Effects of Vibration Therapy on the Physical Function of Critically Ill Adults Trial: A Randomized Controlled Trial.

OBJECTIVES: Vibration therapy uses vibration to rehabilitate physical functions. Recently, it has been demonstrated to be safe for critically ill patients. However, its effects on physical functions are unclear. DESIGN: Randomized controlled trial. SETTING: A single-center, ICU. PATIENTS: Patients were randomly assigned to either vibration therapy coupled with protocolized mobilization or protocolized mobilization alone. We included patients who could sit at the edge of the bed or in a wheelchair during their ICU stay. The exclusion criteria were based on the early mobilization inhibition criteria. INTERVENTIONS: The primary outcome was the Functional Status Score for the ICU (FSS-ICU) at ICU discharge. Secondary outcomes were the Medical Research Council score, ICU-acquired weakness, delirium, ICU Mobility Scale (IMS), and ventilator- and ICU-free days. For safety assessment, vital signs were monitored during the intervention. MEASUREMENTS AND MAIN RESULTS: Among 180 patients, 86 and 90 patients remained in the vibration therapy and control groups, respectively. The mean age was 69 ± 13 vs. 67 ± 16 years in the vibration therapy and control groups, and the Acute Physiology and Chronic Health Evaluation (APACHE) II score was 19 (14-25) vs. 18 (13-23). The total FSS-ICU at ICU discharge was 24 (18-27) and 21 (17-26) in the intervention and control groups, respectively ( p = 0.09), and the supine-to-sit ability significantly improved in the intervention group ( p < 0.01). The secondary outcomes were not significantly different. Vital signs remained stable during vibration therapy. In the predefined subgroup analysis, FSS-ICU improved in the population with a higher body mass index (≥ 23 kg/m 2 ), lower APACHE II scores (< 19), and higher IMS scores (≥ 6). CONCLUSIONS: Vibration therapy did not improve the total FSS-ICU. However, the supine-to-sit ability in the FSS-ICU improved without any adverse event.

Patients With Subacute Sclerosing Panencephalitis in Japan: A 2022 Nationwide Survey.

BACKGROUND: In Japan, the incidence of subacute sclerosing panencephalitis (SSPE) has reduced; however, the medical conditions and factors associated with disease progression remain unclear. METHODS: A nationwide survey of SSPE was conducted using a questionnaire in 2022. We conducted a descriptive analysis of the patients with SSPE in 2022 and Cox proportional hazards analyses for disease progression. We compared the patients with SSPE with those in a 2007 survey. RESULTS: A total of 37 surviving patients with SSPE were enrolled [median age: 32 years (range: 16-52 years)]. No new cases have been identified since 2017 in the survey. Jabbour stage IV was the most common stage (66.7%). The hazard ratios (95% confidence intervals) of male sex and age at the time of measles infection (years) were 2.56 (1.13-5.76) and 0.57 (0.34-0.93), respectively. Compared with those in 2007, the proportion of patients in hospitals decreased from 13.7% to 2.7%, whereas that of patients in nursing facilities increased from 17.6% to 29.7%. The proportions of patients prescribed inosine pranobex, interferon and ribavirin at the time of the survey decreased from 96.1% to 79.4%, 74.8% to 14.3% and 25.3% to 0%, respectively. The proportions of patients with gastrostomy, tracheostomy and ventilator use increased from 5.9% to 69.7%, 23.3% to 60.0% and 10.8% to 32.4%, respectively. CONCLUSIONS: Decreased measles cases in Japan reduced new SSPE cases. However, surviving patients in 2022 had advanced disease stages and needed medical care. Male sex and early measles infection were significantly associated with disease progression.

Questionnaire survey on the conceptual framework, optimal evaluation, and support measures for children's language disorders in Japan using the Delphi method.

Objectives: To compile the opinions of native Japanese speakers on the conceptual framework, optimal evaluation, and support measures for children with language disorders to devise materials on which a consensus can be formed. Design: A quantitative descriptive study using the Delphi method. Setting: Using the Delphi method, 43 clinicians with at least 15 years of experience working professionally with children's language disorders in Japan were surveyed three times via a web-based questionnaire. Thirty-nine items that were carefully selected by the working group were surveyed, and the agreement level was set to ≥80%. Main Outcome Measures: We investigated the following aspects related to developmental language disorder (DLD) among Japanese children: definition, core symptoms, evaluation of core symptoms, relationship with a second language, relationship with other related disorders, support systems, and information availability. Results: Overall, 43 qualified panel members were included in this study. Among the 39 items in the questionnaire, a high level of consensus (≥80%) from the responses of the participants was achieved for five items in Round 1, whereas no consensus (<50%) was achieved for seven items. After revising and integrating the questionnaires into 22 items, we conducted Rounds 2 and 3 and obtained high and medium levels of agreement in 20 items on disease concept, core symptoms, coexisting disorders, and manner of support of DLD in children. Conclusion: Our results clarify the previously ambiguous image of DLD in Japan. Information-sharing strategies that connect professionals, patients, their families, and community members are required in the future. Level of Evidence: 5.

Gene therapy for spinal muscular atrophy is considerably effective when administered as early as possible after birth.

Introduction: Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by muscle atrophy and progressive muscle weakness. Insurance-approved treatments in Japan include antisense oligonucleotide therapy, gene therapy, and small molecule therapy. The efficacy of these therapies varies depending on the timing of treatment initiation. Case presentation: We report the cases of two infants with SMA born in the same region. Patient 1, who had two copies of SMN2, was born before newborn screening (NBS) was started and received onasemnogene abeparvovec therapy at the age of 4 months. Patient 2, who had three copies of SMN2, was born after the start of NBS and was diagnosed and treated with onasemnogene abeparvovec before symptoms appeared. Unfortunately, Patient 1 became bedridden despite receiving gene therapy, while Patient 2 achieved normal motor development. Discussion: Our findings show that treatment timing is an essential factor affecting patients' motor neurodevelopmental outcomes, although our patients did have differences in the number of copies of SMN2. Therefore, a system should be established to allow all newborns to undergo publicly funded NBS for SMA.

Newborn screening for spinal muscular atrophy in Japan: One year of experience.

Spinal muscular atrophy (SMA) is a degenerative neuromuscular disease that causes progressive muscle weakness and atrophy due to loss of the anterior horn cells of the spinal cord. Although effective treatments, such as gene therapy, have emerged in recent years, their therapeutic efficacy depends on a restricted time window of treatment initiation. For the treatment to be effective, it must be started before symptoms of the disease emerge. For this purpose, newborn screening (NBS) for SMA is conducted in many countries worldwide. The NBS program for SMA has been initiated in Japan in several regions, including the Kumamoto Prefecture. We started the NBS program in February 2021 and detected a patient with SMA after screening 13,587 newborns in the first year. Herein, we report our experience with the NBS program for SMA and discuss an issue to be approached in the future.

BCOR-CCNB3 sarcoma arising in the proximal tibia: A case report.

BCL6 corepressor-cyclin B3 (BCOR-CCNB3) fusion sarcoma was classified as an emerging subgroup of undifferentiated small round cell sarcoma in 2020. The incidence of BCOR-CCNB3 fusion sarcoma is reportedly 1.5-14% among undifferentiated unclassified sarcomas, representing a rare entity among primary malignant bone tumors. The present study reports a case of BCOR-CCNB3 fusion sarcoma in the proximal tibia of a boy. A 12-year-old boy presented with a 6-month history of knee pain and a slowly growing mass in the anteromedial aspect of the left proximal tibia. Plain radiography and computed tomography of the knee demonstrated a lytic lesion with cortical destruction of the proximal tibia. Magnetic resonance imaging showed the bone tumor expanding into soft tissue with almost homogeneous hypointensity on T1-weighted imaging and slightly hyperintensity on T2-weighted imaging. On histopathological evaluation, the tumor comprised a proliferation of small, round to ovoid-shaped mesenchymal cells without osteoid formation. Histopathologically, BCOR-CCNB3 sarcoma of bone was finally diagnosed based on immunohistochemical staining and additional molecular analyses. The patient underwent bone tumor resection followed by pre- and post-operative chemotherapy according to a Ewing sarcoma protocol. The patient showed no evidence of local recurrence or distant metastasis at 12 months after completion of adjuvant chemotherapy. We present herein an additional case of BCOR-CCNB3 sarcoma of the proximal tibia, and review the relevant literature on BCOR-CCNB3 sarcoma of bone.

Voriconazole injection may induce delayed methotrexate excretion: a case report and experimental study.

BACKGROUND: We report a case of delayed excretion of methotrexate (MTX) in a pediatric patient on high-dose MTX therapy in response to a change in the concomitant dosage of voriconazole from oral to intravenous. As the intravenous, but not the oral formulation of voriconazole includes sulfobutylether-ß-cyclodextrin (SBECD), which has an anionic residue, we hypothesized that SBECD inhibits the renal excretion of anionic compounds. METHODS: We evaluated the inhibitory effects of SBECD on renal excretion of phenolsulfonphthalein (PSP), which is eliminated in urine via organic anion transport systems. PSP was administered intravenously to rats at 2.5 and 25 mg/kg with or without SBECD pretreatment (320 mg/kg). RESULTS: The plasma concentration of PSP at the dosage of 2.5 mg/kg were comparable between control and SBECD groups. On the other hand, at 25 mg/kg the elimination of PSP was delayed. The clearance of PSP at the dosage of 25 mg/kg was 9.71 ± 1.65 and 4.13 ± 0.76 mL/min/kg in control and SBECD groups, respectively (p < 0.05). This suggested that SBECD partly inhibits the renal excretion of anionic drugs. CONCLUSION: The present case report discusses the delayed elimination of MTX in high dose therapy and possible mechanism involving SBECD as an excipient in concomitant drugs. It seems better to avoid choosing injection containing SBECD for patients undergoing HD-MTX treatment. Further studies are needed to confirm the inhibitory effects of SBECD on the renal excretion of MTX, especially in high-dose regimens.

Mitochondrial DNA depletion syndrome with a mutation in SLC25A4 developing epileptic encephalopathy: A case report.

INTRODUCTION: Autosomal dominant mitochondrial DNA depletion syndrome (MTDPS-12A) is characterized by severe hypotonia from birth due to a mutation in the adenine nucleotide translocator 1 (ANT1). CASE REPORT: A 4-year-old female patient diagnosed with neonatal-onset mitochondrial disease, who had good cognitive function while receiving antiepileptic treatment, presented with sudden-onset status epilepticus with facial and limb myoclonus persisting for more than 30 min. Subsequently, she developed epileptic encephalopathy. Brain MRI showed progressive ventricular enlargement and marked white matter atrophy. She was unable to perform verbal communication or make eye contact and fingertip movements. She lacked any signs of cardiomyopathy. Sanger sequencing demonstrated a heterozygous de novo mutation of c.239G>A (p.Arg80His) in SLC25A4. Her right quadriceps muscle tissue showed lowered complexes I, III, and IV activities and mitochondria DNA depletion (mitochondria/nuclear DNA: 14.6 ± 2.2%) through the quantitative polymerase chain reaction. She was definitively diagnosed with MTDPS-12A. CONCLUSION: Status epilepticus causes encephalopathy in patients with MTDPS-12A. Reducing the energy requirement on the cardiac muscle and brain may be a treatment strategy for patients with MTDPS-12A. Therefore, seizure management and preventive treatment of status epilepticus are considered to be important for maintaining neurodevelopmental outcomes.

Intensive surveillance endoscopy for multiple gastrointestinal tumors in a patient with constitutional mismatch repair deficiency: case report.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is an extremely rare autosomal recessive hereditary disease characterized by the absence of mismatch repair gene activity from birth, which results in brain tumors, colonic polyposis, gastrointestinal cancers, and lymphomas later in life. An aggressive approach, including colectomy or proctocolectomy, is recommended for the treatment of colorectal cancer. Additionally, partial colectomy with subsequent endoscopic surveillance may be an alternative strategy due to poor patient's condition, although there is no evidence of surveillance endoscopy after partial colectomy for CMMRD. CASE PRESENTATION: A 13-year-old male patient with a history of T-lymphoblastic lymphoma underwent total gastrointestinal endoscopy, which revealed rectal cancer, colorectal polyposis, and duodenal adenoma. Differential diagnosis included constitutional mismatch repair deficiency according to its scoring system and microsatellite instability, and subsequent germline mutation testing for mismatch repair genes confirmed the diagnosis of constitutional mismatch repair deficiency based on a homozygous mutation in mutS homolog 6 (MSH6). The patient and his family refused colectomy due to the high risk of malignancies other than colorectal cancer, which could require radical surgery. Therefore, the patient underwent low anterior resection of the rectosigmoid colon for rectal cancer and intensive surveillance endoscopy for the remaining colon polyposis. During the 3-year period after initial surgery, 130 polyps were removed and the number of polyps gradually decreased during 6-months interval surveillance endoscopies, although only one polyp was diagnosed as invasive adenocarcinoma (pT1). CONCLUSIONS: Our experience of short surveillance endoscopy illustrates that this strategy might be one of options according to patient's condition.

Thalamic pulvinar metabolism, sleep disturbances, and hallucinations in dementia with Lewy bodies: Positron emission tomography and actigraphy study.

OBJECTIVES: Although sleep disturbances are prevalent among patients with dementia with Lewy bodies (DLB), their neural substrates remain unclear. We aimed to clarify the neural substrates of sleep disturbances in patients with DLB. METHODS: We evaluated sleep disturbances, neuropsychiatric symptoms, and brain glucose metabolism in 22 patients with probable DLB using actigraphy, the Neuropsychiatric Inventory (NPI), and 18 F-fluorodeoxyglucose (FDG) positron emission tomography, respectively. Total sleep time (TST) and average activity count per minute (AAC) during sleep were calculated for seven consecutive days via actigraphy. We investigated associations between FDG uptake and the actigraphy parameters using Statistical Parametric Mapping version 12b. Spearman's rank correlation coefficients were used to investigate associations among TST, AAC, and clinical symptoms. The level of statistical significance was set at P < .05. P values were adjusted using the Benjamini-Hochberg method for multiple comparisons. This study was registered with ClinicalTrials.gov (NCT00776347). RESULTS: TST exhibited a significant positive association with FDG uptake in the bilateral orbitofrontal cortex and left thalamus, while AAC exhibited a significant negative association with FDG uptake in the left thalamus and the left parieto-occipital region. FDG uptake in the left pulvinar was associated with both TST and AAC. In addition, TST exhibited a significant negative association with the NPI hallucinations score (r = -0.66, P = .001), while AAC exhibited significant positive associations with the NPI delusions (r = 0.70, P < .001) and hallucinations (r = 0.63, P = .002) scores. CONCLUSIONS: TST and bodily activity during sleep are associated with dysfunction of the left pulvinar and the severity of hallucinations in patients with DLB.

Clinical, cytogenetic, and molecular analyses of 17 neonates with transient abnormal myelopoiesis and nonconstitutional trisomy 21.

BACKGROUND: Transient abnormal myelopoiesis (TAM) is a unique myeloproliferative disorder that occurs in neonates with constitutional trisomy 21/Down syndrome (DS). Although TAM also develops in neonates without constitutional trisomy 21, the clinical, cytogenetic, and molecular characteristics of those patients are not fully understood. PROCEDURE: We retrospectively evaluated the clinical and cytogenetic findings and GATA1 mutation status of 17 neonates with TAM and nonconstitutional trisomy 21 tested for GATA1 mutations at our institute, and compared the findings with those of 64 neonates with TAM and constitutional trisomy 21/DS. RESULTS: DS clinical features were observed in five of the 17 (29%) patients. In all patients, both trisomy 21 and GATA1 mutations were detected in diagnostic samples. Over a median follow-up of 33 (range, 0-139) months, early death (< 6 months of age) occurred in four patients (24%). Overall and event-free survivals were not significantly different between the patients with TAM and nonconstitutional trisomy 21 and those with TAM and constitutional trisomy 21/DS (five-year overall survival: 76% ± 10% vs 53% ± 13%, P = 0.40; five-year event-free survival: 55% ± 13% vs 48% ± 12%, P = 0.90). The five-year cumulative incidence of progression to myeloid leukemia of DS was also similar between the groups (21% vs 24%, P = 0.80). CONCLUSIONS: Patients with TAM and nonconstitutional trisomy 21 exhibited similar biology and outcomes to those with TAM and constitutional trisomy 21/DS. The possibility of TAM should be considered even in phenotypically normal neonates with TAM symptoms, for appropriate management.

Oil palm concessions in southern Myanmar consist mostly of unconverted forest.

The increased demand for palm oil has led to an expansion of oil palm concessions in the tropics, and the clearing of abundant forest as a result. However, concessions are typically incompletely planted to varying degrees, leaving much land unused. The remaining forests within such concessions are at high risk of deforestation, as there are normally no legal hurdles to their clearance, therefore making them excellent targets for conservation. We investigated the location of oil palm plantations and the other major crop - rubber plantations in southern Myanmar, and compared them to concession boundaries. Our results show that rubber plantations cover much larger areas than oil palm in the region, indicating that rubber is the region's preferred crop. Furthermore, only 15% of the total concession area is currently planted with oil palm (49,000 ha), while 25,000 ha is planted outside concession boundaries. While this may in part be due to uncertain and/or changing boundaries, this leaves most of the concession area available for other land uses, including forest conservation and communities' livelihood needs. Reconsidering the remaining concession areas can also significantly reduce future emission risks from the region.

Correction to: Factors predicting the recurrence of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children after treatment using the HLH-2004 protocol.

The correct name of the first author should be ''Ryu Yanagisawa'', and not ''Ryu Yanagaisawa'' as given in the original publication of the article.

Factors predicting the recurrence of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children after treatment using the HLH-2004 protocol.

Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) is highly prevalent in Japan. To date, no standard treatment for EBV-HLH has been established owing to the diversity in treatment response and the difficulty in assessing prognostic factors. The present prospective study recruited 27 children with EBV-HLH who were also part of the HLH-2004 study. EBV load in the peripheral blood was monitored at diagnosis and 2, 4, and 8 weeks after treatment initiation. Additionally, T-cell receptor (TCR) clonality and other laboratory data were evaluated. TCR clonality was positive in 14 patients at diagnosis. Seven of 27 patients experienced recurrences after treatment. No correlation was noted among any clinical data at diagnosis of patients with and without recurrence. However, the recurrence rate was significantly higher in patients aged < 2 years and/or those with a high plasma EBV load of > 103 copies/mL 2 weeks after treatment than that in patients without these factors. These findings suggest that a younger age or a high EBV load in plasma at the early phase of treatment is a factor predicting a recurrence and helps guide the intensity of subsequent treatment phases for children with EBV-HLH.

Gastric cancer in children and adolescents in Japan.

BACKGROUND: Very limited data are available on childhood gastric cancer. Using a retrospective survey and literature review, we assessed the clinical features of gastric cancer in children and adolescents. METHODS: We collected information on childhood gastric cancer from pediatricians of 518 hospitals that issue the title of "certified board pediatrician" approved by Japan Pediatric Society, using a questionnaire on background, diagnosis year, onset symptoms, tumor location, histology, nodular gastritis, Helicobacter pylori testing, treatment, and prognosis. Studies were collected using PubMed and the NPO Japan Medical Abstracts Society database. Data for childhood gastric cancer were abstracted from the Japanese Vital Statistics database. RESULTS: Of the 518 hospitals, 349 returned the questionnaire, which identified four patients. Literature review identified 77 cases of gastric cancer, and we analyzed data for 80 children <16 years old. Most patients were >10 years old, and there were no sex differences. Onset symptoms ranged from abdominal pain to non-localized. Sixteen of 44 children had a family history of cancer; 10 had a family history of gastric cancer. Histologically, approximately 80% had undifferentiated-type carcinoma. Prognosis was extremely poor, and two of three tested children were positive for H. pylori infection. Childhood gastric cancer death has been declining. CONCLUSIONS: Childhood gastric cancer is rare in Japan, and information on H. pylori in childhood gastric cancer patients is limited. Declining childhood gastric cancer rates may reflect the decreasing prevalence of infection but further study is necessary to clarify the relationship between H. pylori and gastric cancer.

The possible clinical impact of risperidone on P-glycoprotein-mediated transport of tacrolimus: A case report and in vitro study.

The authors encountered the case of an 8-fold increase in the concentration/dose (C/D) ratio of tacrolimus (TAC) following the coadministration of voriconazole (VRCZ) in a hematopoietic stem cell transplantation (HSCT) recipient. The interaction observed was much greater than expected and the patient had also been treated with oral risperidone (RSP). It was hypothesized that cytochrome P450 (CYP)3A inhibition of the small intestine by voriconazole and P-glycoprotein (P-gp) inhibition of the small intestine by risperidone exerted a synergistic effect on the bioavailability of tacrolimus. The aim of the present study was to evaluate the effect of risperidone on the P-gp-mediated transport of tacrolimus. The transcellular transport of P-gp substrates was examined in Caco-2 and P-gp-expressing renal epithelial LLC-GA5-COL150 cells. In Caco-2 cells, the apical-basal (A-B) transport of rhodamine123 (Rh123) after a 120 min incubation was increased by 47.1%, whereas that in the B-A direction was decreased by 61.7% in the presence of risperidone (100 µm). These results indicate that risperidone showed an inhibitory effect on the P-gp-mediated transport of Rh123. In LLC-GA5-COL150 cells, the A-B transport of tacrolimus after 120 min incubation was increased by 21.7% in the presence of risperidone (100 µm), whereas that in the B-A direction was decreased by 10.7%. These results suggest that risperidone was at least partly involved in the mechanism of the marked increase in the C/D ratio of tacrolimus. This case report provides new insights into the diversity of drug interactions of tacrolimus triggered by the combination of two concomitant drugs.

Effects of donepezil on sleep disturbances in patients with dementia with Lewy bodies: An open-label study with actigraphy.

We investigated whether donepezil, a cholinesterase inhibitor, can be used to treat sleep disturbances in patients with dementia with Lewy bodies (DLB). Sleep disturbances were evaluated with the sleep disturbances item of the Neuropsychiatric inventory (NPI) and an actigraph in 16 DLB patients and 24 normal elderly control (NC) subjects. The presence/absence of nine kinds of sleep symptoms, such as dream enactment, were also evaluated in the DLB patients. The DLB patients were then given 5mg/day donepezil for 14 weeks and evaluated again. Eight of the 16 DLB patients had some sleep disturbances before taking donepezil. The actigraphy data indicated that average activity count per minute in sleep (AAC), which reflects body activity at night, was significantly higher and total sleep time was significantly longer in DLB patients than in NC subjects. The NPI sleep disturbances score significantly improved and the number of DLB patients who had sleep disturbances decreased after taking donepezil. The actigraphy results indicate that the sum of all wake epochs within the sleep period, which reflects the degree of fragmented sleep, and the AAC decreased in the DLB patients after donepezil treatment. These results indicate that donepezil treatment reduced sleep disturbances in DLB patients.

[Hashimoto's encephalopathy presenting with vertigo and muscle weakness in a male pediatric patient].

Hashimoto's encephalopathy is an anti-thyroid antibody-positive autoimmune encephalopathy. We herein report the case of a 13-year-old male patient with subacute vertigo, muscle weakness in the extremities and gait disturbance who was diagnosed with Hashimoto's encephalopathy. He showed no severe impairment of consciousness and no seizures, and there were no abnormalities on the brain MRI. However, epileptic spike and wave complexes were observed on an electroencephalogram, and a decline in blood flow was diffusely observed on brain SPECT (single photon emission computed tomography). His thyroid function was normal, but he was positive for anti-thyroid antibodies, such as anti-TPO (thyroid peroxidase) antibodies. He was also positive for serum anti-NAE (NH2-terminal alpha-enolase) antibodies. Systemic corticosteroid therapy and high-dose intravenous immunoglobulin therapy were effective, greatly improving his quality of life.