes.
The 2021 WHO classification of central nervous system tumors: what neurologists need to know
Authors: Jamshidi Pouya , Brat Daniel J.
Published: October 2022

Purpose of review

The recently published WHO Classification of Tumours, Central Nervous System Tumours, Fifth Edition (WHO CNS-5) introduces substantial clinically relevant changes based on improved understanding of the molecular underpinnings of brain tumor types as biological entities. This review highlights pertinent changes for practicing neurologists.

Recent findings

Diffuse gliomas are now divided into adult and pediatric types. Adult types are greatly simplified, being classified into three groups based on IDH and 1p/19q status, with molecular grading criteria now included. Pediatric types are divided into low-grade or high-grade and further classified based on molecular features corresponding to clinical behavior. While still recognizing previous morphological subtypes, meningioma is now a single tumor type, with greatly advanced correlations between molecular alterations, locations, morphologic subtypes, and grades. For the first time, ependymomas are classified based on integration of anatomical location, histopathology, and molecular alterations. Importantly, WHO CNS-5 includes a number of new tumor types that have similar clinicopathologic features and are grouped together by their distinctive molecular characteristics.

The classification of CNS tumors according to objective, reproducible molecular genetic alterations, provides greater opportunity for neurologists to offer individualized treatment options, enroll homogenous patient populations into clinical trials, and ultimately discover novel therapeutics.
School-located influenza vaccination and community-wide indirect effects: reconciling mathematical models to epidemiologic models
Authors: Arinaminpathy Nimalan , Reed Carrie , Biggerstaff Matthew , Nguyen Anna , Athni Tejas S. , Arnold Benjamin F. , Hubbard Alan , Colford John M. , Reingold Art , Benjamin-Chung Jade
Published: October 2022

Background

Mathematical models and empirical epidemiologic studies (e.g., randomized and observational studies) are complementary tools but may produce conflicting results for a given research question. We used sensitivity analyses and bias analyses to explore such discrepancies in a study of the indirect effects of influenza vaccination.

Methods

We fit an age-structured, deterministic, compartmental model to estimate indirect effects of a school-based influenza vaccination program in California that was evaluated in a previous matched cohort study. To understand discrepancies in their results, we used 1) a model with constrained parameters such that projections matched the cohort study; and 2) probabilistic bias analyses to identify potential biases (e.g., outcome misclassification due to incomplete influenza testing) that, if corrected, would align the empirical results with the mathematical model.

Results

The indirect effect estimate (% reduction in influenza hospitalization among older adults in intervention vs. control) was 22.3% (95% CI 7.6% – 37.1%) in the cohort study but only 1.6% (95% Bayesian credible intervals 0.4 – 4.4%) in the mathematical model. When constrained, mathematical models aligned with the cohort study when there was substantially lower pre-existing immunity among school-age children and older adults. Conversely, empirical estimates corrected for potential bias aligned with mathematical model estimates only if influenza testing rates were 15-23% lower in the intervention vs. comparison site.

Conclusions

Sensitivity and bias analysis can shed light on why results of mathematical models and empirical epidemiologic studies differ for the same research question, and in turn, can improve study and model design.
Targeted Nano Sized Drug Delivery to Heterogeneous Solid Tumor Microvasculatures: Implications for Immunoliposomes Exhibiting Bystander Killing Effect
Authors: Abazari Mohammad Amin , Soltani Madjid , Kashkooli Farshad Moradi
Published: October 2022

Targeted drug delivery to cancer cells utilizing antibodies against oncogenic cell-surface receptors is an emerging therapeutical approach. Here, we developed a computational framework to evaluate the treatment efficacy of free Doxorubicin (Dox) and immunoliposome at different stages of vascular solid tumors. Firstly, three stages of vascularized tumors with different microvascular densities (MVDs) are generated using mathematical modeling of tumor-induced angiogenesis. Secondly, the fluid flow in vascular and interstitial spaces is calculated. Ultimately, convection-diffusion-reaction equations governing on classical chemotherapy (stand-alone Dox) and immunochemotherapy (drug-loaded nanoparticles) are separately solved to calculate the spatiotemporal concentrations of different therapeutic agents. The present model considers the key processes in targeted drug delivery, including association/disassociation of payloads to cell receptors, cellular internalization, linker cleavage, intracellular drug release, and bystander-killing effect. Our results show that reducing MVD decreases the interstitial fluid pressure, allowing higher rates of the drug to enter the tumor microenvironment. Also, immunoliposomes exhibiting bystander-killing effect yield higher drug internalization, which supports a higher intracellular Dox concentration during immunochemotherapy. Bystander-killing effect alongside intracellular Dox release and persistence of immunoliposomes within tumor over a longer period lead to more homogeneous drug distribution and a much greater fraction of killed cancer cells than classical chemotherapy. Our findings also demonstrate drug transport at tumor microvascular networks is increased by decreasing MVD, leading to better treatment outcomes. Present results can be used to improve the treatment efficacy of drug delivery at different stages of vascular tumors.
Evidence of backcross inviability and mitochondrial DNA paternal leakage in sea turtle hybrids
Authors: Vilaça Sibelle T. , Maroso Francesco , Lara Paulo , de Thoisy Benoit , Chevallier Damien , Arantes Larissa Souza , Santos Fabricio R. , Bertorelle Giorgio , Mazzoni Camila J.
Published: October 2022

Hybridization is known to be part of many species’ evolutionary history. Sea turtles have a fascinating hybridization system in which species separated by as much as 43 million years are still capable of hybridizing. Indeed, the largest nesting populations in Brazil of loggerheads (Caretta caretta) and hawksbills (Eretmochelys imbricata) have a high incidence of hybrids between these two species. A third species, olive ridleys (Lepidochelys olivacea), is also known to hybridize although at a smaller scale. Here we used restriction site-associated DNA sequencing (RAD-Seq) markers, mitogenomes, and satellite-telemetry to investigate the patterns of hybridization and introgression in the Brazilian sea turtle population and their relationship with the migratory behaviors between feeding and nesting aggregations. We also explicitly test if the mixing of two divergent genomes in sea turtle hybrids causes mitochondrial paternal leakage. We developed a new species-specific PCR-assay capable of detecting mitochondrial DNA (mtDNA) inheritance from both parental species and performed ultra-deep sequencing to estimate the abundance of each mtDNA type. Our results show that all adult hybrids are first generation (F1) and most display a loggerhead migratory behavior. We detected paternal leakage in F1 hybrids and different proportions of mitochondria from maternal and paternal species. Although previous studies showed no significant fitness decrease in hatchlings, our results support genetically-related hybrid breakdown possibly caused by cytonuclear incompatibility. Further research on hybrids from other populations besides Brazil and between different species will show if backcross inviability and mitochondrial paternal leakage is observed across sea turtle species.