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Despite the tremendous effort in the oncology community, the success rate of anticancer development remained low at 30% to 40% from the Phase 3 study to the regulatory approval. The factors associated with the regulatory approval for market authorization have gained interest in the community to improve the success rate of drug development. Using the data from 208 Phase 3 studies for anticancer drugs, we explored the possible factors associated with the US Food and Drug Administration's (FDA's) approval by multivariate logistic regression analysis. The model incorporated 21 factors from therapeutic context, study design, and outcomes. The hazard ratio (HR) for overall survival (OS) showed a significant association with FDA approval (coefficient: -29.907, P < .001), and the age of control drugs in the market followed (coefficient: -2.581, P = .008). In the model, if the HR for OS changes from 0.75 to 0.85, the probability of FDA approval remarkably decreases from 79.6% to 16.4%. A 50% likelihood of FDA approval is predicted at HR 0.795 for OS. Furthermore, the P-value for the OS test and the width of the confidence interval on HR for OS showed a significant association with the probability of FDA approval. These findings consistently underscore the rigorous standard required for new anticancer drugs to obtain regulatory approval from the FDA., (© 2024 The Author(s). The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60-90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0-2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: This study was approved by the Institutional Review Board of Yokohama City University Faculty of Medicine. After obtaining written informed consent, peripheral blood leukocytes were collected from the patients and their parents., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

Aims: The Pemafibrate for Prevention of Atherosclerotic Diseases in Stroke (PPAR Stroke) study aimed to assess the effects of pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, on the progression of cerebrovascular atherosclerosis in patients with stroke and hypertriglyceridemia., Methods: Ninety-nine patients (mean age, 65.6 years; male, 74.7%) with hypertriglyceridemia and a history of stroke or transient ischemic attack of non-cardioembolic origin were included in this prospective single-arm study. Hypertriglyceridemia was defined as a fasting serum triglyceride (TG) level ≥ 150 mg/dL. All patients were treated with pemafibrate (0.2 mg or 0.1 mg/day) for 2 years. The primary outcome was change in carotid intima-media thickness (IMT) from baseline at 2 years, as assessed using carotid ultrasonography. The secondary outcomes were changes in blood biomarker levels and progression of intracranial artery stenosis on magnetic resonance angiography., Results: The mean TG level significantly decreased from 269 mg/dL at baseline to 139 mg/dL at 2 years (P＜0.001) and high-density lipoprotein cholesterol level increased from 49 to 54 mg/dL (P＜0.001), whereas low-density lipoprotein cholesterol level remained unchanged. Significant reductions in high-sensitivity C-reactive protein and interleukin-6 levels were also observed (P=0.003 and P=0.002, respectively). With regard to mean IMT in the internal carotid arteries, the difference was significant for the left side (1.59 mm at baseline vs. 1.52 mm at 2 years; P=0.009) and borderline significant for the right side (1.32 mm at baseline vs. 1.28 mm at 2 years; P=0.053). Among the 48 stenotic lesions in the intracranial arteries, regression and progression was observed in 9 (18.8%) and 4 (8.3%) cases, respectively., Conclusions: Pemafibrate was observed to have TG-lowering and anti-inflammatory effects and could attenuate atherosclerosis progression in the intra- and extracranial arteries of patients with stroke and hypertriglyceridemia.

Representing data using time-resolved networks is valuable for analyzing functional data of the human brain. One commonly used method for constructing time-resolved networks from data is sliding window Pearson correlation (SWPC). One major limitation of SWPC is that it applies a high-pass filter to the activity time series. Therefore, if we select a short window (desirable to estimate rapid changes in connectivity), we will remove important low-frequency information. Here, we propose an approach based on single sideband modulation (SSB) in communication theory. This allows us to select shorter windows to capture rapid changes in the time-resolved functional network connectivity (trFNC). We use simulation and real resting-state functional magnetic resonance imaging (fMRI) data to demonstrate the superior performance of SSB+SWPC compared to SWPC. We also compare the recurring trFNC patterns between individuals with the first episode of psychosis (FEP) and typical controls (TC) and show that FEPs stay more in states that show weaker connectivity across the whole brain. A result exclusive to SSB+SWPC is that TCs stay more in a state with negative connectivity between subcortical and cortical regions. Based on all the results, we argue that SSB+SWPC is more sensitive for capturing temporal variation in trFNC., Competing Interests: Competing Interests: The authors have declared that no competing interests exist., (© 2024 Massachusetts Institute of Technology.)

Background: Despite several reports on red blood cell (RBC) alloimmunization, the actual prevalence and factors contributing to RBC alloimmunization in transfused patients remain poorly investigated. We examined the association between clinical factors and the development and evanescence of RBC antibodies after transfusion., Study Design and Methods: Each participating institution performed antibody screens before and after RBC transfusion. A survey including patient characteristics, results of antibody screen and identification, antibody screen methods, total amount of RBC transfused, and adverse reactions, was conducted., Results: Between October 2018 and March 2023, 1194 patients were registered at five institutions. Overall, 958 patients underwent at least one follow-up RBC antibody screen after transfusion, revealing new antibody development in 44 (4.6%). Anti-E was identified in 25 patients, anti-Jk a in 5, and anti-c in 4. The number of RBC units transfused was significantly associated with antibody development after transfusion (p < .001). Among 55 patients in whom antibodies were identified after transfusion, including historical antibodies, antibodies evanesced in 18 (33%); anti-E in 7, anti-Jk a in 4, and anti-Le a in 2. Evanescent antibodies were identified more frequently by saline and/or enzyme methods than persistent antibodies (p = .012)., Discussion: The number of RBC units transfused can impact antibody development, and antibodies identified only by saline and/or enzyme methods, deemed clinically insignificant, are likely to have a high evanescence rate. Antibody screen should be carefully performed, especially in those receiving a large number of RBC units. Confirming previous antibody screen results should be performed to prevent omitting evanesced antibodies regardless of clinical relevance., (© 2024 AABB.)

We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute cellular stress in which deficits in rule shifting tasks were elicited, the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade was activated specifically in microglia in the prelimbic cortex. The cognitive deficits were normalized with a pharmacological intervention with a compound (the RR compound) that selectively blocked the initiation of N-GAPDH cascade without affecting glycolytic activity. The normalization was also observed with a microglia-specific genetic intervention targeting the N-GAPDH cascade. At the mechanistic levels, the microglial secretion of High-Mobility Group Box (HMGB), which is known to bind with and regulate the NMDA-type glutamate receptors, was elevated. Consequently, the hyperactivation of the prelimbic layer 5 excitatory neurons, a neural substrate for cognitive inflexibility, was also observed. The upregulation of the microglial HMGB signaling and neuronal hyperactivation were normalized by the pharmacological and microglia-specific genetic interventions. Taken together, we show a pivotal role of cortical microglia and microglia-neuron interaction in stress-induced cognitive inflexibility. We underscore the N-GAPDH cascade in microglia, which causally mediates stress-induced cognitive alteration., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

While macrophage heterogeneity during metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages during MASH regression is poorly understood. Comparing macrophage heterogeneity during MASH progression vs regression, we identified specific macrophage subpopulations that are critical for MASH/fibrosis resolution. We elucidated the restorative pathways and gene signatures that define regression-associated macrophages and establish the importance of TREM2 + macrophages during MASH regression. Liver-resident Kupffer cells are lost during MASH and are replaced by four distinct monocyte-derived macrophage subpopulations. Trem2 is expressed in two macrophage subpopulations: i) monocyte-derived macrophages occupying the Kupffer cell niche (MoKC) and ii) lipid-associated macrophages (LAM). In regression livers, no new transcriptionally distinct macrophage subpopulation emerged. However, the relative macrophage composition changed during regression compared to MASH. While MoKC was the major macrophage subpopulation during MASH, they decreased during regression. LAM was the dominant macrophage subtype during MASH regression and maintained Trem2 expression. Both MoKC and LAM were enriched in disease-resolving pathways. Absence of TREM2 restricted the emergence of LAMs and formation of hepatic crown-like structures. TREM2 + macrophages are functionally important not only for restricting MASH-fibrosis progression but also for effective regression of inflammation and fibrosis. TREM2 + macrophages are superior collagen degraders. Lack of TREM2 + macrophages also prevented elimination of hepatic steatosis and inactivation of HSC during regression, indicating their significance in metabolic coordination with other cell types in the liver. TREM2 imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid handling, and collagen degradation., Competing Interests: Competing interests statement:R.L. serves as a consultant to Aardvark Therapeutics, Altimmune, Arrowhead Pharmaceuticals, AstraZeneca, Cascade Pharmaceuticals, Eli Lilly, Gilead, Glympse bio, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Lipidio, Madrigal, Neurobo, Novo Nordisk, Merck, Pfizer, Sagimet, 89 bio, Takeda, Terns Pharmaceuticals and Viking Therapeutics. C.K.G. is a founder and member of the SAB of Asteroid Pharmaceuticals. A.E.F. is an employee and stockholder of Novo Nordisk. C.K.G. is a stockholder of Asteroid Therapeutics. R.L. is a co-founder and equity holder of LipoNexus Inc. R.L. received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sonic Incytes and Terns Pharmaceuticals.

Background: Kidney transplantation (KT) in children and adolescents with severe motor and intellectual disabilities (SMID) has been a topic of controversy. A multicenter study in Japan showed that KT was not contraindicated for children with multiple handicaps, but no consensus has been reached on KT for patients with SMID. This study aimed to determine whether KT is a viable treatment option for children and adolescents with SMID., Methods: A single-center, retrospective study was conducted on children and adolescents with SMID who underwent KT. SMID was defined based on Oshima's classification. Clinical information was collected through a review of medical records., Results: Of 453 children and adolescents who underwent KT between 1983 and 2023 in our institution, six (1.3%) patients with SMID were identified. One patient received KT twice. All patients underwent living KT. Five patients used medical devices, including gastrostomy and a ventriculoperitoneal shunt, prior to KT. Perioperative complications, including hemothorax related to central venous catheter insertion, ventilator-associated pneumonia, and common iliac artery thrombosis requiring graftectomy, occurred in three patients. One patient required vesicostomy owing to refractory urinary tract infection. There was no significant difference in the graft survival rate between patients with SMID and those without SMID. One patient developed graft failure and died after selecting conservative kidney management., Conclusion: Our study showed a favorable graft survival in children and adolescents with SMID who underwent KT. Although careful perioperative management and continued medical care are required, KT may be a viable option for these patients., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Anterior, lateral, and posterior cutaneous nerve entrapment syndromes have been proposed as etiologies of trunk pain. However, while these syndromes are analogous, comprehensive reports contrasting the three subtypes are lacking. We therefore reviewed the literature on anterior, lateral, and posterior cutaneous nerve entrapment syndrome. We searched the PubMed and Cochrane Library databases twice for relevant articles published between March and September 2022. In addition to 16 letters, technical reports, and review articles, a further 62, 6, and 3 articles concerning anterior, lateral, and posterior cutaneous nerve entrapment syndromes, respectively, were included. These syndromes are usually diagnosed based solely on unique history and examination findings; however, the diagnostic process may be prolonged, and multiple re-evaluations are required. The most common first-line treatment is trigger point injection; however, the management of refractory cases remains unclear. Awareness of this disease should be expanded to medical departments other than general medicine.

Background: This study aimed to clarify the characteristics and survival prediction value of transcranial Doppler microembolic signals (MES) in patients with acute cerebral infarction and active cancer., Methods and Results: Between 2017 and 2022, 1089 cases of acute cerebral infarction were recorded within 7 days of disease onset. Among them, transcranial Doppler was successful in 33 patients who had active cancer, and these data were analyzed in this study. The primary outcomes were stroke recurrence and mortality at 3 months. The study population had the following characteristics [median (interquartile range)]: age, 70 years (63-78); body mass index, 21.6 (20-24), National Institutes of Health Stroke Scale 3 (1-6), and modified Rankin Scale score at discharge 1 (1-4). The most common cancer types were lung (24%), pancreatic (24%), and intestinal (18%). MES was present in 16 of 33 patients (48.5%). The presence and number of MES were significantly associated with the levels of D-dimer ( P <0.001) and C-reactive protein ( P =0.012). Moreover, the presence of MES was associated with multiple ischemic lesions and the 3-territory sign on magnetic resonance imaging. Of the 33 patients, 9 died at 3 months, and 1 had stroke recurrence. On Cox multivariate analysis, using the MES-negative group as a reference, the presence of MES was significantly associated with all-cause death (adjusted hazard ratio, 12.19 [95% CI, 1.45-216.85]; P =0.020)., Conclusions: In patients with acute ischemic stroke and active cancer, the presence of MES was associated with D-dimer and C-reactive protein levels and multiple and 3-territory ischemic lesions, and was predictive of short-term survival.

Background: Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation and is associated with poor graft survival. Patients who do not achieve remission (nonresponders) have an especially poor graft survival. However, the characteristics that may affect graft survival in nonresponders are unknown. This study aimed to determine the clinical characteristics associated with graft survival in nonresponders., Methods: We retrospectively collected the clinical records of patients with FSGS and an age at onset <16 years who experienced posttransplant recurrence of FSGS at six hospitals in Japan from 1993 to 2018., Results: Eight nonresponders with recurrent FSGS were enrolled in this study. The median time to recurrence after kidney transplantation was 1 day (interquartile range, 1-2 days). All patients received therapeutic plasma exchange and methylprednisolone pulse therapy. Rituximab was used as an add-on therapy in three patients. Five patients lost their graft within 2 years after kidney transplantation (rapid group). In contrast, three patients had much longer graft survival (nonrapid group). We compared the clinical characteristics of the rapid and nonrapid groups. Proteinuria tended to be lower in the nonrapid group at the third and subsequent months of therapy. The rapid group had persistent nephrotic syndrome. The rate of reduction in proteinuria was lower in the rapid group than in the nonrapid group., Conclusions: Our study suggests that persistent nephrotic syndrome and a low rate of reduction in proteinuria may predict rapid progression to graft failure in nonresponders., (© 2024 Wiley Periodicals LLC.)

Objectives: To present a rare case of neonatal lupus erythematosus (NLE) associated with suspected hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS)., Case Presentation: A female infant weighing 2,995 g was born to a mother without medical history of any disease. At birth, the patient had erythematous papules on her face and trunk. She was admitted at 1 day of age with elevated C-reactive protein levels. The patient was diagnosed with NLE based on the presence of anti-Ro/SSA and anti-La/SSB antibodies. Thereafter, it became clear that the antibody levels in her mother were also elevated. At 20 days of age, the infant showed elevated transaminases, ferritin, triglyceride, and soluble interleukin-2 receptor levels. Although HLH or MAS was suspected, she did not fulfill the diagnostic criteria. Thereafter, these abnormal values spontaneously improved, and the skin rash improved with the use of topical steroids. The patient was discharged at 39 days of age. At 1 year of age, the patient's growth and development were normal., Conclusion: NLE should be considered in infants with an unexplained skin rash at birth. When a diagnosis is made, close observation of the infant's clinical features is needed to determine whether they will develop HLH or MAS.

Background: Evidence for the pathogenesis and treatment of postacute coronavirus disease 2019 (COVID-19) (long COVID) is lacking. As long COVID symptoms are predicted to have an impact on the global economy, clarification of the pathogenesis is urgently needed. Our experiences indicated that some symptoms were complicated by diseases established before the COVID-19 pandemic., Methods: Using a retrospective, cross-sectional study, we aimed to evaluate the diseases complicating long COVID. Using the medical records of patients with confirmed COVID-19 exhibiting residual symptoms lasting ≥60 days postinfection who visited our clinic in January 2021-February 2023, we investigated the symptoms and diseases observed. We identified diseases that occurred after COVID-19 and excluded those that were exacerbations of existing diseases., Results: During the first visit, the most common symptoms reported in a total of 798 patients were fatigue (523 patients), anxiety (349 patients), and lack of motivation (344 patients). Complicating diseases were observed in 452 patients (57%). There were 115, 65, and 60 patients with postural tachycardia syndrome, postural syndrome without tachycardia, and mood disorders, respectively. Some diseases requiring immediate treatment included pulmonary thromboembolism, purulent shoulder arthritis, cerebellopontine angle tumors, myasthenia gravis, and cervical myelopathy., Conclusion: Not all symptoms that occur after COVID-19 should be treated as long COVID. Similar to normal medical treatment, a list of differential diagnoses should be maintained based on symptoms to obtain definitive diagnoses., Competing Interests: The authors declare no conflict of interest for this article., (© 2024 The Author(s). Journal of General and Family Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Primary Care Association.)

Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest.

Atomic-scale observations of a specific local area would be considerably beneficial when exploring new fundamental materials and devices. The development of hardware-type aberration correction 1,2 in electron microscopy has enabled local structural observations with atomic resolution 3-5 as well as chemical and vibration analysis 6-8 . In magnetic imaging, however, atomic-level spin configurations are analysed by electron energy-loss spectroscopy by placing samples in strong magnetic fields 9-11 , which destroy the nature of the magnetic ordering in the samples. Although magnetic-field-free observations can visualize the intrinsic magnetic fields of an antiferromagnet by unit-cell averaging 12 , directly observing the magnetic field of an individual atomic layer of a non-uniform structure is challenging. Here we report that the magnetic fields of an individual lattice plane inside materials with a non-uniform structure can be observed under magnetic-field-free conditions by electron holography with a hardware-type aberration corrector assisted by post-digital aberration correction. The magnetic phases of the net magnetic moments of (111) lattice planes formed by opposite spin orderings between Fe 3+ and Mo 5+ in a ferrimagnetic double-perovskite oxide (Ba 2 FeMoO 6 ) were successfully observed. This result opens the door to direct observations of the magnetic lattice in local areas, such as interfaces and grain boundaries, in many materials and devices., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Key Clinical Message: A whirl sign on contrast-enhanced abdominal CT scan is indicative of intestine twisted around the mesenteric vessels, and is observed in cases of strangulated obstruction, signaling compromised intestinal circulation. In cases of intestinal volvulus, surgery is necessary to untwist the affected bowel, and resection is necessary if necrosis is present., Abstract: A 31-year-old Japanese man presented with acute lower abdominal pain and vomiting. Contrast-enhanced abdominal computed tomography (CT) revealed a 1440-degree clockwise torsion of superior mesenteric artery and a whirl sign. Intestinal volvulus in adulthood with a background of malrotation is extremely rare. Contrast-enhanced CT is effective for diagnosis., Competing Interests: The authors state that they have no conflict of interest., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: Manual chart review using validated assessment tools is a standardised methodology for detecting diagnostic errors. However, this requires considerable human resources and time. ChatGPT, a recently developed artificial intelligence chatbot based on a large language model, can effectively classify text based on suitable prompts. Therefore, ChatGPT can assist manual chart reviews in detecting diagnostic errors., Objective: This study aimed to clarify whether ChatGPT could correctly detect diagnostic errors and possible factors contributing to them based on case presentations., Methods: We analysed 545 published case reports that included diagnostic errors. We imputed the texts of case presentations and the final diagnoses with some original prompts into ChatGPT (GPT-4) to generate responses, including the judgement of diagnostic errors and contributing factors of diagnostic errors. Factors contributing to diagnostic errors were coded according to the following three taxonomies: Diagnosis Error Evaluation and Research (DEER), Reliable Diagnosis Challenges (RDC) and Generic Diagnostic Pitfalls (GDP). The responses on the contributing factors from ChatGPT were compared with those from physicians., Results: ChatGPT correctly detected diagnostic errors in 519/545 cases (95%) and coded statistically larger numbers of factors contributing to diagnostic errors per case than physicians: DEER (median 5 vs 1, p<0.001), RDC (median 4 vs 2, p<0.001) and GDP (median 4 vs 1, p<0.001). The most important contributing factors of diagnostic errors coded by ChatGPT were 'failure/delay in considering the diagnosis' (315, 57.8%) in DEER, 'atypical presentation' (365, 67.0%) in RDC, and 'atypical presentation' (264, 48.4%) in GDP., Conclusion: ChatGPT accurately detects diagnostic errors from case presentations. ChatGPT may be more sensitive than manual reviewing in detecting factors contributing to diagnostic errors, especially for 'atypical presentation'., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The current study aimed to investigate the effect of Sox9-Cre-directed Nr5a1-conditional knockout (Sox9-Cre;Nr5a1 flox/flox ) on adrenal development. We showed that SOX9 is expressed by adrenocortical cells at E10.5-E11.5 but is extinguished no later than E12.5. The number of adrenocortical cells significantly reduced in Sox9-Cre;Nr5a1 flox/flox mice while the number of cleaved caspase 3-positive cells increased compared to that in the controls at E11.5-E12.5, when the adrenal primordium (AP) is about to expand. This indicated that fetal adrenocortical cells are lost via apoptosis due to Nr5a1 ablation by E12.5. Both medulla formation and encapsulation were perturbed, accompanied by a smaller AP size, in Sox9-Cre;Nr5a1 flox/flox mice during embryonic development. Adult Sox9-Cre;Nr5a1 flox/flox adrenals were hypoplastic and exhibited irregular organization of the medulla with aberrant sex differentiation in the X zone. Additionally, there were histologically eosin-negative vacuolated cells, which were negative for both the X-zone marker 20αHSD and the steroidogenesis marker 3βHSD at the innermost cortex of Sox9-Cre;Nr5a1 flox/flox adrenals. Although Nr5a1 +/- adrenals were hypoplastic, a small number of chromaffin cells were properly located in the center, having normal sex differences in the X-zone. The results collectively provided in-vivo evidence that Nr5a1 plays a critical role in AP expansion and subsequent adrenal development., (© 2024. The Author(s).)

Smell deficits and neurobiological changes in the olfactory bulb (OB) and olfactory epithelium (OE) have been observed in schizophrenia and related disorders. The OE is the most peripheral olfactory system located outside the cranium, and is connected with the brain via direct neuronal projections to the OB. Nevertheless, it is unknown whether and how a disturbance of the OE affects the OB in schizophrenia and related disorders. Addressing this gap would be the first step in studying the impact of OE pathology in the disease pathophysiology in the brain. In this cross-species study, we observed that chronic, local OE inflammation with a set of upregulated genes in an inducible olfactory inflammation (IOI) mouse model led to a volume reduction, layer structure changes, and alterations of neuron functionality in the OB. Furthermore, IOI model also displayed behavioral deficits relevant to negative symptoms (avolition) in parallel to smell deficits. In first episode psychosis (FEP) patients, we observed a significant alteration in immune/inflammation-related molecular signatures in olfactory neuronal cells (ONCs) enriched from biopsied OE and a significant reduction in the OB volume, compared with those of healthy controls (HC). The increased expression of immune/inflammation-related molecules in ONCs was significantly correlated to the OB volume reduction in FEP patients, but no correlation was found in HCs. Moreover, the increased expression of human orthologues of the IOI genes in ONCs was significantly correlated with the OB volume reduction in FEP, but not in HCs. Together, our study implies a potential mechanism of the OE-OB pathology in patients with psychotic disorders (schizophrenia and related disorders). We hope that this mechanism may have a cross-disease implication, including COVID-19-elicited mental conditions that include smell deficits., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Case reports are fundamental to clinical medicine that trace back to ancient Egypt preceding Hippocrates in the history of medicine. Case reports contribute to academic development and new clinical research. However, among cases presented at an annual academic conference for Japanese generalists, only a few cases were later published in peer-reviewed journals, highlighting potential barriers regarding the writing of case reports, such as mentorship absence. This paper aimed to offer guidance and strategies to novice and young general physicians in overcoming barriers and effectively composing case reports for international peer-reviewed journals., Methods: This paper focuses on case reports for general physicians with extensive experience in writing case reports for international peer-reviewed journals. We conducted a narrative review to help beginners and young general physicians in writing case reports and discussed strategies for overcoming these barriers., Results: We propose the following three tips as important processes for writing case reports: recognize the types of suitable cases for case reports; select a journal for submission using a list of candidate journals for general physicians; and organize the discussion section with one theme per paragraph. In addition, we provide a list of journals that specifically focus on case reports, along with important pointers for beginners and young general physicians that will assist authors in the field of general medicine in choosing appropriate journals for submission., Conclusion: We hope that understanding and applying these tips will aid beginners and young general physicians in writing case reports., Competing Interests: The authors report no other conflicts of interest in this work., (© 2024 Ishizuka et al.)

Purpose: To compare the details, oncologists include in discharge letters with what home care physicians need. Although discharge letters are important to share patients' information for home palliative care, few studies have compared the details, especially patients' emotions, regarding what oncologists include in discharge letters and home care physicians' needs., Methods: This cross-sectional study was conducted by sending anonymous, self-administered questionnaires to 500 certified oncologists (OCs) and 500 directors of home care supporting clinics (HCs) in Japan between March and May 2023. The survey considered 20 potential items found in discharge letters, and compared rates of OCs including these items and HCs needs., Results: Of 310 valid responses, 186 were from OCs (average age: 47.7; 29 females) and 124 from HCs (average age: 55.4; 9 females). Major items with lower inclusion rates for OCs included patients' emotions regarding medical conditions (58.4% in OCs vs. 92.6% in HCs, p < 0.001), families' emotions regarding medical conditions (60.0 vs. 92.6%, respectively, p < 0.001), patients' perceptions regarding medical conditions (84.9 vs. 94.3%, respectively, p = 0.011), families' perceptions regarding medical conditions (84.3 vs. 95.1%, respectively, p = 0.004), and potential late-onset treatment-related adverse events (79.3 vs. 92.6%, respectively, p = 0.002). Conversely, OCs included patients' activities of daily living more frequently (96.2 vs. 90.2%, respectively, p = 0.031)., Conclusion: Transitioning to home-based palliative care may necessitate accurate information and consideration of patients' and families' perceptions and emotions regarding medical conditions in discharge letters for continuous provision of high-quality care., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: There are currently no studies that quantitatively compare the relationship of root resorption to the patient's systemic history or craniofacial and intraoral morphology, especially in relation to possible host factors. Thus, this study aimed to clarify the factors associated with root resorption in retained mandibular second deciduous molars with the congenital absence of second premolars and predict the prognosis of retained mandibular second deciduous molars., Methods: A cohort of 5547 patients who visited the orthodontic clinic at Tokyo Medical and Dental University Dental Hospital between 2013 and 2022 was screened. Lateral cephalometric radiographs, panoramic radiographs, upper and lower dental models, and orthodontic treatment questionnaires were used as reference materials to apply the inclusion and exclusion criteria. Ultimately, 111 patients were included in the analyses. The patients were divided into two groups based on the root resorption levels of the retained mandibular second deciduous molars. Those with less root resorption were classified under the good condition (GC) group, whereas those with more root resorption were classified under the poor condition (PC) group. Demographic, clinical, and cephalometric parameters were compared between the groups. A multivariate logistic regression model was used to predict the probability of root resorption., Results: The prevalence of congenitally missing mandibular second premolars with persistent mandibular second deciduous molars was 2.0%. In a total of 111 patients, eighty-three teeth (53.2%) were classified into the GC group, whereas 73 teeth (46.8%) were classified into the PC group. The Frankfort-mandibular plane angle (FMA) [odds ratio (OR): 0.87], Frankfort-mandibular incisor angle (FMIA) (OR: 0.93), overbite (OR: 1.38), adjacent interdental space (OR: 1.46), distance from occlusal plane (OR: 0.80), and caries treatment (OR: 7.05) were significantly associated with the root resorption of the retained mandibular second deciduous molars., Conclusions: Our findings suggest that skeletal morphology, oral morphological patterns, and history contribute to root resorption in retained mandibular second deciduous teeth with congenital absence of subsequent permanent teeth., (© 2024. The Author(s).)

Background: CD34 is a transmembrane phosphoglycoprotein and a marker of hematopoietic and nonhematopoietic stem/progenitor cells. In experimental studies, CD34+ cells are rich sources of endothelial progenitor cells and can promote neovascularization and endothelial repair. The potential role of CD34+ cells in stroke patients remains unclear., Aims: We aimed to assess the prognostic effect of circulating CD34+ cell levels on the risk of vascular events and functional prognosis in stroke patients., Patients and Methods: In this prospective observational study, patients with ischemic stroke were consecutively enrolled within 1 week of onset and followed up for 1 year. Patients were divided into three groups according to tertiles of the level of circulating CD34+ cells (Tertile 1, <0.51/µL; Tertile 2, 0.51-0.96/µL; and Tertile 3, >0.96/µL). The primary outcome was a composite of major adverse cardiovascular events (MACEs), including nonfatal stroke, nonfatal acute coronary syndrome, major peripheral artery disease, and vascular death. The secondary outcomes included the modified Rankin scale (mRS) scores., Results: A total of 524 patients (mean age, 71.3 years; male, 60.1%) were included. High CD34+ cell levels were associated with younger age ( p  < 0.001) and low National Institutes of Health Stroke Scale scores at admission ( p  = 0.010). No significant differences were found in the risk of MACEs among the three groups (annual rates: 15.0%, 13.4%, and 12.6% in Tertiles 1, 2, and 3, respectively; log-rank p  = 0.70). However, there were significant differences in the mRS scores at 3 months (median (interquartile range); 2 (1-4), 1 (1-3), and 1 (0-2) in Tertiles 1, 2, and 3, respectively; p  = 0.010) and 1 year (3 (1-4), 2 (1-4), and 1 (0-3); p  < 0.001) among these groups. After multivariable adjustments, a higher CD34+ cell level was independently associated with good functional outcomes (mRS score of 0-2) at 3 months (adjusted odds ratio (OR), 1.43; 95% confidence interval (CI), 1.01-2.05) and 1 year (adjusted OR, 1.53; 95% CI, 1.09-2.16)., Conclusion: Although no correlations were found between circulating CD34+ cell levels and vascular event risk, elevated CD34+ cell levels were associated with favorable functional recovery in stroke patients., Data Access Statement: Data supporting the findings of this study are available from the corresponding author on reasonable request., Clinical Trial Registration: The TWMU Stroke Registry is registered at https://upload.umin.ac.jp as UMIN000031913., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.K. received personal fees from Kyowa Kirin, grants and personal fees from Daiichi Sankyo, and grants from Bayer and Dainihon–Sumitomo outside the submitted work. Other authors have no conflicts of interest to disclose.

Case reports provide scientific knowledge and opportunities for new clinical research. However, it is estimated that less than 5% of cases presented by Japanese generalists at academic conferences are published due to various barriers such as the complex process of writing articles, conducting literature searches, the significant time required, the reluctance to write in English, and the challenge of selecting appropriate journals for publication. Therefore, the purpose of this opinion paper is to provide clinicians with practical tips for writing case reports that promote diagnostic excellence. In recent years, clinical practitioners have been striving for diagnostic excellence and optimal methods to accurately and comprehensively understand the patient's condition. To write a case report, it is essential to be mindful of the elements of diagnostic excellence and consider the quality of the diagnostic reasoning process. We (the authors) are seven academic generalists who are members of the Japanese Society of Hospital General Medicine (JSHGM) - Junior Doctors Association, with a median of 7 years after graduation and extensive experience publishing case reports in international peer-reviewed journals. We conducted a narrative review and discussed ways to write case reports to promote diagnostic excellence, leveraging our unique perspectives as academic generalists. Our review did not identify any reports addressing the critical points in writing case reports that embody diagnostic excellence. Therefore, this report proposes a methodology that describes the process involved in writing diagnostic excellence-promoting case reports and provides an overview of the lessons learned. Based on our review and discussion, we explain the essential points for promoting diagnostic excellence through case reports categorized into seven components of clinical reasoning. These strategies are useful in daily clinical practice and instrumental in promoting diagnostic excellence through case reports., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Nishizawa et al.)

Possible roles of anti-nephrin antibodies in post-transplant recurrent focal segmental glomerulosclerosis (FSGS) have been reported recently. To confirm these preliminary results, we performed a multi-institutional study of 22 Japanese pediatric kidney transplant recipients with FSGS including eight genetic FSGS and 14 non-genetic (presumed primary) FSGS. Eleven of the 14 non-genetic FSGS patients had post-transplant recurrent FSGS. Median (interquartile range) plasma levels of anti-nephrin antibodies in post-transplant recurrent FSGS measured using ELISA were markedly high at 899 (831, 1292) U/mL (cutoff 231 U/mL) before transplantation or during recurrence. Graft biopsies during recurrence showed punctate IgG deposition co-localized with nephrin that had altered localization with increased nephrin tyrosine phosphorylation and Src homology and collagen homology A expressions. Graft biopsies after remission showed no signals for IgG and a normal expression pattern of nephrin. Anti-nephrin antibody levels decreased to 155 (53, 367) U/mL in five patients with samples available after remission. In patients with genetic FSGS as in those with non-genetic FSGS without recurrence, anti-nephrin antibody levels were comparable to those of 30 control individuals, and graft biopsies had no signals for IgG and a normal expression pattern of nephrin. Thus, our results suggest that circulating anti-nephrin antibodies are a possible candidate for circulating factors involved in the pathogenesis of post-transplant recurrent FSGS and that this may be mediated by nephrin phosphorylation. Larger studies including other ethnicities are required to confirm this finding., (Copyright © 2023 International Society of Nephrology. All rights reserved.)

Background: This study aimed to assess the effects of left ventricular diastolic dysfunction (LVDD) on vascular outcomes among patients with stroke of noncardioembolic origins., Methods: This prospective observational study enrolled 563 patients with noncardioembolic stroke (mean age, 67.9 years; 66.7% men and 33.3% women individuals) registered in the Tokyo Women's Medical University Stroke Registry between 2013 and 2020. Then, patients were divided into the LVDD and non-LVDD groups. The primary outcome was a composite of major adverse cardiovascular events, including nonfatal stroke, nonfatal acute coronary syndrome, and vascular death 1 year after stroke onset. The effect of LVDD on vascular events was assessed using multivariable Cox regression analyses., Results: A total of 130 (23.1%) patients had any grade of LVDD, and patients with LVDD had a higher risk of major adverse cardiovascular event at 1 year than those without LVDD (annual rate, 20.9% versus 10.8%; log-rank P =0.001). The multivariable Cox proportional hazards regression model demonstrated that the presence of LVDD was independently associated with the major adverse cardiovascular event risk (hazard ratio, 1.79 [95% CI, 1.02-3.12]; P =0.019). Furthermore, the LVDD grade was proportional to the risk of major adverse cardiovascular events and recurrent stroke., Conclusions: LVDD may be associated with further vascular events after a noncardioembolic stroke, suggesting the importance of LVDD evaluations in risk stratification and secondary prevention in patients with noncardioembolic stroke., Registration: URL: https://upload.umin.ac.jp; Unique identifier: UMIN000031913., Competing Interests: Disclosures Dr Kitagawa reports personal fees from Kyowa Kirin, grants and personal fees from Daiichi Sankyo, grants from Bayer, and grants from Dainihon Sumitomo outside the submitted work. The other authors report no conflicts.

Aim: Depressive disorder is often evaluated using established rating scales. However, consistent data collection with these scales requires trained professionals. In the present study, the "rater & estimation-system" reliability was assessed between consensus evaluation by trained psychiatrists and the estimation by 2 models of the AI-MADRS (Montgomery-Asberg Depression Rating Scale) estimation system, a machine learning algorithm-based model developed to assess the severity of depression., Methods: During interviews with trained psychiatrists and the AI-MADRS estimation system, patients responded orally to machine-generated voice prompts from the AI-MADRS structured interview questions. The severity scores estimated from two models of the AI-MADRS estimation system, the max estimation model and the average estimation model, were compared with those by trained psychiatrists., Results: A total of 51 evaluation interviews conducted on 30 patients were analyzed. Pearson's correlation coefficient with the scores evaluated by trained psychiatrists was 0.76 (95% confidence interval 0.62-0.86) for the max estimation model, and 0.86 (0.76-0.92) for the average estimation model. The ANOVA ICC rater & estimation-system reliability with the evaluation scores by trained psychiatrists was 0.51 (-0.09 to 0.79) for the max estimation model, and 0.75 (0.55-0.86) for the average estimation model., Conclusion: The average estimation model of AI-MADRS demonstrated substantially acceptable rater & estimation-system reliability with trained psychiatrists. Accumulating a broader training dataset and the refinement of AI-MADRS interviews are expected to improve the performance of AI-MADRS. Our findings suggest that AI technologies can significantly modernize and potentially revolutionize the realm of depression assessments., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Remote ischemic conditioning (RIC) has attracted much attention as a protective strategy for the heart and brain, although the underlying mechanisms remain unclear. We hypothesized that RIC enhances collateral circulation during cerebral ischemia through endothelial function and mitigates both early ischemic change and final infarct volume. We tested the RIC and sham procedure 30 min after permanent middle cerebral artery occlusion (MCAO) in male mice. Collateral circulation was examined during the procedure with 2D color-coded ultrasound imaging. Immediately after four cycles of RIC, early ischemic lesions on magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and development of pial collateral vessels were examined. The neurological signs and infarct volume with TTC were examined until 48 h after daily RIC. As compared with sham procedure, RIC enhanced collateral circulation, diminished early ischemic lesions, enlarged pial collaterals, and mitigated infarct volume. Next, we examined the effect of inhibitor of nitric oxide synthase (NOS) and Akt on the beneficial effect of RIC in MCAO. Both allosteric Akt inhibitor, 8-[4-(1-Aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3(2H)-one (MK2206), and two NOS inhibitors, N5-(1-Iminoethyl)-L-ornithine dihydrochloride (L-NIO) and NG-Nitro-L-arginine methyl ester hydrochloride (L-NAME), counteracted the beneficial effect of RIC on collateral circulation, early lesions, pial anastomosis, and infarct volume. In permanent MCAO, RIC could enhance collateral circulation through leptomeningeal anastomosis with Akt-eNOS pathway and diminish early lesion and final infarct volume., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Conventional chemotherapy is based on the maximum tolerated dose (MTD) and requires treatment-free intervals to restore normal host cells. MTD chemotherapy may induce angiogenesis or immunosuppressive cell infiltration during treatment-free intervals. Low-dose metronomic (LDM) chemotherapy is defined as frequent administration at lower doses and causes less inflammatory change, whereas MTD chemotherapy induces an inflammatory change. Although several LDM regimens have been applied, LDM cisplatin (CDDP) has been rarely reported. This study addressed the efficacy of LDM CDDP on tumour endothelial cell phenotypic alteration compared to MTD CDDP., Methods: Tumour growth and metastasis were assessed in bladder cancer-bearing mice treated with LDM or MTD gemcitabine (GEM) and CDDP. To elucidate the therapeutic effects of LDM CDDP, the change of tumour vasculature, tumour-infiltrating immune cells and inflammatory changes were evaluated by histological analysis and mRNA expression in tumour tissues., Results: Tumour growth and bone metastasis were more suppressed by LDM CDDP + MTD GEM treatment than MTD CDDP + MTD GEM. Myeloid-derived suppressor cell accumulation was reduced by LDM CDDP, whereas inflammatory change was induced in the tumour microenvironment by MTD CDDP., Conclusion: LDM CDDP does not cause inflammatory change unlike MTD CDDP, suggesting that it is a promising strategy in chemotherapy., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Systemic effects associated with hormones and cytokines secreted by tumor cells can cause paraneoplastic syndrome. Leukemoid reactions and hypercalcemia are relatively common manifestations of paraneoplastic syndrome. Here, we describe the case of a 90-year-old woman who presented with leukocytosis and hypercalcemia and was diagnosed with granulocyte-colony stimulating factor (G-CSF)-producing cervical cancer with elevated levels of parathyroid hormone-related protein (PTHrP). The patient visited our hospital complaining of general fatigue and anorexia. On admission, she presented with marked leukocytosis, hypercalcemia, and an increase in C-reactive protein level. On the basis of abdominal magnetic resonance imaging and histopathological examination, the patient was diagnosed with cervical cancer. Additional tests confirmed elevated plasma levels of G-CSF, PTHrP, and serum interleukin-6. Immunostaining of pathological specimens of the uterine cervix showed expression of G-CSF in tumor cells. The patient was diagnosed with G-CSF-producing cervical cancer accompanied by elevation of PTHrP levels. As a treatment for hypercalcemia, discontinuation of oral vitamin D derivative and administration of saline and elcatonin were ineffective, and therapeutic intervention with zoledronic acid hydrate was required. Considering the patient's advanced age, surgical resection of cervical cancer was not performed. She died from congestive heart failure approximately 3 months after hospitalization. This case was indicated to be a paraneoplastic syndrome in which G-CSF and PTHrP-induced leukocytosis and hypercalcemia. To the best of our knowledge, there have been no reports of G-CSF-producing cervical cancer with elevated PTHrP levels, and our case is the first report., (© 2023. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

Psychosis (including symptoms of delusions, hallucinations, and disorganized conduct/speech) is a main feature of schizophrenia and is frequently present in other major psychiatric illnesses. Studies in individuals with first-episode (FEP) and early psychosis (EP) have the potential to interpret aberrant connectivity associated with psychosis during a period with minimal influence from medication and other confounds. The current study uses a data-driven whole-brain approach to examine patterns of aberrant functional network connectivity (FNC) in a multi-site dataset comprising resting-state functional magnetic resonance images (rs-fMRI) from 117 individuals with FEP or EP and 130 individuals without a psychiatric disorder, as controls. Accounting for age, sex, race, head motion, and multiple imaging sites, differences in FNC were identified between psychosis and control participants in cortical (namely the inferior frontal gyrus, superior medial frontal gyrus, postcentral gyrus, supplementary motor area, posterior cingulate cortex, and superior and middle temporal gyri), subcortical (the caudate, thalamus, subthalamus, and hippocampus), and cerebellar regions. The prominent pattern of reduced cerebellar connectivity in psychosis is especially noteworthy, as most studies focus on cortical and subcortical regions, neglecting the cerebellum. The dysconnectivity reported here may indicate disruptions in cortical-subcortical-cerebellar circuitry involved in rudimentary cognitive functions which may serve as reliable correlates of psychosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Liver fibrosis of different etiologies is a serious health problem worldwide. There is no effective therapy available for liver fibrosis except the removal of the underlying cause of injury or liver transplantation. Development of liver fibrosis is caused by fibrogenic myofibroblasts that are not present in the normal liver, but rather activate from liver resident mesenchymal cells in response to chronic toxic or cholestatic injury. Many studies indicate that liver fibrosis is reversible when the causative agent is removed. Regression of liver fibrosis is associated with the disappearance of activated myofibroblasts and resorption of the fibrous scar. In this review, we discuss the results of genetic tracing and cell fate mapping of hepatic stellate cells and portal fibroblasts, their specific characteristics, and potential phenotypes. We summarize research progress in the understanding of the molecular mechanisms underlying the development and reversibility of liver fibrosis, including activation, apoptosis, and inactivation of myofibroblasts., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: None.

Background: Coronavirus disease 2019 (COVID-19) sequelae, also known as long COVID, can present with various symptoms. Among these symptoms, autonomic dysregulation, particularly postural orthostatic tachycardia syndrome (POTS), should be evaluated. However, previous studies on the treatment of POTS complicated by COVID-19 are lacking. Therefore, this study aimed to investigate the treatment course of long COVID complicated by POTS., Methods: The medical records of patients who complained of fatigue and met the criteria for POTS diagnosis were reviewed. We evaluated the treatment days, methods and changes in fatigue score, changes in heart rate on the Schellong test, and social situation at the first and last visits., Results: Thirty-two patients with long COVID complicated by POTS were followed up (16 males; median age: 28 years). The follow-up period was 159 days, and the interval between COVID-19 onset and initial hospital attendance was 97 days. Some patients responded to β-blocker therapy. Many patients had psychiatric symptoms that required psychiatric intervention and selective serotonin reuptake inhibitor prescription. Changes in heart rate, performance status, and employment/education status improved from the first to the last visit. These outcomes were believed to be because of the effects of various treatment interventions and spontaneous improvements., Conclusions: Our study suggests that the condition of 94% of patients with POTS complicated by long COVID will improve within 159 days. Therefore, POTS evaluation should be considered when patients with long COVID complain of fatigue, and attention should be paid to psychological symptoms and the social context., Competing Interests: The authors have stated explicitly that there are no conflicts of interest in connection with this article., (© 2023 The Authors. Journal of General and Family Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Primary Care Association.)