bluuebunny/crossref_metadata_2025 huggingface dataset:
Capitalizing on Service Failures: Implications for Customer Engagement and Loyalty
Authors: Zahoor Adil
Published: February 2022

This study examines the driver influence of service recovery performance (SRP) on customer engagement (CE) and customer loyalty (CL) in the Indian retail banking setting. Data collected from a sample of 457 customers who had recent experiences of service failure formed the basis of the empirical investigation. All constructs under examination were measured through structured questionnaires developed in previous research work in this area of study. However, the validity and reliability of the scales were reassessed before the final data analysis. Empirical results indicate that SRP positively influences CE and, concomitantly, CL. Further, CE fully mediates the relationship between service recovery and CL. In addition, it was observed that the structural linkages among SRP, CE and CL are significantly moderated by the gender of the customer. Banking companies are, therefore, advised to consider service failures as an opportunity, rather than a threat, to nurture CE and loyalty. Also, the gender of the customer (male/female) must be considered in deciding the recovery approach.
The Intricate Relationship Between Client Perceptions of Physician Empathy and Physician Self-Assessment: Lessons for Reforming Clinical Practice
Authors: Abdulkader Rizwan Suliankatchi , Venugopal Deneshkumar , Jeyashree Kathiresan , Al Zayer Zainab , Senthamarai Kannan K. , Jebitha R.
Published: February 2022

Objectives: Clinical empathy is an important predictor of patient outcomes. Several factors affect physician’s empathy and client perceptions. We aimed to assess the association between physician and client perception of clinical empathy, accounting for client, physician, and health system factors. Methods: We conducted a hospital-based cross-sectional study in 3 departments (family medicine, internal medicine, and surgery) of King Saud Medical City in Riyadh, Saudi Arabia. We interviewed 30 physicians and 390 clients from 3 departments. Physicians completed the Jefferson Scale of Empathy (JSE) and the clients responded to the Jefferson Scale of Patient Perceptions of Physician Empathy (JSPPPE). We used a hierarchical multilevel generalized structural equation approach to model factors associated with JSE and JSPPPE and their inter-relationship. Results: Mean (SD) score of client-rated physician empathy was 26.6 (6) and that of physician self-rated was 111 (12.8). We found no association between the 2 ( b  =  0.06; 95% confidence intervals CI: −0.1, 0.21), even after adjusting for client, physician, and health system factors. Physician's nationality (0.49; 0.12, 0.85), adequate consultation time (1.05; 0.72, 1.38), and trust (1.33; 0.9, 1.75) were positively associated whereas chronic disease (−0.32; −0.56, −0.07) and higher waiting times (−0.26; −0.47, −0.05) were negatively associated. Conclusion: A physician's self-assessed empathy does not correlate with clients’ perception. We recommend training and monitoring to enhance clinical empathy.
Dismantle Ableism, Accept Disability: Making the Case for Anti-Ableism in Medical Education
Authors: Kaundinya Trisha , Schroth Samantha
Published: February 2022

There currently exists an exciting impetus for increased diversity among medical trainees and improved equity in medical care received by patients. Yet, inclusion of disability within these efforts is often forgotten, allowing the current cultural narrative of ableism to shape medical training. National structural challenges as early as medical school admissions and ableist barriers throughout the educational pipeline have yielded 1) a concerningly low prevalence of medical students and physicians in the US who identify as disabled and 2) propagation of systemic misunderstandings on disability in our healthcare system. This perspective addresses the need for a re-evaluation of diversity in medicine which includes ability status and a commitment to anti-ableism as a critical part of the conversation. We propose reforms and important considerations that could have meaningful implications necessary for improving the culture of disability inclusion in medical education.
Spatial Inequality and Untouchability: Ambedkar’s Gaze on Caste and Space in Hindu Villages
Authors: Patel Anil Kumar
Published: February 2022

Forced exclusion and historical injustices based on caste and space are perpetuated throughout Indian history. Although, a great deal of literature on the caste system of India and village communities is available, very little attention has been paid to its socio-spatial dimensions, and, here comes Ambedkar. Drawing, mainly, from the writings of Dr Ambedkar, the article focusses on the territorial segmentation and cosmological codes of social conduct, resulting in the worst forms of inequality and untouchability in Hindu villages. The aim of the article is to trace the trajectory of socio-spatial segregation between untouchables and caste Hindus in the contours of socio-religious settings that resulted in the worst forms of exploitation and oppression. The main argument of the article involves Dr Ambedkar’s critique of caste-based inequality, foregrounding the socio-spatial segregational patterns and social interactions in the Hindu villages. It establishes that there is an involuntary and forced socio-spatial compartmentalisation and ‘ghettoisation’ of lower strata functioning through the institution of caste, which derives authority from the Hindu religion and religious texts. It is argued that for Dr Ambedkar, space (segmented territories) played a critical role in both the perpetuation and evanescence of untouchability, and that in socio-spatial context, disadvantages of caste discrimination are internalised and articulated in the formal–informal structures of Hindu villages.
The declining appeal of mega-events in entrepreneurial cities: From Los Angeles 1984 to Los Angeles 2028
Authors: Lauermann John
Published: February 2022

Mega-events appear to be losing their appeal as tools for urban development. Events have long been funded by local governments on the promise that they can act as a catalyst for economic growth. But constituents and leaders are questioning that approach, disrupting the relationship between municipalities and global sports institutions. These political shifts are analyzed with a comparative study of Olympic planning and urban politics in American cities, from the Los Angeles 1984 Olympics to present-day preparations for the Los Angeles 2028 Olympics (during this period, Olympic planning also occurred in Atlanta, Boston, Chicago, Los Angeles, New York, and Salt Lake City). The paper examines the development, mobility, and contestation of an “LA model” of mega-event planning, which emphasizes municipal fiscal conservativism, and which has provided a political rationale for city leaders to invest in mega-events. The travels of the model illustrate the evolving role of mega-events in the political economy of entrepreneurial cities.
Do the Winners Really Take It all? Exploring Entrepreneurial Learning in Start-Up Competitions
Authors: Stolz Lennard , Sternberg Rolf
Published: February 2022

Originating from business plan competitions at universities, start-up competitions (SUCs) are nowadays a widely used policy tool to foster entrepreneurial learning among a larger group of potential and nascent entrepreneurs. While the literature on entrepreneurial learning highlights the importance of participants’ prior experiences, studies on learning in SUCs often ignore these experiences, but detect different perceptions of the learning outcomes from SUCs. To address this research gap, we explore configurations of prior experience and the participation routines of entrepreneurs at SUCs. To do so, we apply fuzzy-sets qualitative comparative analysis (fsQCA) to in-depth interview data from 26 participants at two German SUCs. Based on theories on entrepreneurial learning, insights from the interviews, and our empirical results from fsQCA, we identify one necessary condition and two specific configurations of conditions that lead to the outcome. The absence of entrepreneurial knowledge was found to be a necessary condition for entrepreneurial learning in SUCs. Prior industry experience is part of both solutions, but whether the presence or absence of it is important depends on whether it is combined with active participation in the competition. We present implications for policymakers, entrepreneurs, and researchers.
MR- safety: Evaluation of compliance with screening routines using a structured screening interview
Authors: Hansson Boel , Simic Matea , Olsrud Johan , Markenroth Bloch Karin , Owman Titti , Sundgren Pia C , Björkman-Burtscher Isabella M
Published: February 2022

Background

Magnetic resonance (MR) safety procedures are designed to allow patients, research subjects and personnel to enter the MR-scanner room under controlled conditions and without the risk to be harmed during the examination. Ferromagnetic objects in the MR-environment or inside the human body represent the main safety risks potentially leading to human injuries. Screening for MR-safety risks with dedicated procedures is therefore mandatory. As human errors during the screening procedure might align and lead to an incident compliance is essential.

Purpose

To evaluate compliance with a documented structured MR-safety screening process.

Method

Written and signed MR-safety screening documentation collected at a national 7T MR facility during a four-year period was evaluated for compliance of trained personnel with multi-step MR-safety routines. We analysed whether examinations were performed or why they were not performed. Data analysis further included descriptive statistics of the study population (age, gender and patient or healthy volunteer status), identification of missing documents and omitted or incorrect answers, and whether these compliance shortcomings concerned predominantly administrative or MR-safety related issues.

Results

Documentation of the screening process in 1819 subjects was incomplete in 19% of subjects. The most common documentation shortcoming was omitted fields. Out of 478 omitted answer-fields in 307 subjects, 36% were of administrative nature and 64% related directly to MR-safety issues.

Conclusion

Compliance with MR-safety screening procedures cannot be taken for granted and deficiencies to comply with screening routines were revealed. Documentation shortcomings concerned both administrative and MR-safety related issues.
Prevalence of Anxiety, Depression, and Post-Traumatic Stress Disorder among Children and Adolescents with Cancer: A Systematic Review and Meta-Analysis
Authors: Al-Saadi Laila S. , Chan Moon Fai , Al-Azri Mohammed
Published: February 2022

Assessment of psychological and emotional disorders is an important indicator of well-being among children and adolescents with cancer. This review aimed to determine the prevalence rates of three major psychological disorders in this population, including anxiety, depression, and post-traumatic stress disorder (PTSD). Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Various databases were searched to identify cross-sectional studies assessing anxiety, depression, and PTSD among children and adolescents with cancer. The Joanna Briggs Institute checklist was used to assess research quality. Of the 40 studies included in the literature review, 33 measured anxiety, 28 focused on depression, and nine assessed PTSD. A total of 18 studies were incorporated into the meta-analysis, with pooled prevalence rates of anxiety, depression and PTSD found to be 13.92% (n  =  1,971; 95% confidence interval [CI]  =  10.23–18.07%), 20.43% (n  =  1,990, 95% CI  =  13.85–27.93%), and 20.90% (n  =  755, 95% CI  =  13.28–29.73%), respectively. Mental health and psychological interventions are essential for children and adolescents diagnosed with cancer. Future work should be undertaken in different regions, such as the Middle East or Africa, or South America when assessing the prevalence of psychological disorders in children and adolescents diagnosed with cancer.
Obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) frontline treatment for high-risk chronic lymphocytic leukemia
Authors: Huber Henriette , Edenhofer Simone , von Tresckow Julia , Robrecht Sandra , Zhang Can , Tausch Eugen , Schneider Christof , Bloehdorn Johannes , Fürstenau Moritz , Dreger Peter , Ritgen Matthias , Illmer Thomas , Illert Anna L. , Dürig Jan , Böttcher Sebastian , Niemann Carsten U. , Kneba Michael , Fink Anna-Maria , Fischer Kirsten , Döhner Hartmut , Hallek Michael , Eichhorst Barbara , Stilgenbauer Stephan
Published: February 2022

Despite considerable treatment advances with targeted therapies for patients with chronic lymphocytic leukemia (CLL) deemed high-risk [del(17p) and/or TP53 mutation], the outcome is still inferior compared with other CLL patients. Combining multiple agents with distinct mechanisms of action may further improve outcomes. CLL2-GIVe is an open-label, multicenter trial which enrolled patients with previously untreated CLL with del(17p) and/or TP53 mutation. Patients received induction therapy with obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) for cycles 1 through 6 and consolidation therapy with venetoclax and ibrutinib for cycles 7 through 12. Ibrutinib monotherapy was continued for cycles 13 through 36 in patients not reaching a complete response (CR) with serial undetectable minimal residual disease (uMRD) after consolidation. The primary endpoint was CR rate at cycle 15 (final restaging). Secondary endpoints included MRD, survival, and safety. All 41 patients enrolled between September 2016 and August 2018 received study treatment and were included in efficacy and safety populations. With a CR rate of 58.5% at cycle 15, the primary endpoint was met (95% CI: 42.1-73.7; P < .001). At final restaging, 78.0% of patients had uMRD in peripheral blood (PB); 65.9% of patients had uMRD in bone marrow (BM). Estimated progression-free survival (PFS) and overall survival (OS) rates at 24 months were both 95.1%. Adverse events were reported in all patients; most were low grade (grade ≥3: 23.9%). Two deaths were reported (cardiac failure and ovarian carcinoma), neither related to study treatment. The CLL2-GIVe treatment regimen has a manageable safety profile and is a first-line treatment of good efficacy for patients with high-risk CLL.
Deletion of Y chromosome before allogeneic hematopoietic stem cell transplantation in male recipients with female donors
Authors: Tamaki Masaharu , Kameda Kazuaki , Kimura Shun-ichi , Harada Naonori , Uchida Naoyuki , Doki Noriko , Tanaka Masatsugu , Ikegame Kazuhiro , Sawa Masashi , Katayama Yuta , Miyakoshi Shigesaburo , Ara Takahide , Kanda Junya , Onizuka Makoto , Fukuda Takahiro , Atsuta Yoshiko , Kanda Yoshinobu , Yakushijin Kimikazu , Nakasone Hideki
Published: February 2022

The graft-versus-leukemia (GVL) effect is one of the curative mechanisms of allogeneic hematopoietic stem cell transplantation (allo-HCT). H-Y antigens, which are encoded by Y chromosome, are important targets of the GVL effect. Thus, deletion of the Y chromosome (del[Y]) might cause the GVL effect to deteriorate in a transplantation involving a female donor and male recipient, although the clinical significance of the del(Y) group remains to be elucidated. In this study, we evaluated adult male patients who underwent allo-HCT between 2010 and 2019 in Japan. There were 155 cases in the del(Y) group and 4149 cases without del(Y) who underwent female-to-male allo-HCT. Del(Y) was significantly associated with inferior overall survival (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.00-1.53; P = .049) and an increased risk of relapse (HR, 1.40; 95% CI, 1.08-1.80; P = .0098) in multivariate analyses. There was no significant difference in nonrelapse mortality between recipients with and without del(Y) (HR, 1.08; 95% CI, 0.769-1.51; P = .67). In contrast, del(Y) was not significantly associated with any clinical outcomes in the cohort of male-to-male allo-HCT. A higher incidence of relapse might have been caused by attenuation of the GVL effect resulting from a lack of H-Y antigens. Because a GVL effect resulting from sex mismatch may not be expected in men with del(Y) who undergo allo-HCT with a female donor, additional post–allo-HCT strategies might be required to prevent disease relapse.
The roles of Eph receptors, neuropilin-1, P2X7, and CD147 in COVID-19-associated neurodegenerative diseases: inflammasome and JaK inhibitors as potential promising therapies
Authors: Zalpoor Hamidreza , Akbari Abdullatif , Samei Azam , Forghaniesfidvajani Razieh , Kamali Monireh , Afzalnia Azadeh , Manshouri Shirin , Heidari Fatemeh , Pornour Majid , Khoshmirsafa Majid , Aazami Hossein , Seif Farhad
Published: February 2022

The novel coronavirus disease 2019 (COVID-19) pandemic has spread worldwide, and finding a safe therapeutic strategy and effective vaccine is critical to overcoming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, elucidation of pathogenesis mechanisms, especially entry routes of SARS-CoV-2 may help propose antiviral drugs and novel vaccines. Several receptors have been demonstrated for the interaction of spike (S) protein of SARS-CoV-2 with host cells, including angiotensin-converting enzyme (ACE2), ephrin ligands and Eph receptors, neuropilin 1 (NRP-1), P2X7, and CD147. The expression of these entry receptors in the central nervous system (CNS) may make the CNS prone to SARS-CoV-2 invasion, leading to neurodegenerative diseases. The present review provides potential pathological mechanisms of SARS-CoV-2 infection in the CNS, including entry receptors and cytokines involved in neuroinflammatory conditions. Moreover, it explains several neurodegenerative disorders associated with COVID-19. Finally, we suggest inflammasome and JaK inhibitors as potential therapeutic strategies for neurodegenerative diseases.
Comparison of cardiovascular magnetic resonance characteristics and clinical prognosis in left ventricular noncompaction patients with and without arrhythmia
Authors: Zhou Zi-qi , He Wen-chong , Li Xiao , Bai Wei , Huang Wei , Hou Rui-lai , Wang Yi-ning , Guo Ying-kun
Published: February 2022

Background

Left ventricular noncompaction (LVNC) is a rare type of cardiomyopathy, and one of its clinical manifestations is arrhythmia. Cardiovascular magnetic resonance (CMR) is valuable for the diagnosis and prognosis of LVNC. However, studies are lacking on the use of CMR for LVNC patients with arrhythmia. This study aimed to characterize and compare CMR features and prognosis in LVNC patients with and without arrhythmia.

Methods

Eighty-four LVNC patients diagnosed by CMR were enrolled retrospectively in this study. Clinical data, arrhythmia characteristics, and CMR parameters were collected. Patients were divided into different groups according to the arrhythmia characteristics and CMR manifestations for statistical analysis and comparison. Ventricular tachycardia (VT), ventricular fibrillation (Vf), ventricular flutter (VFL), III° atrioventricular block (III° AVB), Wolff–Parkinson–White syndrome (WPW) and ventricular escape (VE) were defined as malignant arrhythmias and benign arrhythmias included premature ventricular contraction, atrial premature beats, atrial fibrillation, supraventricular tachycardia, supraventricular premature beat, bundle branch block, atrial flutter and sinus tachycardia. The outcome events were defined as a composition event of cardiac death, rehospitalization for heart failure, heart transplantation, and implantation of an implantable cardioverter defibrillator (ICD).

Results

Sixty-seven LVNC patients (79.76%) mainly presented with arrhythmia, including premature ventricular beat (33 patients [27.73%]), bundle branch block (14 patients [11.77%]), electrocardiogram waveform changes (18 patients [15.13%]), and ventricular tachycardia (11 patients [9.24%]). The cardiac function and structure parameters had no significant difference among the nonarrhythmia group, benign arrhythmia group, and malignant arrhythmia group. However, the presence of late gadolinium enhancement (LGE) was higher in the malignant arrhythmia group than in the other two groups (p = 0.023). At a mean follow-up of 46 months, cardiac events occurred in twenty-three patients (46.94%). Kaplan–Meier analysis showed that there was no statistically significant difference in prognosis among the nonarrhythmia, benign, and malignant arrhythmia groups, but the patients with arrhythmia and association with LGE + or left ventricular ejection fraction (LVEF) < 30% had a higher risk than patients with LGE- or LVEF > 30% (LGE +, HR = 4.035, 95% CI 1.475–11.035; LVEF < 30%, HR = 8.131, 95% CI 1.805–36.636; P < 0.05).

Conclusions

In LVNC patients, the types of arrhythmias are numerous and unrepresentative, and arrhythmia is not the prognostic factor. Arrhythmia combined with presence of LGE or LVEF < 30% is associated with poor prognosis in LVNC patients.
Cross-sectional household transmission study of Cryptosporidium shows that C. hominis infections are a key risk factor for spread
Authors: McKerr Caoimhe , Chalmers Rachel M. , Elwin Kristin , Ayres Heather , Vivancos Roberto , O’Brien Sarah J. , Christley Robert M.
Published: February 2022

Background

Infection with the Cryptosporidium parasite causes over 4000 cases of diagnosed illness (cryptosporidiosis) in England and Wales each year. The incidence of sporadic disease has not been sufficiently established, and how frequently this arises from contact with other infected people is not well documented. This project aimed to explore potential transmission in the home and attempt to identify asymptomatic infections, which might play a role in transmission. Risk factors and characteristics associated with spread of infection in the home were described including any differences between Cryptosporidium species.

Methods

The study identified cryptosporidiosis cases from North West England and Wales over a year and invited them and their household to take part. Each household was sent a study pack containing study information and a questionnaire, and stool sample kits to provide samples from consenting household members. Cryptosporidium-positive stool samples, identified by immunofluorescence microscopy, were characterised using molecular methods to help describe any patterns of transmission. Characteristics of households with and without additional cases were described, and compared using odds ratios (OR) and a multivariable logistic regression identified independent risk factors for household transmission. Data collection ran for one year, beginning in September 2018 with an initial pilot phase.

Results

We enrolled 128 index cases and their households. Additional illness occurred in over a quarter of homes, each reporting an average of two additional cases. The majority of these were undiagnosed and unreported to surveillance. This burden was even greater in households where the index case was infected with C. hominis versus C. parvum, or the index case was under five years old, with mums and siblings most at risk of secondary infection. Only having an index case of C. hominis was independently associated with transmission in the multivariable model (OR 4.46; p = 0.01).

Conclusions

Cryptosporidium was a considerable burden in the home. At-risk homes were those where the index was less than five years old and/or infected with C. hominis. Of particular risk were female caregivers and siblings. Hygiene advice should be specifically directed here.

This work provides evidence for humans as sources of C. hominis infection and that person-person is a key pathway. We recommend that all stools submitted for the investigation of gastrointestinal pathogens are tested for Cryptosporidium to better capture cases, inclusion of speciation data in routine surveillance, and the consideration of specific clinical advice on prevention for high-risk homes.
Novel heterozygous compound TRMT5 mutations associated with combined oxidative phosphorylation deficiency 26 in a Chinese family: a case report
Authors: Wu Shuiyan , Li Weixi , Bai Zhenjiang , Huang Saihu , Yang Daoping , Chen Hongmei , Li Ying , Liu Ying , Lv Haitao
Published: February 2022

Background

Combined oxidative phosphorylation deficiency 26 (COXPD26) is an autosomal recessive disorder characterized by early onset, developmental delay, gastrointestinal dysfunction, shortness of breath, exercise intolerance, hypotonia and muscle weakness, neuropathy, and spastic diplegia. This disease is considered to be caused by compound heterozygous mutations in the TRMT5 gene.

Case presentation

In this study, we report a female child with COXPD26 manifesting as shortness of breath, gastrointestinal dysmotility, severe developmental delay, muscle hypotonia and weakness, exercise intolerance, renal and hepatic defects, and recurrent seizures with spastic diplegia. Interestingly, the hepatic feature was first observed in a COXPD26 patient. Medical exome sequencing with high coverage depth was employed to identify potential genetic variants in the patient. Novel compound heterozygous mutations of the TRMT5 gene were detected, which were c.881A>C (p.E294A) from her mother and c.1218G>C (p.Q406H) and c.1481C>T (p.T494M) from her father.

Conclusion

The newly emerged clinical features and mutations of this patient provide useful information for further exploration of genotype–phenotype correlations in COXPD26.
A novel case of prolonged Ifosfamide encephalopathy and long-term treatment with methylene blue: a case report and review of literature
Authors: Chain Gabriel , Kalia Mudit , Kestenbaum Karen , Pappas Lara , Sechser-Perl Anna , Campino Gadi Abebe , Zaghloul Nibal
Published: February 2022

Background

Encephalopathy following Ifosfamide treatment is a well-described phenomenon that is typically treated with Methylene Blue (MB). Chloroacetaldehyde, a potentially neurotoxic metabolite of Ifosfamide is hypothesized to cause this encephalopathy. Current guidelines for treatment is to stop Ifosfamide and provide supportive care. MB acts to inhibit Chloroacetaldehyde formation and has been described as a therapy and prophylaxis for Ifosfamide-encephalopathy. MB is effective within 30 min and lasts up to 3 days. Prolonged encephalopathy and MB therapy has not been described in the literature as lasting longer than 30 days following treatment.

Case presentation

We present the case of an 11-year-old female with autistic spectrum disorder and recurrent episodes of severe somnolence for 7 months following Ifosfamide therapy for her Non-Germinomatous Germ Cell Tumor (GCT). Periods of somnolence occurred prior to receiving cranial RT. Administration of MB gave immediate but limited response, with resolution of somnolence lasting 1-2 days between administrations. The somnolence could not be explained by neuroimaging or laboratory evaluation, but EEG indicated persistent encephalopathy.

Conclusion

A literature review determines that neurotoxicity is a side effect of Ifosfamide, but this effect has not been described persisting longer than 30 days. Our case continued to require treatment with MB for 7 months following cessation of therapy. We report these novel clinical findings, and hypothesize that there could be a genetic/metabolic component linking this reaction to Ifosfamide with the case patient’s pre-existing autism. This possible association may also correlate to the already-established link between autism and the development of GCTs. This hypothesis leads to further discussion on the suitable usage of Ifosfamide in children with co-morbidities and the necessity of screening prior to its usage.
Estimation the medical cost of multiple sclerosis in Iran; 2019–2020
Authors: Asadollahi Mina , Darvishi Ali , Azimi Amirreza , Annabi Majid , Jafariazar Zahra , Heshmat Ramin
Published: February 2022

Background

Due to the high and increasing economic burden of chronic diseases, including Multiple sclerosis (MS), we aimed to investigate the medical cost of MS in Iran.

Methods

This is a descriptive cross-sectional study which conducted using comprehensive national prescription data from Iran’s Health Insurance Organization (IHIO) and rehabilitation data from Ministry of Health and Iran Welfare Organization. The time period considered for this study was 2019–2020. In order to calculate the medical cost of MS, the cost-of-illness (COI) method was used based on the prevalence-based approach and the cost of medications, determining and diagnosing the MS risk, follow-up and rehabilitation was estimated.

Results

The total medical cost of MS in Iran in 2019–2020 was estimated at $238,124,160, which medications and rehabilitation services had the largest share in the medical cost of MS in Iran with 80 and 19%, respectively, and the cost share of determining and diagnosing of the disease risk accounted for about less than 1%. The total medication cost was estimated to be equal to $192,298 thousand. The total cost of determining and diagnosing of the MS risk was estimated at $348,574 and the total cost of rehabilitation services for all MS subgroups in 2019–2020 was estimated at $45,477,205.

Conclusions

Results of calculating the medical cost of MS in Iran in 2019–2020 showed a significant burden on the Iranian health care system and society, among which the medication cost had the largest share, which requires serious attention of health system policymakers.
Systematic review of Mendelian randomization studies on risk of cancer
Authors: Markozannes Georgios , Kanellopoulou Afroditi , Dimopoulou Olympia , Kosmidis Dimitrios , Zhang Xiaomeng , Wang Lijuan , Theodoratou Evropi , Gill Dipender , Burgess Stephen , Tsilidis Konstantinos K.
Published: February 2022

Background

We aimed to map and describe the current state of Mendelian randomization (MR) literature on cancer risk and to identify associations supported by robust evidence.

Methods

We searched PubMed and Scopus up to 06/10/2020 for MR studies investigating the association of any genetically predicted risk factor with cancer risk. We categorized the reported associations based on a priori designed levels of evidence supporting a causal association into four categories, namely robust, probable, suggestive, and insufficient, based on the significance and concordance of the main MR analysis results and at least one of the MR-Egger, weighed median, MRPRESSO, and multivariable MR analyses. Associations not presenting any of the aforementioned sensitivity analyses were not graded.

Results

We included 190 publications reporting on 4667 MR analyses. Most analyses (3200; 68.6%) were not accompanied by any of the assessed sensitivity analyses. Of the 1467 evaluable analyses, 87 (5.9%) were supported by robust, 275 (18.7%) by probable, and 89 (6.1%) by suggestive evidence. The most prominent robust associations were observed for anthropometric indices with risk of breast, kidney, and endometrial cancers; circulating telomere length with risk of kidney, lung, osteosarcoma, skin, thyroid, and hematological cancers; sex steroid hormones and risk of breast and endometrial cancer; and lipids with risk of breast, endometrial, and ovarian cancer.

Conclusions

Despite the large amount of research on genetically predicted risk factors for cancer risk, limited associations are supported by robust evidence for causality. Most associations did not present a MR sensitivity analysis and were thus non-evaluable. Future research should focus on more thorough assessment of sensitivity MR analyses and on more transparent reporting.
The risk of all-cause and cause-specific mortality in people prescribed mirtazapine: an active comparator cohort study using electronic health records
Authors: Joseph Rebecca M. , Jack Ruth H. , Morriss Richard , Knaggs Roger David , Butler Debbie , Hollis Chris , Hippisley-Cox Julia , Coupland Carol
Published: February 2022

Background

Studies have reported an increased risk of mortality among people prescribed mirtazapine compared to other antidepressants. The study aimed to compare all-cause and cause-specific mortality between adults prescribed mirtazapine or other second-line antidepressants.

Methods

This cohort study used English primary care electronic medical records, hospital admission records, and mortality data from the Clinical Practice Research Datalink (CPRD), for the period 01 January 2005 to 30 November 2018. It included people aged 18–99 years with depression first prescribed a selective serotonin reuptake inhibitor (SSRI) and then prescribed mirtazapine (5081), a different SSRI (15,032), amitriptyline (3905), or venlafaxine (1580). Follow-up was from starting to stopping the second antidepressant, with a 6-month wash-out window, censoring at the end of CPRD follow-up or 30 November 2018. Age-sex standardised rates of all-cause mortality and death due to circulatory system disease, cancer, or respiratory system disease were calculated. Survival analyses were performed, accounting for baseline characteristics using inverse probability of treatment weighting.

Results

The cohort contained 25,598 people (median age 41 years). The mirtazapine group had the highest standardised mortality rate, with an additional 7.8 (95% confidence interval (CI) 5.9–9.7) deaths/1000 person-years compared to the SSRI group. Within 2 years of follow-up, the risk of all-cause mortality was statistically significantly higher in the mirtazapine group than in the SSRI group (weighted hazard ratio (HR) 1.62, 95% CI 1.28–2.06). No significant difference was found between the mirtazapine group and the amitriptyline (HR 1.18, 95% CI 0.85–1.63) or venlafaxine (HR 1.11, 95% CI 0.60–2.05) groups. After 2 years, the risk was significantly higher in the mirtazapine group compared to the SSRI (HR 1.51, 95% CI 1.04–2.19), amitriptyline (HR 2.59, 95% CI 1.38–4.86), and venlafaxine (HR 2.35, 95% CI 1.02–5.44) groups. The risks of death due to cancer (HR 1.74, 95% CI 1.06–2.85) and respiratory system disease (HR 1.72, 95% CI 1.07–2.77) were significantly higher in the mirtazapine than in the SSRI group.

Conclusions

Mortality was higher in people prescribed mirtazapine than people prescribed a second SSRI, possibly reflecting residual differences in other risk factors between the groups. Identifying these potential health risks when prescribing mirtazapine may help reduce the risk of mortality.
Spatial maps of hepatocellular carcinoma transcriptomes highlight an unexplored landscape of heterogeneity and a novel gene signature for survival
Authors: Zhao Nan , Zhang Yanhui , Cheng Runfen , Zhang Danfang , Li Fan , Guo Yuhong , Qiu Zhiqiang , Dong Xueyi , Ban Xinchao , Sun Baocun , Zhao Xiulan
Published: February 2022

Background

Hepatocellular carcinoma (HCC) often presents with satellite nodules, rendering current curative treatments ineffective in many patients. The heterogeneity of HCC is a major challenge in personalized medicine. The emergence of spatial transcriptomics (ST) provides a powerful strategy for delineating the complex molecular landscapes of tumours.

Methods

In this study, the heterogeneity of tissue-wide gene expression in tumour and adjacent nonneoplastic tissues using ST technology were investigated. The transcriptomes of nearly 10,820 tissue regions and identified the main gene expression clusters and their specific marker genes (differentially expressed genes, DEGs) in patients were analysed. The DEGs were analysed from two perspectives. First, two distinct gene profiles were identified to be associated with satellite nodules and conducted a more comprehensive analysis of both gene profiles. Their clinical relevance in human HCC was validated with Kaplan–Meier (KM) Plotter. Second, DEGs were screened with The Cancer Genome Atlas (TCGA) database to divide the HCC cohort into high- and low-risk groups according to Cox analysis. HCC patients from the International Cancer Genome Consortium (ICGC) cohort were used for validation. KM analysis was used to compare the overall survival (OS) between the high- and low-risk groups. Univariate and multivariate Cox analyses were applied to determine the independent predictors for OS.

Results

Novel markers for the prediction of satellite nodules were identified and a tumour clusters-specific marker gene signature model (6 genes) for HCC prognosis was constructed.

Conclusion

The establishment of marker gene profiles may be an important step towards an unbiased view of HCC, and the 6-gene signature can be used for prognostic prediction in HCC. This analysis will help us to clarify one of the possible sources of HCC heterogeneity and uncover pathogenic mechanisms and novel antitumour drug targets.
Inhibition of post-surgery tumour recurrence via a sprayable chemo-immunotherapy gel releasing PD-L1 antibody and platelet-derived small EVs
Authors: Zhao Jian , Ye Hao , Lu Qi , Wang Kaiyuan , Chen Xiaofeng , Song Jiaxuan , Wang Helin , Lu Yutong , Cheng Maosheng , He Zhonggui , Zhai Yinglei , Zhang Haotian , Sun Jin
Published: February 2022

Background

Melanoma is the most serious type of skin cancer, and surgery is an effective method to treat melanoma. Unfortunately, local residual micro-infiltrated tumour cells and systemic circulating tumour cells (CTCs) are significant causes of treatment failure, leading to tumour recurrence and metastasis.

Methods

Small EVs were isolated from platelets by differential centrifugation, and doxorubicin-loaded small EVs (PexD) was prepared by mixing small EVs with doxorubicin (DOX). PexD and an anti-PD-L1 monoclonal antibody (aPD-L1) were co-encapsulated in fibrin gel. The synergistic antitumour efficacy of the gel containing PexD and aPD-L1 was assessed both in vitro and in vivo.

Results

Herein, we developed an in situ-formed bioresponsive gel combined with chemoimmunotherapeutic agents as a drug reservoir that could effectively inhibit both local tumour recurrence and tumour metastasis. In comparison with a DOX solution, PexD could better bind to tumour cells, induce more tumour immunogenic cell death (ICD) and promote a stronger antitumour immune response. PexD could enter the blood circulation through damaged blood vessels to track and eliminate CTCs. The concurrent release of aPD-L1 at the tumour site could impair the PD-1/PD-L1 pathway and restore the tumour-killing effect of cytotoxic T cells. This chemoimmunotherapeutic strategy triggered relatively strong T cell immune responses, significantly improving the tumour immune microenvironment.

Conclusion

Our findings indicated that the immunotherapeutic fibrin gel could “awaken” the host innate immune system to inhibit both local tumour recurrence post-surgery and metastatic potential, thus, it could serve as a promising approach to prevent tumour recurrence.

Graphical Abstract
Multiscale imaging of therapeutic anti-PD-L1 antibody localization using molecularly defined imaging agents
Authors: Hagemans Iris M. , Wierstra Peter J. , Steuten Kas , Molkenboer-Kuenen Janneke D. M. , van Dalen Duco , ter Beest Martin , van der Schoot Johan M. S. , Ilina Olga , Gotthardt Martin , Figdor Carl G. , Scheeren Ferenc A. , Heskamp Sandra , Verdoes Martijn
Published: February 2022

Background

While immune checkpoint inhibitors such as anti-PD-L1 antibodies have revolutionized cancer treatment, only subgroups of patients show durable responses. Insight in the relation between clinical response, PD-L1 expression and intratumoral localization of PD-L1 therapeutics could improve patient stratification. Therefore, we present the modular synthesis of multimodal antibody-based imaging tools for multiscale imaging of PD-L1 to study intratumoral distribution of PD-L1 therapeutics.

Results

To introduce imaging modalities, a peptide containing a near-infrared dye (sulfo-Cy5), a chelator (DTPA), an azide, and a sortase-recognition motif was synthesized. This peptide and a non-fluorescent intermediate were used for site-specific functionalization of c-terminally sortaggable mouse IgG1 (mIgG1) and Fab anti-PD-L1. To increase the half-life of the Fab fragment, a 20 kDa PEG chain was attached via strain-promoted azide-alkyne cycloaddition (SPAAC). Biodistribution and imaging studies were performed with111In-labeled constructs in 4T1 tumor-bearing mice. Comparing our site-specific antibody-conjugates with randomly conjugated antibodies, we found that antibody clone, isotype and method of DTPA conjugation did not change tumor uptake. Furthermore, addition of sulfo-Cy5 did not affect the biodistribution. PEGylated Fab fragment displayed a significantly longer half-life compared to unPEGylated Fab and demonstrated the highest overall tumor uptake of all constructs. PD-L1 in tumors was clearly visualized by SPECT/CT, as well as whole body fluorescence imaging. Immunohistochemistry staining of tumor sections demonstrated that PD-L1 co-localized with the fluorescent and autoradiographic signal. Intratumoral localization of the imaging agent could be determined with cellular resolution using fluorescent microscopy.

Conclusions

A set of molecularly defined multimodal antibody-based PD-L1 imaging agents were synthesized and validated for multiscale monitoring of PD-L1 expression and localization. Our modular approach for site-specific functionalization could easily be adapted to other targets.

Graphical Abstract
Identification and validation of serum autoantibodies in children with B-cell acute lymphoblastic leukemia by serological proteome analysis
Authors: Yu Runhong , Yang Shiwei , Liu Yufeng , Zhu Zunmin
Published: February 2022

Background

B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy of childhood. Even though significant progresses have been made in the treatment of B-ALL, some pediatric B-ALL have still poor prognosis. The identification of tumor autoantibodies may have utility in early cancer diagnosis and immunotherapy. In this study, we used serological proteome analysis (SERPA) to screen serum autoantibodies of pediatric B-ALL, aiming to contribute to the early detection of B-ALL in children.

Methods

The total proteins from three pooled B-ALL cell lines (NALM-6, REH and BALL-1 cells) were separated using two-dimensional gel electrophoresis (2-DE), which was followed by Western blot by mixed serum samples from children with B-ALL (n=20) or healthy controls (n=20). We analyzed the images of 2-D gel and Western blot by PDQuest software, and then identified the spots of immune responses in B-ALL samples compared with those in control samples. The proteins from spots were identified using mass spectrometry (MS). The autoantibodies against alpha-enolase (α-enolase) and voltage-dependent anion-selective channel protein 1 (VDAC1) were further validated in sera from another 30 children with B-ALL and 25 normal individuals by the use of enzyme-linked immunosorbent assay (ELISA). The protein expression levels of the candidate antigens α-enolase and VDAC1 in B-ALL were thoroughly studied by immunohistochemical analysis.

Results

Utilizing the SERPA approach, α-enolase and VDAC1 were identified as candidate autoantigens in children with B-ALL. The frequencies of autoantibodies against α-enolase and VDAC1 in children with B-ALL were 27% and 23% by using ELISA analysis, respectively, which were significantly higher than those in normal controls (4% and 0, p<0.05). Immunohistochemical analysis showed the expression of α-enolase and VDAC1 was positive in 95% and 85% of B-ALL patients, respectively, but negative expression levels were showed in the control group.

Conclusions

This study incidated that α-enolase and VDAC1 may be the autoantigens associated with B-ALL. Therefore, α-enolase and VDAC1 autoantibodies may be the potential serological markers for children with B-ALL.
Efficacy and safety of endovascular brachytherapy combined with transarterial chemoembolization for the treatment of hepatocellular carcinoma patients with type III or IV portal vein tumor thrombosis
Authors: Li Ling , Cheng Niangmei , Huang Xinhui , Weng Xiadi , Jiao Yubin , Liu Jingfeng , Guo Wuhua
Published: February 2022

Background

The purpose of this study was to evaluate the efficacy and safety of endovascular brachytherapy (EVBT) combined with transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC) complicated with type III OR IV portal vein tumor thrombosis (PVTT) and to further analyze the prognostic predictors for the patients with HCC and PVTT.

Methods

We retrospectively analyzed the medical records of 54 patients who were diagnosed with HCC complicated with type III or IV PVTT and received EVBT combined with modified TACE treatment from January 2017 to June 2019. Adverse events, treatment response, overall survival (OS), progression-free survival (PFS), and stent patency were analysed to evaluate the efficacy and safety of this treatment. The independent prognostic predictors of OS were also statistically analyzed by the cox regression model.

Results

No adverse events occurred in the enrolled patients receiving EVBT combined with TACE treatment. The objective response and disease control rates were 42.6% and 96.3% respectively within 4 weeks after the treatment. The median OS and PFS were 209 days and 138 days, respectively. Cumulative stent patency rate was 70.4% at the last follow-up. AFP ≥ 400 ng/ml, ECOG PS > 1, Child Pugh grade B, and non-hemihepatic HCC were independent risk predictors to evaluate the OS of HCC patient with type III or IV PVTT.

Conclusions

EVBT combined with TACE was a relatively effective and safe strategy to treat HCC patients with type III or IV PVTT.
Combining serum inflammation indexes at baseline and post treatment could predict pathological efficacy to anti‑PD‑1 combined with neoadjuvant chemotherapy in esophageal squamous cell carcinoma
Authors: Zhang Xinke , Gari A. , Li Mei , Chen Jierong , Qu Chunhua , Zhang Lihong , Chen Jiewei
Published: February 2022

Background

The neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) have been used to predict therapeutic response in different tumors. However, no assessments of their usefulness have been performed in esophageal squamous cell carcinoma (ESCC) patients receiving anti‑PD‑1 combined with neoadjuvant chemotherapy.

Methods

The respective data of 64 ESCC patients receiving anti‑PD‑1 combined with neoadjuvant chemotherapy were analyzed. Whether NLR, LMR, PLR, and SII at baseline and post-treatment might predict pathological response to anti‑PD‑1 plus neoadjuvant chemotherapy, and cutoff values of these parameters were all determined by ROC curve analysis.

Results

NLR (cutoff = 3.173, AUC = 0.644, 95% CI 0.500–0.788, P = 0.124, sensitivity = 1.000, specificity = 0.373), LMR (cutoff = 1.622, AUC = 0.631, 95% CI 0.477–0.784, P = 0.161, sensitivity = 0.917, specificity = 0.137), PLR (cutoff = 71.108, AUC = 0.712, 95% CI 0.575–0.849, P = 0.023, sensitivity = 1.000, specificity = 0.059), and SII at baseline (cutoff = 559.266, AUC = 0.681, 95% CI 0.533–0.830, P = 0.052, sensitivity = 0.373, specificity = 1.000) seemed to be a useful predictor for distinguishing responders from non-responders. Combining NLR with SII at baseline (AUC = 0.729, 95% CI 0.600–0.858, P = 0.014, sensitivity = 0.917, specificity = 0.510), LMR and SII at baseline (AUC = 0.735, 95% CI 0.609–0.861, P = 0.012, sensitivity = 1.000 specificity = 0.471), PLR and SII at baseline (AUC = 0.716, 95% CI 0.584–0.847, P = 0.021, sensitivity = 1.000 specificity = 0.431), and LMR and PLR at post-treatment in the third period (AUC = 0.761, 95% CI 0.605–0.917, P = 0.010, sensitivity = 0.800, specificity = 0.696) might slightly increase the prediction ability to determine patients who have response or no response. Finally, combining LMR at baseline, SII at post-treatment in the second period with PLR at post-treatment in the third period could be considered a better predictor for discriminating responders and non-responders than single or dual biomarkers (AUC = 0.879, 95% CI 0.788–0.969, P = 0.0001, sensitivity = 0.909, specificity = 0.800).

Conclusions

The models we constructed allowed for the accurate and efficient stratification of ESCC patients receiving anti-PD-1 plus chemotherapy and are easily applicable for clinical practice at no additional cost.