bluuebunny/crossref_metadata_2025 huggingface dataset:
N-terminally truncated Aβ4-x proteoforms and their relevance for Alzheimer’s pathophysiology
Authors: Rostagno Agueda , Cabrera Erwin , Lashley Tammaryn , Ghiso Jorge
Published: June 2022

Background

The molecular heterogeneity of Alzheimer’s amyloid-β (Aβ) deposits extends well beyond the classic Aβ1-40/Aβ1-42 dichotomy, substantially expanded by multiple post-translational modifications that increase the proteome diversity. Numerous truncated fragments consistently populate the brain Aβ peptidome, and their homeostatic regulation and potential contribution to disease pathogenesis are largely unknown. Aβ4-x peptides have been reported as major components of plaque cores and the limited studies available indicate their relative abundance in Alzheimer’s disease (AD).

Methods

Immunohistochemistry was used to assess the topographic distribution of Aβ4-x species in well-characterized AD cases using custom-generated monoclonal antibody 18H6—specific for Aβ4-x species and blind for full-length Aβ1-40/Aβ1-42—in conjunction with thioflavin-S and antibodies recognizing Aβx-40 and Aβx-42 proteoforms. Circular dichroism, thioflavin-T binding, and electron microscopy evaluated the biophysical and aggregation/oligomerization properties of full-length and truncated synthetic homologues, whereas stereotaxic intracerebral injections of monomeric and oligomeric radiolabeled homologues in wild-type mice were used to evaluate their brain clearance characteristics.

Results

All types of amyloid deposits contained the probed Aβ epitopes, albeit expressed in different proportions. Aβ4-x species showed preferential localization within thioflavin-S-positive cerebral amyloid angiopathy and cored plaques, strongly suggesting poor clearance characteristics and consistent with the reduced solubility and enhanced oligomerization of their synthetic homologues. In vivo clearance studies demonstrated a fast brain efflux of N-terminally truncated and full-length monomeric forms whereas their oligomeric counterparts—particularly of Aβ4-40 and Aβ4-42—consistently exhibited enhanced brain retention.

Conclusions

The persistence of aggregation-prone Aβ4-x proteoforms likely contributes to the process of amyloid formation, self-perpetuating the amyloidogenic loop and exacerbating amyloid-mediated pathogenic pathways.
Antioxidant potential of Pediococcus pentosaceus strains from the sow milk bacterial collection in weaned piglets
Authors: Wang Leli , Liu Qihang , Chen Yuwei , Zheng Xinlei , Wang Chuni , Qi Yining , Dong Yachao , Xiao Yue , Chen Cang , Chen Taohong , Huang Qiuyun , Zhai Zongzhao , Long Cimin , Yang Huansheng , Li Jianzhong , Wang Lei , Zhang Gaihua , Liao Peng , Liu Yong-Xin , Huang Peng , Huang Jialu , Wang Qiye , Chu Huanhuan , Yin Jia , Yin Yulong
Published: June 2022

Background

In modern animal husbandry, breeders pay increasing attention to improving sow nutrition during pregnancy and lactation to favor the health of neonates. Sow milk is a main food source for piglets during their first three weeks of life, which is not only a rich repository of essential nutrients and a broad range of bioactive compounds, but also an indispensable source of commensal bacteria. Maternal milk microorganisms are important sources of commensal bacteria for the neonatal gut. Bacteria from maternal milk may confer a health benefit on the host.

Methods

Sow milk bacteria were isolated using culturomics followed by identification using 16S rRNA gene sequencing. To screen isolates for potential probiotic activity, the functional evaluation was conducted to assess their antagonistic activity against pathogensin vitroand evaluate their resistance against oxidative stress in damagedDrosophilainduced by paraquat. In a piglet feeding trial, a total of 54 newborn suckling piglets were chosen from nine sows and randomly assigned to three treatments with different concentrations of a candidate strain. Multiple approaches were carried out to verify its antioxidant function including western blotting, enzyme activity analysis, metabolomics and 16S rRNA gene amplicon sequencing.

Results

The 1240 isolates were screened out from the sow milk microbiota and grouped into 271 bacterial taxa based on a nonredundant set of 16S rRNA gene sequencing. Among 80Pediococcusisolates, a newPediococcus pentosaceusstrain (SMM914) showed the best performance in inhibition ability against swine pathogens and in aDrosophilamodel challenged by paraquat. Pretreatment of piglets with SMM914 induced the Nrf2-Keap1 antioxidant signaling pathway and greatly affected the pathways of amino acid metabolism and lipid metabolism in plasma. In the colon, the relative abundance ofLactobacilluswas significantly increased in the high dose SMM914 group compared with the control group.

Conclusion

P. pentosaceusSMM914 is a promising probiotic conferring antioxidant capacity by activating the Nrf2-Keap1 antioxidant signaling pathway in piglets. Our study provided useful resources for better understanding the relationships between the maternal microbiota and offspring.
Ethacrynic acid is an inhibitor of human factor XIIIa
Authors: Kar Srabani , Vu Kayla , Mottamal Madhusoodanan , Al-Horani Rami A.
Published: June 2022

Background

Ethacrynic acid (EA) is a loop diuretic that is approved orally and parenterally to manage edema-associated diseases. Nevertheless, it was earlier reported that it is also associated with bleeding upon its parenteral administration. In this report, we investigated the effects of EA on human factor XIIIa (FXIIIa) of the coagulation process using a variety of techniques.

Methods

A series of biochemical and computational methods have been used in this study. The potency and efficacy of human FXIIIa inhibition by EA was evaluated using a bisubstrate-based fluorescence trans-glutamination assay under near physiological conditions. To establish the physiological relevance of FXIIIa inhibition by EA, the effect on FXIIIa-mediated polymerization of fibrin(ogen) as well as the formation of fibrin(ogen) – α2-antiplasmin complex was evaluated using SDS-PAGE experiments. The selectivity profile of EA against other coagulation proteins was assessed by evaluating EA’s effect on human clotting times in the activated partial thromboplastin time (APTT) and the prothrombin time (PT) assays. We also used molecular modeling studies to put forward a putative binding mode for EA in the active site of FXIIIa. Results involving EA were the average of at least three experiments and the standard error ± 1 was provided. In determining the inhibition parameters, we used non-linear regression analysis.

Results

FXIIIa is a transglutaminase that works at the end of the coagulation process to form an insoluble, rigid, and cross-linked fibrin rich blood clot. In fact, inhibition of FXIIIa-mediated biological processes has been reported to result in a bleeding diathesis. Inhibition of FXIIIa by EA was investigated given the nucleophilic nature of the thiol-containing active site of the enzyme and the Michael acceptor-based electrophilicity of EA. In a bisubstrate-based fluorescence trans-glutamination assay, EA inhibited FXIIIa with a moderate potency (IC50 ~ 105 µM) and efficacy (∆Y ~ 66%). In SDS-PAGE experiments, EA appears to significantly inhibit the FXIIIa-mediated polymerization of fibrin(ogen) as well as the formation of fibrin(ogen) – α2-antiplasmin complex which indicates that EA affects the physiological functions of FXIIIa. Interestingly, EA did not affect the clotting times of human plasma in the APTT and the PT assays at the highest concentration tested of 2.5 mM suggesting the lack of effects on the coagulation serine proteases and potentially the functional selectivity of EA with respect to the clotting process. Molecular modeling studies demonstrated that the Michael acceptor of EA forms a covalent bond with catalytic residue of Cys314 in the active site of FXIIIa.

Conclusions

Overall, our studies indicate that EA inhibits the physiological function of human FXIIIa in vitro which may potentially contribute to the bleeding complications that were reported with the association of the parenteral administration of EA.
Quantum hybridization negative differential resistance from non-toxic halide perovskite nanowire heterojunctions and its strain control
Authors: Lee Juho , Khan Muhammad Ejaz , Kim Yong-Hoon
Published: June 2022

While low-dimensional organometal halide perovskites are expected to open up new opportunities for a diverse range of device applications, like in their bulk counterparts, the toxicity of Pb-based halide perovskite materials is a significant concern that hinders their practical use. We recently predicted that lead triiodide (PbI3) columns derived from trimethylsulfonium (TMS) lead triiodide (CH3)3SPbI3 (TMSPbI3) by stripping off TMS ligands should be semimetallic, and additionally ultrahigh negative differential resistance (NDR) can arise from the heterojunction composed of a TMSPbI3 channel sandwiched by PbI3 electrodes. Herein, we computationally explore whether similar material and device characteristics can be obtained from other one-dimensional halide perovskites based on non-Pb metal elements, and in doing so deepen the understanding of their mechanistic origins. First, scanning through several candidate metal halide inorganic frameworks as well as their parental form halide perovskites, we find that the germanium triiodide (GeI3) column also assumes a semimetallic character by avoiding the Peierls distortion. Next, adopting the bundled nanowire GeI3-TMSGeI3-GeI3 junction configuration, we obtain a drastically high peak current density and ultrahigh NDR at room temperature. Furthermore, the robustness and controllability of NDR signals from GeI3-TMSGeI3-GeI3 devices under strain are revealed, establishing its potential for flexible electronics applications. It will be emphasized that, despite the performance metrics notably enhanced over those from the TMSPbI3 case, these device characteristics still arise from the identical quantum hybridization NDR mechanism.
Laparoscopic surgery for duodenal perforation due to a diverticulum with heterotopic pancreas: a case report
Authors: Tsukihara Shu , Onda Shinji , Son Kyonsu , Ito Daisuke , Kanno Hironori , Morikawa Toshiaki , Hanyu Nobuyoshi , Eto Ken
Published: June 2022

Background

Heterotopic pancreas (HP) refers to the presence of abnormally located pancreatic tissue without any anatomic or vascular continuity with the main body of the pancreas. HP can occur in the gastrointestinal tract and be complicated by gastrointestinal bleeding, pancreatitis, obstruction, or malignant generation. Specifically, perforation of the gastrointestinal tract because of HP is extremely rare.

Case presentation

A 91-year-old woman was diagnosed with duodenal perforation, and an emergency laparoscopic operation was performed. The operative findings indicated a tumor and duodenal wall perforation. The tumor and the perforated site were resected with a linear stapler. Histopathological examination revealed the presence of HP tissue in the submucosal layer around the diverticulum without any signs of inflammation. The perforated site was not covered by HP tissues, and the duodenal wall might have been weaker than the other areas, which could have caused the internal pressure to increase and led to the perforation.

Conclusions

Preoperative HP diagnosis is difficult, and it is crucial to consider HP as the differential diagnosis in gastrointestinal perforations. The duodenal diverticula can be perforated due to increased internal pressure of the duodenum caused by the imbalanced localization of HP.
A cross-sectional study design to assess the sexual experiences and contraceptive use of adolescents and youths attending high school and college in Jimma town
Authors: Tucho Gudina Terefe , Workneh Netsanet , Abera Mubarek , Abafita Jemal
Published: June 2022

Background

Adolescents and youths in Ethiopia have limited access to reproductive health services designed to address their needs. Therefore, the study aims to assess adolescents' and youth’s sexual practice, contraceptive use, and behavioral patterns towards safe sexual exercise.

Methods

A quantitative cross-sectional study design was used on 374 students selected from high school and vocational colleges to assess their sexual experience and contraceptive use and related perceptions using pre-tested self-administered semi-structured questionnaires. We used descriptive analyses to report their sexual and reproductive health status and logistic regression to examine the association between contraceptive use and other variables.

Results

The results show that 52.7% of the respondents (students) migrated or moved from rural to urban to continue their high school and college education at urban. 41.7% of the respondents were with less than 18 years, of which 75.9% of them already initiated sexual intercourse. Of all the students who started sexual intercourse (51.1%), only 30.9% used contraceptives, but condom use accounts for 49.2%. Overall, 84.8% of those who practiced sexual intercourse were at risk of acquiring sexually transmitted diseases due to not using a condom. About 3% of the respondents reported unwanted pregnancy experiences, of which 64% of these pregnancies were reported to be aborted.

Conclusion

Adolescents and youths attending high schools and College are at increased risk of acquiring HIV and unwanted pregnancy due to low levels of contraceptive use. Specifically, a designed youths-friendly reproductive health service is needed to avert related problems and contribute to sustainable development goals.
Near is more: learning efficiency in research and development innovation among interlocking firms
Authors: Lin Yu-En , Yu Jia-Qi , Chih Hsiang-Hsuan , Ho Kung-Cheng
Published: June 2022

Research question/issue

This study examines whether geographic proximity produces a proximity preference as interlocking firms observe each other and learn innovative behaviors through information transmission among interlocking directors.

Research findings/insights

We study the performance of A-share-listed companies in China from 2007 to 2017 on the basis of resource dependence theory, agglomeration effect theory, and Porter’s competitive theory. When target firms learn about research and development–related innovation behaviors from interlocking firms closer to them, they experience more efficient learning effects and have improved convergent traits. Moreover, this proximity advantage increases the willingness of the target firm to communicate with and learn from interlocking firms closer to them. Highly developed areas and research and development–intensive industries positively affect the learning efficiency of interlocking firms.

Theoretical/academic implications

Our conclusion is consistent with resource dependence theory; target firms in highly developed areas are more willing to imitate and study nearby interlocking firms to maintain their peer relations, innovation potential, and competitiveness. Our conclusion is also consistent with competition theory, which states that the exchange of information between target firms in highly research and development–intensive industries and distant interlocking firms increases innovation differentiation, innovation potential, and competitiveness, even when such exchange has a high cost.

Practitioner/policy implications

The results support resource dependence theory and peers' effects. The information obtained by interlocking directorates through external social relations guides firm decision-making, and closer distances reveal more obvious effects.
Can investors profit by utilizing technical trading strategies? Evidence from the Korean and Chinese stock markets
Authors: Ni Yensen , Day Min-Yuh , Cheng Yirung , Huang Paoyu
Published: June 2022

The idea of this study is derived from observing the profitability of stock investments following the phenomena of continuously rising (or falling) prices of stocks and continuously overbought (or oversold) signals emitted by technical indicators. We employ the standard event study approach and technical trading strategies to explore whether investors would exploit profits in trading the constituent stocks of the Korea Composite Stock Price Index 50 and Shanghai Stock Exchange 50 when the aforementioned continuous phenomena occur. We find that both the Korean and Chinese stock markets are not fully efficient; this finding may enhance the robustness of the existing literature. In addition, we reveal that contrarian strategies are appropriate for the trading stocks listed on the Korean stock market for all the cases investigated in this study. However, momentum strategies are appropriate for the Chinese stock market when continuously rising stock prices and overbought signals are simultaneously observed. These findings imply that the difference in investor behaviors between the Korean and Chinese stock markets might result in dissimilar trading strategies being employed for these two markets.
The impact of carbon emission trading policy on firms’ green innovation in China
Authors: Yu Hongxin , Jiang Yaohui , Zhang Zhaowen , Shang Wen-Long , Han Chunjia , Zhao Yuanjun
Published: June 2022

This study aims to examine the green innovation effect of the carbon emissions pilot policy in China. First, using the difference-in-differences method and regressions of instrumental variables using the data from Chinese listed firms, we verify that the policy promotes green innovation among regulated firms and is more pronounced among state-owned enterprises, firms in the eastern region, and those with lower financing constraints. Furthermore, this positive effect spreads downstream relative to the regulated firms through input–output linkages, but reduces green innovation to upstream firms. Accordingly, such diffusion of innovation is achieved through the price mechanism. The results necessitate the introduction of various derivatives to mobilize the market to reduce the speculative volatility of carbon prices. In addition, relevant supporting policies must be established to encourage corporate innovation to reduce the crowding-out effect owing to emission reduction and the nonmarket factors.
Remimazolam anesthesia for transcatheter mitral valve repair in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome: a case report
Authors: Kitaura Atsuhiro , Kosumi Reiko , Iwamoto Tatsushige , Nakao Shinichi
Published: June 2022

Background

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is characterized by cardiac depression, respiratory failure, myopathy, and anesthesia for affected patients is challenging. Although several anesthetics have been safely employed, there are no reports on remimazolam used in those patients.

Case presentation

A 47-year-old male with MELAS syndrome was diagnosed with mitral regurgitation and scheduled for transcatheter mitral valve repair under general anesthesia. Anesthesia was induced with remimazolam and remifentanil (0.3 µg/kg/min). Remimazolam was administered at 12 mg/kg/h until loss of consciousness for approximately 1 min. Anesthesia was maintained with 1.1–1.2 mg/kg/h of remimazolam and 0.1 µg/kg/min of remifentanil without circulatory collapse or severe metabolic acidosis. The tracheal tube was removed in the operating room.

Conclusion

Remimazolam may be a new option for anesthesia for MELAS syndrome patients with depressed heart function.
A practical solution to estimate the sample size required for clinical prediction models generated from observational research on data
Authors: Baeza-Delgado Carlos , Cerdá Alberich Leonor , Carot-Sierra José Miguel , Veiga-Canuto Diana , Martínez de las Heras Blanca , Raza Ben , Martí-Bonmatí Luis
Published: June 2022

Background

Estimating the required sample size is crucial when developing and validating clinical prediction models. However, there is no consensus about how to determine the sample size in such a setting. Here, the goal was to compare available methods to define a practical solution to sample size estimation for clinical predictive models, as applied to Horizon 2020 PRIMAGE as a case study.

Methods

Three different methods (Riley’s; “rule of thumb” with 10 and 5 events per predictor) were employed to calculate the sample size required to develop predictive models to analyse the variation in sample size as a function of different parameters. Subsequently, the sample size for model validation was also estimated.

Results

To develop reliable predictive models, 1397 neuroblastoma patients are required, 1060 high-risk neuroblastoma patients and 1345 diffuse intrinsic pontine glioma (DIPG) patients. This sample size can be lowered by reducing the number of variables included in the model, by including direct measures of the outcome to be predicted and/or by increasing the follow-up period. For model validation, the estimated sample size resulted to be 326 patients for neuroblastoma, 246 for high-risk neuroblastoma, and 592 for DIPG.

Conclusions

Given the variability of the different sample sizes obtained, we recommend using methods based on epidemiological data and the nature of the results, as the results are tailored to the specific clinical problem. In addition, sample size can be reduced by lowering the number of parameter predictors, by including direct measures of the outcome of interest.
Claw sign of brachial plexopathy on 18F-FDG PET/CT in neurolymphomatosis following successful treatment of lymphoma
Authors: Doran Simon , Lambe Gerard , Nasoodi Afshin
Published: June 2022

Neurolymphomatosis is a rare neurological manifestation associated with non-Hodgkin’s lymphoma. Here we present a case of brachial plexus neurolymphomatosis in a patient with relapsed non-Hodgkin’s lymphoma exquisitely demonstrated on 18F-FDG PET/CT. It highlights the characteristic imaging features and importance of multimodality imaging in diagnosing neurolymphomatosis.
Biological control of citrus canker pathogen Xanthomonas citri subsp. citri using Rangpur lime endophytic bacteria
Authors: Nugroho Yogi Adhi , Suharjono Suharjono , Widyaningsih Sri
Published: June 2022

Background

Rangpur lime (RL) is a common rootstock cultivar used worldwide. However, it is known to have a high susceptibility to citrus canker (CC). To meet the increasing demand for healthy citrus seedlings, this research aimed to study the potency of RL endophytic bacteria as a biocontrol agent of the CC pathogen Xanthomonas citri subsp. citri. The isolates were collected from healthy RL leaves and subjected to in vitro and in planta antagonistic tests against XCC, alongside its cell-free supernatant (CFS). Potential isolates were identified according to their 16S rDNA sequence similarities.

Results

As many as 21 isolates were obtained from the leaves of healthy RL trees. Two (B1 and C8) isolates demonstrated promising inhibitory activity against XCC. Based on the in vitro assays, the cell suspensions (CS) of these isolates could effectively inhibit the growth of XCC, with an optimum clear zone diameter of 8.41 and 7.51 mm, respectively. Consistent with CS, their CFSs also displayed similar antagonistic potencies against XCC with the highest clear zone recorded being 7.23 mm and 6.22 mm, respectively. Further investigations revealed that the minimum inhibitory concentration of B1 and C8 CFSs was 25 µg/ml. It was also found that both CFSs were sensitive to high heat and very low pH, but stable in the presence of proteinase-K. In the in vivo assay, both CS and CFS treatments of B1 and C8 could effectively protect the Rangpur lime from CC. Treated plants had significantly lower disease incidences and developed less severe symptoms than the control plants. Based on their 16S rDNA sequence, B1 and C8 were identified as Staphylococcus pasteuri and Staphylococcus warneri, respectively.

Conclusion

It was concluded that Staphylococcus pasteuri and Staphylococcus warneri could be promising biocontrol agents of XCC. These bacterial isolates can be used as an alternative prevention measure to CC as opposed to commonly used chemicals.
Electrolyte’s imbalance role in atrial fibrillation: Pharmacological management
Authors: Rafaqat Saira , Rafaqat Sana , Khurshid Huma , Rafaqat Simon
Published: June 2022

The contribution of the perpetuation of atrial fibrillation is caused by electrical remodeling in which calcium, sodium and potassium channels could refer to changes in the ion channel protein expression, development of fibrosis, gene transcription and ion channel redistribution. Calcium and magnesium could influence the risk of atrial fibrillation which is the leading cause of cardiac death, heart failure and ischemic stroke. The elevated serum concentration of calcium had a higher range of in-patient’s mortality, increased total cost of hospitalization and increased length of hospital stay as compared to those without hypercalcemia in atrial fibrillation patients. Moreover, chloride channels could affect homeostasis, atrial myocardial metabolism which may participate in the development of atrial fibrillation. Up to a 50% risk of incidence of AF are higher in which left ventricular hypertrophy, sudden cardiovascular death and overall mortality relate to a low serum magnesium level. Additionally, magnesium prevents the occurrence of AF after cardiac surgery, whereas greater levels of serum phosphorus in the large population-based study and the related calcium–phosphorus products were linked with a greater incidence of AF. Numerous clinical studies had shown the high preoperative risk of AF that is linked with lower serum potassium levels. The conventional risk factor of increased risk of new onset of AF events could independently link with high dietary sodium intake which enhances the fibrosis and inflammation in the atrium but the mechanism remains unknown. Many drugs were used to maintain the electrolyte imbalance in AF patients.
Human herpesvirus 6B infection in mesial temporal lobe epilepsy: a meta-analysis
Authors: Tong Jingyi , Zou Qin , Wang Sheng , Liu Jiaqi , Chen Rong , Chen Yongmin , Zhao Wenjie , Ma Lin , Li Qifu
Published: June 2022

Background

Whether human herpesvirus 6B (HHV-6B) can affect mesial temporal lobe epilepsy (MTLE) remains controversial. The present meta-analysis was aimed to evaluate whether HHV-6B is significantly associated with MTLE.

Methods

Six studies were included in this meta-analysis, comprising 183 MTLE patients and 75 controls. In these studies, HHV-6B infection in astrocytes and brain samples of MTLE patients and controls was investigated by polymerase chain reaction and immunofluorescence.

Results

The frequency of HHV-6B infection detection is significantly higher in the MTLE group than in the control group (OR = 9.42, 95%CI: 3.66–24.25), P < 0.00001). Although febrile convulsion is strongly associated with MTLE, the formation of febrile convulsion leading to MTLE is not associated with HHV-6B infection (OR = 2.68, 95%CI: 0.93–7.73), P = 0.07). Moreover, the HHV-6B-specific antigen is co-localized to cells positive for GFAP that morphologically resemble astrocytes. HHV-6B mainly infects astrocytes, oligodendrocytes and microglia, and could damage the vascular endothelial cells of the central nervous system.

Conclusions

There is an association between HHV-6B infection and MTLE. Future large-scale, multi-center, controlled, prospective studies are required to confirm these findings. In addition, the exact mechanism underlying the effects of HHV-6B infection on MTLE needs to be further investigated.
A comparison of nutritional status in patients with neuroblastoma in Rwanda and United Kingdom: a cross-sectional observational study conducted by the OxPLORE collaboration
Authors: Manirambona Emery , Gunawardana Shannon , Hathaway Hugh , Lakhoo Kokila , Ford Kathryn , Kanyamuhunga Aimable
Published: June 2022

Background

Cancer is a major global health concern and a leading cause of death in paediatric populations worldwide. Malnutrition contributes to a poor prognosis and remains the most common comorbidity leading to death in children with cancer. This retrospective study was developed through Oxford Paediatrics Linking Oncology Research with Electives (OxPLORE)—a medical student-led collaboration of paediatric surgeons and oncologists from low- and middle-income (LMIC) and high-income (HIC) countries. The aim of this study was twofold; firstly, to investigate the nutritional status and outcomes of neuroblastoma paediatric patients in two OxPLORE centres. Secondly, to facilitate the development of research skills of medical students as part of the OxPLORE initiative.

Results

Nine neuroblastoma patients were identified (YY, n = 4, XX, n = 5) over the study period. Nutritional status was poorer in YY patients (median z-score − 1.57 cf. − 0.7, t = 1.16, p = 0.28), which correlated with poorer survival in the YY cohort (75%), as compared to the XX cohort (100%). YY patients were older at presentation than the XX cohort (57 cf. 13 months, t = 1.959 p = 0.09). Further, tumour presentation was at a later stage in the YY group (75% stage IV).

Conclusion

This collaboration has shown a correlation in disparities in nutritional status and outcome of neuroblastoma in paediatric populations in YY and XX. These findings can inform institutional quality improvement. Further, this pilot study has highlighted the potential for medical students to undertake international research collaborations.
Laparoscopic surgery of urachal remnants in children: 3-center experience and comparison to an open approach
Authors: Isaev Yaroslav , Bertozzi Mirko
Published: June 2022

Background

Since the first description by Trondsen in 1993, laparoscopy has become the preferred method of surgery of urachal remnants in children. Some authors call it the “gold standard.” Nonetheless, the comparison with open surgery in the literature is limited to several tens of patients. In this paper, we aim to summarize our experience reporting data of a large group of patients.

Results

We conducted a retrospective analysis of anonymized data from patients who underwent surgical interventions at three clinical centers. A total of 78 boys and 33 girls (M:F 2.36:1) were included in our study. Eighty-seven of them underwent mini-invasive surgery (group 1); 24 were operated in a conventional manner (group 2). The predominant form of the urachal anomaly found was the cyst (58.5%), while an umbilical sinus was present in 47 patients (42.3%), a bladder diverticulum in 7 (6.3%), and a patent urachus in 3 cases (2.7%). The average duration of surgery was 60.7 min (20–192 min) in group 1 and 42.7 min (20–90 min) in group 2; excluding the cases with simultaneous interventions, the average duration was found to be 54.5 and 39.7 min, respectively. Twenty-nine simultaneous operations for associated pathologies were performed in 19 cases (21.8%) in our MIS group, in 8 of them (9.19%) for a preoperatively unknown associated pathology, compared to 4 simultaneous operations performed in 4 patients (16.7%) in the open surgery group. We observed intra-operative complications in 2 cases in Group 1; early postoperative complications included hematuria in 14 cases (16%). The duration of postoperative analgesia was significantly shorter in the MIS group.

Conclusions

Laparoscopic surgery has better cosmetic results and allows for additional diagnostics and simultaneous operations that in turn lead to a shorter duration of postoperative analgesia, but has a longer duration in comparison to an open technique.
Relation between panoramic mandibular index and disease activity in patients with rheumatoid arthritis
Authors: El-Din Mounir Serage , Farouk Hesham Mohamed , Teleb Raghdaa Mohamed , Hashaad Nashwa Ismail
Published: June 2022

Background

DEXA scan could be unavailable at some health centers, and radiologic examination of the mandible and oral cavity is considered more commonly used radiologic test that can predict, diagnose, or even follow-up on any defect in bone mineralization. The aim of this study was to elucidate the ability of panoramic radiograph to detect osteoporosis in rheumatoid arthritis patients and correlate panoramic mandibular index with RA disease activity and severity parameters.

Results

The sensitivity of panoramic mandibular index for diagnosis of osteoporosis was 96% in group Ι (primary OP) and 70% in group ΙΙ (RA patients). The positive predictive value of PMI was 67% in group Ι and 55% in group ΙΙ. The negative predictive value of PMI was 34% in group Ι and was 46% in group ΙΙ. The cutoff value of PMI for diagnosis of OP was ≤ 0.31 in group Ι and ≤ 0.17 in group ΙΙ. In group I, there were significant correlations between panoramic mandibular index and patient’s ages, weights, T score at L1-4, T score at femoral neck, and T score at forearm while there were insignificant correlations between PMI and patients’ heights. In group ΙΙ, there were significant correlations between PMI, patients’ ages, weights, disease durations, SHARP score, ESR, RF, T score at L1-4, T score at femoral neck, and T score at forearm, while there were insignificant correlations between PMI and patients’ heights, DAS, and CRP.

Conclusions

Panoramic radiography could have a potential usability in the diagnosis of osteoporosis in rheumatoid arthritis patients regardless of displaying insignificant correlation with disease activity.
Psoriatic arthritis treatment to the target: a consensus, evidence-based clinical practice recommendations for the management of psoriatic arthritis and its concomitant clinical manifestations
Authors: El Miedany Yasser , El Gaafary Maha , GadAllah Naglaa , Mansour Mona , Fathy Nihal , Hassan Waleed , Mortada Mohamed , Galal Salwa , Eissa Mervat , Tabra Samar Abdelhamed , Foad Nermeen , Ali Rehab , Medhat Basma , El Olemy Gehan , Adel Yasmin , Ghaleb Rasha , El-Latif Eiman Abd , Saber Sally , Elkaraly Nourhan , Abu-Zaid Mohammed Hassan
Published: June 2022

Background

We aimed to provide up-to-date, evidence-based and consensus-based recommendations for Treat-to-Target management of psoriatic arthritis (PsA) and associated clinical manifestations.

In this recommendations, 14 key clinical questions were identified by scientific committee according to the Patient/Population, Intervention, Comparison, Outcomes and Timing (PICOT) approach. Literature Review team performed a systematic review to summarize evidence advocating the benefits and harms of available pharmacologic and non-pharmacologic therapies for psoriatic arthritis. Subsequently, recommendations were formulated. The level of evidence was determined for each section using the Oxford Centre for Evidence-based Medicine (CEBM) system. A 3-round Delphi process was conducted with 19 experts whom were drawn from different governorates and health centers across Egypt with diverse in their experiences, including private, governmental workplace, tertiary university hospitals, and insurance hospitals. All rounds were conducted online. A consensus was achieved on the direction and the strength of the recommendations.

Results

An online questionnaire was sent to an expert panel who participated in the three rounds (response rate 100%). At the end of round 3, a total of 51 recommendation items, categorized into 6 sections to address the main 6 psoriatic arthritis categories, were obtained. Agreement with the recommendations (rank 7–9) ranged from 89.5 to 100%. Consensus was reached (i.e., ≥ 75%of respondents strongly agreed or agreed) on the wording of all the 51 clinical standards identified by the scientific committee. Algorithms for the management of psoriatic arthritis have been suggested.

Conclusion

These recommendations provide an updated consensus on the pharmacological treatment of psoriatic arthritis and strategies to reach optimal treat-to-target outcomes in in common clinical scenarios, based on a combination of evidence and expert opinion. Best treatment decisions should be tailored to each individual patient situation.
Mental health outcomes in patients with a long-term condition: analysis of an Improving Access to Psychological Therapies service
Authors: Seaton Natasha , Moss-Morris Rona , Norton Sam , Hulme Katrin , Hudson Joanna
Published: June 2022

Background

Having a long-term condition (LTC) significantly affects mental health. UK policy requires effective mental health provisions for patients with an LTC, generally provided by Improving Access to Psychological Therapies (IAPT) services. National IAPT data suggest that patients with an LTC typically demonstrate poorer outcomes compared with patients without an LTC. However, exploration of confounding factors and different outcome variables is limited.

Aims

To establish the association of LTC status with demographic and clinical factors, and clinical mental health outcomes.

Method

Anonymised patient-level data from a London IAPT service during January 2019 to October 2020 were used in this cohort study, to compare differences between LTC and non-LTC groups on sociodemographic and clinical variables. Binary logistic and multiple linear regression models were constructed for binary outcome variables (recovery and reliable improvement) and continuous outcomes (distress and functioning), respectively.

Results

Patients with an LTC were more likely to be female; older; from a Black, mixed or other ethnic background; and have greater social deprivation. Across the four clinical outcomes (recovery, reliable improvement, final psychological distress and final functioning), having an LTC significantly predicted poorer outcomes even after controlling for sociodemographic and clinical baseline variables. For three outcome variables, greater social deprivation and being discharged during the COVID-19 pandemic also predicted poorer clinical outcomes.

Conclusions

LTC status has a negative effect on mental health outcomes in IAPT services, independent of associated variables such as severity of baseline mental health symptoms, ethnicity and social deprivation. Effective psychological treatment for patients with an LTC remains an unresolved priority.
Anal Cancer: Emerging Standards in a Rare Disease
Authors: Eng Cathy , Ciombor Kristen K. , Cho May , Dorth Jennifer A. , Rajdev Lakshmi N. , Horowitz David P. , Gollub Marc J. , Jácome Alexandre A. , Lockney Natalie A. , Muldoon Roberta L. , Washington Mary Kay , O'Brian Brittany A. , Benny Amala , Lebeck Lee Cody M. , Benson Al B. , Goodman Karyn A. , Morris Van Karlyle
Published: June 2022

The social stigma surrounding an anal cancer diagnosis has traditionally prevented open discussions about this disease. However, as recent treatment options and an increasing rate of diagnoses are made worldwide, awareness is growing. In the United States alone, 9,090 individuals were expected to be diagnosed with anal cancer in 2021. The US annual incidence of squamous cell carcinoma of the anus continues to increase by 2.7% yearly, whereas the mortality rate increases by 3.1%. The main risk factor for anal cancer is a human papillomavirus infection; those with chronic immunosuppression are also at risk. Patients with HIV are 19 times more likely to develop anal cancer compared with the general population. In this review, we have provided an overview of the carcinoma of the anal canal, the role of screening, advancements in radiation therapy, and current trials investigating acute and chronic treatment–related toxicities. This article is a comprehensive approach to presenting the existing data in an effort to encourage continuous international interest in anal cancer.
Mismatch Repair-Deficient Colorectal Cancer: Building on Checkpoint Blockade
Authors: Jin Zhaohui , Sinicrope Frank A.
Published: June 2022

Colorectal cancer (CRC) with deficient DNA mismatch repair (dMMR) is characterized by hypermutation leading to abundant neoantigens that activate an antitumor immune response in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) have transformed the treatment of this subset of CRC and other solid tumors with dMMR, by producing frequent and durable responses that extend patient survival. Recently, the anti–programmed death-1 (PD-1) antibody pembrolizumab was shown to produce significantly longer progression-free survival with fewer adverse events compared with chemotherapy as first-line treatment of metastatic CRC (mCRC) with dMMR. Accordingly, single-agent pembrolizumab represents a new standard of care for dMMR mCRCs including patients with Lynch syndrome and the more common sporadic cases. Furthermore, data indicate that the combination of PD-1 and cytotoxic T-cell lymphocyte-4 inhibitors was more effective than single-agent PD-1 inhibition in patients with dMMR mCRCs, suggesting nonredundant mechanisms of action. Although the benefit of ICIs is currently limited to metastatic disease, studies evaluating ICIs as neoadjuvant and adjuvant therapy in earlier-stage dMMR CRC are ongoing. Despite success of ICIs in the treatment of metastatic dMMR cancers, an appreciable proportion of these tumors demonstrate intrinsic or acquired resistance, and biomarkers to identify these patients are needed. Advances in the understanding of immunotherapy resistance mechanisms hold promise for both biomarker identification and development of novel strategies to circumvent treatment resistance. In this review, we present a comprehensive overview of the evidence for the role of immunotherapy in the treatment of dMMR CRC, discuss resistance mechanisms, and outline potential strategies to circumvent primary and secondary resistance with the goal of broadening the benefit of ICIs.
Metabolic Slowing Vanished 5 Years After Sleeve Gastrectomy in Patients With Obesity and Prediabetes/Diabetes
Authors: Bettini Silvia , Milan Gabriella , Favaretto Francesca , Fabris Roberto , Dal Prà Chiara , Quinto Giulia , Cosma Chiara , Vettor Roberto , Busetto Luca
Published: June 2022

Background

Resting energy expenditure (REE) decreases after weight loss more than expected according to body composition changes. Metabolic adaptation (MA) or metabolic slowing represents the difference between measured (m) and predicted (p) REE, and it is not clear whether it persists in the long-term. The aim of this study is to evaluate MA occurring 1 year (V1) and 5 years (V5) after laparoscopic sleeve gastrectomy (LSG) in patients with obesity and normal glucose tolerance, prediabetes (preDM) and type 2 diabetes (T2DM).

Methods

We reassessed 37 patients (14 males/23 females) of 44.8 ± 10 years old, since they registered all the biochemical, body composition, and REE assessments at baseline (V0), V1, and V5. Physical activity (PA) was assessed by interview and questionnaire.

Results

Patients displayed a percentage of weight loss of 31.5 ± 7.4% at V1 and a weight regain of 8.9 ± 7.5% at V5. Comparing V1 and V5, fat mass showed a slight increase (P = 0.011), while free fat mass remained unchanged (P = 0.304). PA improved at V1 (P < 0.001), remaining stable at V5 (P = 0.9). Measured REE (mREE) displayed a 31.2% reduction with a corresponding decrease of predicted REE (pREE) of 21.4% at V1, compared with V0 (P = 0.005), confirming a significant MA at V1. Conversely, no difference between mREE and pREE was observed at V5 (P = 0.112).

Conclusion

Our results suggested that only patients with preDM and T2DM displayed MA at V1, which vanished 5 years after LSG. Patients who practiced more PA prevent MA after surgery-induced wight loss.
Selpercatinib Treatment of RET-Mutated Thyroid Cancers Is Associated With Gastrointestinal Adverse Effects
Authors: Tsang Venessa , Gill Anthony , Gild Matti , Lurie Brett , Blumer Lucy , Siddall Rhonda , Clifton-Bligh Roderick , Robinson Bruce
Published: June 2022

Context

Metastatic medullary thyroid carcinoma (MTC) and radioactive iodine–refractory differentiated thyroid carcinoma (RAI-R DTC) have poor prognosis and limited treatment options. Selpercatinib (LOXO-292), a selective kinase inhibitor targeting the RET gene, has shown a 69% to 79% objective response rate in this cohort with benefits in other tumors including lung cancer harboring the same oncogenic driver. Published reports describe only 17% of patients experiencing gastrointestinal (GI) adverse effects (AEs), which is in contrast to our local experience.

Objective

Here we characterize the AEs and correlate them with radiological and histopathological findings.

Methods

Sequential patients enrolled in LIBRETTO-001 at Royal North Shore Hospital, Sydney, Australia, with available imaging (n = 22) were recruited. Patients had regular visits with AEs documented and computed tomography (CT) scans every 3 months. CT at screening, at time of GI AE, and at most recent follow-up were reviewed and scored. Endoscopic examination was performed in 5 patients.

Results

Of 22 patients in this cohort, the majority had somatic RET alterations (n = 18), most commonly p.Met918Thr (n = 14). Ten patients (50%) developed GI AEs. Dose reduction was required in 8 of the 10 patients, but none discontinued therapy. The majority had stable disease (n = 17). Gastric and small-bowel edema was evident in symptomatic patients after a median time of 67 weeks’ treatment. Histological correlation in 5 patients revealed mucosal edema correlating with radiological evidence of congestion and edema.

Conclusion

GI AEs with selpercatinib may be more common than previously described. Most are self-limiting but often require dose adjustments. Histological evidence of mucosal edema observed in conjunction with the radiological findings of congestion and wall thickening suggest bowel-wall edema is a predominant mechanism of abdominal pain in these patients.
Normal HDL Cholesterol Efflux and Anti-Inflammatory Capacities in Type 2 Diabetes Despite Lipidomic Abnormalities
Authors: Denimal Damien , Benanaya Sara , Monier Serge , Simoneau Isabelle , Pais de Barros Jean-Paul , Le Goff Wilfried , Bouillet Benjamin , Vergès Bruno , Duvillard Laurence
Published: June 2022

Objective

To assess whether, in type 2 diabetes (T2D) patients, lipidomic abnormalities in high-density lipoprotein (HDL) are associated with impaired cholesterol efflux capacity and anti-inflammatory effect, 2 pro-atherogenic abnormalities.

Design and Methods

This is a secondary analysis of the Lira-NAFLD study, including 20 T2D patients at T0 and 25 control subjects. Using liquid chromatography/tandem mass spectrometry, we quantified 110 species of the main HDL phospholipids and sphingolipids. Cholesterol efflux capacity was measured on THP-1 macrophages. The anti-inflammatory effect of HDL was measured as their ability to inhibit the tumor necrosis factor α (TNFα)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) on human vascular endothelial cells (HUVECs).

Results

The cholesterol-to-triglyceride ratio was decreased in HDL from T2D patients compared with controls (-46%, P = 0.00008). As expressed relative to apolipoprotein AI, the amounts of phosphatidylcholines, sphingomyelins, and sphingosine-1-phosphate were similar in HDL from T2D patients and controls. Phosphatidylethanolamine-based plasmalogens and ceramides (Cer) were, respectively, 27% (P = 0.038) and 24% (P = 0.053) lower in HDL from T2D patients than in HDL from controls, whereas phosphatidylethanolamines were 41% higher (P = 0.026). Cholesterol efflux capacity of apoB-depleted plasma was similar in T2D patients and controls (36.2 ± 4.3 vs 35.5 ± 2.8%, P = 0.59). The ability of HDL to inhibit the TNFα-induced expression of both VCAM-1 and ICAM-1 at the surface of HUVECs was similar in T2D patients and controls (-70.6 ± 16.5 vs -63.5 ± 18.7%, P = 0.14; and -62.1 ± 13.2 vs -54.7 ± 17.7%, P = 0.16, respectively).

Conclusion

Despite lipidomic abnormalities, the cholesterol efflux and anti-inflammatory capacities of HDL are preserved in T2D patients.