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Hepatitis C virus (HCV) causes a systemic infection inducing hepatic and extrahepatic diseases. These latter involve cardiovascular system, kidney, brain, endocrine, glucose, and lipid metabolism, and the immune system. HCV infection is associated with an increased risk of morbidity and mortality for both hepatic and extrahepatic events. Direct-acting antivirals (DAA), introduced in the most recent years for HCV treatment, are effective in up to 99% of cases and have changed the clinical scenarios and management of these patients.The literature on the impact of HCV clearance by DAA on both hepatic and extrahepatic disease outcomes has been analyzed and discussed in this review in order to summarize the full therapeutic potential and its weaknesses.Patients achieving HCV clearance have improved hepatic and extrahepatic diseases, quality of life and survival. They have lower incidence of cardiovascular disease, type 2 diabetes, kidney damage, and immuno-mediated manifestations. However, the improvements are related to the degree of pre-treatment organ damage. Therefore, a significant percentage of patients with advanced disease remains at risk of morbidity and mortality and must be monitored in the post-treatment. In addition, data emphasize the importance of starting treatment during the early stages of HCV infection.

Although rape has been linked to risk for suicidal ideation and attempts, there are scant data on the efficacy of brief interventions to reduce suicidality among recent rape victims. This secondary analysis of a randomized controlled trial investigated whether a video intervention delivered in the emergency department (ED), cortisol measured at the ED, and prior rape history predicted postrape suicidal ideation independently or in combination with the other predictors. Participants were 235 women aged 15-71 years who presented to the ED for a sexual assault medical forensic examination and were randomly assigned to either receive a video intervention that addressed avoidance and promoted healthy coping strategies or standard care prior to the examination. Participants also provided a blood sample for cortisol and completed at least one of three follow-ups at 6 weeks, 3 months, or 6 months postrape. The intervention conferred protection against suicidal ideation among women with elevated cortisol and a prior rape; however, it did not reduce risk for women without a prior rape, particularly those with elevated cortisol. It may be important to consider the influence of prior rape and neuroendocrine reactivity in developing treatments to address suicidal ideation among rape victims. More specifically, there appears to be value in screening victims for prior rape and administering this brief intervention to reduce suicidal ideation; however, other avenues should be explored for victims without a prior rape history. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Highlights • The impact of the COVID-19 pandemic may be especially potent for individuals with PTSD. • PE is a well-established and efficacious treatment for PTSD. • Clinical practice strategies aid in implementation of PE during the COVID-19 pandemic., The unprecedented effects and duration of the COVID-19 crisis are likely to elevate the population’s level of anxiety due to psychological stress, economic hardship, and social isolation. This effect may be especially potent for individuals with preexisting mental health conditions, such as posttraumatic stress disorder (PTSD). Prolonged Exposure (PE) therapy is a highly effective treatment for PTSD across trauma-exposed populations, and has been implemented effectively via telehealth. Nevertheless, PE implementation via telehealth may require specific adaptations during the COVID-19 crisis due to public health mandates calling for sheltering in place and physical distancing. This paper discusses strategies for implementing PE for PTSD during the COVID-19 pandemic, which may also be applied to other situations in which physical distancing must be considered.

Background and aims Diabetic retinopathy (DR) is the most common microvascular complication of diabetes. Diabetic macroangiopathies, particularly cardiovascular (CV) diseases, seem closely related to diabetes microvascular complications. Aspirin represents the most prescribed compound in CV prevention. Aspirin impact on DR is still object of debate. As it is already recommended among diabetics at high CV risk, aim of this study was to assess a potential relationship between DR and aspirin therapy, in a type 2 diabetes cohort of patients screened through telemedicine. Methods and results NO Blind is a cross-sectional, multicenter, observational study, which involved nine Italian outpatient clinics. Primary endpoint was the assessment of the relationship between aspirin treatment and DR. 2068 patients were enrolled in the study, subsequently split in two subpopulations according to either the presence or absence of DR. Overall, 995 subjects were under aspirin therapy. After adjusting for most common potential confounders, age and gender, aspirin reveals significantly associated with DR (OR: 1.72, 95%CI: 1.58–2.89, p = 0.002) and proliferative DR (PDR) (OR: 1.89, 95%CI: 1.24–2.84, p = 0.003). Association comes lost further adjusting for MACEs (OR: 1.28, 95%CI: 0.85–1.42, p = 0.157) (Model 4) and eGFR (OR: 0.93; 95%CI: 0.71–1.22; p = 0.591) (Model 5). Conclusion In this multicenter cross-sectional study including a large sample of outpatients with T2DM, we showed that aspirin was not associated with DR after adjustment for several cardio-metabolic confounders. However, as partially confirmed by our findings, and related to the well-known pro-hemorrhagic effect of aspirin, its use should be individually tailored, even by telemedicine tools.

Auoxo3 is a gold(iii) compound endowed with cytotoxic activity towards a variety of malignant cells. Encapsulation of Auoxo3 within horse spleen ferritin (Ft) improves the selectivity of the gold compound towards cancer cells over normal cells. In the current work, the changes in protein expression are presented in response to MCF-7 stimulation with Auoxo3-encapsulated Ft versus the free Au(iii) compound by a label-free proteomics approach. A 159-protein dataset showed significant changes between the stimulations with Auoxo3 and Auoxo3-encapsulated Ft, suggesting that this cellular perturbation caused the alteration of different cellular processes. In detail, roughly 30% of proteins were downregulated mainly in the spliceosome complex (U2AF1, SF3B2, PRPF4, SNSRP200, EFTUD2, PRPF6, and PRPF8) in agreement with the cytostatic effect observed during cellular growth. Another 30% of proteins were upregulated primarily in glutathione biosynthesis, suggesting an alteration of the redox potential, as validated by Western blot analyses. To the best of our knowledge, this work represents the first large scale proteomics study on the effects of a gold-based drug encapsulated within the Ft nanocage on cancer cells.

The onset of the COVID‐19 pandemic disrupted many aspects of daily life and required a rapid and unprecedented shift in psychotherapy delivery from in‐person to telemental health. In the present study, we explored the impact of the pandemic on individuals’ ability to participate in posttraumatic stress disorder (PTSD) psychotherapy and the association between the impact of COVID‐19 impact on health and financial well‐being and psychotherapy participation. Participants (N = 161, 63.2% male, M age = 42.7 years) were United States military veterans (n = 108), active duty military personnel (n = 12), and civilians (n = 6), who were participating in one of nine PTSD treatment trials. The results indicate a predominately negative COVID‐19 impact on therapy participation, although some participants (26.1%) found attending therapy sessions through telehealth to be easier than in‐person therapy. Most participants (66.7%) reported that completing in vivo exposure homework became harder during the pandemic. Moreover, the impact of the pandemic on PTSD symptom severity and daily stress were each associated with increased difficulty with aspects of therapy participation. The findings highlight the unique challenges to engaging in PTSD treatment during the pandemic as well as a negative impact on daily stress and PTSD severity, both of which were related to treatment engagement difficulties.

Patients with inflammatory bowel disease have an increased risk of thromboembolic complications, especially during the active phase of the disease. Cerebral thromboembolism is a rare extra-intestinal complication, associated with high risk of morbidity and mortality. Due to the nonspecific clinical presentation and low incidence, a cerebral thromboembolic event may be undiagnosed. For this reason neurological symptoms, such as headache, should not be underestimated in inflammatory bowel disease patients. The paper describes a case of a three-year-old girl with ulcerative colitis complicated by cerebral thrombosis.

The current study explored whether prolonged exposure (PE), delivered in person or via home-based telehealth, had a therapeutic effect on psychosocial functioning in combat Veterans with posttraumatic stress disorder (PTSD). The effects of home-based telehealth on these metrics were also evaluated. In addition, we examined whether race, type of war conflict, and service-connected disability rating moderated the effect of PE on psychosocial functioning and whether PTSD, anxiety, and/or depression mediated the effect of PE on psychosocial functioning. We did not find moderating or mediating effects in our study. Improvements in PTSD, depression, and anxiety were associated with improvements in psychosocial functioning. We did not identify statistically significant differences in scores representing change in overall and each domain of psychosocial functioning between groups. Within-group analysis indicated psychosocial functioning improved in both groups but was mostly not statistically significant. However, some clinically relevant improvement may have occurred. [ Journal of Psychosocial Nursing and Mental Health Services, 59 (2), 31–40.]

Water reabsorption along the collecting duct is dependent on the function of aquaporin 2 (AQP2). Currently, information on microRNA (miRNA)-mediated, post-transcriptional regulation of AQP2, which may influence water reabsorption, is limited. In mice, ablation of the Dicer enzyme (crucial for miRNA maturation) in AQP2-expressing cells induces nephrogenic diabetes insipidus (NDI) with dysregulation of the miRNA profile. A major finding is the identification of miRNAs associated with NDI through mediating epigenetic control of AQP2. This study offers novel targets for AQP2 regulation and potential treatment for governing renal water reabsorption.Background MicroRNAs (miRNAs), formed by cleavage of pre-microRNA by the endoribonuclease Dicer, are critical modulators of cell function by post-transcriptionally regulating gene expression.Methods Selective ablation of Dicer in AQP2-expressing cells (DicerAQP2Cre+ mice) was used to investigate the role of miRNAs in the kidney collecting duct of mice.Results The mice had severe polyuria and nephrogenic diabetes insipidus, potentially due to greatly reduced AQP2 and AQP4 levels. Although epithelial sodium channel levels were decreased in cortex and increased in inner medulla, amiloride-sensitive sodium reabsorption was equivalent in DicerAQP2Cre+ mice and controls. Small-RNA sequencing and proteomic analysis revealed 31 and 178 significantly regulated miRNAs and proteins, respectively. Integrated bioinformatic analysis of the miRNAome and proteome suggested alterations in the epigenetic machinery and various transcription factors regulating AQP2 expression in DicerAQP2Cre+ mice. The expression profile and function of three miRNAs (miR-7688-5p, miR-8114, and miR-409-3p) whose predicted targets were involved in epigenetic control (Phf2, Kdm5c, and Kdm4a) or transcriptional regulation (GATA3, GATA2, and ELF3) of AQP2 were validated. Luciferase assays could not demonstrate direct interaction of AQP2 or the three potential transcription factors with miR-7688-5p, miR-8114, and miR-409textendash3p. However, transfection of respective miRNA mimics reduced AQP2 expression. Chromatin immunoprecipitation assays demonstrated decreased Phf2 and significantly increased Kdm5c interactions at the Aqp2 gene promoter in DicerAQP2Cre+ mice, resulting in decreased RNA Pol II association.Conclusions Novel evidence indicates miRNA-mediated epigenetic regulation of AQP2 expression.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely associated, and liver fibrosis has been related to macrovascular complications. We examined whether liver fibrosis, diagnosed by FibroScan® , correlates with chronic vascular complications in a cohort of T2DM. METHODS: We recruited 394 outpatients with T2DM attending five Italian diabetes centres who underwent liver ultrasonography (US), FibroScan® and extensive evaluation of macrovascular and microvascular diabetic complications. RESULTS: Steatosis by US was present in 89%. Almost all patients (96%) were on hypoglycaemic drugs, 58% had at least one chronic vascular complication, 19% a macrovascular complication (prior myocardial infarction and/or ischaemic stroke) and 33% a microvascular one (26% chronic kidney disease [CKD]; 16% retinopathy; 6% neuropathy). In all, 171 (72%) patients had CAP ≥ 248dB/m (ie hepatic steatosis), whereas 83 (21%) patients had LSM ≥ 7.0/6.2 kPa (M/XL probes) (significant liver fibrosis). CAP was not associated with any macro/microvascular complications, whereas LSM ≥ 7.0/6.2 kPa was independently associated with prior cardiovascular disease (adjusted OR 3.3, 95%CI 1.2-8.8; P = .02) and presence of microvascular complications (adjusted OR 4.2, 95%CI 1.5-11.4; P = .005), mainly CKD (adjusted OR 3.6, 95%CI 1.3-10.1; P = .01) and retinopathy (adjusted OR 3.7, CI 95% 1.2-11.9; P = .02). Neither diabetes duration nor haemoglobin A1c differed according to CAP or LSM values. CONCLUSION: Significant fibrosis, detected by FibroScan® , is independently associated with increased prevalence of macrovascular and microvascular complications, thus opening a new scenario in the use of this tool for a comprehensive evaluation of hepatic and vascular complications in patients with T2DM.

BACKGROUND: Military sexual trauma (MST) is notably prevalent among military personnel and can result in mental and physical health problems, including posttraumatic stress disorder (PTSD). Although there are several evidence-based treatments for MST-related PTSD, including Prolonged Exposure therapy (PE), it is unclear what factors are associated with premature termination (i.e., dropout) from this treatment. Given the popularity of PE as an evidence-based treatment for PTSD, the examination of variables that influence dropout from PE among women veterans with MST is warranted. Identification of these specific factors may assist clinicians in addressing the unique symptom profiles and potential barriers to treatment access for individual MST survivors. METHODS: The current study presents secondary data analyses from an ongoing randomized clinical trial that compared the effectiveness of PE delivered in person to delivery via telemedicine for women veterans with MST-related PTSD (n = 136). RESULTS: A total of 50% of participants dropped out from the study (n = 68). Difficulties with emotion regulation at baseline were associated with treatment dropout (odds ratio = 1.03, p < .01), while baseline PTSD and demographic factors were not. CONCLUSIONS: Findings from the current study indicate that emotion regulation skills deficits contribute to PE dropout and may be an appropriate target to address in future clinical trials for PTSD.

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder resulting in absent puberty and infertility. The genetic architecture is complex with multiple loci involved, variable expressivity, and incomplete penetrance. The majority of cases are sporadic, consistent with a disease affecting fertility. The current study aims to investigate mosaicism as a genetic mechanism for CHH, focusing on de novo rare variants in CHH genes. We evaluated 60 trios for de novo rare sequencing variants (RSV) in known CHH genes using exome sequencing. Potential mosaicism was suspected among RSVs with altered allelic ratios and confirmed using customized ultradeep sequencing (UDS) in multiple tissues. Among the 60 trios, 10 probands harbored de novo pathogenic variants in CHH genes. Custom UDS demonstrated that three of these de novo variants were in fact postzygotic mosaicism—two in FGFR1 (p.Leu630Pro and p.Gly348Arg), and one in CHD7 (p.Arg2428*). Statistically significant variation across multiple tissues (DNA from blood, buccal, hair follicle, urine) confirmed their mosaic nature. We identified a significant number of de novo pathogenic variants in CHH of which a notable number (3/10) exhibited mosaicism. This report of postzygotic mosaicism in CHH patients provides valuable information for accurate genetic counseling.

This paper describes feasibility of and patient and peer satisfaction with a Veteran-to-Veteran peer support program purposefully integrated into prolonged exposure (PE) for post-traumatic stress disorder (PTSD) to address barriers contributing to dropout from both in person and telemedicine delivered PE. Specifically, patients who had dropped out of PE were offered the opportunity to return to treatment, this time with a peer who themselves had completed PE, who would join them during a limited number of PE in vivo exposure homework trials. About half of the Veterans who dropped out indicated willingness to return to treatment, noting the peer as central to this decision, and about a third actually returned to treatment. Participants reported high satisfaction with the program, as did peers. Peers reported that their own symptoms were not exacerbated by engaging in exposure homework with the patients. While in the military, service members are trained to leverage the power of the group toward mission-specific tasks; and this training appears relevant to PTSD treatment in the present context.

Leveraging technology to provide evidence‐based therapy for posttraumatic stress disorder (PTSD), such as prolonged exposure (PE), during the COVID‐19 pandemic helps ensure continued access to first‐line PTSD treatment. Clinical video teleconferencing (CVT) technology can be used to effectively deliver PE while reducing the risk of COVID‐19 exposure during the pandemic for both providers and patients. However, provider knowledge, experience, and comfort level with delivering mental health care services, such as PE, via CVT is critical to ensure a smooth, safe, and effective transition to virtual care. Further, some of the limitations associated with the pandemic, including stay‐at‐home orders and physical distancing, require that providers become adept at applying principles of exposure therapy with more flexibility and creativity, such as when assigning in vivo exposures. The present paper provides the rationale and guidelines for implementing PE via CVT during COVID‐19 and includes practical suggestions and clinical recommendations.

Limited research on elder abuse among American Indians and Alaska Natives (AIANs) suggests a higher prevalence of abuse. Using data from the National Elder Mistreatment Study (NEMS), we compared contextual characteristics and elder mistreatment prevalence rates from a community-based sample of AIAN ( n = 195) and Black ( n = 437) and White ( n = 5,013) respondents. There were differences in the prevalence of 16 abuse types and the 23 contextual variables. AIAN respondents had more similarities compared with Black respondents than White respondents, though differences existed. The cumulative prevalence of emotional, physical, and sexual mistreatment in the past year, neglect, and financial abuse by a family member for the AIAN group was 33%, almost double the 17.1% reported in the NEMS study. Over their lifetime, 29.7% of AIAN respondents reported experiencing two or more types of neglect, exploitation, or mistreatment. Almost one fourth of AIAN respondents reported emotional abuse since 60 years of age (the most commonly occurring abuse type)—nearly double that of White respondents. This is the first study to offer comparative prevalence of elder abuse for both AIAN older males and females that draws from a nationally representative sample. The study also provides descriptive analysis of important contextual information within the AIAN population, an underrepresented racial group in elder abuse research. Disaggregating nonmajority racial groups to examine contextual variables and the prevalence of elder mistreatment in the NEMS data set specific to AIAN respondents fills a knowledge gap. Known prevalence of various abuse typologies among AIAN elders can be useful in setting priorities for community planning and response, and in prioritization of funding for future research on causative mechanisms by abuse type, screening, and interventions at various levels. Findings may facilitate development of culturally specific evidence-based prevention and intervention practices aimed at needs specific to AIAN older adults.

Background Concussion affects almost 4 million individuals annually. There are many sideline screening tools available to assist in the detection of sports-related concussion. The King-Devick (K-D) test in association with Mayo Clinic utilizes rapid number naming to test saccadic eye movements in order to screen for concussion. An ideal screening tool for concussion would correctly identify all athletes with active concussion. The accuracy of K-D testing compared with other sideline screening tools is undetermined. Objective To critically assess current evidence regarding the utility of K-D testing as a sideline screening tool for acute concussion and compare K-D testing to other sideline concussion assessments. Methods The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of concussion neurology and neuro-ophthalmology. Results A recent meta-analysis was selected for critical appraisal. Cohorts analyzing athletes with sports-related concussion were selected, and utilized K-D testing as the main baseline and sideline assessment of concussion. K-D testing was found to have a high sensitivity and specificity for detecting concussion when there was worsening from baseline. Conclusion K-D testing has high sensitivity and specificity for detecting sideline concussion. Compared with other sideline screening tools that do not include vision testing, it has greater accuracy. Screening for concussion is optimized when multiple testing modalities are used in conjunction.

Background: Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs. Results: The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met. Conclusion: This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.

BACKGROUND Complicated grief (CG) is a bereavement-specific syndrome distinct from but commonly comorbid with posttraumatic stress disorder (PTSD). While bereavement is common among military personnel (Simon et al., 2018), there is little research on the impact of CG comorbidity on PTSD treatment outcomes. METHODS To evaluate the impact of comorbid CG on PTSD treatment outcomes we analyzed data from a randomized trial comparing prolonged exposure, sertraline, and their combination in veterans with a primary diagnosis of combat-related PTSD (n = 194). Assessment of PTSD, trauma-related guilt, functional impairment, and suicidal ideation and behavior occurred at baseline and weeks 6, 12, and 24 during the 24-week trial. RESULTS CG was associated with lower PTSD treatment response (odds ratio (OR) = 0.29, 95% confidence interval (CI) [0.12, 0.69], p = 0.005) and remission (OR = 0.28, 95% CI [0.11, 0.71], p = 0.007). Those with CG had greater severity of PTSD (p = 0.005) and trauma-related guilt (

OBJECTIVE This study examined clinical and retention outcomes following variable length prolonged exposure (PE) for posttraumatic stress disorder (PTSD) delivered by one of three treatment modalities (i.e., home-based telehealth [HBT], office-based telehealth [OBT], or in-home-in-person [IHIP]). METHOD A randomized clinical trial design was used to compare variable-length PE delivered through HBT, OBT, or IHIP. Treatment duration (i.e., number of sessions) was determined by either achievement of a criterion score on the PTSD Checklist for Diagnostic and Statistical Manual-5 (DSM-5; PTSD Checklist for DSM-5) for two consecutive sessions or completion of 15 sessions. Participants received PE via HBT (n = 58), OBT (n = 59) or IHIP (n = 58). Data were collected between 2012 and 2018, and PTSD was diagnosed using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), administered at baseline, posttreatment, and 6 months following treatment completion. The primary clinical outcome was CAPS-5 PTSD severity. Secondary outcomes included self-reported PTSD and depression symptoms, as well as treatment dropout. RESULTS The clinical effectiveness of PE did not differ by treatment modality across any time point; however, there was a significant difference in treatment dropout. Veterans in the HBT (odds ratio [OR] = 2.67; 95% confidence interval [CI] = 1.10, 6.52; p = .031) and OBT (OR = 5.08; 95% CI = 2.10; 12.26; p

OBJECTIVE: The purpose of this study was to determine if there was agreement between a new point‐of‐care (POC) lactate analyzer and a handheld laboratory analyzer when measuring blood lactate concentration in cats. DESIGN: Prospective observational study. SETTING: University veterinary teaching hospital. ANIMALS: Fifty‐four cats that presented to an emergency service. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Lactate concentrations as measured by the handheld laboratory analyzer ranged from 0.3 to 15.4 mmol/L. Agreement analysis of the handheld laboratory analyzer and the POC lactate meter demonstrated a bias, −0.06 and limits of agreement ranging from −0.87 to 0.99 mmol/L. Regression analysis demonstrated a coefficient of determination (R²) of 0.98. CONCLUSION: Results of the present study indicate that the POC lactate meter provided results that are in agreement with a handheld laboratory analyzer when measuring lactate in clinically ill patients.

OBJECTIVE To compare results of a commercially available device for oscillometrically measured blood pressure (OBP) with invasively measured blood pressure (IBP) in awake and anesthetized dogs. ANIMALS 19 adult dogs (mean ± SD body weight, 17.8 ± 7.5 kg). PROCEDURES Blood pressures were measured in dogs while they were awake and anesthetized with isoflurane. The OBP was recorded on a thoracic limb, and IBP was simultaneously recorded from the median caudal artery. Agreement between OBP and IBP was evaluated with the Bland-Altman method. Guidelines of the American College of Veterinary Internal Medicine (ACVIM) were used for validation of the oscillometric device. RESULTS In awake dogs, mean bias of the oscillometric device was −11.12 mm Hg (95% limits of agreement [LOA], −61.14 to 38.90 mm Hg) for systolic arterial blood pressure (SAP), 9.39 mm Hg (LOA, −28.26 to 47.04 mm Hg) for diastolic arterial blood pressure (DAP), and −0.85 mm Hg (LOA, −40.54 to 38.84 mm Hg) for mean arterial blood pressure (MAP). In anesthetized dogs, mean bias was −12.27 mm Hg (LOA, −47.36 to 22.82 mm Hg) for SAP, −3.92 mm Hg (LOA, −25.28 to 17.44 mm Hg) for DAP, and −7.89 mm Hg (LOA, −32.31 to 16.53 mm Hg) for MAP. The oscillometric device did not fulfill ACVIM guidelines for the validation of such devices. CONCLUSIONS AND CLINICAL RELEVANCE Agreement between OBP and IBP results for awake and anesthetized dogs was poor. The oscillometric blood pressure device did not fulfill ACVIM guidelines for validation. Therefore, clinical use of this device cannot be recommended.

Crusted scabies (CS) is a severe form of scabies caused by hyper-infestation of mites in the horny layer of the epidermis that thickens and forms warty crusts.1 Although it has been described mainly in immunosuppressed individuals, it has been also observed in otherwise healthy patients.1 We are living the coronavirus disease 2019 (COVID-19) outbreak, that is a mild/moderate disease in children.2-4 However, SARS-CoV-2 infection may induce significant changes in the host's immune response.5,6.

Non-Alcoholic Fatty Liver Disease (NAFLD) is caused by the accumulation of fat in over 5% of hepatocytes in the absence of alcohol consumption. NAFLD is considered the hepatic manifestation of metabolic syndrome (MS). Recently, an expert consensus suggested as more appropriate the term MAFLD (metabolic-associated fatty liver disease). Insulin resistance (IR) plays a key role in the development of NAFLD, as it causes an increase in hepatic lipogenesis and an inhibition of adipose tissue lipolysis. Beyond the imbalance of adipokine levels, the increase in the mass of visceral adipose tissue also determines an increase in free fatty acid (FFA) levels. In turn, an excess of FFA is able to determine IR through the inhibition of the post-receptor insulin signal. Adipocytes secrete chemokines, which are able to enroll macrophages inside the adipose tissue, responsible, in turn, for the increased levels of TNF-α. The latter, as well as resistin and other pro-inflammatory cytokines such as IL-6, enhances insulin resistance and correlates with endothelial dysfunction and an increased cardiovascular (CV) risk. In this review, the role of diet, intestinal microbiota, genetic and epigenetic factors, low-degree chronic systemic inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress on NAFLD have been addressed. Finally, the clinical impact of NAFLD on cardiovascular and renal outcomes, and its direct link with type 2 diabetes have been discussed.

Glycogen Storage Disease type 1b (GSDIb) is a genetic disorder with long term severe complications. Accumulation of the glucose analog 1,5-anhydroglucitol-6-phosphate (1,5AG6P) in neutrophils inhibits the phosphorylation of glucose in these cells, causing neutropenia and neutrophil dysfunctions. This condition leads to serious infections and inflammatory bowel disease (IBD) in GSDIb patients. We show here that dapagliflozin, an inhibitor of the renal sodium-glucose co-transporter-2 (SGLT2), improves neutrophil function in an inducible mouse model of GSDIb by reducing 1,5AG6P accumulation in myeloid cells.

Optimal dual antiplatelet therapy (DAPT) strategy in high-bleeding risk (HBR) patients presenting with acute coronary syndrome remains debated. We sought to investigate the use of clopidogrel versus ticagrelor in HBR patients with acute coronary syndrome and their impact on ischemic and bleeding events at 1year. In the START-ANTIPLATELET registry (NCT02219984), consecutive patients with ≥ 1 HBR criteria were stratified by DAPT type in clopidogrel versus ticagrelor groups. The primary endpoint was net adverse clinical endpoints (NACE), defined as a composite of all-cause death, myocardial infarction, stroke, and major bleeding. Of 1209 patients with 1-year follow-up, 553 were defined at HBR, of whom 383 were considered eligible for the study as on DAPT with clopidogrel (174 or 45.4%) or ticagrelor (209 or 54.6%). Clopidogrel was more often administered in patients at increased ischemic and bleeding risk, while ticagrelor in those undergoing percutaneous coronary intervention. Mean DAPT duration was longer in the ticagrelor group. At 1year, after multivariate adjustment, no difference in NACEs was observed between patients on clopidogrel versus ticagrelor (19% vs. 11%, adjusted hazard ratio 1.27 [95% CI 0.71–2.27], p = 0.429). Age, number of HBR criteria, and mean DAPT duration were independent predictors of NACEs. In a real-world registry of patients with acute coronary syndrome, 45% were at HBR and frequently treated with clopidogrel. After adjustment for potential confounders, the duration of DAPT, but not DAPT type (stratified by clopidogrel vs. ticagrelor), was associated with the risk of ischemic and bleeding events at 1year.

A 27-year-old man noted imbalance and staggering when walking. Vertigo, nausea, vomiting, and mild fever developed. This was presumed to be due to an inner ear infection, and antibiotics were prescribed. He began experiencing intermittent left face and arm numbness, bilateral hearing loss and tinnitus. Audiography indicated low-frequency hearing loss in both ears, left worse than right. He reported headaches and neck stiffness, and his family noticed that he was moody, easily aggravated, and confused, with slow mentation. Magnetic resonance imaging showed patchy, nodular, leptomeningeal enhancement involving both cerebral hemispheres and the posterior fossa, with scattered hyperintense T2 signal changes of the internal capsule and prominent abnormal signal changes in the corpus callosum. Cerebrospinal fluid analysis was remarkable for a markedly increased protein concentration and white blood cells. Eye examination showed 20/20 vision in both eyes with a superior visual field defect in the right eye. Retinal whitening was noted in the vascular distribution of the inferotemporal arcade. Intravenous fluorescein angiography showed delayed filling in this region consistent with a branch retinal artery occlusion and scattered areas of arteriolar wall hyperfluorescence. A diagnosis of Susac syndrome was made on the basis of the branch retinal artery occlusion, magnetic resonance imaging findings, and hearing deficit. Intravenous methylprednisolone was given, followed oral prednisone, which resulted in substantial improvement in headaches and cognition. Cyclophosphamide was also started at the same time as intravenous methylprednisolone. A new visual field defect developed due to a branch retinal artery occlusion in the left eye, which prompted initiation of intravenous immunoglobulin and transition from cyclophosphamide to rituximab. He had no recurrent branch retinal artery occlusions or other relapses of his underlying Susac syndrome on this treatment regimen. Susac syndrome was initially described as a microangiopathy of the brain and retina. It is an idiopathic autoimmune disorder that primarily affects the brain, eye, and inner ear.

A 71-year-old woman had development of generalized fatigue over 1 week, along with low-grade fever. The fever resolved, but the fatigue persisted. Subsequently, retro-orbital and head discomfort developed. One month later, she had blurred vision. An ophthalmic examination revealed mild dyschromatopsia, bilateral visual field constriction, bilateral marked optic disc edema, and vitreous cells graded as vitreous haze score 2.0. Magnetic resonance imaging of the brain showed confluent abnormal areas of T2 hyperintensity without mass effect or enhancement involving the subcortical and periventricular white matter in the cerebral hemispheres bilaterally, basal ganglia, pons, and left thalamus. She had 2 lumbar punctures, which showed normal opening pressures. Cerebrospinal fluid analysis showed an increased white blood cell count cytologically consistent with reactive pleocytosis with a predominance of lymphocytes. The cerebrospinal fluid protein level was increased and cultures were negative for organisms. Immunostain confirmed polyclonal plasma cells and a possible T-cell proliferative disorder. The cerebrospinal fluid and serum were positive for collapsin-response mediator protein 5-immunoglobulin G and microtubule-associated protein 1B- immunoglobulin G antibodies at high titers. Computed tomography of the chest, abdomen, and pelvis showed an indeterminate pulmonary nodule in the upper lobe. Bronchoscopy identified thickened mucosa in the right lower lung consistent with small cell carcinoma. Positron emission tomography showed abnormal hypermetabolic areas of the ascending colon. Biopsy revealed tubulovillous adenoma of the ascending colon, and the patient underwent a right-sided colon resection and anastomosis. The patient was diagnosed with paraneoplastic optic neuropathy (collapsin-response mediator protein 5-immunoglobulin G–associated optic neuropathy and vitritis). Intravenous methylprednisolone was given for 5 days, followed by a prolonged course of oral prednisone, with slight visual improvement. The patient underwent a right-sided thoracotomy with biopsy of the right lower lobe, the results of which were consistent with small cell undifferentiated carcinoma. Paraneoplastic neurologic syndromes are a heterogeneous group of disorders associated with various systemic cancers and with other mechanisms believed to be immune mediated. Paraneoplastic visual syndromes can precede or follow a diagnosis of cancer.

This paper describes the design of an automated device to detect air bubbles during a neuroangiography, a medical procedure that takes images of the blood vessels in the brain. In the neuroangiography procedure, a saline solution is injected into the patient through a catheter without the presence of any air bubbles. If an air bubble enters the bloodstream of the patient it may cause an air embolism, therefore, it is crucial that all air bubbles are detected and removed during the surgery. The current process relies on a nurse to constantly monitor the intravenous(IV) line for bubbles and pinch the line manually if a bubble is detected. They must also ensure that the pressure of the saline bag is maintained within a certain range and the saline bag does not become empty. The device discussed in this paper was designed to implement these tasks automatically so the nurse’s work level stress would decrease, and their focus and energy could be directed to the patient’s well-being. Simulation and hardware implementation results of the bubble detection device are presented.

Children with intellectual disability/neurodevelopmental delay (ID-ND) commonly ingest foreign bodies (FB) and often present complications due to peculiar aspects of their condition. The aim of this paper is to report the experience of two centers in the management of ID-ND patients after FB ingestion and to discuss a possible algorithm for clinical practice. We retrospectively evaluated data of patients managed for FB ingestion (period: 2017–2021), focusing on those with ID-ND, specifically demographics and baseline diagnosis, elements related to the event, symptoms, time to endoscopy, FB location, endoscopic details, and follow-up. A total of 457 patients were managed in the study period and 19 had ID-ND (mean age 9.8 ± 3.5 years, 15 males). A total of 16/19 (84.2%) were symptomatic and required an operative approach. Recurrent ingestions and multiple FB were found in 2 and 11 patients, respectively. Endoscopy (mean time 65.6 ± 41 min) was effective in 14 cases (73.6%) and 6 patients (31.6%) developed a complication. FB ingestion in ID-ND patients represents a challenging condition for the clinician and a potentially dangerous situation. It should be addressed specifically by a multidisciplinary team considering a tailored diagnostic and management protocol.

Despite the availability of effective treatments, hepatitis C virus (HCV) still remains a threat to public health. HCV is capable to trigger, behind liver damage, extrahepatic manifestations, including cardiovascular disease and type 2 diabetes (T2DM). A close association has been reported between HCV infection and cardiovascular disease due to imbalances in metabolic pathways and chronic inflammation. HCV through both direct and indirect mechanisms causes a higher incidence of ischemic stroke, acute coronary syndrome, heart failure and peripheral arterial disease. In addition, a higher risk of death from cardiovascular events has been showed in HCV patients. Insulin resistance is a hallmark of HCV infection and represents the link between HCV and T2DM, which is one of the most frequent HCV-associated extrahepatic manifestations. The pathological basis of the increased risk of T2DM in HCV infection is provided by the alterations of the molecular mechanisms of IR induced both by the direct effects of the HCV proteins, and by the indirect effects mediated by chronic inflammation, oxidative stress and hepatic steatosis. T2DM increases the risk of compensated and decompensate cirrhosis and hepatocellular carcinoma as well as increases the risk of cardiovascular disease, lower limb amputation and end stage renal disease. Current evidence suggests that HCV eradication reduces the incidence and mortality of cardiovascular disease and T2DM, further underling the importance of public health strategies for eradication the infection. The aim of this review was to update evidence and management of interaction between HCV, cardiovascular disease, and T2DM in the era of DAA treatment.

Potassium depletion affects AQP2 expression and the cellular composition of the kidney collecting duct. This, in turn, contributes to the development of a secondary form of nephrogenic diabetes insipidus and hypokalemic nephropathy. Here we show that after 14 days of potassium depletion, the cellular fraction of A-type intercalated cells increases while the fraction of principal cells decreases along the outer medullary collecting duct in rats. The intercalated cells acquired a novel distribution pattern forming rows of cells attached to each other. These morphological changes occur progressively and reverse after 7 days of recovery on normal rat chow diet. The cellular remodeling mainly occurred in the inner stripe of outer medulla similar to the previously seen effect of lithium on the collecting duct cellular profile. The cellular remodeling is associated with the appearance of cells double labelled with both specific markers of principal and type-A intercalated cells. The appearance of this cell type was associated with the downregulation of the Notch signaling via the Hes1 pathways. These results show that the epithelium of the collecting duct has a high degree of plasticity and that Notch signaling likely plays a key role during hypokalemia.

Purpose We aimed to assess the role of radiologists, cardiologists, and other medical and non-medical figures in cardiac magnetic resonance imaging (MRI) research in the last 34 years, focusing on first and last authorship, number of published studies, and journal impact factors (IF). Methods Articles in the field of cardiac MRI were considered in this systematic review and retrospective bibliometric analysis. For included studies, the first and last authors were categorized as cardiologists, radiologists/nuclear medicine physicians, medical doctors (MD) with specialties in both cardiology and radiology/nuclear medicine, and other MD and non-MD. Differences in the number of papers published overall and by year and institution location for the first and last author category were assessed. Mean IF differences between author categories were also investigated. Results A total of 2053 articles were included in the final analysis. For the first authors (n = 2011), 52% were cardiologists, 22% radiologists/nuclear medicine physicians, 16% other MD, 10% other non-MD, and 1% both cardiologists and radiologists/nuclear medicine physicians. Similarly, the last authors (n = 2029) resulted 54% cardiologists, 22% radiologists/nuclear medicine physicians, 15% other MD, 8% other non-MD, and 2% both cardiologists and radiologists/nuclear medicine physicians. No significant differences due to institution location in the first and last authorship proportions were found. Average journal IF was significantly higher for cardiologist first and last authors when compared to that of radiologists/nuclear medicine physicians (both p < 0.0001). Conclusion Over 50% of studies in the field of cardiac MRI published in the last 34 years are conducted by cardiologists.

In this paper, we propose a model for the optimisation of driving speed profiles on metro lines, to reduce overall energy consumption. The proposed model optimises the maximum speed to be maintained on each section between two stations; the functions that link this maximum speed to the travel time on the section and the corresponding energy consumption are built using a microscopic railway simulation software. The results obtained are promising and show how it is possible to achieve traction energy savings of over 25% compared to non-optimised operations.

Recently, telemedicine has become remarkably important, due to increased deployment and development of digital technologies. National and international guidelines should consider its inclusion in their updates. During the COVID-19 pandemic, mandatory social distancing and the lack of effective treatments has made telemedicine the safest interactive system between patients, both infected and uninfected, and clinicians. A few potential evidence-based scenarios for the application of telemedicine have been hypothesized. In particular, its use in diabetes and complication monitoring has been remarkably increasing, due to the high risk of poor prognosis. New evidence and technological improvements in telemedicine application in diabetic retinopathy (DR) have demonstrated efficacy and usefulness in screening. Moreover, despite an initial increase for devices and training costs, teleophthalmology demonstrated a good cost-to-efficacy ratio; however, no national screening program has yet focused on DR prevention and diagnosis. Lack of data during the COVID-19 pandemic strongly limits the possibility of tracing the real management of the disease, which is only conceivable from past evidence in normal conditions. The pandemic further stressed the importance of remote monitoring. However, the deployment of device and digital application used to increase screening of individuals and monitor progression of retinal disease needs to be easily accessible to general practitioners.

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by infertility and the absence of puberty. Defects in GnRH neuron migration or altered GnRH secretion and/or action lead to a severe gonadotropin-releasing hormone (GnRH) deficiency. Given the close developmental association of GnRH neurons with the olfactory primary axons, CHH is often associated with anosmia or hyposmia, in which case it is defined as Kallmann syndrome (KS). The genetics of CHH are heterogeneous, and >40 genes are involved either alone or in combination. Several CHH-related genes controlling GnRH ontogeny encode proteins containing fibronectin-3 (FN3) domains, which are important for brain and neural development. Therefore, we hypothesized that defects in other FN3-superfamily genes would underlie CHH. Next-generation sequencing was performed for 240 CHH unrelated probands and filtered for rare, protein-truncating variants (PTVs) in FN3-superfamily genes. Compared to gnomAD controls the CHH cohort was statistically enriched for PTVs in neuron-derived neurotrophic factor (NDNF) (p = 1.40 x 10(-6)). Three heterozygous PTVs (p.Lys62*, p.Tyr128Thrfs*55, and p.Trp469*, all absent from the gnomAD database) and an additional heterozygous missense mutation (p.Thr201Ser) were found in four KS probands. Notably, NDNF is expressed along the GnRH neuron migratory route in both mouse embryos and human fetuses and enhances GnRH neuron migration. Further, knock down of the zebrafish ortholog of NDNF resulted in altered GnRH migration. Finally, mice lacking Ndnf showed delayed GnRH neuron migration and altered olfactory axonal projections to the olfactory bulb; both results are consistent with a role of NDNF in GnRH neuron development. Altogether, our results highlight NDNF as a gene involved in the GnRH neuron migration implicated in KS.

Heat treatments induce chemical/physical modifications, which may affect the stability to enzymatic digestion and consequently the allergenicity of food proteins to a varying extent, depending on the time/temperature regimen. Herein, we evaluated the stability to digestion of whole tree nut (walnuts, hazelnuts and almonds) allergens in a food digestion model reflecting the real one by, taking into consideration the allergen-containing processed (roasted) food. To this aim, whole raw and roasted tree nuts were subjected to in vitro digestion combining the harmonized oral-gastric-duodenal digestion models with brush border membrane enzymes (BBM) to simulate the jejunal degradation of peptides. The degradation of allergens was monitored by integrated proteomic/peptidomic and bio-informatic tools. Roasting increased digestibility of tree nuts, since very few peptides were detected in digested samples (6.5 kDa fraction). After BBM digestion step, the degradation of peptides was enhanced in roasted walnuts and hazelnuts compared to the raw counterpart. Conversely, almond allergens showed a different behaviour, since the presence of resistant peptides was more evident for roasted almonds, probably because of the hydrolysis of high molecular weight aggregates generated during roasting. Our results provide new insight into the relationship between thermal processing and metabolic fate of tree nut allergens, highlighting the importance of investigating the digestion stability of whole allergenic food, rather than purified proteins.

Objective: The current study is an analysis of predictors of posttraumatic stress disorder (PTSD) treatment response in a clinical trial comparing (1) prolonged exposure plus placebo (PE + PLB), (2) PE + sertraline (PE + SERT), and (3) sertraline + enhanced medication management (SERT + EMM) with predictors including time since trauma (TST), self-report of pain, alcohol use, baseline symptoms, and demographics. Methods: Participants (N = 196) were veterans with combat-related PTSD (DSM-IV-TR) of at least 3 months' duration recruited between 2012 and 2016 from 4 sites in the 24-week PROlonGed ExpoSure and Sertraline (PROGrESS) clinical trial (assessments at weeks 0 [intake], 6, 12, 24, 36, and 52). Results: Across treatment conditions, (1) longer TST was predictive of greater week 24 PTSD symptom improvement (β = 1.72, P = .01) after adjusting for baseline, (2) higher baseline pain severity was predictive of smaller symptom improvement (β = -2.96, P = .003), and (3) Hispanic patients showed greater improvement than non-Hispanic patients (β = 12.33, P = .03). No other baseline characteristics, including alcohol consumption, were significantly predictive of week 24 improvement. Comparison of TST by treatment condition revealed a significant relationship only in those randomized to the PE + SERT condition (β = 2.53, P = .03). Longitudinal analyses showed similar results. Conclusions: The finding that longer TST shows larger symptom reductions is promising for PTSD patients who might not seek help for years following trauma. Higher baseline pain severity robustly predicted attenuated and slower response to all treatment conditions, suggesting a common neuropathologic substrate. Finally, in the current study, alcohol use did not impede the effectiveness of pharmacotherapy for PTSD. Trial Registration: ClinicalTrials.gov identifier: NCT01524133.

Posttraumatic stress disorder (PTSD) is highly prevalent among veterans. Although there are effective treatment approaches for PTSD, such as Prolonged Exposure (PE) and Cognitive Processing Therapy, many providers trained in these approaches do not use them, or use them without sufficient fidelity, and veterans drop out of these treatments at very high rates. The time intensive nature of these treatments is frequently cited as a barrier to receiving the treatment among veterans and delivering the treatment among providers. According, there is an urgent need to establish more efficient and effective PTSD treatment approaches in order to meet the needs of veterans seeking care. Written exposure therapy (WET) is an efficient, exposure-based treatment, and may represent a plausible alternative treatment option to address PTSD in veterans. Although WET has been found to be effective and non-inferior to more time intensive trauma-focused treatment, it has not yet been investigated with a veteran sample. In an ongoing randomized controlled trial (RCT) we are investigating whether WET is non-inferior in treating PTSD compared with the more time intensive PE. The study sample will include 150 men and women veterans diagnosed with PTSD who are randomly assigned to either WET (n = 75) or PE (n = 75). Participants are assessed prior to treatment and 10-, 20-, and 30-weeks after the first treatment session. The primary outcome is PTSD symptom severity assessed with the Clinician Administered PTSD Scale for DSM-5. Establishing that PTSD can be treated effectively with fewer treatment sessions would represent a significant advance in improving access to evidence-based care for veterans with PTSD.

BACKGROUND AND OBJECTIVES: Prescription opioid (PO) misuse is increasing and is associated with overdose. Individuals who experienced a recent sexual assault are at risk for increased substance use, yet limited interventions target PO misuse after sexual assault. The current study examined the efficacy of video interventions on PO misuse after sexual assault. METHODS: Adolescent girls and women (n = 154) were recruited in the context of a sexual assault medical forensic exam in the emergency department. Effects of a Prevention of Post-Rape Stress (PPRS) video and a Pleasant Imagery and Relaxation Instruction (PIRI) video were compared to treatment as usual (TAU) during a sexual assault medical forensic exam on PO misuse. Participants reported if they had used POs for non-medical purposes since the sexual assault at 1.5 month follow-up. RESULTS: Results from a logistic regression analysis indicated that participants with a prior sexual assault were less likely to misuse prescription opioids 1.5 months after the assault in the PIRI condition compared to TAU. There were no main effects for video condition and no interactions for the PPRS condition on PO misuse. DISCUSSION AND CONCLUSIONS: Providing the PIRI video, or teaching other types of mindfulness or relaxation exercises, may be warranted as a secondary prevention for individuals during the sexual assault medical forensic exam for those with a prior sexual assault history. SCIENTIFIC SIGNIFICANCE: This research provides an initial examination of the impact of mindfulness skills recently after traumatic event exposure on PO misuse. CLINICAL TRIALS REGISTRATION: NCT01430624

Mutations in the CHD7 gene, encoding for the chromodomain helicase DNA-binding protein 7, are found in approximately 60% of individuals with CHARGE syndrome (coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear abnormalities and/or hearing loss). Herein, we present a clinical case of a 14-year-old male presenting for evaluation of poor growth and pubertal delay highlighting the diagnostic challenges of CHARGE syndrome. The patient was born full term and underwent surgery at 5 days of life for bilateral choanal atresia. Developmental milestones were normally achieved. At age 14 his height and weight were -2.04 and -1.74 standard deviation score respectively. He had anosmia as well as prepubertal testes and micropenis (4 cm×1 cm). The biological profile showed low basal serum testosterone and gonadotropins (testosterone, 0.2 nmol/L; luteinizing hormone, 0.5 U/L; follicle-stimulating hormone, 1.3 U/L), and otherwise normal pituitary function and normal imaging of the hypothalamic-pituitary area. The constellation of choanal atresia, anosmia, mild dysmorphic features, micropenis and delayed puberty were suggestive of CHARGE syndrome. Targeted genetic testing of CHD7 was performed revealing a de novo heterozygous CHD7 mutation (c.4234T>G [p.Tyr1412Asp]). Further paraclinical investigations confirmed CHARGE syndrome. Despite the presence of suggestive features, CHARGE syndrome remained undiagnosed in this patient until adolescence. Genetic testing helps clarify the phenotypic and genotypic spectrum to facilitate diagnosis, thus promoting optimal follow-up, treatment, and appropriate genetic counselling.

Objectives This is a small preliminary but novel study assessing the feasibility of repetitive transcranial magnetic stimulation (rTMS) delivery to veterans with posttraumatic stress disorder (PTSD) while they simultaneously receive prolonged exposure (PE) therapy. Methods A prospective, randomized, double-blinded, active sham-controlled design combined weekly sessions of rTMS and standard PE at the Veterans Administration Hospital. Eight adult patients received a full course of protocol-driven PE therapy and were randomly assigned to receive either rTMS or sham rTMS. Repetitive transcranial magnetic stimulation was delivered to the right or left prefrontal cortex with a figure-eight solid core coil at 120% motor threshold, 10 Hz, 5-second train duration, and 10-second intertrain interval for 30 minutes (6000 pulses) weekly for 5 weeks (30,000 stimuli). Results Of the 12 veterans consented, 8 completed the study treatment protocol. The dropout rate was 34%, roughly equivalent to the pooled average dropout rates observed in traditional PE therapy with Operation Enduring Freedom/Operation Iraqi Freedom veterans with PTSD, suggesting that veterans had no difficulty tolerating the addition of rTMS to PE therapy and that this is a feasible study design for larger trials in the future. Clinician-Administered PTSD Symptom scores reflected a general nonsignificant trend toward improvement, and subjects with comorbid major depression appeared to experience significant antidepressant benefit with treatment despite the fact that the doses used in this protocol were much smaller than those used to treat patients with major depressive disorder. Conclusions This pilot study demonstrates the safety and feasibility of rTMS delivery to PTSD patients while they simultaneously receive PE. This unique approach to the treatment of PTSD highlights the need for further studies with larger sample sizes to assess treatment outcomes.

The initiation and maintenance of reproductive capacity in humans is dependent on pulsatile secretion of the hypothalamic hormone GnRH. Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that results from the failure of the normal episodic GnRH secretion, leading to delayed puberty and infertility. CHH can be associated with an absent sense of smell, also termed Kallmann syndrome, or with other anomalies. CHH is characterized by rich genetic heterogeneity, with mutations in >30 genes identified to date acting either alone or in combination. CHH can be challenging to diagnose, particularly in early adolescence where the clinical picture mirrors that of constitutional delay of growth and puberty. Timely diagnosis and treatment will induce puberty, leading to improved sexual, bone, metabolic, and psychological health. In most cases, patients require lifelong treatment, yet a notable portion of male patients (∼10% to 20%) exhibit a spontaneous recovery of their reproductive function. Finally, fertility can be induced with pulsatile GnRH treatment or gonadotropin regimens in most patients. In summary, this review is a comprehensive synthesis of the current literature available regarding the diagnosis, patient management, and genetic foundations of CHH relative to normal reproductive development.

46,XY differences and/or disorders of sex development (DSD) are clinically and genetically heterogeneous conditions. Although complete androgen insensitivity syndrome has a strong genotype–phenotype correlation, the other types of 46,XY DSD are less well defined, and thus, the precise diagnosis is challenging. This study focused on comparing the relationship between clinical assessment and genetic findings in a cohort of well-phenotyped patients with 46,XY DSD. The study was an analysis of clinical investigations followed by genetic testing performed on 35 patients presenting to a single center. The clinical assessment included external masculinization score (EMS), endocrine profiling and radiological evaluation. Array-comparative genomic hybridization (array-CGH) and sequencing of DSD-related genes were performed. Using an integrated approach, reaching the definitive diagnosis was possible in 12 children. The correlation between clinical and genetic findings was higher in patients with a more severe phenotype (median EMS 2.5 vs 6; P = 0.04). However, in 13 children, at least one variant of uncertain significance was identified, and most times this variant did not correspond to the original clinical diagnosis. In three patients, the genetic studies guided further clinical assessment which resulted in a reclassification of initial clinical diagnosis. Furthermore, we identified eight patients harboring variants in more than one DSD genes, which was not seen in controls (2.5%; P = 0.0003). In summary, taking into account potential challenges in reaching the definitive diagnosis in 46,XY DSD, only integrated approach seems to be the best routine practice.

Background and Aims Glycogenosis I type b (GsdI-b) is a rare metabolic disease and immune disorder characterized by hepato-renal glycogen accumulation caused by a deficiency in the Glucose-6-phosphate transporter (G6PT). G6PT transports glucose-6-phosphate (G6P) from cytoplasm to endoplasmic reticulum (ER) where a G6Pase catalyses the hydrolysis of G6P in glucose and phosphate. G6PT deficiency lead to impaired glucose homeostasis, myeloid disfunction and long-term risk of hepatocellular adenomas. No causal therapy is so far available for GSDI-b patients besides a dietary approach to control glycemia and the use of Granulocyte Colony-Stimulating Factor (GCSF) to improve neutropenia. Over time, these supports increase the chronicity of GSDI-b with some complications. A mouse model recapitulating the GDSI-b has been recently generated by inducing G6PT suppression after tamoxifen injection. Here, we characterized the renal phenotype of TM-G6PT-/- mice model focusing on the molecular mechanisms that lead to renal dysfunction. Finally, we evaluated the efficiency of Dapagliflozin, a selective inhibitor of SGLT2, on kidney functions in terms of therapeutic effect. Method Machine learning approach to computer based evaluation of renal morphology was used to analyze the renal sections from TM-G6PT-/- treated with or without dapagliflozin. Results: G6PT is expressed in all renal zones and a severe downregulation of G6PT mRNA expression in whole kidney of TM-G6PT-/- mice can be observed. TM-G6PT-/- mice show tubular vacuolization and overall cellular dysfunction of PT due to a high glycogen accumulation. TM-G6PT-/- mice manifest glycosuria, phosphaturia and polyuria associated with a down regulation of main transporters of PT cells. The urine concentrating defect is due to a primarily role of G6PT in CNT/CD cells confirmed by a downregulation of AQP2, main water channel along CD segments. This mouse model recapitulates the human GSD-Ib renal phenotype characterized by a disfunction of PT but also CNT/CD cells. In order to evaluate whether targeting the glucose metabolism would improve the renal phenotype of these mice we limited glucose flux across the apical membrane of PT cells, applying the SGLT2-inhibitor dapagliflozin to reduce new glycogen formation. After one month of treatment, Dapagliflozin prevents glycogen accumulation in TM-G6PT-/- mice and ameliorates the main dysregulated markers of PT function. This finding was paralleled by an improvement of the histological features of kidney morphology in dapagliflozin treated TM-G6PT-/- mice. Conclusion Our data provide evidence that treatment with dapagliflozin ameliorates intracellular glycogen storage and improves the renal functions in TM-G6PT-/- mice.