Current Clinical Problems Research Articles

Metallo-β-lactamase-mediated antimicrobial resistance and progress in inhibitor discovery.

Resistance to β-lactam antibiotics is rapidly growing, substantially due to the spread of serine-β-lactamases (SBLs) and metallo-β-lactamases (MBLs), which efficiently catalyse β-lactam hydrolysis. Combinations of a β-lactam antibiotic with an SBL inhibitor have been clinically successful; however, no MBL inhibitors have been developed for clinical use. MBLs are a worrying resistance vector because they catalyse hydrolysis of all β-lactam antibiotic classes, except the monobactams, and they are being disseminated across many bacterial species worldwide. Here we review the classification, structures, substrate profiles, and inhibition mechanisms of MBLs, highlighting current clinical problems due to MBL-mediated resistance and progress in understanding and combating MBL-mediated resistance.

Current clinical problems associated with hymenal atresia

Current clinical problems associated with hymenal atresia

A descriptive study of Parkinson disease and atypical parkinsonisms in the Annuals of the Pathological Autopsy Cases in Japan.

Although many entities have been established within the broad spectrum of Parkinson disease (PD) and atypical parkinsonisms, they are often difficult to differentiate. To clarify the current clinical diagnostic conditions and problems in PD and atypical parkinsonisms, we analyzed volumes of the Annuals of the Pathological Autopsy Cases in Japan. Among 130 105 autopsies conducted from 2007 to 2016 throughout Japan, patients were included in the study if they had been either clinically or pathologically diagnosed with PD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal degeneration (CBD). Autopsy rates were 6.4% for clinically diagnosed PD, 34.1% for MSA, 16.3% for PSP, and 17.4% for CBD. The specificities and sensitivities of clinical diagnoses were 88.0% and 82.0% for PD, 95.2% and 86.0% for MSA, 82.7% and 73.2% for PSP, and 55.4% and 57.7% for CBD, respectively. Clinical diagnoses had relatively high accuracy, but low autopsy rates are of concern. Many patients with rarer disorders were clinically misdiagnosed with PD, a more common disorder. Autopsy rates, irrespective of specific disorders, should be increased to detect rare diseases. Increasing autopsy rates will increase the available clinical information regarding pathologically confirmed patients and contribute to more accurate clinical diagnoses.

Abstracts of the 45th National Congress of the Italian Association for the Study of Pain

The National Congress of the Italian Association for the Study of Pain (AISD) has represented for more than 40 years a significant moment of multidisciplinary scientific debate to which experts and professionals engaged in research and clinical practice contribute. Due to the pandemic, the 2020 and 2021 Congresses took place in virtual mode, still enjoying great participation success, also thanks to the scientific contents, with constant reference to the most frequent and current clinical problems that are faced in daily practice. For the 2022 edition of the National Congress, the AISD Board of Directors has decided to take a step towards normality proposing a hybrid event, accessible both onsite (Naples, 22–24 September) and online (www.congressoaisd.it). The main themes of the scientific program and of the poster and communication session concern acute and chronic pain, osteoarthritis and postoperative pain, pharmacotherapy of chronic low back pain and minimally invasive spine surgery, pain and neuroinflammation, autoimmune and neurodegenerative diseases, controversies and challenges in fibromyalgia, gender differences in headache and neuropathic pain, pain in the general practitioner’s office, palliative care, oncologic pain, pain and guidelines etc., just to mention some of the main themes discussed, respecting, as it was always done, research and assistance criteria, in the context of the multidisciplinary characteristic of our scientific society. The Italian Association for the Study of Pain is the Italian Chapter of the IASP®, International Association for the Study of Pain and of the European Pain Federation, EFIC®. It has been active since 1976. More information are available on the website www.aisd.it.

Dielectric Elastomer Actuators, Neuromuscular Interfaces, and Foreign Body Response in Artificial Neuromuscular Prostheses: A Review of the Literature for an In Vivo Application.

The inability to replace human muscle in surgical practice is a significant challenge. An artificial muscle controlled by the nervous system is considered a potential solution for this. Here, this is defined as a neuromuscular prosthesis. Muscle loss and dysfunction related to musculoskeletal oncological impairments, neuromuscular diseases, trauma or spinal cord injuries can be treated through artificial muscle implantation. At present, the use of dielectric elastomer actuators working as capacitors appears a promising option. Acrylic or silicone elastomers with carbon nanotubes functioning as the electrode achieve mechanical performances similar to human muscle in vitro. However, mechanical, electrical, and biological issues have prevented clinical application to date. Here materials and mechatronic solutions are presented which can tackle current clinical problems associated with implanting an artificial muscle controlled by the nervous system. Progress depends on the improvement of the actuation properties of the elastomer, seamless or wireless integration between the nervous system and the artificial muscle, and on reducing the foreign body response. It is believed that by combining the mechanical, electrical, and biological solutions proposed here, an artificial neuromuscular prosthesis may be a reality in surgical practice in the near future.

Consensus of Chinese experts on clinical detection of molecular markers of colorectal cancer

Colorectal cancer is one of the malignant tumors with the highest morbidity and mortality in China. With the research of precision medicine concept and tumor-related molecular markers, appropriate detection and application of colorectal cancer-related molecular markers has become an important part of current clinical practice. In order to effectively solve the current clinical problems and improve clinicians' understanding and application of molecular markers on colorectal cancer, the Chinese Society of Clinical Oncology(CSCO) Colorectal Cancer Expert Committee organized experts in related fields to write an expert consensus on molecular markers of colorectal cancer based on recent domestic and international clinical trial and clinical experience. The consensus mainly provides guidance on testing specimens, molecular markers and testing methods, and interpretation of testing results. It aims to provide clinicians with standardized clinical reference for diagnosis and treatment, and standard and effective treatment for patients with colorectal cancer.

Reality of Gastric Cancer in Young Patients: The Importance and Difficulty of the Early Diagnosis, Prevention and Treatment.

Gastric cancer usually arises in middle-aged to older patients, and is rarely found in younger patients. The clin-ical characteristics, etiology, prognosis, preventive methods and treatment of gastric cancer in young patients have not been fully investigated because of its low prevalence. In this review, we discuss the current under-standing and clinical problems associated with gastric cancer in young patients. Helicobacter pylori (H. pylori), which is a major cause of gastric cancer, especially in older populations, is closely associated with gastric cancer in young patients as well as in older patients. Gastric cancer in young patients tends to be diagnosed at an advanced stage with alarm symptoms. However, young patients with advanced gastric cancer tend to have a favorable general condition and organ function, so they can tolerate intensive systematic chemotherapy. Unfortunately, the prognosis of gastric cancer in young patients with an advanced stage is not favorable. We should not take this rare disease lightly, given its poor prognosis if patients are diagnosed at an unresectable stage. The evaluation of the H. pylori infection status and performance of H. pylori eradication therapy to prevent gastric cancer in young patients as well as the development of more intensive chemotherapy regimens for unre-sectable gastric cancer in young patients are warranted.

Surface Modification by Nanobiomaterials for Vascular Tissue Engineering Applications.

Treatment of cardiovascular disease has achieved great success using artificial implants, particularly synthetic-polymer made grafts. However, thrombus formation and restenosis are the current clinical problems need to be conquered. New biomaterials, modifying the surface of synthetic vascular grafts, have been created to improve long-term patency for the better hemocompatibility. The vascular biomaterials can be fabricated from synthetic or natural polymers for vascular tissue engineering. Stem cells can be seeded by different techniques into tissue-engineered vascular grafts in vitro and implanted in vivo to repair the vascular tissues. To overcome the thrombogenesis and promote the endothelialization effect, vascular biomaterials employing nanotopography are more bio-mimic to the native tissue made and have been engineered by various approaches such as prepared as a simple surface coating on the vascular biomaterials. It has now become an important and interesting field to find novel approaches to better endothelization of vascular biomaterials. In this article, we focus to review the techniques with better potential improving endothelization and summarize for vascular biomaterial application. This review article will enable the development of biomaterials with a high degree of originality, innovative research on novel techniques for surface fabrication for vascular biomaterials application.

FIRST LINE FAMILY THERAPY THROUGHOUT THE WORLD AND IN INDIA

The aim of family counseling is to regulate the emotional health of family members, to improve relationships and interactions with each other and to provide family functionalities in the functions of families. Family practice is a branch of expertise that provides continuous and multi-faceted health services to families and individuals who are responsible, and intertwined with clinical and behavioral sciences, including all age groups, both sexes, all systems and diseases. All of the primary care physicians should be able to evaluate individuals with current clinical problems and diagnosed chronic diseases, analyze with their roles within the family, provide counseling to families by examining existing psychological needs, and demonstrate a co-operative approach with family therapists when necessary.

How computer simulations of the human heart can improve anti‐arrhythmia therapy

Over the last decade, the state-of-the-art in cardiac computational modelling has progressed rapidly. The electrophysiological function of the heart can now be simulated with a high degree of detail and accuracy, opening the doors for simulation-guided approaches to anti-arrhythmic drug development and patient-specific therapeutic interventions. In this review, we outline the basic methodology for cardiac modelling, which has been developed and validated over decades of research. In addition, we present several recent examples of how computational models of the human heart have been used to address current clinical problems in cardiac electrophysiology. We will explore the use of simulations to improve anti-arrhythmic pacing and defibrillation interventions; to predict optimal sites for clinical ablation procedures; and to aid in the understanding and selection of arrhythmia risk markers. Together, these studies illustrate how the tremendous advances in cardiac modelling are poised to revolutionize medical treatment and prevention of arrhythmia.

The Impending Epidemic of Chronic Cardiopulmonary Disease and Multimorbidity: The Need for New Research Approaches to Guide Daily Practice

Mortality caused by acute cardiopulmonary disease is decreasing, and in many countries the population is aging rapidly. Yet, the life-years gained are often spent with multiple chronic and slowly progressive conditions, and this particularly applies to patients with cardiopulmonary disease. Affected individuals often have multiple diagnoses related to the cardiopulmonary-metabolic axis with accelerated aging and gradually progressive failure of organs that provide the body with oxygen and nutrients. This more or less reflects an "engine running out of fuel." This, for instance, is the case with the concurrent presence of COPD and heart failure in one patient that is often combined with other comorbidities such as atrial fibrillation, renal failure, or diabetes. This asks for a paradigm shift: away from single-disease-oriented patient management and toward patient-tailored multimorbidity medicine. Daily clinical practice is already recognizing this on a daily basis, yet clinical research and guidelines are still lagging behind. Thus, novel research approaches are needed to better guide evidence-based clinical practice. These approaches include the construction of diagnostic models to predict the presence of multiple diseases simultaneously, individual patient data meta-analysis as a method to examine variation in the effects of treatments or diagnostic tests depending on comorbidity, and the construction of therapeutic prediction models that predict the therapeutic effect of drugs based on the presence (or absence) of relevant comorbidity. We argue that multimorbidity should be regarded as a "friend" and not as a "foe" in clinical research addressing the current clinical problems in daily practice.

Surgery for thoracic aortic disease in Japan: evolving strategies toward the growing enemies.

Recent advances in surgery for thoracic aorta have been described, including data by the annual survey of the Japanese Association for Thoracic Surgery. Current clinical problems in aortic root surgery, brain protection during aortic arch surgery, spinal cord protection during thoracoabdominal aortic surgery, acute aortic dissection and endovascular stenting have been discussed.

The role of mTOR inhibitors in the prevention of organ rejection in adult liver transplant patients: a focus on everolimus

Liver transplantation remains the therapy of choice for patients with end-stage liver disease and in selected cases of hepatocellular carcinoma. While short-term allograft survival has improved significantly in recent years, there has been little improvement in long-term survival after liver transplantation. A growing body of evidence on factors influencing the long-term outcomes and the safety profiles of existing immunosuppressive agents after liver transplant points to a need to continue searching for alternative strategies. The calcineurin inhibitors (CNIs) (cyclosporine and tacrolimus) currently represent the backbone of most immunosuppressor regimens. They have had a revolutionary effect on the overall success of transplantation, as is reflected in greatly reduced rates of acute rejection. However, the CNIs have significant toxici - ties that produce renal dysfunction, cardiovascular disease, and other unwanted effects, such as malignancies. The recognition of these risk factors has sparked interest in regimens that limit exposure to CNIs. Nowadays, the use of immunosuppressive drugs with different mechanisms of action, which allow for a reduction or avoidance of CNIs, is common. Everolimus, which belongs to the mammalian target-of-rapamycin inhibitor family and is best known for its use in kidney and heart transplantation, has recently been approved for liver transplantation. This overview discusses the emerging evidence on the role of everolimus in the prevention of rejection after liver transplantation, in de novo transplants, conversion regimens, or as a rescue therapy. In addition, some of the most relevant and current clinical problems related to everolimus in this field are discussed.

Tumor Heterogeneity Revealed byKRAS,BRAF, andPIK3CAPyrosequencing:KRASandPIK3CAIntratumor Mutation Profile Differences and Their Therapeutic Implications

Current clinical problems in colorectal cancer (CRC) diagnostics and therapeutics include the disease complexity, tumor heterogeneity, and resistance to targeted therapeutics. In the present study, we examined 171 CRC adenocarcinomas from Greek patients undergoing surgery for CRC to determine the frequency of KRAS, BRAF, and PIK3CA point mutations from different areas of tumors in heterogeneous specimens. Ninety two out of 171 (53.8%) patients were found to bear a KRAS mutation in codons 12/13. Of the 126 mutations found, 57.9% (73/126) were c.38G>A mutations (p.G13D) and 22.2% (28/126) were c.35G>T (p.G12V). Remarkably, RAS mutations in both codons 12 and 13 were recorded in the same tumor by pyrosequencing. Moreover, differences in KRAS mutations between tumor center and periphery revealed tumor heterogeneity in 50.7% of the specimens. BRAF c.1799T>A (V600E) mutations were moderately detected in 4/171 (2.3%) specimens, whereas most PIK3CA mutations were revealed by pyrosequencing 6/171 (3.5%). Remarkable tumor heterogeneity is revealed, where double mutations of KRAS in the same tumor and different KRAS mutation status between tumor core and margin are detected with high frequency. It is expected that these findings will have a major impact in cancer diagnosis and personalized therapies.

糖尿病性腎症診療の課題とその成因に基づく解析

糖尿病性腎症診療の課題とその成因に基づく解析

P.18.4 Physical activity profile and barriers to physical activity in individuals with myotonic dystrophy

Individuals with myotonic dystrophy (DM) type 1 are less active than healthy individuals, which may result in secondary complications and decreased functional abilities. Therefore, the purpose of this study was to document the physical activity profile and barriers to physical activity in persons with DM. Individuals with DM were recruited during the Empower 2011 patient and family conference sponsored by the Myotonic Dystrophy Foundation. Participants were asked to complete a survey that included a Demographic/Clinical profile, the Barriers to Physical Activity and Disability Survey and the International Physical Activity Questionnaire. Physical activity in terms of number of days and time (in 10 min increments) over the past 7 days was reported. A multiple regression model including age, number of current clinical problems, and the number of barriers reported was used to predict the amount of sedentary time (sitting time). 107 (53% male) participants with DM (65% DM1) reported finger and hand weakness, fatigue, day time sleepiness, gastrointestinal issues, and leg weakness as the most common clinical problems. Participation in at least 1 day of activity was reported by 15% of the participants for gardening, 69% for household activities, 42% for leisure time walking, and 22% for moderate intensity level leisure time activities. Lack of energy and motivation were the most common barriers to physical activity reported. Number of barriers was a significant predictor of the amount of time spent sitting. Persons with DM have decreased physical activity and spend a significant time sedentary and are limited by a lack of energy and motivation. Administration of this survey at the conference may have influenced the report of physical activity as it may have been modified due to travel and conference participation. Further investigation is needed to better understand additional factors that contribute to inactivity.

A reflective practice intervention for professional development, reduced stress and improved patient care—A qualitative developmental evaluation

ObjectiveProfessional capabilities, such as empathy and patient-centeredness, decline during medical education. Reflective practice is advocated for teaching these capabilities. The Clinical Reflection Training (CRT) is a reflective practice intervention using the professional dilemmas faced by medical students during clinical practice. The aim of this study was to evaluate students’ perceptions of the helpfulness of the CRT and its effects on their medical education. MethodsEighteen semi-structured interviews were conducted with medical students who had participated in the CRT. Content analysis was used to analyze the interview data. ResultsMedical students did not feel adequately prepared to manage the difficult personal and interpersonal problems frequently encountered in clinical practice. They reported that the CRT reduces stress, improves patient care and serves as a tool for professional development. ConclusionThe CRT may be a useful tool for developing professionalism during medical education, reducing stress and enhancing the quality of patient care. Practice implicationsProviding students with reflective practice training that draws on their current personal clinical problems in order to improve their clinical work may be a productive investment in personal professional development, physician health, and quality improvement.

Health-related quality of life and its determinants in children with a congenital diaphragmatic hernia

BackgroundThe development of new therapeutics has led to progress in the early management of congenital diaphragmatic hernia (CDH) in pediatric intensive care units (PICU). Little is known about the impact on the quality of life (QoL) of children and their family. The aim of this study was to assess the impact of CDH treated according to the most recent concepts and methods outlined above on child survivors’ QoL and their parents’ QoL.Patients and methodsThis study incorporated a cross-sectional design performed in two PICU (Marseille, France). Families of CDH survivors born between 1999 and 2008 were eligible. The following data were recorded: socio-demographics, antenatal history and delivery, initial hospitalization history. Self-reported data were collected by mail, including current clinical problems of the children (13-symptom list), children’s QoL (Kidscreen-27 questionnaire), and parents’ QoL (Short-Form 36 questionnaire). Children’s QoL score was compared with controls and QoL of survivors of childhood leukemia. Parent’s QoL was compared with controls. Non-parametric statistics were employed.ResultsForty-two families agreed to participate and questionnaires were completed by 32 of them. Twenty-one children had a current clinical problems related to CDH. All the QoL scores of CHD survivors were significantly lower compared with controls. The physical well-being dimension was significantly higher for CHD survivors compared with survivors of childhood leukemia. Gastro-esophageal reflux at discharge, antenatal diagnosis, length of stay in the PICU, and neuropsychological and respiratory issues significantly impacted QoL scores of children. The parents of CHD survivors had significantly poorer score in emotional role dimension compared with controls.ConclusionThe impact of CDH on QoL seems to be important and must be understood by clinicians who treat these children and their parents.

Abstract CN04-03: Development of NSAID eflornithine combinations for treating cancer risk factors

Abstract Nonsteroidal anti-inflammatory drugs (NSAIDS) have been found to be potent inhibitors of carcinogenesis in both preclinical models and in randomized controlled prospective clinical trials in humans. NSAIDS exert their anti-carcinogenic effects by inhibiting cyclooxygenases (COXs) involved in arachidonic acid metabolism and by COX-independent mechanisms. Empirical data indicates eflornithine (difluoromethylornithine or DFMO), an enzyme-activated inhibitor of ornithine decarboxylase (ODC) (Meyskens and Gerner, 1999), is one of the most potent agents known acting in combination with NSAIDS to inhibit carcinogenesis in rodent models (Steele and Lubet, 2010). At least part of the rationale for combining NSAIDS with eflornithine for inhibition of carcinogenesis is that eflornithine inhibits the activity of ODC, the first enzyme in polyamine synthesis, while NSAIDS activate the spermidine/spermine acetyltransferase (SAT1), which targets polyamines for export by specific solute carrier transporters (Gerner and Meyskens, 2009). Thus, NSAIDS and eflornithine both reduce tissue levels of the growth-associated polyamines, but by complementary mechanisms. A clinical trial of the combination of eflornithine and the NSAID sulindac showed dramatic treatment-associated reductions of metachronous colorectal adenomas in patients with prior sporadic colorectal polyps (Meyskens et al., 2008). Several clinical trials in progress or soon to commence will further test the hypothesis that NSAID eflornithine combinations can successfully treat cancer risk factors in patients with specific cancers, or risk of cancer. One group of clinical trials involves patients with neuroblastoma (NB). Patients with poor prognosis NB often have tumors in which MYCN is overexpressed. Preclinical data indicates that MYCN as well as c-MYC drive expression of ODC and other genes in the polyamine pathway, and that inhibiting this pathway with eflornithine suppressed carcinogenesis in mouse models of NB (Hogarty et al., 2008). Likewise, COX-2 is expressed in NB tumors and cell lines, and COX-2 inhibitors such as celecoxib can suppress the growth of NB xenografts (Ponthan et al., 2007). The Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) and the New Approaches to Neuroblastoma Therapy (NANT) group are conducting clinical trials to evaluate the safety and efficacy of eflornithine alone or in combination with NSAIDS and other agents in patients with high risk NB. The NMTRC is conducting an especially novel prevention trial of eflornithine in patients with high risk NB in remission (NCT01586260). Eflornithine NSAID combinations are also being evaluated in other MYC-associated diseases. Familial adenomatous polyposis (FAP) is a genetic syndrome associated with increased risk of colon cancer and other neoplasia and is caused by mutation/deletions in the adenomatous polyposis coli (APC) tumor suppressor gene. MYC mediates intestinal tumorigenesis (Ignatenko et al., 2006) and combinations of eflornithine and NSAIDS are potent inhibitors of intestinal carcinogenesis (Ignatenko et al., 2008) in murine models of FAP. Notable is the change in clinical management of FAP patients over the past two decades. FAP is now managed primarily by surgery, with duodenal polyposis and desmoid disease constituting two current significant clinical problems. An international consortium will be evaluating the combination of eflornithine and sulindac in adult patients with FAP, using time to FAP-related events as the primary outcome (NCT01483144). This same combination will be evaluated in patients with prior sporadic colon cancer in a study to be conducted by a national cooperative group (S0820, Adenoma and second primary prevention trial, NCT01349881) (Rial et al., 2012). These and other trials have been designed to include assessment of a range of biological correlates, including genetic (Zell et al., 2010), tissue (Thompson et al., 2010) and urinary markers (Hiramatsu et al., 2005) of disease prognosis and prediction of treatment responses, including therapy-associated toxicities. Citation Format: Eugene W. Gerner. Development of NSAID eflornithine combinations for treating cancer risk factors. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN04-03.

A conceptual framework for interprofessional shared decision making in home care: protocol for a feasibility study.

BackgroundShared decision making (SDM) is fundamental to informed consent and client-centered care. So far, SDM frameworks have been limited to the client-physician dyad, even though care is increasingly delivered by interprofessional (IP) teams. IP collaboration is especially essential in home care, one of health care's most rapidly growing areas. This study will assess whether it is possible to practice SDM in IP home care.Methods/DesignWe will use a qualitative case study and a quantitative survey to capture the macro, meso and micro levels of stakeholders in home care. The case study will follow the knowledge-to-action process framework to evaluate the work of an IP home care team at a Quebec City health center. Sources of data will include one-on-one interviews with patients, family caregivers or surrogates and significant others, and administrators; a focus group of home care health professionals; organizational documents; and government policies and standards. The interview guide for the interviews and the focus group will explore current practices and clinical problems addressed in home care; factors that could influence the implementation of the proposed IP approach to SDM; the face and content validity of the approach; and interventions to facilitate the implementation and evaluation of the approach. The survey will ask 300 health professionals working in home care at the health center to complete a questionnaire based on the Theory of Planned Behaviour that measures their intentions to engage in an IP approach to SDM. We will use our analysis of the individual interviews, the focus group and the survey to elaborate a toolkit for implementing an IP approach to SDM in home care. Finally, we will conduct a pilot study in Alberta to assess the transferability of our findings.DiscussionWe believe that developing tools to implement IP SDM in home care is essential to strengthening Canada's healthcare system and furthering patient-centered care. This study will contribute to the evaluation of IP SDM delivery models in home care. It will also generate practical, policy-oriented knowledge regarding the barriers and facilitators likely to influence the practice of IP SDM in home care.