bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel loading protocol combines highly efficient encapsulation of exogenous therapeutic toxin with preservation of extracellular vesicles properties, uptake and cargo activity
Authors: Zuppone Stefania , Zarovni Natasa , Noguchi Kosuke , Loria Francesca , Morasso Carlo , Lõhmus Andres , Nakase Ikuhiko , Vago Riccardo
Published: May 2024

Extracellular vesicles (EVs) have mostly been investigated as carriers of biological therapeutics such as proteins and RNA. Nevertheless, small-molecule drugs of natural or synthetic origin have also been loaded into EVs, resulting in an improvement of their therapeutic properties. A few methods have been employed for EV cargo loading, but poor yield and drastic modifications of vesicles remain unsolved challenges. We tested a different strategy based on temporary pH alteration through incubation of EVs with alkaline sodium carbonate, which resulted in conspicuous exogenous molecule incorporation. In-depth characterization showed that vesicle size, morphology, composition, and uptake were not affected. Our method was more efficient than gold-standard electroporation, particularly for a potential therapeutic toxin: the plant Ribosome Inactivating Protein saporin. The encapsulated saporin resulted protected from degradation, and was efficiently conveyed to receiving cancer cells and triggered cell death. EV-delivered saporin was more cytotoxic compared to the free toxin. This approach allows both the structural preservation of vesicle properties and the transfer of protected cargo in the context of drug delivery.

Graphic Abstract
Role of preoperative zinc, magnesium and budesonide gargles in Postoperative Sore Throat (POST) - a randomised control trial
Authors: Bhanwra Aakanksha , Palta Sanjeev , Saroa Richa , Saxena Puja , Bhanwra Sangeeta , Jain Aditi
Published: May 2024

Background

Post-operative sore throat (POST) has an incidence ranging from 21 to 80%. To prevent the development of POST, several pharmacological measures have been tried. Aim of this study was to compare the efficacy of preoperative zinc, magnesium and budesonide gargles in reducing the incidence and severity of POST in patients who underwent endotracheal intubation for elective surgeries.

Methods

We conducted a prospective, randomized, double-blind, controlled equivalence trial in 180 patients admitted for elective surgical procedures under general anaesthesia. Patients were randomised into three groups; group Z received 40 mg Zinc, group M received 250 mg Magnesium Sulphate and group B received 200 µg Budesonide in the form of 30 ml tasteless and colourless gargle solutions. Sore throat assessment and haemodynamic recording was done postoperatively at immediate recovery (0 h) and 2, 4, 6, 8, 12 and 24 h post-operatively. POST was graded on a four-point scale (0–3).

Results

POST score was comparable at all recorded time points i.e. 0,2,4,6,8,12 and 24 h. Maximum incidence was seen at 8 h in group B (33.3%) and the minimum incidence was at 24 h in group Z (10%) (p > 0.05). It was found that the incidence of POST was more in the surgeries lasting longer than 2 h in all groups. This difference was found to be statistically significant in Groups M and B. The incidence of POST was found to be comparable between laparoscopic and open procedures.

Conclusion

Magnesium, zinc and budesonide have an equivocal effect in the prevention of POST at different time points. The incidence of sore throat increases significantly in surgeries lasting more than two hours if magnesium or budesonide have been used as premedicant. Duration of surgery is an independent predictor for POST.

Trial registration

CTRI/2021/05/033741 Date-24/05/2021(Clinical Trial Registry of India).
Diastolic/systolic blood pressure ratio for predicting febrile children with sepsis and progress to septic shock in the emergency department
Authors: Mu Chun-Ting , Lin Ying-Jui , Chen Chih-Ho , Hsia Shao-Hsuan , Lin Jainn-Jim , Chan Oi-Wa , Yen Chen-Wei , Chiu Chun-Che , Chang Han-Pi , Su Ya-Ting , Lee En-Pei
Published: May 2024

Objective

Given the scarcity of studies analyzing the clinical predictors of pediatric septic cases that would progress to septic shock, this study aimed to determine strong predictors for pediatric emergency department (PED) patients with sepsis at risk for septic shock and mortality.

Methods

We conducted chart reviews of patients with ≥ 2 age-adjusted quick Sequential Organ Failure Assessment score (qSOFA) criteria to recognize patients with an infectious disease in two tertiary PEDs between January 1, 2021, and April 30, 2022. The age range of included patients was 1 month to 18 years. The primary outcome was development of septic shock within 48 h of PED attendance. The secondary outcome was sepsis-related 28-day mortality. Initial important variables in the PED and hemodynamics with the highest and lowest values during the first 24 h of admission were also analyzed.

Results

Overall, 417 patients were admitted because of sepsis and met the eligibility criteria for the study. Forty-nine cases progressed to septic shock within 48 h after admission and 368 were discharged without progression. General demographics, laboratory data, and hemodynamics were analyzed by multivariate analysis. Only the minimum diastolic blood pressure/systolic blood pressure ratio (D/S ratio) during the first 24 h after admission remained as an independent predictor of progression to septic shock and 28-day mortality. The best cutoff values of the D/S ratio for predicting septic shock and 28-day mortality were 0.52 and 0.47, respectively.

Conclusions

The D/S ratio is a practical bedside scoring system in the PED and had good discriminative ability in predicting the progression of septic shock and in-hospital mortality in PED patients. Further validation is essential in other settings.
A Chinese adaptation of the Patient Health Questionnaire for Adolescents (PHQ-A): factor structure and psychometric properties
Authors: Chen Yu-Qi , Huang Xiao-Jie , Yang Fan , Yang Jing-Jing , Zhong Jing , Yao Kai-Min , Kuang Jing-Xiao , Xu Ming-Zhi
Published: May 2024

Background

To examine the factor structure and psychometric properties of the Patient Health Questionnaire for Adolescents (PHQ-A) in Chinese children and adolescents with major depressive disorder (MDD).

Methods

A total of 248 MDD patients aged between 12 and 18 years were recruited and evaluated by the Patient Health Questionnaire for Adolescents (PHQ-A), the Center for Epidemiological Survey Depression Scale (CES-D), the Mood and Feelings Questionnaire (MFQ), and the improved Clinical Global Impression Scale, Severity item (iCGI-S). Thirty-one patients were selected randomly to complete the PHQ-A again one week later. Confirmatory factor analysis (CFA) was used to test the construct validity of the scale. Reliability was evaluated by Macdonald Omega coefficient. Pearson correlation coefficient was used to assess the item-total correlation and the correlation of PHQ-A with CES-D and MFQ respectively. Spearman correlation coefficient was used to assess test-retest reliability. The optimal cut-off value, sensitivity, and specificity of the PHQ-A were achieved by estimating the Receiver Operating Characteristics (ROC) curve.

Results

CFA reported adequate loadings for all items, except for item 3. Macdonald Omega coefficient of the PHQ-A was 0.87. The Spearman correlation coefficient of the test-retest reliability was 0.70. The Pearson correlation coefficients of the PHQ-A with CES-D and MFQ were 0.87 and 0.85, respectively (p < 0.01). By taking the iCGI-S as the remission criteria for MDD, the optimal cut-off value, sensitivity and specificity of the PHQ-A were 7, 98.7%, 94.7% respectively.

Conclusion

The PHQ-A presented as a unidimensional construct and demonstrated satisfactory reliability and validity among the Chinese children and adolescents with MDD. A cut-off value of 7 was suggested for remission.
Prolonged grief disorder in an inpatient psychiatric sample: psychometric properties of a new clinical interview and preliminary prevalence
Authors: Rueger Mirjam Sophie , Lechner-Meichsner Franziska , Kirschbaum Lotte , Lubik Silke , Roll Sibylle C. , Steil Regina
Published: May 2024

Background

Prolonged Grief Disorder (PGD) was newly included in the ICD-11 and DSM-5-TR. It is not yet part of the standard assessments in many healthcare systems, including psychiatric wards. Because disordered grief is associated with suicidality, sleep problems and substance use disorders, an investigation into PGD in psychiatric inpatients is warranted.

Method

We interviewed N = 101 psychiatric inpatients who were admitted to the open psychiatric wards and the day hospital of a German psychiatric hospital and who had lost a person close to them. Assessments comprised clinical interviews and self-report instruments covering PGD and other mental disorders. We specifically developed the International Interview for Prolonged Grief Disorder according to ICD-11 (I-PGD-11) for the study and examined its psychometric properties.

Results

The prevalence rate of PGD among bereaved patients according to ICD-11 was 16.83% and according to DSM-5-TR 10.89%. The I-PGD-11 showed good psychometric properties (Mc Donald’s ω = 0.89, ICC = 0.985). Being female, having lost a child or spouse, and unnatural or surprising circumstances of the death were associated with higher PGD scores.

Trial registration

Approval was obtained by the ethics committee of the of the Goethe University Frankfurt (2021-62, 2023-17) and the Chamber of Hessian Physicians (2021-2730-evBO). The study was preregistered (https://doi.org/10.17605/OSF.IO/K98MF).

Limitations

We only assessed inpatients of one psychiatric clinic in Germany, limiting the generalizability of our findings.

Conclusion

The present study underlines the importance of exploring loss and grief in psychiatric inpatients and including PGD in the assessments. Given that a significant minority of psychiatric inpatients has prolonged grief symptoms, more research into inpatient treatment programs is needed.
Thoracolumbar fractures patients undergoing posterior pedicle screw fixation can benefit from drainage
Authors: Sun Jing-yu , Zhao Ning , Chen Hua , Chen Chun-hui
Published: May 2024

Purpose

To explore whether it is necessary to put drain tubes after posterior pedicle screw fixation of thoracolumbar fractures.

Methods

From April 2020 to January 2023, a total of 291 patients with recent thoracolumbar fractures (AO type-A or type-B) who received the pedicle screw fixation operation were enrolled retrospectively. In 77 patients, drain tubes were used in the pedicle screw fixation surgery, while no drain tubes were placed in the other group. After gleaning demographic information and results of lab examination and imageology examination, all data were put into a database. Independent-sample t-tests, Pearson Chi-Square tests, Linear regression analysis, and correlation analysis were then performed.

Results

Compared to the control group, the drainage group had significantly lower postoperative CRP levels (P = 0.047), less use of antipyretics (P = 0.035), higher ADL scores (P = 0.001), and lower NRS scores (P < 0.001) on the 6th day after surgery. Other investigation items, such as demographic information, operation time, intraoperative blood loss, body temperature, and other preoperative and postoperative lab results, showed no significant differences.

Conclusions

The use of a drain tube in the pedicle screw fixation of thoracolumbar fractures is correlated with the improvement of patients’ living and activity ability and the reduction of inflammation, postoperative fever and pain.
Sexual and gender minority content in undergraduate medical education in the United States and Canada: current state and changes since 2011
Authors: Streed Carl G. , Michals Amy , Quinn Emily , Davis John A. , Blume Kylie , Dalke Katharine B. , Fetterman David , Garcia Gabriel , Goldsmith Elizabeth , Greene Richard E. , Halem Jessica , Hedian Helene F. , Moring Isabel , Navarra May , Potter Jennifer , Siegel Jennifer , White William , Lunn Mitchell R. , Obedin-Maliver Juno
Published: May 2024

Purpose

To characterize current lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI +) health-related undergraduate medical education (UME) curricular content and associated changes since a 2011 study and to determine the frequency and extent of institutional instruction in 17 LGBTQI + health-related topics, strategies for increasing LGBTQI + health-related content, and faculty development opportunities.

Method

Deans of medical education (or equivalent) at 214 allopathic or osteopathic medical schools in Canada and the United States were invited to complete a 36-question, Web-based questionnaire between June 2021 and September 2022. The main outcome measured was reported hours of LGBTQI + health-related curricular content.

Results

Of 214 schools, 100 (46.7%) responded, of which 85 (85.0%) fully completed the questionnaire. Compared to 5 median hours dedicated to LGBTQI + health-related in a 2011 study, the 2022 median reported time was 11 h (interquartile range [IQR], 6–16 h, p < 0.0001). Two UME institutions (2.4%; 95% CI, 0.0%-5.8%) reported 0 h during the pre-clerkship phase; 21 institutions (24.7%; CI, 15.5%-33.9%) reported 0 h during the clerkship phase; and 1 institution (1.2%; CI, 0%-3.5%) reported 0 h across the curriculum. Median US allopathic clerkship hours were significantly different from US osteopathic clerkship hours (4 h [IQR, 1–6 h] versus 0 h [IQR, 0–0 h]; p = 0.01). Suggested strategies to increase content included more curricular material focusing on LGBTQI + health and health disparities at 55 schools (64.7%; CI, 54.6%-74.9%), more faculty willing and able to teach LGBTQI + -related content at 49 schools (57.7%; CI, 47.1%-68.2%), and more evidence-based research on LGBTQI + health and health disparities at 24 schools (28.2%; CI, 18.7%-37.8%).

Conclusion

Compared to a 2011 study, the median reported time dedicated to LGBTQI + health-related topics in 2022 increased across US and Canadian UME institutions, but the breadth, efficacy, or quality of instruction continued to vary substantially. Despite the increased hours, this still falls short of the number of hours based on recommended LGBTQI + health competencies from the Association of American Medical Colleges. While most deans of medical education reported their institutions’ coverage of LGBTQI + health as ‘fair,’ ‘good,’ or ‘very good,’ there continues to be a call from UME leadership to increase curricular content. This requires dedicated training for faculty and students.
Circulating-tumour DNA methylation of HAND1 gene: a promising biomarker in early detection of colorectal cancer
Authors: Shavali Mehrdad , Moradi Arash , Tahmaseb Mohammad , Mohammadian Kamal , Ganji Shahla Mohammad
Published: May 2024

Background

Colorectal cancer (CRC) is one of the significant global health concerns with an increase in cases. Regular screening tests are crucial for early detection as it is often asymptomatic in the initial stages. Liquid biopsies, a non-invasive approach that examines biomarkers in biofluids, offer a promising future in diagnosing and screening cancer. Circulating-tumour DNA (ctDNA) is the genetic material in biofluids released into the circulatory system by cells. ctDNA is a promising marker for monitoring patients since cancer cells display distinct DNA methylation patterns compared to normal cells. The potential of our research to contribute to early detection and improved patient outcomes is significant.

Aims

The primary objective of this research project was to explore the HAND1 methylation levels in plasma ctDNA as a potential biomarker for diagnosing CRC and evaluate the methylation level of the well-established gene SPET9 to compare it with the methylation level of HAND1.

Materials and methods

Plasma samples were collected from 30 CRC patients and 15 healthy individuals, with CRC samples obtained pre-treatment. ctDNA was extracted and treated with bisulfite for methylation status assessment. Quantitative methylation-specific PCR (qMS-PCR) was performed for HAND1 and SEPT9, using β-actin (ACTB gene) as a reference. The study aims to evaluate the potential of these genes as diagnostic biomarkers for CRC, contributing to early detection and improved patient outcomes.

Results

Our study yielded significant results: 90% of CRC patients (27 out of 30) had hypermethylation in the SEPT9 gene, and 83% (25 out of 30) exhibited hypermethylation in the HAND1 gene. The methylation levels of both genes were significantly higher in CRC patients than in healthy donors. These findings underscore the potential of SEPT9 and HAND1 methylation as promising biomarkers for diagnosing CRC, potentially leading to early detection and improved patient outcomes.

Conclusion

These findings highlight the potential of SEPT9 and HAND1 methylation as promising biomarkers for diagnosing CRC. However, further research and validation studies are needed to confirm these findings and to explore their clinical utility in CRC diagnosis and management.
Contraceptive behavior of women in India after induced abortion
Authors: Das Labhita , Shekhar Chander
Published: May 2024

Putting an end to the silent pandemic of unsafe abortion is a major public health concern globally. Adoption of post-abortion contraception is documented as a significant contributor to reduce the number of unintended pregnancies and number of induced abortions. This study aimed at investigating the post abortion contraceptive behavior of Indian women exploring the determinants of post-abortion contraceptive uptake. Retrospective calendar data for 6,862 women aged 15–49 years from fifth round of National Family Health Survey (2019–2021) was used for the study. Multinomial logistic regression method was used to model the determinant factors to post-abortion contraceptive uptake. 72.6% women reported adopting no method of contraception after the abortion procedure. A total of 27.4% women adopted some method of contraception after abortion. 14% women preferred adopting short term modern methods. Women in early reproductive age group which is the most vulnerable group in experiencing unintended pregnancies are less likely to adopt any contraceptive method after abortion. Uptake of post abortion contraception is quite low in India. Effort should be taken in the direction of bringing awareness through provision of targeted contraceptive counselling after abortion.
A human pluripotent stem cell-derived in vitro model of the blood–brain barrier in cerebral malaria
Authors: Gopinadhan Adnan , Hughes Jason M. , Conroy Andrea L. , John Chandy C. , Canfield Scott G. , Datta Dibyadyuti
Published: May 2024

Background

Blood–brain barrier (BBB) disruption is a central feature of cerebral malaria (CM), a severe complication of Plasmodium falciparum (Pf) infections. In CM, sequestration of Pf-infected red blood cells (Pf-iRBCs) to brain endothelial cells combined with inflammation, hemolysis, microvasculature obstruction and endothelial dysfunction mediates BBB disruption, resulting in severe neurologic symptoms including coma and seizures, potentially leading to death or long-term sequelae. In vitro models have advanced our knowledge of CM-mediated BBB disruption, but their physiological relevance remains uncertain. Using human induced pluripotent stem cell-derived brain microvascular endothelial cells (hiPSC-BMECs), we aimed to develop a novel in vitro model of the BBB in CM, exhibiting enhanced barrier properties.

Methods

hiPSC-BMECs were co-cultured with HB3var03 strain Pf-iRBCs up to 9 h. Barrier integrity was measured using transendothelial electrical resistance (TEER) and sodium fluorescein permeability assays. Localization and expression of tight junction (TJ) proteins (occludin, zonula occludens-1, claudin-5), cellular adhesion molecules (ICAM-1, VCAM-1), and endothelial surface markers (EPCR) were determined using immunofluorescence imaging (IF) and western blotting (WB). Expression of angiogenic and cell stress markers were measured using multiplex proteome profiler arrays.

Results

After 6-h of co-culture with Pf-iRBCs, hiPSC-BMECs showed reduced TEER and increased sodium fluorescein permeability compared to co-culture with uninfected RBCs, indicative of a leaky barrier. We observed disruptions in localization of occludin, zonula occludens-1, and claudin-5 by IF, but no change in protein expression by WB in Pf-iRBC co-cultures. Expression of ICAM-1 and VCAM-1 but not EPCR was elevated in hiPSC-BMECs with Pf-iRBC co-culture compared to uninfected RBC co-culture. In addition, there was an increase in expression of angiogenin, platelet factor-4, and phospho-heat shock protein-27 in the Pf-iRBCs co-culture compared to uninfected RBC co-culture.

Conclusion

These findings demonstrate the validity of our hiPSC-BMECs based model of the BBB, that displays enhanced barrier integrity and appropriate TJ protein localization. In the hiPSC-BMEC co-culture with Pf-iRBCs, reduced TEER, increased paracellular permeability, changes in TJ protein localization, increase in expression of adhesion molecules, and markers of angiogenesis and cellular stress all point towards a novel model with enhanced barrier properties, suitable for investigating pathogenic mechanisms underlying BBB disruption in CM.
SIMS study of fine-scale distribution of U, Th and Pb in meteorites
Authors: Yi Keewook , Amelin Yuri
Published: May 2024

We report developing a procedure for measuring concentrations of U, Th and Pb (including all natural Pb isotopes) to establish the distribution of these elements in meteorite minerals and correctly interpret Pb-isotopic ages of meteorites. The concentrations were measured on KBSI SHRIMP IIe by peak jumping using a discrete-dynode secondary electron multiplier. The concentrations were calculated relative to BCR-2G glass and monitored by analysis of the NIST glasses SRM-615 and SRM-617 as secondary reference materials. The detection limits using the spot sizes of ca. 180 μm2, primary O2− beam current of 10.6 nA, and with amplifier dark noise of 0.015 counts per second are ~ 0.2 parts per billion (ppb) for U (500 s integration), ~ 0.6 ppb for Pb (100 s integration for each of the major isotopes), and ~ 1.2 ppb for Th (100 s integration). Analyses of the NIST glasses confirm that the measured concentrations of U and Th are consistent with their certified values, while the Pb concentrations are about four times too low, most likely due to the compositional mismatch between the primary and secondary reference materials. The achieved level of sensitivity and concentration precision (~ 20–30%) is adequate for measuring U, Th and Pb distributions in both rock-forming and accessory minerals in chondrites, achondrites, and their components.
Appraisal of lacustrine aquifer’s groundwater potentiality and its hydrogeological modelling in southeastern Peshawar, Pakistan: implications for environmental geology, and geotechnical engineering
Authors: Shahzad Syed Muzyan , Shahzad Asim , Janjuhah Hammad Tariq , Kontakiotis George , Fanidi Meryem , Ishfaque Muhammad , Shah Sajjad Ahmad , Makri Panayota
Published: May 2024

The Peshawar Basin is a part of the lower Himalayas that contains an enormous amount of groundwater storage. The evaluation of groundwater potential in the southern Peshawar district was done using well logging, lithostratigraphic properties, and combined hydrogeological and geophysical techniques. A total of 13 Vertical Electrical Sounding (VES) profiles were utilised to assess potential groundwater zones for surface resistivity studies. The aquifer system was delineated by comparing the data from five boreholes with the VES findings. An exploration of super-saturated groundwater potential was conducted, utilising parameters such as transmissivity (T), hydraulic conductivity (K), storativity, and the Dar Zarrouk analysis. The Dar Zarrouk analysis yielded average values of transverse resistance (TR), longitudinal conductance (S), and anisotropy (λ), which were determined to be 8069.12, 0.51, and 0.561, respectively. Similarly, average values of transmissivity (T), hydraulic conductivity (K), and storativity were obtained, resulting in 28.67, 0.24, and 0.000177, respectively. The saturated confined layer, characterized by highly saturated zones, was identified to begin at a depth of approximately 119 m and extend down to the lower boundary of the aquifer. The examined aquifer is composed of clay, sand, gravel, boulders, and loose layers of lacustrine mud that are interlayered to form an unconsolidated groundwater aquifer system. The aquifers in the region are highly developed and consisted of unconfined, semi-confined, and confined aquifer systems. As a result, it is possible to use the aquifer for groundwater development in the study area because of its low -to-medium discharge.
Hydrocolpos causing bowel obstruction in a preterm newborn: a case report
Authors: Jouza Martin , Rejdova Ingrid , Cintula Lukas , Jouzova Anna , Jabandziev Petr
Published: May 2024

Background

Imperforate hymen is the most common congenital defect of the female urogenital tract. The spectrum of clinical manifestations is broad, ranging from mild cases undiagnosed until adolescence to severe cases of giant intraabdominal masses. The most common complication of hydrocolpos is bladder compression, resulting in obstructive uropathy and hydronephrosis.

Case presentation

We present here the case of a preterm neonate who was admitted to the surgical neonatal intensive care unit for bowel obstruction. The baby did not appear septic or unwell, a small amount of meconium passed frequently, and no bilious gastric residuals occurred. Based on these findings, acute abdominal obstruction was doubtful, and the surgeon chose a conservative (watch and wait) approach. Subsequently, we performed abdominal ultrasound and magnetic resonance imaging based on unclear information about a suspicious abdominal mass raised by the gynecologist shortly before the emergency C-section. The final diagnosis was congenital hydrocolpos due to imperforate hymen. The pediatric gynecologist indicated an incision of the imperforate hymen under general anesthesia. The incision resolved abdominal distention as well as the bowel obstruction.

Conclusion

The presentation of hydrocolpos was not typical (no bulging in the vaginal introitus) in our case, and clinical symptoms implied acute bowel obstruction shortly after birth. The surgeon chose a conservative (watch and wait) approach as the baby did not appear unwell on the second day of life. Fortunately, diagnostic laparotomy was not required as the next step in bowel obstruction management. All clinical symptoms resolved after a minor surgical procedure.
Unanticipated pathological clearance in two cases of clinical T4b dMMR/MSI-h advanced colorectal cancer: the potential of immune checkpoint inhibitors despite positive positron-emission tomography results
Authors: Nakamura Daigaku , Yanagita Takeshi , Fujii Yoshiaki , Watanabe Kaori , Suzuki Takuya , Ushigome Hajime , Nishigaki Ruriko , Sugimura Naomi , Tanaka Mamoru , Ogawa Ryo , Takahashi Hiroki , Shimura Takaya , Hotta Yuji , Matsuo Yoichi , Kondo Masahiro , Furukawa-Hibi Yoko , Takiguchi Shuji
Published: May 2024

Background

The standard treatment for colorectal cancer consists of surgery and chemotherapy, which can be combined to improve outcomes. Immune checkpoint inhibitors (ICI) are a significant advancement in the standard treatment of metastatic, unresectable colorectal cancer with deficient mismatch repair (dMMR). However, limited data are available about the use of ICI in the neoadjuvant and conversion settings. Here, we present two cases treated with ICI.

Case presentation

Case 1: A 75-year-old male with a large, borderline resectable rectal cancer diagnosed as cT4bN1bM0 who underwent neoadjuvant chemotherapy, followed by combination ICI consisting of ipilimumab and nivolumab. After four courses of ICI, the tumor significantly shrank, but positron emission tomography still showed a positive result and R0 resection was performed. Pathological analysis revealed no residual cancer cells. The patient has been monitored without adjuvant chemotherapy, and no recurrences have occurred after one year. Case 2: A 60-year-old male with locally advanced sigmoid colon cancer who received neoadjuvant treatment with pembrolizumab. The tumor partially shrank after three courses, and continued pembrolizumab monotherapy resulted in further tumor shrinkage which still showed positive positron emission tomography. Curative sigmoidectomy with partial resection of the ileum and bladder was performed, and the pathological outcome was pCR. There was no viable tumor in the specimen. The patient has been monitored without adjuvant chemotherapy for six months, and no recurrence has been observed.

Conclusions

The present study reports two cases, including a large, borderline resectable rectal cancer after failure of chemotherapy followed by combination treatment with nivolumab and ipilimumab and one case of sigmoid colon cancer after pembrolizumab treatment, which resulted in pathological complete response. However, it remains unknown whether ICI therapy can replace surgery or diminish the optimal extent of resection, or whether adjuvant chemotherapy is needed after surgery in the case of achieving pCR after ICI therapy. Overall, this case report suggests that ICI before colorectal surgery can be effective and potentially a ‘watch-and-wait” strategy could be used for cases in which ICI is effective.
Engaging patient and community stakeholders in the optimization of the Compassionate And Loving Mindset towards heart health risk (CALM Hearts) physical activity intervention: a description of initial work and protocol for future engagement activities
Authors: Chudyk Anna Maria , Kullman Sasha , Pool Donna , Duhamel Todd Ashley , Ashe Maureen , Strachan Shaelyn
Published: May 2024

Background

Participatory research approaches systematically integrate the perspectives of individuals, organizations, or communities that have a direct interest in a study’s processes and outcomes (i.e., stakeholders) in research design and implementation. This supports interventions that are developed “by, not for” end-users, thereby increasing acceptability, uptake, and adherence. However, participatory approaches are relatively under-utilized in intervention development and behavioral change intervention research, in part, due to inadequate reporting of methodology. Therefore, to improve transparency in planning and reporting, we (a) describe how we engaged patients and community organizations (i.e., patient and community partners) in grant development for a self-compassion and physical activity behaviour change intervention for women with cardiovascular risk factors and (b) present a protocol for engaging patient and community partners in the optimization and implementation of the intervention moving forward.

Methods

Our participatory research approach was guided by the Strategy for Patient-Oriented Research patient engagement framework and our prior stakeholder engagement work. Four patients and three community partners were engaged at the level of Involve, meaning their perspectives informed directions, processes, and decisions at major project milestones. Specifically, patient and community partners engaged in three separate meetings during grant development wherein they: (a) established a Terms of Reference to guide engagement activities and expectations; (b) shaped the grant through guided conversations about research priorities, outcomes, and intervention delivery components that could be targeted for optimization and (c) co-developed a protocol that specifies how relationships will be initiated with future patient partners, proposes engagement activities across the research cycle, and includes plans for formal evaluation of engagement processes.

Conclusions

Participatory research approaches provide valuable insights into the development of behavioural interventions, especially when stakeholders can partner early and have a meaningful impact. By detailing our engagement activities to date, we hope to model an approach to engaging stakeholders in behavioral intervention development and demonstrate the impacts of doing so.
A multi-agent adaptive deep learning framework for online intrusion detection
Authors: Soltani Mahdi , Khajavi Khashayar , Jafari Siavoshani Mahdi , Jahangir Amir Hossein
Published: May 2024

The network security analyzers use intrusion detection systems (IDSes) to distinguish malicious traffic from benign ones. The deep learning-based (DL-based) IDSes are proposed to auto-extract high-level features and eliminate the time-consuming and costly signature extraction process. However, this new generation of IDSes still needs to overcome a number of challenges to be employed in practical environments. One of the main issues of an applicable IDS is facing traffic concept drift, which manifests itself as new (i.e. , zero-day) attacks, in addition to the changing behavior of benign users/applications. Furthermore, a practical DL-based IDS needs to be conformed to a distributed (i.e. , multi-sensor) architecture in order to yield more accurate detections, create a collective attack knowledge based on the observations of different sensors, and also handle big data challenges for supporting high throughput networks. This paper proposes a novel multi-agent network intrusion detection framework to address the above shortcomings, considering a more practical scenario (i.e., online adaptable IDSes). This framework employs continual deep anomaly detectors for adapting each agent to the changing attack/benign patterns in its local traffic. In addition, a federated learning approach is proposed for sharing and exchanging local knowledge between different agents. Furthermore, the proposed framework implements sequential packet labeling for each flow, which provides an attack probability score for the flow by gradually observing each flow packet and updating its estimation. We evaluate the proposed framework by employing different deep models (including CNN-based and LSTM-based) over the CIC-IDS2017 and CSE-CIC-IDS2018 datasets. Through extensive evaluations and experiments, we show that the proposed distributed framework is well adapted to the traffic concept drift. More precisely, our results indicate that the CNN-based models are well suited for continually adapting to the traffic concept drift (i.e. , achieving an average detection rate of above 95% while needing just 128 new flows for the updating phase), and the LSTM-based models are a good candidate for sequential packet labeling in practical online IDSes (i.e. , detecting intrusions by just observing their first 15 packets).
Challenges faced by a hospital administrator
Authors: Sarla Gurmeet Singh
Published: May 2024

A hospital is a very complex organization because it works on all days, at all hours uninterruptedly. The people visiting a hospital are in pain, and the people working in a hospital are diverse ranging from highly skilled medical, paramedical, and technical staff to unskilled employees working as runners, female attendants, and house-keeping staff making it a unique place to be or work in. Hence, a hospital administrator who is at the helm of affairs needs to be mature and tactful in dealing with the staff. A hospital administrator is a professional who oversees the daily operations of a hospital by planning, directing, and coordinating health services. In view of the peculiar nature of the hospital as an organization, the hospital administrator needs to have a multidisciplinary approach applying the principles of public administration, behavioral science, and management skills. He needs to have a balanced approach and find a middle path for multiple issues which are likely to crop up almost daily while working in a hospital. Hospital managers need to possess expertise in the form of strategic skills, perceptive skills, human relation skills, work experience, and personal characteristics in the form of motivation, self-confidence, and courage of decision-making. Hospital administrators should be capable to solve any number of problems quickly and efficiently and must know the best ways to approach a conflict so as not to escalate the situation. The primary focus of hospital administrator is on ensuring high-quality patient care and efficient hospital services and use their administrative skills to manage budgets, funding, and resources.
Digital sleep clinic: assessing efficacy of continuous positive airway pressure through sleep staging via connected devices: a study protocol
Authors: Ben Messaoud Raoua , Baillieul Sébastien , Tamisier Renaud , Terrail Robin , Bailly Sébastien , Joyeux-Faure Marie , Pépin Jean-Louis
Published: May 2024

Background

Obstructive sleep apnea (OSA) is a multisystemic chronic disease with disabling symptoms, cardiometabolic comorbidities and reduction in physical activity. Continuous positive airway pressure (CPAP) is the standard treatment for OSA. Only a few studies have characterized trajectories of sleep parameters upon initiation of CPAP and these are limited to one or two nights of polysomnographic recording in a sleep laboratory. This is due to the cost of carrying out these studies and poor tolerance by patients of multiple nights of polysomnographic recordings. No study has characterized sleep over multiple nights before and after CPAP initiation, assessing the multidimensional efficacy of CPAP on patient reported outcomes, objective and subjective sleep quality, oximetry, glucose control and physical activity.

New digital technologies enable overnight sleep studies over several nights in the patient’s home, with a reliability of sleep characterization equivalent to polysomnographic recording.

The primary aim of this study is to investigate objective slow wave sleep (SWS or N3) quality before CPAP and during the first month of the treatment.

Secondary objectives are to assess changes in the following parameters before CPAP and during the first month of the treatment: other objective sleep parameters and sleep stages evolution (W, N1, N2 and REM), nocturnal oxygen desaturations, 24-h blood glucose profile, daily physical activity (the daily steps count), and patient reported outcomes.

Methods

Seventy patients prescribed CPAP for OSA will be recruited at Grenoble Alpes University Hospital (France) and monitored for 5 weeks using validated innovative wearable connected devices (the Dreem 3 headband, a pedometer, an oximeter, and a continuous glucose sensor) enabling them to track their own sleep and physiological parameters at home before and after CPAP initiation.

Discussion

By pooling data from the CPAP telemonitoring and other connected devices we should be able to follow the multidimensional trajectories of patients after the initiation of CPAP. This will enable us to determine whether objective changes in sleep parameters in the first few weeks of CPAP treatment are associated with improvements in daytime sleepiness, quality of life, treatment adherence, glucose control and physical activity. The data will provide integrated markers of treatment efficacy and will allow adapted personalized management of OSA in the short and long-term.

Trial registration

Clinicaltrials (NCT05197855).
Student Zone: SEG student programs help further education and launch careers
Authors: Dostal Jessica
Published: May 2024

SEG offers a variety of programs that are tailored for students. The programs help students by furthering knowledge beyond the classroom, teaching important career skills, providing hands-on experience, and more. Recently, we spoke with past participants of our student programs who are currently in the workforce.
Prognostic Implications of Small Cell Lung Cancer Transcriptional Subtyping for CNS Metastases
Authors: Tringale Kathryn R. , Skakodub Anna , Egger Jacklynn , Eichholz Jordan , Yu Yao , Gomez Daniel , Rimner Andreas , Li Bob , Yamada Yoshiya , Wilcox Jessica , Moss Nelson , Imber Brandon S. , Rekhtman Natasha , Baine Marina K. , Rudin Charles M. , Pike Luke R.G.
Published: May 2024

PURPOSE

Small cell lung cancer (SCLC) often metastasizes to the brain and has poor prognosis. SCLC subtypes distinguished by expressing transcriptional factors ASCL1 or NEUROD1 have been identified. This study investigates the impact of transcription factor–defined SCLC subtype on incidence and outcomes of brain metastases (BMs).

METHODS

Patients with SCLC with ASCL1 (A) and NEUROD1 (N) immunohistochemical expression status were identified and classified: (1) A+/N–, (2) A+/N+, (3) A–/N+, and (4) A–/N–. Cumulative incidence competing risk analyses were used to assess incidence of CNS progression. Cox proportional hazards models were used for multivariable analyses of overall survival (OS) and CNS progression-free survival (CNS-PFS).

RESULTS

Of 164 patients, most were either A+/N– or A+/N+ (n = 62, n = 63, respectively). BMs were present at diagnosis in 24 patients (15%). Among them, the 12-month cumulative incidence of subsequent CNS progression was numerically highest for A+/N– (50% [95% CI, 10.5 to 74.7]; P = .47). Among those BM-free at diagnosis, the 12-month cumulative incidence of CNS progression was numerically the highest for A+/N– (16% [95% CI, 7.5 to 27.9]) and A–/N+ (9.1% [95% CI, 0.0 to 34.8]; P = .20). Both subtypes, A+/N– and A–/N+, had worse OS compared with A+/N+ (A+/N–: hazard ratio [HR], 1.62 [95% CI, 1.01 to 2.51]; P < .05; A–/N+: HR, 3.02 [95% CI, 1.35 to 6.76]; P = .007). Excellent response rates (28, 65% CR/PR) across subtypes were seen in patients who had CNS-directed radiotherapy versus systemic therapy alone (9, 36% CR/PR).

CONCLUSION

To our knowledge, this report is the first to investigate CNS-specific outcomes based on transcription factor subtypes in patients with SCLC. BM-free patients at diagnosis with A+/N– or A–/N+ subtypes had worse outcomes compared with those with transcriptional factor coexpression. Further investigation into the mechanisms and implications of SCLC subtyping on CNS-specific outcomes is warranted to ultimately guide personalized care.
55-Year Follow-Up of the First Adult Patient With Craniopharyngioma Treated With Gamma Knife Radiosurgery
Authors: Buwaider Ali , Backlund Erik-Olof , Almqvist Per , Lippitz Bodo , Fletcher-Sandersjöö Alexander , Bartek Jiri
Published: May 2024

In May 1968, Lars Leksell and Erik-Olof Backlund achieved a pioneering breakthrough by performing the first Gamma Knife radiosurgery (GKRS) on a craniopharyngioma (CP). Today, more than 50 years later, this patient remains under continuous monitoring, providing the longest documented follow-up of a GKRS-treated CP. This case report provides a complete record of the patient’s preoperative presentation, surgical assessment, GKRS, and an extensive long-term follow-up with multiple interventions. The investigation involved analysis of archived and digitalized patient records and radiological images. The patient was a 21-year-old female who presented with amenorrhea and low levels of gonadotropins. Pneumoencephalography showed a calcified 2 × 2.5 cm mass located in the suprasellar region, indicative of a CP. Subsequent stereotactic puncture confirmed a predominantly solid nature of the CP. Given the size and composition of the tumor, the surgical team opted for GKRS. Dose planning was performed manually, with coordinates determined using Leksell’s stereotactic frame. The tumor was targeted with a total dose of 50 Gy using 179 beams of 60Co. Over the subsequent 55 years, the patient underwent radiological and clinical follow-ups. Throughout this period, 4 cystic tumor recurrences occurred and were managed by stereotactic puncture and Yttrium-90 instillation radiotherapy. The solid component remained stable without repeated GKRS. The patient suffered lateral quadrant anopsia and endocrinological deficits, necessitating pharmaceutical intervention. Despite these challenges, the patient is still living an active life at age 76 years. This case stands as historic evidence of long-term safety and efficacy of GKRS for CPs.
Molecular functions of ANKLE2 and its implications in human disease
Authors: Fishburn Adam T. , Florio Cole J. , Lopez Nick J. , Link Nichole L. , Shah Priya S.
Published: May 2024

Ankyrin repeat and LEM domain-containing 2 (ANKLE2) is a scaffolding protein with established roles in cell division and development, the dysfunction of which is increasingly implicated in human disease. ANKLE2 regulates nuclear envelope disassembly at the onset of mitosis and its reassembly after chromosome segregation. ANKLE2 dysfunction is associated with abnormal nuclear morphology and cell division. It regulates the nuclear envelope by mediating protein-protein interactions with barrier to autointegration factor (BANF1; also known as BAF) and with the kinase and phosphatase that modulate the phosphorylation state of BAF. In brain development, ANKLE2 is crucial for proper asymmetric division of neural progenitor cells. In humans, pathogenic loss-of-function mutations in ANKLE2 are associated with primary congenital microcephaly, a condition in which the brain is not properly developed at birth. ANKLE2 is also linked to other disease pathologies, including congenital Zika syndrome, cancer and tauopathy. Here, we review the molecular roles of ANKLE2 and the recent literature on human diseases caused by its dysfunction.
Neuromodulatory Contribution to Muscle Force Production after Short-Term Unloading and Active Recovery
Authors: MARTINO GIOVANNI , VALLI GIACOMO , SARTO FABIO , FRANCHI MARTINO V. , NARICI MARCO V. , DE VITO GIUSEPPE
Published: May 2024

Purpose

Prior evidence has shown that neural factors contribute to the loss of muscle force after skeletal muscle disuse. However, little is known about the specific neural mechanisms altered by disuse. Persistent inward current (PIC) is an intrinsic property of motoneurons responsible for prolonging and amplifying the synaptic input, proportionally to the level of neuromodulation, thus influencing motoneuron discharge rate and force production. Here, we hypothesized that short-term unilateral lower limb suspension (ULLS) would reduce the neuromodulatory input associated with PIC, contributing to the reduction of force generation capacity. In addition, we tested whether physical exercise would restore the force generation capacity by reestablishing the initial level of neuromodulatory input.

Methods

In 12 young adults, we assessed maximal voluntary contraction pre- and post-10 d of ULLS and after 21 d of active recovery (AR) based on resistance exercise. PIC was estimated from high-density surface electromyograms of the vastus lateralis muscle as the delta frequency (ΔF) of paired motor units calculated during isometric ramped contractions.

Results

The values of ΔF were reduced after 10 d of ULLS (−33%, P < 0.001), but were fully reestablished after the AR (+29.4%, P < 0.001). The changes in estimated PIC values were correlated (r = 0.63, P = 0.004) with the reduction in maximal voluntary contraction after ULLS (−29%, P = 0.002) and its recovery after the AR (+28.5%, P = 0.003).

Conclusions

Our findings suggest that PIC estimates are reduced by muscle disuse and may contribute to the loss of force production and its recovery with exercise. Overall, this is the first study demonstrating that, in addition to peripheral neuromuscular changes, central neuromodulation is a major contributor to the loss of force generation capacity after disuse, and can be recovered after resistance exercise.