CFAP47 is a novel causative gene implicated in X-linked polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a well-described condition in which ~80% of cases have a genetic explanation, while the genetic basis of sporadic cystic kidney disease in adults remains unclear in ~30% of cases. This study aimed to identify novel genes associated with polycystic kidney disease (PKD) in patients with sporadic cystic kidney disease in which a clear genetic change was not identified in established genes. A next-generation sequencing panel analyzed known genes related to renal cysts in 118 sporadic cases, followed by whole-genome sequencing on 47 unrelated individuals without identified candidate variants. Three male patients were found to have rare missense variants in the X-linked gene Cilia And Flagella Associated Protein 47 (CFAP47). CFAP47 was expressed in primary cilia of human renal tubules, and knockout mice exhibited vacuolation of tubular cells and tubular dilation, providing evidence that CFAP47 is a causative gene involved in cyst formation. This discovery of CFAP47 as a newly identified gene associated with PKD, displaying X-linked inheritance, emphasizes the need for further cases to understand the role of CFAP47 in PKD.

Rhabdomyolysis Complicated with Hyponatremia Due to Water Intoxication and Severe Aspiration Pneumonia: Description of a Patient with Chronic Schizophrenia and Literature Review.

Hyponatremia due to water intoxication is frequently observed in patients with chronic schizophrenia. We herein present a 49-year-old man who developed schizophrenia at the age of 23 and had been admitted to the closed ward of our hospital for 7 years. He was found by a round nurse standing at the bedside, covering both ears with his hands and making groaning noises. He was disoriented and immediately after being returned to bed, a general tonic-clonic seizure occurred. Severe hyponatremia (Na 104 mEq/L) was noted and intravenous sodium correction was started. A few hours later, due to glossoptosis and massive vomiting, ventilation got worse to the point where he had to be put on a ventilator. On the following day, he developed aspiration pneumonia and antimicrobial treatment was started. In addition, a blood sample taken 36 hours later revealed an extensive elevation of creatine kinase (41,286 U/L), pointing to a possibility of rhabdomyolysis as a complication. Subsequently, the general condition gradually improved with antimicrobial therapy and sodium correction. He eventually recovered without any complications including central pontine myelinolysis. He had no history of polydipsia before this event but it was later found that esophageal stricture triggered complusive fluid intake, resulting in acute hyponatremia, seizure, aspiration pneumonia and rhabdomyolysis. A brief discussion will be provided on the issues surrounding hyponatremia, rhabdomyolysis and schizophrenia.

Refractory Peritonitis Related to Peritoneal Dialysis Caused by Enterococcus gallinarum: A Case Report.

A 65-year-old woman with a history of peritoneal dialysis undergoing hemodialysis at our hospital presented with a fever after experiencing gastroenteritis symptoms. She had an implanted peritoneal dialysis catheter for draining chylous ascites. After commencing empirical treatment with meropenem, peritoneal effluent samples revealed an increased white blood cell count, and peritonitis was diagnosed. Enterococcus gallinarum was detected in blood and effluent cultures. Meropenem was changed to vancomycin based on susceptibility testing but subsequently restarted and thereafter changed to ampicillin following exacerbation of peritonitis. Finally, catheter removal led to complete recovery. E. gallinarum is vancomycin-resistant and a rare cause of peritonitis.

Psychological distress among early medical residents: A 2-year longitudinal cohort study over seven years in Japan.

BACKGROUND: Early medical residents are expected to have a higher prevalence of burnout due to physical and psychological stressors. However psychological distress associated with burnout has not been adequately investigated in a longitudinal manner. We therefore examined the longitudinal trajectory of depression and its associated factors among early medical residents. METHODS: In this cohort study, medical residents (n = 215) who started rotation at the University of Yamanashi Hospital during 2012 to 2018 were recruited and asked to complete the Brief Job Stress Questionnaire (BJSQ), Center for Epidemiologic Studies Depression Scale (CESD), Brief Scale for Coping Profile (BSCP) and Athens Insomnia Scale (AIS) at the time of exit from each clinical department for up to two years over seven years. Factors associated with the CES-D scores were statistically explored, with a cutoff score of 16 to denote depression. RESULTS: The CES-D was completed by 205 residents. The average CES-D score was 10.3 ± 8.0 and the scores were lower in the 2nd versus 1st year of residency (11.3 ± 6.7 versus 9.2 ± 7.0). Multiple regression analysis of BJSQ/BSCP/AIS on CES-D revealed that insomnia had a significant impact on the CES-D scores. Apart from insomnia, avoidance and suppression and peer support had significant effects. Resilient residents, who showed the maximum CES-D score of under 16 consistently throughout the residency, was better in terms of changing a point of view, active solution and changing mood. Women were more likely to express emotions to others, while they reported more job control in the first year. CONCLUSIONS: Our results have high clinical relevance to challenge psychological burnout among early medical residents, offering some possible clues for prevention such as reduced burden, more flexibility during the first year and strengthening coworker support. Insomnia exerted moderate to strong effects on depression and monitoring of sleep appears indispensable in this specific population.

Depression and Associated Factors Among the Elderly Population in an Urban Tertiary Geriatric Hospital in Bangladesh.

Background: Geriatric depression becoming a serious concern worldwide, but no studies addressed depression among patients attending outpatient department of a tertiary geriatric care hospital in Bangladesh. Methods: This cross-sectional study was conducted in face-to-face interview using the Geriatric Depression Scale (GDS-15) to measure depression among 230 elderly outpatients (60-80 years old) who visited the hospital for medical reasons in Dhaka city; a variety of socio-demographic, behavioral, and psycho-social variables as well as history of chronic diseases were assessed to detect factors associated with depression. Results: The prevalence of depression was 81.7%; 52.6%, 25.2%, and 3.9% showed mild, moderate and severe depression (the GDS scores 5-8, 9-11, and 12-15), respectively. In logistic regression models, the associated factors included marital status, occupational status, educational status, physical activity, and history of cerebrovascular diseases or stroke. The prevalence of depression was generally higher than other reports elsewhere, and the reason behind this may include the use of the GDS-15 and the setting to carry out this study. Conclusion: Nationally representative investigations are warranted to further address depression among the elderly in Bangladesh; these findings would be helpful for future studies and intervention programs.

[The Current Status of Medications in Psychiatry].

Pathophysiology of most psychiatric disorders is elusive to date and psychopharmacotherapy remains in a sense empiric. Still efforts have been made to take advantage of novel mechanisms of action or drug repurposing in order to challenge the current situations. This narrative note briefly discusses a part of such attempts.

Absence of ULK1 decreases AMPK activity in the kidney, leading to chronic kidney disease progression.

AMP-activated protein kinase (AMPK) inactivation in chronic kidney disease (CKD) leads to energy status deterioration in the kidney, constituting the vicious cycle of CKD exacerbation. Unc-51-like kinase 1 (ULK1) is considered a downstream molecule of AMPK; however, it was recently reported that the activity of AMPK could be regulated by ULK1 conversely. We demonstrated that AMPK and ULK1 activities were decreased in the kidneys of CKD mice. However, whether and how ULK1 is involved in the underlying mechanism of CKD exacerbation remains unknown. In this study, we investigated the ULK1 involvement in CKD, using ULK1 knockout mice. The CKD model of Ulk1-/- mice exhibited significantly exacerbated renal function and worsening renal fibrosis. In the kidneys of the CKD model of Ulk1-/- mice, reduced AMPK and its downstream ß-oxidation could be observed, leading to an energy deficit of increased AMP/ATP ratio. In addition, AMPK signaling in the kidney was reduced in control Ulk1-/- mice with normal renal function compared to control wild-type mice, suggesting that ULK1 deficiency suppressed AMPK activity in the kidney. This study is the first to present ULK1 as a novel therapeutic target for CKD treatment, which regulates AMPK activity in the kidney.

Electroconvulsive Therapy in a Patient With Depression on Hemodialysis: A Review of the Literature.

ABSTRACT: Evidence on electroconvulsive therapy (ECT) for people receiving chronic hemodialysis has been rather scarce in the literature. We report the case of a 74-year-old male patient with major depressive disorder on chronic hemodialysis for 14 years with numerous physical complications including abdominal aortic aneurysm, ossification of the posterior longitudinal ligament, and cerebral stroke. Several antidepressant drugs failed to improve the patient, but judicious implementation of a total of 6 ECT sessions under a close liaison with medical experts brought him into remission without any notable adverse effects. In particular, flumazenil, as well as rocuronium and sugammadex, was used together with a strict control of blood pressure. We thoroughly discuss the case and provide a literature review on such topics as assessment of physical complications, medications used for anesthesia, electrode placement, and timing of hemodialysis during ECT sessions, which identified a clear need for more research on this medically challenging issue.

Predictors of response to pharmacotherapy in children and adolescents with psychiatric disorders: A combined post hoc analysis of four clinical trial data.

OBJECTIVE: The prediction of response to pharmacotherapy has not been sufficiently explored in children and adolescents with psychiatric disorders, which was addressed in this study. METHODS: Data from four double-blind, placebo-controlled studies (sertraline and fluvoxamine for anxiety disorders, risperidone for autistic disorder, and fluoxetine for major depressive disorder) in children and adolescents funded by the National Institute of Mental Health were used. The response was defined as a score of 1 or 2 on the Clinical Global Impression-Global Improvement (CGI-I) at the endpoint. Logistic regression analysis was performed to evaluate associations between response status and the following variables: sex, diagnosis, treatment allocation, and CGI-Severity of Illness (CGI-S) score at baseline. Moreover, the presence of early improvement (a score of ≤3 in the CGI-I) at Week 1 was added to the independent variables in an additional binary logistic regression analysis, using the data from two studies. RESULTS: A total of 599 patients were included in the analysis. In the binary logistic regression analysis, active drug use (odds ratio [OR] = 8.64, P < 0.001) and female sex (OR = 1.89, P = 0.002) were significantly associated with treatment response. In the second binary logistic regression, the presence of early improvement in the CGI-I (OR = 3.47, P = 0.009), as well as active drug use (OR = 15.05, P < 0.001) and female sex (OR = 2.87, P = 0.016), were associated with subsequent responses. CONCLUSION: Allocation to active drugs, female sex, and early improvement may predict treatment response to pharmacotherapy among children and adolescents with psychiatric disorders.

Dopaminergic dysfunction and excitatory/inhibitory imbalance in treatment-resistant schizophrenia and novel neuromodulatory treatment.

Antipsychotic drugs are the mainstay in the treatment of schizophrenia. However, one-third of patients do not show adequate improvement in positive symptoms with non-clozapine antipsychotics. Additionally, approximately half of them show poor response to clozapine, electroconvulsive therapy, or other augmentation strategies. However, the development of novel treatment for these conditions is difficult due to the complex and heterogenous pathophysiology of treatment-resistant schizophrenia (TRS). Therefore, this review provides key findings, potential treatments, and a roadmap for future research in this area. First, we review the neurobiological pathophysiology of TRS, particularly the dopaminergic, glutamatergic, and GABAergic pathways. Next, the limitations of existing and promising treatments are presented. Specifically, this article focuses on the therapeutic potential of neuromodulation, including electroconvulsive therapy, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Finally, we propose multivariate analyses that integrate various perspectives of the pathogenesis, such as dopaminergic dysfunction and excitatory/inhibitory imbalance, thereby elucidating the heterogeneity of TRS that could not be obtained by conventional statistics. These analyses can in turn lead to a precision medicine approach with closed-loop neuromodulation targeting the detected pathophysiology of TRS.

[Pathological Complete Response and Long-Term Survival of a Gastric Neuroendocrine Carcinoma Patient Treated by Neoadjuvant Chemotherapy].

A 64-year-old man with gastric tumor in the antrum had been diagnosed with gastric neuroendocrine carcinoma(NEC) by biopsy and multiple lymph node metastases(#3 and #6)by abdominal computed tomography. After staging laparoscopy showed that there were no non-curative factors, neoadjuvant chemotherapy(S-1/cisplatin[CDDP]: 2 courses)and distal gastrectomy and D2 lymph node dissection were performed. The pathological diagnosis was shown as pathological complete response(pCR). After adjuvant chemotherapy(S-1/CDDP: 2 courses, S-1: 6 courses)was administered, the patient is alive at 8 years without recurrence.

MAP Bayesian modelling combining striatal dopamine receptor occupancy and plasma concentrations to optimize antipsychotic dose regimens in individual patients.

AIMS: Develop a robust and user-friendly software tool for the prediction of dopamine D2 receptor occupancy (RO) in patients with schizophrenia treated with either olanzapine or risperidone, in order to facilitate clinician exploration of the impact of treatment strategies on RO using sparse plasma concentration measurements. METHODS: Previously developed population pharmacokinetic models for olanzapine and risperidone were combined with a pharmacodynamic model for D2 RO and implemented in the R programming language. Maximum a posteriori Bayesian estimation was used to provide predictions of plasma concentration and RO based on sparse concentration sampling. These predictions were then compared to observed plasma concentration and RO. RESULTS: The average (standard deviation) response times of the tools, defined as the time required for the application to predict parameter values and display the output, were 2.8 (3.1) and 5.3 (4.3) seconds for olanzapine and risperidone, respectively. The mean error (95% confidence interval) and root mean squared error (95% confidence interval) of predicted vs. observed concentrations were 3.73 ng/mL (-2.42-9.87) and 10.816 ng/mL (6.71-14.93) for olanzapine, and 0.46 ng/mL (-4.56-5.47) and 6.68 ng/mL (3.57-9.78) for risperidone and its active metabolite (9-OH risperidone). Mean error and root mean squared error of RO were -1.47% (-4.65-1.69) and 5.80% (3.89-7.72) for olanzapine and -0.91% (-7.68-5.85) and 8.87% (4.56-13.17) for risperidone. CONCLUSION: Our monitoring software predicts concentration-time profiles and the corresponding D2 RO from sparsely sampled concentration measurements in an accessible and accurate form.

Generation of NPHP1 knockout human pluripotent stem cells by a practical biallelic gene deletion strategy using CRISPR/Cas9 and ssODN.

CRISPR/Cas9 genome editing underwent remarkable progress and significantly contributed to the development of life sciences. Induced pluripotent stem cells (iPSCs) have also made a relevant contribution to regenerative medicine, pharmacological research, and genetic disease analysis. However, knockout iPSC generation with CRISPR/Cas9 in general has been difficult to achieve using approaches such as frameshift mutations to reproduce genetic diseases with full-length or nearly full-length gene deletions. Moreover, splicing and illegitimate translation could make complete knockouts difficult. Full-length gene deletion methods in iPSCs might solve these problems, although no such approach has been reported yet. In this study, we present a practical two-step gene-editing strategy leading to the precise, biallelic, and complete deletion of the full-length NPHP1 gene in iPSCs, which is the first report of biallelic (compound heterozygous) full-gene deletion in iPSCs using CRISPR/Cas9 and single-stranded oligodeoxynucleotides mainly via single-strand template repair (SSTR). Our strategy requires no selection or substances to enhance SSTR and can be used for the analysis of genetic disorders that are difficult to reproduce by conventional knockout methods.

Catheter-related bloodstream infection in patients With severe anorexia nervosa.

PURPOSE: Anorexia nervosa (AN) may be treated with intravenous hyperalimentation (IVH) that may be associated with catheter-related bloodstream infection (CRBSI). DESIGN AND METHODS: Retrospective chart review was conducted to compare those who developed CRBSI were compared with those who did not. FINDINGS: Of 34 patients, 17 episodes of AN treated with IVH were identified, of which five resulted in CRBSI. The average body mass index at admission was low at 12.2. Patients who needed physical restraint during IVH had a higher (albeit statistically nonsignificant) risk. Also, those with purging had numerically lower risk. PRACTICE IMPLICATIONS: CRBSI complicated IVH in 29.4% instances of severe life-threatening AN in our sample. Whether physical restraints and no purging constitute a risk factor of CRBSI needs to be further investigated.

[A Case of Long-Term Survival by Multidisciplinary Surgical Treatment for Metastatic Multi-Organ Metastasis after Radical Resection of Esophageal Cancer].

A 78-year-old man with advanced thoracic esophageal cancer underwent radical esophagectomy after neoadjuvant chemotherapy with cisplatin plus 5-FU. He had left adrenal metastasis 10 months after surgery and removed it, but 3 months later he had liver metastases. After 2 courses of chemotherapy with nedaplatin plus 5-FU, resection was performed. One course of nedaplatin plus 5-FU for adjuvant chemotherapy was added, but the patient was followed up without another chemotherapy after surgery because of intestinal obstruction due to infection and increase of the lymphatic cyst in the abdominal cavity. Six months after the liver resection, nodules appeared in the right lung, and 4 months later, multiple nodules extending to both lungs were observed. Therefore, it was judged that there were multiple lung metastases, and administration of nivolumab was started. He has been 3 years since the recurrence of esophageal cancer and 17 months after the start of nivolumab administration, but the recurrence lesion is only progressing to lung metastasis.

Cancellation of outpatient appointments in patients with attention-deficit/hyperactivity disorder.

BACKGROUND: Regular visit to psychiatric clinic is essential for successful treatment of any psychiatric condition including attention-deficit/hyperactivity disorder (AD/HD). However, cancellation of outpatient appointments in patients with AD/HD, which represents a significant medical loss, has not been systematically investigated to our knowledge. METHODS: A systematic chart review was conducted for patients visiting the Shimada Ryoiku medical Center for Challenged Children in Japan at the age of ≤15 years from January to December 2013. The primary outcome measure was the cancellation rate, defined as the number of missed visits divided by the number of scheduled visits. The cancellation rates during 24 months after the first visit were compared between outpatients with AD/HD and other psychiatric disorders, including pervasive developmental disorders (PDD), and developmental coordination disorders and/or communication disorders (DCD-CD). A generalized linear model with binomial distribution was used to examine factors associated with cancellation rates exclusively in the AD/HD group. RESULTS: We included 589 patients (mean ± SD age, 5.6 ± 3.4 years; 432 males) in the analysis. The cancellation rate in patients with AD/HD was 12.3% (95% confidence interval [CI]: 10.0-15.1), which was significantly higher than in those with PDD (5.6%, 95% CI: 3.8-8.3) and DCD-CD (5.3%, 95% CI: 3.6-7.8). Prescriptions of osmotic-release oral system-methylphenidate (OROS-MPH) and antipsychotics were associated with fewer cancellations in AD/HD patients (odds ratios: 0.61, 95% CI: 0.39-0.95 and 0.49, 95% CI: 0.25-0.95, respectively), although these significances did not find in the subgroup analysis including only patients with ≥ 6 years old. CONCLUSIONS: Patients with AD/HD were more likely to miss appointments compared to those with other psychiatric disorders. The impact of AD/HD medications as well as potential psychiatric symptoms of their parents or caregivers on appointment cancellations needs to be evaluated in more detail in future investigations.

Comorbid Psychiatric Disorders in Patients Hospitalized for Pulmonary Embolism and Acute Myocardial Infarction: A Japanese Nationwide Database Study.

Objective: While the most common cause of sudden cardiac arrest (SCA) in the general population is ischemic cardiac disease including acute myocardial infarction (AMI), previous preliminary data highlighted pulmonary embolism (PE) as a common cause of SCA among psychiatric patients. The aim of this study was to examine the proportion of patients with comorbid psychiatric disorders among patients hospitalized for either AMI or PE using a Japanese nationwide database.Methods: This study used Diagnosis Procedure Combination (DPC) data between April 2013 and March 2018 provided by the Ministry of Health, Labor, and Welfare. The DPC data included information on the causes of hospitalization and comorbidities of psychiatric diseases among inpatients in all acute care hospitals in Japan. The proportions of patients with schizophrenia (ICD-10 code F20), mood disorders (F31 or F32), and no psychiatric disorders were analyzed among patients who were hospitalized for AMI and PE.Results: The data from 351,159 AMI patients (mean age = 70.3 years) and 52,036 PE patients (mean age = 69.2 years) were used. Mortality rates were 8.0%-14.4% in AMI patients and 4.3%-9.8% in PE patients. The AMI group was predominantly male. The proportions of patients with schizophrenia and mood disorder were significantly higher in the PE group than in the AMI group (schizophrenia: 2.53% [1,314/52,036] vs 0.55% [1,922/351,159], P < .001; mood disorder: 2.94% [1,532/52,036] vs 0.60% [2,099/351,159], P < .001).Conclusions: The results highlight the importance of PE as a major cause of SCA in this specific population and the need for preventive measures to mitigate the mortality gap among patients with psychiatric disorders.

Clinical Characteristics of Patients with Schizophrenia Maintained without Antipsychotics: A Cross-sectional Survey of a Case Series.

OBJECTIVE: While antipsychotics are necessary for relapse prevention in the treatment of schizophrenia in general, some minority of patients may be maintained without continuous antipsychotic treatment. However, the characteristics of such patients are not well known and previous reports have not evaluated key elements such as physical comorbidities and functioning. METHODS: Among 635 patients with schizophrenia who participated in a 12-year follow-up, those who were maintained without antipsychotic treatment for at least one year after the study were investigated. The patients underwent comprehensive assessments, including Positive and Negative Syndrome Scale (PANSS) for psychopathology, Cumulative Illness Rating Scale for Geriatrics (CIRS-G) for physical comorbidities, and Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz), Barthel Index, and EuroQoL five dimensions (EQ5D) for function. RESULTS: Six patients were included (mean ± standard deviation age, 66.8 ± 17.4 years; 4 inpatients). The four inpatients were old (77.8 ± 4.8 years) and chronically ill (duration of illness, 49.3 ± 12.5 years) with a high PANSS score (total score, 118.0 ± 9.8; negative syndrome subscale, 41.3 ± 6.9), low functioning (FACT-Sz, 9.8 ± 3.6; Barthel Index, 8.8 ± 9.6), and serious physical comorbidities (CIRS-G, 15.5 ± 1.1). By contrast, the two outpatients were relatively young (45.0 ± 12.0 years) and clinically in good condition (PANSS total score, 44.5 ± 0.5; Barthel Index, 100 for both; EQ5D, 0.85 ± 0.04). CONCLUSION: Although the number is limited, two types of patients with schizophrenia were identified who were free from ongoing antipsychotic treatment; 1) older chronic inpatients with serious physical comorbidities, and 2) younger outpatients with milder impairments. Future explorations are needed to identify those who will be successfully withdrawn from continuous antipsychotic treatment.