Role of Actionable Genes in Pursuing a True Approach of Precision Medicine in Monogenic Diabetes

Monogenic diabetes is a genetic disorder caused by one or more variations in a single gene. It encompasses a broad spectrum of heterogeneous conditions, including neonatal diabetes, maturity onset diabetes of the young (MODY) and syndromic diabetes, affecting 1–5% of patients with diabetes. Some of these variants are harbored by genes whose altered function can be tackled by specific actions (“actionable genes”). In suspected patients, molecular diagnosis allows the implementation of effective approaches of precision medicine so as to allow individual interventions aimed to prevent, mitigate or delay clinical outcomes. This review will almost exclusively concentrate on the clinical strategy that can be specifically pursued in carriers of mutations in “actionable genes”, including ABCC8, KCNJ11, GCK, HNF1A, HNF4A, HNF1B, PPARG, GATA4 and GATA6. For each of them we will provide a short background on what is known about gene function and dysfunction. Then, we will discuss how the identification of their mutations in individuals with this form of diabetes, can be used in daily clinical practice to implement specific monitoring and treatments. We hope this article will help clinical diabetologists carefully consider who of their patients deserves timely genetic testing for monogenic diabetes.

The impact of clinical and population strategies on coronary heart disease mortality: an assessment of Rose’s big idea

Background Coronary heart disease (CHD), the leading cause of death worldwide, has declined in many affluent countries but it continues to rise in industrializing countries. Objective To quantify the relative contribution of the clinical and population strategies to the decline in CHD mortality in affluent countries. Design Meta-analysis of cross-sectional and prospective studies. Data sources PubMed and Web of Science from January 1, 1970 to December 31, 2019. Method We combined and analyzed data from 22 cross-sectional and prospective studies, representing 500 million people, to quantify the relative decline in CHD mortality attributable to the clinical strategy and population strategy. Result The population strategy accounted for 48% (range = 19 to 73%) of the decline in CHD deaths and the clinical strategy accounted for 42% (range = 25 to 56%), with moderate inconsistency of results across studies. Conclusion Since 1970, a larger fraction of the decline in CHD deaths in industrialized countries was attributable to reduction in CHD risk factors than medical care. Population strategies, which are more cost-effective than clinical strategies, are under-utilized.

Clinical strategy of repeat biopsy in patients with atypical small acinar proliferation (ASAP)

Atypical small acinar proliferation (ASAP) occurs in approximately 5% of prostate biopsies. Approximately 30–40% of patients with ASAP have biopsy detectable prostate cancer (PCa) within 5 years. Current guidelines recommend a repeat biopsy within 3–6 months after the initial diagnosis. The aim of the present study was to examine the association between ASAP and subsequent diagnosis of clinically significant PCa (csPCa). The need for immediate repeat biopsy was also evaluated. We identified 212 patients with an ASAP diagnosis on their first biopsy at our institution between February 2006 and March 2018. Of these patients, 102 (48.1%) had at least one follow-up biopsy. Clinicopathologic features including rates of subsequent PCa and csPCa were assessed. Thirty-five patients subsequently underwent radical prostatectomy (RP). Their pathologic results were reviewed. csPCa was defined as the presence of Gleason score (GS) ≥ 3 + 4 in ≥ 1 biopsy core. Adverse pathology (AP) was defined as high-grade (primary Gleason pattern ≥ 4) or non-organ-confined disease (pT3/N1) after RP. Of 102 patients, 87 (85.3%), 13 (12.7%), and 2 (2.0%) had one, two, and three follow-up biopsies, respectively. Median time from the initial ASAP diagnosis to the 2nd follow-up biopsy and the last follow-up biopsy were 21.9 months (range 1–129 months) and 27.7 months (range 1–129 months), respectively. Of these patients, 46 (45.1%) were subsequently diagnosed with PCa, including 20 (19.6%) with csPCa. Only 2 (2.0%) patients had GS ≥ 8 disease. Five (4.9%) patients had number of positive cores > 3. Of 35 patients who subsequently underwent RP, seven (20%) had AP after RP and 17 (48.6%) showed GS upgrading. Of these 17 patients, the vast majority (16/17, 94.1%) had GS upgrading from 3 + 3 to 3 + 4. 45.1% of patients with an initial diagnosis of ASAP who had repeat prostate biopsy were subsequently diagnosed with PCa and 19.6% were found to have csPCa. Our findings add further evidence that after a diagnosis of ASAP, a repeat biopsy is warranted and that the repeat biopsy should not be postponed.

Implications of Gut Microbiota in Complex Human Diseases

Humans, throughout the life cycle, from birth to death, are accompanied by the presence of gut microbes. Environmental factors, lifestyle, age and other factors can affect the balance of intestinal microbiota and their impact on human health. A large amount of data show that dietary, prebiotics, antibiotics can regulate various diseases through gut microbes. In this review, we focus on the role of gut microbes in the development of metabolic, gastrointestinal, neurological, immune diseases and, cancer. We also discuss the interaction between gut microbes and the host with respect to their beneficial and harmful effects, including their metabolites, microbial enzymes, small molecules and inflammatory molecules. More specifically, we evaluate the potential ability of gut microbes to cure diseases through Fecal Microbial Transplantation (FMT), which is expected to become a new type of clinical strategy for the treatment of various diseases.

Pattern

Pattern is central in the pattern-focused case conceptualization approach. This chapter highlights the five basic treatment challenges for each of the eight common patterns in everyday clinical practice. It first defines pattern and provides a clinical strategy for quickly identifying and differentiating the basic patterns. Then, it describes eight patterns: avoidant, borderline, dependent, histrionic, narcissistic, obsessive–compulsive, paranoid, and passive–aggressive. Each of these patterns is discussed in the following format: pattern description, pattern development, pattern types and triggers, and treatment challenges. Clinicians who understand patterns and can identify them easily in clients are more likely to be able to explain and guide treatment, as well as anticipate treatment challenges.

Predictive usefulness of RT-PCR testing in different patterns of Covid-19 symptomatology: analysis of a French cohort of 12,810 outpatients

Reverse transcriptase polymerase chain reaction (RT-PCR) is a key tool to diagnose Covid-19. Yet it may not be the most efficient test in all patients. In this paper, we develop a clinical strategy for prescribing RT-PCR to patients based on data from COVIDOM, a French cohort of 54,000 patients with clinically suspected Covid-19, including 12,810 patients tested by RT-PCR. We use a machine-learning algorithm (decision tree) in order to predict RT-PCR results based on the clinical presentation. We show that symptoms alone are sufficient to predict RT-PCR outcome with a mean average precision of 86%. We identify combinations of symptoms that are predictive of RT-PCR positivity (90% for anosmia/ageusia) or negativity (only 30% of RT-PCR+ for a subgroup with cardiopulmonary symptoms): in both cases, RT-PCR provides little added diagnostic value. We propose a prescribing strategy based on clinical presentation that can improve the global efficiency of RT-PCR testing.

BMSC-derived Exosomes Protect Against Delayed Encephalopathy after Acute Carbon Monoxide Poisoning in Rats via Blockade of Notch Signaling

Objective: Our aim was to probe the therapeutic effect by which (BMSC-ex) protect against (DEACMP) in rat models in vivo. Methods: BMSC-ex were successfully characterized and proven to pass the blood brain barrier and migrate to the injured brain area. Rats were randomly divided into six groups and the cognitive function of mice was evaluated by the morris water maze. The severity of pathological changes was evaluated by HE staining and LFB staining. The expression of cytokines was detected by ELISA. Immunohistochemical staining and western blot analysis were utilized to detect the protein expression of Foxp3、CD4、MBP、Notch1 and Hess1 in brain tissue.Results: We found that BMSC-ex significantly reduced inflammation, increased the levels of (Tregs), relieved demyelination, and ameliorated the cognitive impairment in DEACMP rats. Furthermore, inhibiting the Notch pathway led to a partial reversal of the effect of BMSC-ex in mice.Conclusions: BMSC-ex relieved the severity of demyelination in the DEACMP rat models by regulating Tregs subsets and the expression of Notch signaling. Hence BMSC-ex play a protected role in DEACMP by upregulating Tregs and the regulatory components of Notch signaling and this may provide a new clinical strategy for the treatment of DEACMP patients.

The Role of the Smartphone in the Diagnosis of Vestibular Hypofunction: A Clinical Strategy for Teleconsultation during the COVID-19 Pandemic and Beyond

Introduction Vestibular disorders (VDs) are highly prevalent in primary care. Although in general they comprise conditions that are not life-threatening, they are associated with significant functional and physical disability. However, the current coronavirus disease 2019 (COVID-19) pandemic has imposed limitations on the standard treatment of benign conditions, including VDs. In this context, other resources may aid in the diagnosis and management of patients with VDs. It is well known that teleconsultation and teletreatment are both safe and effective alternatives to manage a variety of conditions, and we maintain that VDs should be among these. Objective To develop a preliminary model of clinical guidelines for the evaluation by teleconsultation of patients with suspected diagnosis of vestibular hypofunction during the COVID-19 pandemic and beyond. Methods A bibliographic review of the diagnostic feasibility in VDs by teleconsultation was carried out in the LILACS, SciELO, MEDLINE, and PubMed databases; books and specialized websites were also consulted. The legal, regulatory, and technical issues involving digital consultations were reviewed. Results We found 6 field studies published between 1990 and 2020 in which the efficiency of teleconsultations was observed in the contexts of epidemics and environmental disorders and disadvantageous geographical conditions. After reviewing them, we proposed a strategy to examine and address vestibular complaints related to vestibular hypofunction. Conclusion The creation of a digital vestibular management algorithm for the identification, counseling, initial intervention, monitoring and targeting of people with possible vestibular hypofunction seems to be feasible, and it will provide a reasonable alternative to in-person evaluations during the COVID-19 pandemic and beyond.