bluuebunny/crossref_metadata_2025 huggingface dataset:
Self-reported impacts of the COVID-19 pandemic among people who use drugs: a rapid assessment study in Montreal, Canada
Authors: Minoyan Nanor , Høj Stine Bordier , Zolopa Camille , Vlad Dragos , Bruneau Julie , Larney Sarah
Published: April 2022

Background

People who use drugs (PWUD) are at high risk of experiencing indirect harms of measures implemented to curb the spread of COVID-19, given high reliance on services and social networks. This study aimed to document short-term changes in behaviours and health-related indicators among PWUD in Montreal, Canada following declaration of a provincial health emergency in Quebec.

Methods

We administered a structured rapid assessment questionnaire to members of an existing cohort of PWUD and individuals reporting past-year illicit drug use recruited via community services. Telephone and in-person interviews were conducted in May–June and September–December 2020. Participants were asked to report on events and changes since the start of the health emergency (March 13, 2020). Descriptive analyses were performed.

Results

A total of 227 participants were included (77% male, median age = 46, 81% Caucasian). 83% and 41% reported past six-month illicit drug use and injection drug use, respectively. 70% of unstably housed participants reported increased difficulty finding shelter since the start of the health emergency. 48% of opioid agonist treatment recipients had discussed strategies to avoid treatment disruptions with providers; 22% had missed at least one dose. Many participants perceived increased difficulty accessing non-addiction health care services. Adverse changes were also noted in indicators pertaining to income, drug markets, drug use frequency, and exposure to violence; however, many participants reported no changes in these areas. Among persons reporting past six-month injection drug use, 79% tried to access needle-syringe programmes during the health emergency; 93% of those obtained services. 45% tried to access supervised injection sites, of whom 71% gained entry.

Conclusions

This snapshot suggests mixed impacts of the COVID-19 pandemic on PWUD in Montreal in the months following declaration of a provincial health emergency. There were signals of increased exposure to high-risk environments as well as deteriorations in access to health services. Pandemic-related measures may have lasting impacts among vulnerable subgroups; continued monitoring is warranted.
Leiomyosarcoma in the extremities and trunk wall: systematic review and meta-analysis of the oncological outcomes
Authors: Kannan Sudhir , Chong Han Hong , Chew Bryan , Ferguson Jay Dee , Galloway Euan , McCulloch Thomas , Rankin Kenneth S. , Ashford Robert U.
Published: April 2022

Background

Leiomyosarcomas are aggressive malignancies which can occur on the trunk and extremities whose pathogenesis is poorly understood. We aim to quantify the prognostic impact of various clinical and pathological markers on survival and recurrence of leiomyosarcomas.

Methods

We conducted a systematic review as per PRISMA protocol. Survival, local recurrence, and metastasis were the outcome measures. Data were extracted from the studies for the outcome variables; the resultant odds ratios (OR) and 95% confidence interval (CI) were used for the synthesis of a forest plot.

Results

Our search revealed thirteen studies comprising 1380 patients. Seven of these 13 publications were since 2012. Our analysis showed that tumor size larger than 5 cm adversely affected the outcome with an OR 3.39 (2.26–5.10, p < 0.01). Other factors which reduced the overall survival were positive margins of excision OR 2.12 (1.36–3.32, p < 0.01). A reduced risk of metastasis has strongly associated the use of radiotherapy with OR 10.84 (4.41–26.61, p < 0.01). Only a few studies analyzed the impact of factors on local recurrence.

Conclusions

Size larger than 5 cm and positive margins of excision are associated with poor overall survival. In comparison, the use of adjuvant radiotherapy was associated with a lower metastatic rate. There is a need for methodically high-quality studies with more uniform study design and reporting to evaluate the impact of various risk factors on local recurrence and metastases.

Level of evidence

Level 1 Prognostic
Using modeling and scenario analysis to support evidence-based health workforce strategic planning in Malawi
Authors: Berman Leslie , Prust Margaret L. , Maungena Mononga Agnes , Boko Patrick , Magombo Macfarlane , Teshome Mihereteab , Nkhoma Levison , Namaganda Grace , Msukwa Duff , Gunda Andrews
Published: April 2022

Background

A well-trained and equitably distributed workforce is critical to a functioning health system. As workforce interventions are costly and time-intensive, investing appropriately in strengthening the health workforce requires an evidence-based approach to target efforts to increase the number of health workers, deploy health workers where they are most needed, and optimize the use of existing health workers. This paper describes the Malawi Ministry of Health (MoH) and collaborators’ data-driven approach to designing strategies in the Human Resources for Health Strategic Plan (HRH SP) 2018–2022.

Methods

Three modelling exercises were completed using available data in Malawi. Staff data from districts, central hospitals, and headquarters, and enrollment data from all health training institutions were collected between October 2017 and February 2018. A vacancy analysis was conducted to compare current staffing levels against established posts (the targeted number of positions to be filled, by cadre and work location). A training pipeline model was developed to project the future available workforce, and a demand-based Workforce Optimization Model was used to estimate optimal staffing to meet current levels of service utilization.

Results

As of 2017, 55% of established posts were filled, with an average of 1.49 health professional staff per 1000 population, and with substantial variation in the number of staff per population by district. With current levels of health worker training, Malawi is projected to meet its establishment targets in 2030 but will not meet the WHO standard of 4.45 health workers per 1000 population by 2040. A combined intervention reducing attrition, increasing absorption, and doubling training enrollments would allow the establishment to be met by 2023 and the WHO target to be met by 2036. The Workforce Optimization Model shows a gap of 7374 health workers to optimally deliver services at current utilization rates, with the largest gaps among nursing and midwifery officers and pharmacists.

Conclusions

Given the time and significant financial investment required to train and deploy health workers, evidence needs to be carefully considered in designing a national HRH SP. The results of these analyses directly informed Malawi’s HRH SP 2018–2022 and have subsequently been used in numerous planning processes and investment cases in Malawi. This paper provides a practical methodology for evidence-based HRH strategic planning and highlights the importance of strengthening HRH data systems for improved workforce decision-making.
A systematic review of the literature on the impact of the Seguro Popular
Authors: Colchero M. A. , Gómez R. , Bautista-Arredondo S.
Published: April 2022

Background

The Seguro Popular (SP) was launched in 2004 to increase access to healthcare and reduce catastrophic expenditures among the Mexican population. To document the evidence on its effectiveness, we conducted a systematic review of impact evaluations of the SP.

Methods

We included papers using rigorous quasi-experimental designs to assess the effectiveness of the SP. We evaluated the quality of each study and presented the statistical significance of the effects by outcome category.

Results

We identified 26 papers that met the inclusion criteria. Sixteen studies that evaluated the impact of SP on financial protection found consistent and statistically significant positive effects in 55% of the 65 outcomes analyzed. Nine studies evaluating utilization of health services for the general and infant populations found effectiveness on 40% of 30 outcomes analyzed. Concerning screening services for hypertension, diabetes, and cervical and prostate cancer, we found three studies evaluating 14 outcomes and finding significant effects on 50% of them. Studies looking at the impact of SP on diabetes, hypertension, and general health care and treatment evaluated 19 outcomes and found effects on 21% of them. One study assessed five diabetes monitoring services and found positive effects on four of them. The only study on morbidity and mortality found positive results on three of the four outcomes of interest.

Conclusion

We found mixed evidence on the impact of SP on financial protection, healthcare utilization, morbidity and mortality. In the 26 studies included in this review, researchers found positive effects in roughly half of the outcomes and null results on the rest.
XGBoost-based and tumor-immune characterized gene signature for the prediction of metastatic status in breast cancer
Authors: Li Qingqing , Yang Hui , Wang Peipei , Liu Xiaocen , Lv Kun , Ye Mingquan
Published: April 2022

Background

For a long time, breast cancer has been a leading cancer diagnosed in women worldwide, and approximately 90% of cancer-related deaths are caused by metastasis. For this reason, finding new biomarkers related to metastasis is an urgent task to predict the metastatic status of breast cancer and provide new therapeutic targets.

Methods

In this research, an efficient model of eXtreme Gradient Boosting (XGBoost) optimized by a grid search algorithm is established to realize auxiliary identification of metastatic breast tumors based on gene expression. Estimated by ten-fold cross-validation, the optimized XGBoost classifier can achieve an overall higher mean AUC of 0.82 compared to other classifiers such as DT, SVM, KNN, LR, and RF.

Results

A novel 6-gene signature (SQSTM1, GDF9, LINC01125, PTGS2, GVINP1, and TMEM64) was selected by feature importance ranking and a series of in vitro experiments were conducted to verify the potential role of each biomarker. In general, the effects of SQSTM in tumor cells are assigned as a risk factor, while the effects of the other 5 genes (GDF9, LINC01125, PTGS2, GVINP1, and TMEM64) in immune cells are assigned as protective factors.

Conclusions

Our findings will allow for a more accurate prediction of the metastatic status of breast cancer and will benefit the mining of breast cancer metastasis-related biomarkers.
Ethnomedicinal landscape: distribution of used medicinal plant species in Nepal
Authors: Kunwar Ripu M. , Baral Bikash , Luintel Sanjeev , Uprety Yadav , Poudel Ram C. , Adhikari Binaya , Adhikari Yagya P. , Subedi Suresh C. , Subedi Chandra K. , Poudel Prakash , Paudel Hem R. , Paudel Basanta , Kunwar Laxmi Mahat , Upadhayaya Kul S. , Bhattarai Shandesh , Pyakurel Dipesh , Kutal Durga H. , Pandey Pramod , Bhandari Ananta , Thapa Gokarna J. , Zambrana Narel Y. Paniagua , Bussmann Rainer W.
Published: April 2022

Background

The risk of losing traditional knowledge of medicinal plants and their use and conservation is very high. Documenting knowledge on distribution and use of medicinal plants by different ethnic groups and at spatial scale on a single platform is important from a conservation planning and management perspective. The sustainable use, continuous practice, and safeguarding of traditional knowledge are essential. Communication of such knowledge among scientists and policy makers at local and global level is equally important, as the available information at present is limited and scattered in Nepal.

Methods

In this paper, we aimed to address these shortcomings by cataloguing medicinal plants used by indigenous ethnic groups in Nepal through a systematic review of over 275 pertinent publications published between 1975 and July 2021. The review was complemented by field visits made in 21 districts. We determined the ethnomedicinal plants hotspots across the country and depicted them in heatmaps.

Results

The heatmaps show spatial hotspots and sites of poor ethnomedicinal plant use documentation, which is useful for evaluating the interaction of geographical and ethnobotanical variables. Mid-hills and mountainous areas of Nepal hold the highest number of medicinal plant species in use, which could be possibly associated with the presence of higher human population and diverse ethnic groups in these areas.

Conclusion

Given the increasing concern about losing medicinal plants due to changing ecological, social, and climatic conditions, the results of this paper may be important for better understanding of how medicinal plants in use are distributed across the country and often linked to specific ethnic groups.
Intrathecal morphine in combination with bupivacaine as pre-emptive analgesia in posterior lumbar fusion surgery: a retrospective cohort study
Authors: Trivedi R. , John J. , Ghodke A. , Trivedi J. , Munigangaiah S. , Dheerendra S. , Balain B. , Ockendon M. , Kuiper J.
Published: April 2022

Background

The purpose of this study was to evaluate the efficacy of intrathecal morphine (ITM) in combination with bupivacaine as pre-emptive analgesia in patients undergoing posterior lumbar fusion surgery. This is in comparison with traditional opioid analgesics such as intravenous (IV) morphine.

Methods

Two groups were identified retrospectively. The first (ITM group) included patients who had general anaesthesia (GA) with low-dose spinal anaesthesia prior to induction using 1–4 mls of 0.25% bupivacaine and 0.2 mg ITM. 1 ml of 0.25% bupivacaine was administered per hour of predicted surgery time, up to a maximum of 4 ml. The insertion level for the spinal anaesthetic corresponded to the spinal level of the iliac crest line and the level at which the spinal cord terminated. The control group had GA without any spinal anaesthesia. Patients were instead administered opioid analgesia in the form of IV morphine or diamorphine. The primary outcome was the consumption of opioids administered intraoperatively and in recovery, and over the first 48 h following discharge from the post-anaesthesia care unit (PACU). Total opioid dose was measured, and a morphine equivalent dose was calculated. Secondary outcomes included visual analogue scale (VAS) pain scores in recovery and at day two postoperatively, and the length of stay in hospital.

Results

For the ITM group, the median total amount of IV morphine equivalent administered intraoperatively and in recovery, was 0 mg versus 17 mg. The median total amount morphine equivalent, administered over the first 48 h following discharge from PACU was 20 mg versus 80 mg. Both are in comparison with the control group. The median length of stay was over 1 day less and the median VAS for pain in recovery was 6 points lower. No evidence was found for a difference in the worst VAS for pain at day two postoperatively.

Conclusion

ITM in combination with bupivacaine results in a significantly decreased use of perioperative opioids. In addition, length of hospital stay is reduced and so too is patient perceived pain intensity.

Trial registration The study was approved by the ethics committee at The Robert Jones and Agnes Hunt Orthopaedic Hospital as a service improvement project (Approval no. 1617_004).
Three-dimensional visualization of electroacupuncture-induced activation of brown adipose tissue via sympathetic innervation in PCOS rats
Authors: Gao Hongru , Tong Xiaoyu , Hu Wei , Wang Yicong , Lee Kuinyu , Xu Xiaoqing , Shi Jiemei , Pei Zhenle , Lu Wenhan , Chen Yuning , Zhang Ruonan , Wang Zheyi , Wang Ziyu , Han Chengzhi , Wang Yu , Feng Yi
Published: April 2022

Background

Low-frequency electroacupuncture (EA) has been shown to ameliorate obesity and reproductive dysfunctions in patients with polycystic ovary syndrome (PCOS), and further explorations in PCOS-like rats showed that EA could affect white adipose tissue. However, the function and neuromodulation of brown adipose tissue (BAT) in PCOS and after EA treatment have remained unknown. The present study focused on the role of BAT in PCOS-like rats and its relationship with EA and characterized the three-dimensional (3D) innervation of BAT associated with activation molecules.

Methods

Female rats (21 days old) were implanted with dihydrotestosterone or fed with a high fat diet to establish PCOS-like and obesity models, respectively, and then EA treatment at “Guilai” (ST 29) and “Sanyinjiao” (SP 6) was carried out for 4 weeks. In the present study, morphological analysis, 3D imaging, molecular biology, and other experimental techniques were used to study the sympathetic nerves and activity of BAT.

Results

PCOS-like rats showed both obvious weight gain and reproductive dysfunction, similar to what was seen in obese rats except for the absence of reproductive dysfunction. The body weight gain was mainly caused by an increase in white adipose tissue, and there was an abnormal decrease in BAT. Because both the lipid metabolism and reproductive disorders could be improved with bilateral EA at “Guilai” (ST 29) and “Sanyinjiao” (SP 6), especially the restoration of BAT, we further investigated the neuromodulation and inflammation in BAT and identified the sympathetic marker tyrosine hydroxylase as one of the key factors of sympathetic nerves. Modified adipo-clearing technology and 3D high-resolution imaging showed that crooked or dispersed sympathetic nerves, but not the twisted vasculature, were reconstructed and associated with the activation of BAT and are likely to be the functional target for EA treatment.

Conclusion

Our study highlights the significant role of BAT and its sympathetic innervations in PCOS and in EA therapy.
Identifying patients with Lynch syndrome using a universal tumor screening program in an integrated healthcare system
Authors: Crain Philip R. , Zepp Jamilyn M. , Gille Sara , Jenkins Lindsay , Kauffman Tia L. , Shuster Elizabeth , Goddard Katrina A.B. , Wilfond Benjamin S. , Hunter Jessica Ezzell
Published: April 2022

Introduction

Lynch syndrome (LS) is associated with an increased risk of colorectal (CRC) and endometrial (EC) cancers. Universal tumor screening (UTS) of all individuals diagnosed with CRC and EC is recommended to increase identification of LS. Kaiser Permanente Northwest (KPNW) implemented a UTS program for LS among individuals newly diagnosed with CRC in January 2016 and EC in November 2016. UTS at KPNW begins with immunohistochemistry (IHC) of tumor tissue to determine loss of mismatch repair proteins associated with LS (MLH1, MSH2, MSH6, and PMS2)., IHC showing loss of MLH1 is followed by reflex testing (automatic testing) to detect the presence of the BRAF V600E variant (in cases of CRC) and MLH1 promoter hypermethylation to rule out likely sporadic cases.

Materials and methods

Individuals newly diagnosed with CRC and EC were identified between the initiation of the respective UTS programs and July 2018. Electronic medical records were reviewed to extract patient data related to UTS, including IHC and reflex testing results, date of referrals to the genetics department, and results of germline genetic testing for LS.

Results

313 out of 362 individuals diagnosed with CRC and 61 out of 64 individuals diagnosed with EC who were eligible were screened by IHC for LS. Most (47/52 or 90%, including 46/49 CRC and 1/3 EC) individuals that were not screened by IHC only had a biopsy sample available. Fourteen individuals (3.7% overall, including 13/313 CRC and 1/61 EC) received an abnormal result after reflex testing and were referred for genetic counseling. Of these, 10 individuals (71% overall, including 9/13 CRC and 1/1 EC) underwent germline genetic testing for LS. Five individuals diagnosed with CRC were found to have pathogenic variants. in PMS2 (n = 3), MLH1 (n = 1), and MSH6 (n = 1). No pathogenic variants were identified in individuals diagnosed with EC.

Conclusions

UTS identified individuals at risk for LS. Most individuals who screened positive for LS had follow-up germline genetic testing for LS. The consistent use of biopsy samples is an opportunity to improve UTS.
Inertial effects due to eruption-induced atmospheric disturbances identified by superconducting gravimeter observations at Matsushiro, Japan
Authors: Imanishi Yuichi
Published: April 2022

The violent eruption of Hunga Tonga-Hunga Ha’apai volcano on January 15, 2022 induced strong atmospheric disturbances, which traveled around the world as atmospheric Lamb waves. When this wave passed through the superconducting gravimeter station at Matsushiro, Japan, a large signal of gravity changes was recorded. Also, barometers installed around Matsushiro recorded wave trains of pressure changes. Analysis of the barometer data revealed that the atmospheric disturbances traveled as plane waves. Applying the theory of atmospheric loading for traveling plane waves, the observed gravity changes were well reproduced by a sum of three components of atmospheric loading, namely, Newtonian, free-air and inertial effects. In particular, the inertial effect of atmospheric loading, which is rarely observed, was clearly identified in the gravity data. From the theoretical modeling, an estimate of rigidity in the shallow region of the Earth was also obtained.

Graphic Abstract
Four cases of gastric adenocarcinoma and proximal polyposis of the stomach treated by robotic total gastrectomy
Authors: Iwakawa Yosuke , Yoshikawa Kozo , Okamoto Koichi , Takayama Tetsuji , Tokunaga Takuya , Nakao Toshihiro , Nishi Masaaki , Takasu Chie , Kashihara Hideya , Wada Yuma , Yoshimoto Toshiaki , Yamashita Shoko , Shimada Mitsuo
Published: April 2022

Background

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a rare disease and characterized by a unique point mutation in the promoter 1B region of the adenomatous polyposis coli (APC) gene. There are two aims in surgery for GAPPS; the first is prophylactic gastrectomy, and the second is excising concurrent cancer. We performed robotic total gastrectomy (RTG) for four cases of GAPPS.

Case presentation

Case 1 was a woman in her 40 s whose sister had died from gastric cancer. Mutational analysis revealed mutation of APC exon 1B. We performed prophylactic gastrectomy. Case 2 was a woman in her 30 s who had a mutation of APC exon 1B, and preoperative biopsy revealed suspected adenocarcinoma. Case 3 was a woman in her 40 s who was diagnosed with gastric cancer with multiple polyps in the stomach and a mutation of APC exon 1B. Case 4 was a woman in her 20 s in whom biopsy revealed low-grade dysplasia of a raised lesion. She had a mutation in APC exon 1B. We performed RTG with D1 + lymphadenectomy in all patients, and there were no intraoperative complications.

Conclusions

Patients with GAPPS are mainly followed regularly with repeat biopsy, and tumors are detected in an early stage. As the safety of robotic surgery for the early gastric cancer is reported, RTG is an option for these patients. This is the first report of RTG for GAPPS patients.
Proton beam therapy causing pericarditis – a rare case of radiation induced cardiotoxicity
Authors: Gupta Rahul , Lin Muling , Freedman Gary M. , Sundlof Deborah W. , Fadlon Cheri Silverstein
Published: April 2022

Acute pericarditis is caused by the inflammation of the pericardium which can result in an effusion around the heart. Proton beam therapy causing radiation-induced pericarditis is not a well-known cause of pericarditis. We present a case of a patient with Li-Fraumeni Syndrome who developed acute onset pericarditis, presumed to be secondary to proton beam therapy.
Screening and biocontrol evaluation of indigenous native Trichoderma spp. against early blight disease and their field assessment to alleviate natural infection
Authors: Imran Muhammad , Abo-Elyousr Kamal A. M. , Mousa Magdi A. , Saad Maged M.
Published: April 2022

Background

Early blight disease of tomato caused by pathogenic fungi Alternaria solani is the most significant and common disease throughout the world as well as in Kingdom of Saudi Arabia. The aim of this study was to isolate and identify native Trichoderma species from the Jeddah region in Saudi Arabia; evaluate their antagonistic potential against A. solani; and study their influence early blight disease severity in greenhouse and in open field.

Results

The present study focused to explore the biocontrolling potential of native Trichoderma spp. against A. solani strain to compare with a conventional fungicide. Out of 21, 3 Trichoderma isolates showed an antifungal activity and significantly inhibited the mycelial growth of pathogen that were identified as Trichoderma atroviride, T. harzianum and T. longibrachiatum by their ITS region sequence analysis. Strong in vitro mycelial growth suppression (70.66%) was also recorded at 400 ppm Mancozeb (90%WP®) fungicide. Further, these Trichoderma bioagents and fungicide were further evaluated in greenhouse (artificially inoculated) and in field on naturally infected tomato plants. In greenhouse, (13.74%) disease severity after T. harzianum treatment was recorded, followed by T. longibrachiatum (25.83%) and T. atroviride (21.67%). The disease severity after fungicide (50 mg/L; 10 ml per plant) application was (7.91%). Further, positive impact on the plant biomarkers was demonstrated by all selected Trichoderma isolates in greenhouse. Under natural infection in season I, the disease severity (%) after T. longibrachiatum, T. atroviride and T. harzianum treatments was 11.5, 13.26 and 16.81%, respectively, followed by control (32.12%), whereas 7.18% disease severity was recorded after fungicide application.

Conclusions

The results revealed that native Trichoderma of this region had potential to mitigate the early blight disease intensity in field.
Is hypoalbuminemia a risk factor for high-dose methotrexate toxicity in children with acute lymphoblastic leukemia?
Authors: Barakat Shaimaa , Assem Hala , Salama Mostafa , Mikhael Neveen , El Chazli Yasmine
Published: April 2022

Background

Repeated high-dose methotrexate (HDMTX) is a critical component of contemporary childhood acute lymphoblastic leukemia (ALL) treatment regimens. Serum albumin is considered a carrier of methotrexate (MTX) in the blood. Hypoalbuminemia is not a rare finding in children with leukemia. This study aimed to investigate the relationship between pre-infusion serum albumin and possible HDMTX toxicities.

Methods

Thirty Egyptian children with ALL were consecutively enrolled in the study between May 2018 and July 2020. They were prospectively followed up while receiving HDMTX during the consolidation phase of the TOTAL study XV protocol. HDMTX was administered intravenously as a 24-h infusion every 2 weeks. Doses of 2.5 g/m2were used for low-risk patients and 5 g/m2for standard/high-risk patients. The Common Terminology Criteria for Adverse Events (V.4.03) was used to report the observed toxicities after HDMTX cycles. Plasma MTX levels were estimated at 24 h (MTX24) from the beginning of HDMTX infusion in the first consolidation cycle. Serum albumin level was determined before HDMTX administration, and pre-infusion hypoalbuminemia was defined when serum albumin was <3.5 g/dL.

Results

The patients’ age ranged from 2.3 to 13.3 years at diagnosis, and most of them had B cell ALL (86.7%). Overall, 120 HDMTX cycles were analyzed, equally distributed between low and standard/high risk. Grade 3–4 anemia, grades 3–4 thrombocytopenia, febrile neutropenia, and oral mucositis were significantly more frequent in HDMTX cycles with pre-infusion hypoalbuminemia than those with normal pre-infusion albumin (p=0.003,p=0.007,p=0.006, andp=0.001, respectively). In addition, pre-infusion hypoalbuminemia was significantly associated with additional hospitalization due to HDMTX toxicity (p=0.031). Most HDMTX toxicities were comparable irrespective of the MTX dose. Oral mucositis was more frequently encountered in the 2.5 g/m2than the 5 g/m2HDMTX cycles (46.7 vs. 26.7%,p=0.023). A significantly longer hospitalization (due to HDMTX toxicity) was observed in the 5 g/m2HDMTX cycles (median= 7 days vs. 4 days,p=0.012).

Conclusions

Serum albumin levels should be checked before starting HDMTX cycles, especially in resource-limited settings where malnutrition is common, and serum MTX monitoring may not be available. Optimizing serum albumin levels before HDMTX may help decrease the possibility of HDMTX toxicities.
Maternal supplementation of α-lipoic acid attenuates prenatal cytarabine exposure-induced oxidative stress, steroidogenesis suppression and testicular damage in F1 male rat fetus
Authors: Namoju Ramanachary , Chilaka Naga Kavitha
Published: April 2022

Background

Cytarabine (Ara-C) is an anticancer drug, which is considered as the mainstay in the treatment of hematological malignancies, known to cause various teratogenic effects. Alpha-lipoic acid (ALA) is a natural antioxidant and its supplementation proved to improve pregnancy outcomes in several pathological conditions. We aimed at exploring the benefits of maternal supplementation of ALA against in-utero Ara-C exposure-induced testicular toxicity in rat fetuses.

Methods

Pregnant rats (dams) received normal saline (control group), ALA 200 mg/kg (ALA group), Ara-C 12.5 mg/kg (Ara-C 12.5 group), Ara-C 25 mg/kg (Ara-C 25 group), and Ara-C 25 mg/kg + ALA 200 mg/kg (protection group) from gestational day (GD)8 to GD21. Ara-C and ALA were administered via the intraperitoneal and oral routes, respectively. The day of parturition was considered as postnatal day (PND)1. On PND1, all the live male pups were collected. The maternal parameters evaluated include (a) food intake, (b) bodyweight, and (c) oxidative stress (OS) markers. The fetal parameters evaluated include (a) bodyweight, (b) anogenital distances (AGD), (c) testicular weight (d) testicular testosterone levels (e) testicular histopathology, and (f) morphometrical parameters.

Results

A significant and dose-dependent decrease in maternal food intake, weight gain, and an increase in oxidative stress (OS) were observed in the pregnant rats of the Ara-C groups as compared to pregnant rats of the control group. Further, a significant and dose-dependent (a) reduction in bodyweight, AGD, testicular weight, and testosterone levels, (b) increase in OS, and (c) structural and morphometrical anomalies in fetal testes were observed in fetuses of Ara-C groups as compared to fetuses of the control rats. These deleterious effects observed in the Ara-C groups were found to be diminished in the pregnant rats and fetuses of the Protection group as compared to the pregnant rats and fetuses of the Ara-C 25 group.

Conclusions

From the results of this study, we conclude that the maternal supplementation of ALA may ameliorate the Ara-C exposure-induced impairment in prenatal development and function of the testes in the rat fetuses. However, future experimental and clinical studies are warranted to explore the possible mechanisms involved in the protection offered by maternal supplementation of ALA against Ara-C induced testicular toxicity.

Graphical Abstract
International clinician perspectives on pandemic-associated stress in supporting people with intellectual and developmental disabilities
Authors: Howkins Joshua , Hassiotis Angela , Bradley Elspeth , Levitas Andrew , Sappok Tanja , Sinai Amanda , Thakur Anupam , Shankar Rohit
Published: April 2022

Background

People living with intellectual and developmental disabilities (IDD) have suffered disproportionately in health outcomes and general well-being during the COVID-19 pandemic. There is emerging evidence of increased psychological distress. Increased strain has also fallen on clinicians managing the psychological needs of people with IDD, in the context of learning new technologies, staff shortages, reduced services and paused training opportunities.

Aims

To examine clinicians’ experiences of patient care, clinical management and the impact of care delivery.

Method

A mixed fixed-response and free-text survey comprising 28 questions covering four areas (responder demographics, clinical practice, changes to local services and clinician experiences) was developed, using the STROBE guidance. It was disseminated through an exponential snowballing technique to clinicians in seven high-income countries. Quantitative data were analysed and presented with Microsoft Excel. Qualitative data were coded and thematically analysed, and presented with in-text quotations.

Results

There were 139 respondents, mostly senior physicians (71%). Two-thirds reported over 10 years working in the field. Quantitative findings include increased clinician stress (77%), referrals (53%), patient distress presentations (>70%), patient isolation (73%) and carer burden (89%), and reduced patient participation in daily activities (86%). A third reported increased psychotropic prescribing. Qualitative analysis outlined changes to clinical practice, particularly the emergence and impact of telehealth.

Conclusions

In the countries surveyed, the pandemic has not only had a significant impact on people with IDD, but also their carers and clinicians. A proactive, holistic international response is needed in preparedness for future public health emergencies.
The Effect of Intravenous Mannitol Combined With Normal Saline in Preventing Cisplatin-Induced Nephrotoxicity: A Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Sainamthip Panot , Saichaemchan Siriwimon , Satirapoj Bancha , Prasongsook Naiyarat
Published: April 2022

PURPOSE

Nephrotoxicity is a major dose-limiting toxicity among patients with cancer who were treated with cisplatin. Although no standard approach is available to prevent cisplatin-induced nephrotoxicity, administering intravenous isotonic saline is recommended. Additionally, mannitol combined with hydration has been evaluated, but none of them have been established. Our study aimed to determine the efficacy of mannitol combined hydration to prevent cisplatin-induced nephrotoxicity.

PATIENTS AND METHODS

This study was a phase II, randomized, placebo-controlled design. All patients with solid cancers who were treated with cisplatin (n = 48) were randomly assigned to receive either placebo (n = 25) or 20 g of mannitol (n = 23) after completing 2 L of prehydration and receiving cisplatin. Serum creatinine, blood urea nitrogen, electrolyte, and glomerular filtration rate (GFR) were measured at baseline and days 2 and 7. Moreover, GFR was calculated based on the 24-hour urine creatinine clearance rate to assess renal function at baseline and 48 hours after receiving cisplatin. Severity of nausea and vomiting was evaluated using Common Terminology Criteria for Adverse Events.

RESULTS

No difference was found regarding baseline characteristics between the two groups. Seven of 23 patients (37.4%) in the mannitol group and 10 of 25 patients (40%) in the placebo group increased serum creatinine level ≥ 0.3 mg/dL at 48 hours after intervention ( P value = .48). Patients receiving mannitol exhibited significantly lower incidence of 24-hour urine GFR below 60 mL/min/1.73 m than those in the placebo group (13.6% v 48.0% in the placebo group; P value = .012). Univariate analysis showed the greatest benefit for administering mannitol among patients receiving cisplatin > 80 mg/m2, or patients receiving concomitant radiation.

CONCLUSION

Mannitol combined with hydration significantly prevented cisplatin-induced nephrotoxicity. Additionally, mannitol should be particularly considered among patients with cancer, treated with cisplatin > 80 mg/m2, or patients receiving concomitant radiation.
Serum Follicle-Stimulating Hormone and 5-Year Change in Adiposity in Healthy Postmenopausal Women
Authors: Mattick Lindsey J , Bea Jennifer W , Singh Lawanya , Hovey Kathleen M , Banack Hailey R , Wactawski-Wende Jean , Manson JoAnn E , Funk Janet L , Ochs-Balcom Heather M
Published: April 2022

Context

Evidence from animal studies suggests that the gradual rise in follicle-stimulating hormone (FSH) during reproductive senescence may contribute to the change in adiposity distribution characteristic of menopause. The potential independent role the interrelationships of FSH and estradiol (E2) may play in postmenopausal adiposity changes are not well studied.

Objective

Our objective was to evaluate the associations of FSH and dual x-ray absorptiometry (DXA)-derived adiposity measures, with consideration of estradiol and postmenopausal hormone therapy use.

Methods

In a sample of 667 postmenopausal women from the Women’s Health Initiative Buffalo OsteoPerio Ancillary Study, we studied the associations of serum FSH and E2 levels with dual x-ray absorptiometry (DXA)-derived adiposity measures via cross-sectional and longitudinal analyses (5-year follow-up).

Results

In cross-sectional analyses, FSH levels were inversely associated with all measures of adiposity in models adjusted for age, years since menopause, smoking status, pack-years, and hormone therapy (HT) use; these associations were not influenced by adjustment for serum E2. In longitudinal analyses, the subset of women who discontinued HT over follow-up (n = 242) experienced the largest increase in FSH (+33.9 mIU/mL) and decrease in E2 (–44.3 pg/mL) and gains in all adiposity measures in unadjusted analyses. In adjusted analyses, an increase in FSH was associated with a gain in percentage of total body fat, total body fat mass, and subcutaneous adipose tissue (SAT).

Conclusion

While cross-sectional findings suggest that FSH is inversely associated with adiposity, our longitudinal findings suggest that greater increases in FSH were associated with greater increases in percentage of total body fat, total body fat mass, and SAT. Future studies are needed to provide additional insight into FSH-adiposity mechanisms in larger samples.
Enterocyte HKDC1 Modulates Intestinal Glucose Absorption in Male Mice Fed a High-fat Diet
Authors: Zapater Joseph L , Wicksteed Barton , Layden Brian T
Published: April 2022

Hexokinase domain containing protein-1, or HKDC1, is a widely expressed hexokinase that is genetically associated with elevated 2-hour gestational blood glucose levels during an oral glucose tolerance test, suggesting a role for HKDC1 in postprandial glucose regulation during pregnancy. Our earlier studies utilizing mice containing global HKDC1 knockdown, as well as hepatic HKDC1 overexpression and knockout, indicated that HKDC1 is important for whole-body glucose homeostasis in aging and pregnancy, through modulation of glucose tolerance, peripheral tissue glucose utilization, and hepatic energy storage. However, our knowledge of the precise role(s) of HKDC1 in regulating postprandial glucose homeostasis under normal and diabetic conditions is lacking. Since the intestine is the main entry portal for dietary glucose, here we have developed an intestine-specific HKDC1 knockout mouse model, HKDC1Int–/–, to determine the in vivo role of intestinal HKDC1 in regulating glucose homeostasis. While no overt glycemic phenotype was observed, aged HKDC1Int–/– mice fed a high-fat diet exhibited an increased glucose excursion following an oral glucose load compared with mice expressing intestinal HKDC1. This finding resulted from glucose entry via the intestinal epithelium and is not due to differences in insulin levels, enterocyte glucose utilization, or reduction in peripheral skeletal muscle glucose uptake. Assessment of intestinal glucose transporters in high-fat diet–fed HKDC1Int–/– mice suggested increased apical GLUT2 expression in the fasting state. Taken together, our results indicate that intestinal HKDC1 contributes to the modulation of postprandial dietary glucose transport across the intestinal epithelium under conditions of enhanced metabolic stress, such as high-fat diet.
Insulin Null β-cells Have a Prohormone Processing Defect That Is Not Reversed by AAV Rescue of Proinsulin Expression
Authors: Ramzy Adam , Edeer Nazde , Baker Robert K , O’Dwyer Shannon , Mojibian Majid , Verchere C Bruce , Kieffer Timothy J
Published: April 2022

Up to 6% of diabetes has a monogenic cause including mutations in the insulin gene, and patients are candidates for a gene therapy. Using a mouse model of permanent neonatal diabetes, we assessed the efficacy of an adeno-associated virus (AAV)-mediated gene therapy. We used AAVs with a rat insulin 1 promoter (Ins1) regulating a human insulin gene (INS; AAV Ins1-INS) or native mouse insulin 1 (Ins1; AAV Ins-Ins1) to deliver an insulin gene to β-cells of constitutive insulin null mice (Ins1−/−Ins2−/−) and adult inducible insulin-deficient mice [Ins1−/−Ins2f/f PdxCreER and Ins1−/−Ins2f/f mice administered AAV Ins1-Cre)]. Although AAV Ins1-INS could successfully infect and confer insulin expression to β-cells, insulin null β-cells had a prohormone processing defect. Secretion of abundant proinsulin transiently reversed diabetes. We reattempted therapy with AAV Ins1-Ins1, but Ins1−/−Ins2−/− β-cells still had a processing defect of both replaced Ins1 and pro-islet amyloid polypeptide (proIAPP). In adult inducible models, β-cells that lost insulin expression developed a processing defect that resulted in impaired proIAPP processing and elevated circulating proIAPP, and cells infected with AAV Ins1-Ins1 to rescue insulin expression secreted proinsulin. We assessed the subcellular localization of prohormone convertase 1/3 (PC1/3) and detected defective sorting of PC1/3 to glycogen-containing vacuoles and retention in the endoplasmic reticulum as a potential mechanism underlying defective processing. We provide evidence that persistent production of endogenous proinsulin within β-cells is necessary for β-cells to be able to properly store and process proinsulin.
Peptidergic G Protein–Coupled Receptor Regulation of Adrenal Function: Bench to Bedside and Back
Authors: Lenzini Livia , Caroccia Brasilina , Seccia Teresa Maria , Rossi Gian Paolo
Published: April 2022

An altered secretion of adrenocortical and adrenomedullary hormones plays a role in the clinical syndromes of primary aldosteronism (PA), Cushing, and pheochromocytoma.

Moreover, an altered production of adrenocortical hormones and/or an abnormal release of factors by the adrenal medulla are involved in several other diseases, including high blood pressure, congestive heart failure, liver cirrhosis, nephrotic syndrome, primary reninism, renovascular hypertension, Addison disease, Bartter, Gitelman, and virilization syndromes. Understanding the regulation of adrenal function and the interactions between adrenal cortex and medulla is, therefore, the prerequisite for mechanistic understanding of these disorders.

Accumulating evidence indicates that the modulation of adrenal hormone biosynthesis is a process far more complex than originally thought, as it involves several factors, each cooperating with the other. Moreover, the tight vascular and neural interconnections between the adrenal cortex and medulla underlie physiologically relevant autocrine/paracrine interactions involving several peptides. Besides playing a pathophysiological role in common adrenal diseases, these complex mechanisms could intervene also in rare diseases, such as pheochromocytoma concomitant with adrenal Cushing or with PA, and PA co-occurring with Cushing, through mechanisms that remain to be fully understood at the molecular levels. Heterodimerization of G protein–coupled receptors (GPCRs) induced by peptide signaling is a further emerging new modulatory mechanism capable of finely tuning adrenal hormones synthesis and release.

In this review we will examine current knowledge on the role of peptides that act via GPCRs in the regulation of adrenal hormone secretion with a particular focus on autocrine-paracrine signals.
A GOVERNANÇA CORPORATIVA E OS FATORES MACROECONÔMICOS INFLUENCIAM A ALAVANCAGEM DAS EMPRESAS BRASILEIRAS LISTADAS NA B3?
Authors: Araújo Flávia Barbosa de Brito , Vilela Eunice Henriques Pereira , Jesuka Duterval , Penedo Antônio Sergio Torres
Published: April 2022

Este estudo tem como objetivo analisar a influência dos mecanismos de Governança Corporativa e dos fatores macroeconômicos em relação à alavancagem das empresas brasileiras listadas na B3. O modelo propõe o uso das Redes Neurais Artificiais em conjunto com regressão linear múltipla com dados em painel.  O período de análise compreende os anos de 2010 a 2018, e a amostra é composta por 619 empresas, totalizando 5571 observações. A coleta de dados foi realizada nos Formulários de Referência (FR), no Economática e nos relatórios anuais.  Como resultado, o modelo de RNAs apresentou desempenho preditivo satisfatório, e, por meio deste, não foi observada influência das variáveis de Governança e Fatores Macroeconômicos sobre a alavancagem das empresas, contrariando a literatura existente. Em contrapartida, o modelo de regressão confirma em parte com a literatura, principalmente para variáveis relacionadas à composição do conselho e ao crescimento anual em nível país.
FATORES CRÍTICOS PARA A CAPACIDADE DE EXPANSÃO INTERNACIONAL DE MICRO E PEQUENAS EMPRESAS BRASILEIRAS: UM ESTUDO DE CASOS MÚLTIPLOS
Authors: Prado Ana Raquel Mechlin , Azevedo Ingrid Gomes de , Ferro Laura Bianco
Published: April 2022

O acirramento da globalização fez que a internacionalização se tornasse uma oportunidade, ou até mesmo, uma forma de sobrevivência para empresas brasileiras. Desse modo, a identificação dos fatores que influenciam na sua capacidade de expansão internacional torna-se fundamental. Quando se abordam empresas de menores portes, o debate é ainda mais relevante, pois não são poucos os obstáculos enfrentados ao se lançarem no mercado internacional. Assim, o objetivo deste estudo foi identificar os fatores mais críticos que influenciam a capacidade de expansão internacional das micro e pequenas empresas brasileiras. Para tanto, fez-se um estudo de casos múltiplos com uma micro e duas pequenas empresas brasileiras de setores distintos. Partindo deste estudo, identificou-se que fatores como qualidade do produto, parcerias e conhecimento sobre diferenças culturais são críticos para o sucesso das empresas estudadas.
O IMPACTO DA PANDEMIA E DA TEMPERATURA NA RENTABILIDADE DA EMPRESA: EVIDÊNCIA DO SETOR DE ENERGIA ELÉTRICA DO BRASIL
Authors: Rosa Arthur Antonio Silva , Meneses Jeanluca Fonseca , Carvalho Luciano Ferreira
Published: April 2022

O objetivo deste artigo é analisar o efeito da pandemia e da temperatura sobre a rentabilidade das companhias, em um comparativo do setor de energia do Brasil, ante as empresas no geral. O período de análise foi de 2011 até 2020, sendo utilizados indicadores de rentabilidade como variáveis dependentes de uma regressão linear múltipla com dados em painel. Os resultados apontam que a variável temperatura apresenta uma relação positiva com o ROE no setor de energia. Também se utilizaram dados macroeconômicos como variáveis de controle, PIB, IPCA e Selic e verificou-se que o IPCA possui relação negativa com as variáveis de rentabilidade, enquanto o preço da energia elétrica possui uma relação positiva com a rentabilidade das empresas do setor. A variável pandemia apresentou significância para dois dos modelos utilizados, de forma que, para o setor de energia, a relação se apresentou positiva e, para os setores em geral, negativa.