Significance of Serum Leucine-rich Alpha-2 Glycoprotein as a Diagnostic Marker in Pediatric Inflammatory Bowel Disease.

Serum leucine-rich alpha-2 glycoprotein (LRG) has been utilized for adult inflammatory bowel disease (IBD); however, its efficacy in pediatric IBD remains unknown. The aim of this study was to compare the diagnostic accuracy of serum LRG for pediatric IBD with that of current inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). This retrospective case-control study included pediatric patients, aged <16 years, who underwent colonoscopy and/or esophagogastroduodenoscopy between April 2017 and March 2022. All eligible patients were divided into two groups: patients with IBD, diagnosed with ulcerative colitis and Crohn's disease, and non-IBD controls. The optimal cut-off value of serum LRG for IBD diagnosis was determined from receiver operating characteristic analysis, and diagnostic accuracy of serum LRG was compared to serum ESR and CRP. A total of 53 patients (24 with IBD and 29 non-IBD controls) met the inclusion criteria. The cut-off value of serum LRG for IBD diagnosis was determined to be 19.5 µg/ml. At this cut-off value, serum LRG had a positive predictive value (PPV) of 0.80 and negative predictive value (NPV) of 0.88. In contrast, PPV and NPV were 0.78 and 0.70 for serum ESR and 0.82 and 0.72 for serum CRP, respectively. Serum LRG can be a potential diagnostic marker for pediatric IBD, with higher diagnostic accuracy than that of the conventional serum markers ESR and CRP.

Endosurgery workshop to improve the confidence of novice pediatric surgeons in performing laparoscopic hepaticojejunostomy.

PURPOSE: This study assessed the efficacy of a high-impact, short-term workshop in honing the laparoscopic hepaticojejunostomy technical skills and self-confidence of novice pediatric surgeons, focusing on vertical needle driving and knot tying. METHODS: Lectures, hands-on sessions, pre- and post-workshop evaluations, and training using porcine models were conducted to refine basic and advanced skills. The "hepaticojejunostomy simulator" was used for comparative analysis of precision in pre- and post-workshop vertical needle driving and knot tying. Participants self-evaluated their skills and confidence on a 5-point scale. RESULTS: After the workshop, eight inexperienced pediatric surgeons demonstrated a significant improvement in hepaticojejunostomy suturing task completion rates and needle-driving precision at the jejunum and hepatic duct. However, the A-Lap Mini Endoscopic Surgery Skill Assessment System indicated no significant improvements in most assessed parameters, except for the full-layer closure score (p = 0.03). However, a significant increase in participants' confidence levels in performing laparoscopic hepaticojejunostomy was observed. CONCLUSION: The workshop augmented technical proficiency and confidence in young pediatric surgeons. The combination of lectures, practical exposure, and model training is an effective educational strategy in pediatric surgical instruction.

Contrast-enhanced ultrasonographic findings in torsion of the appendix testis or epididymis in children: a case series.

PURPOSE: Torsion of the appendix testis or epididymis is a cause of acute scrotum in children. Ultrasonography with color Doppler is the first-choice modality for diagnosis. However, this method requires skill and experience to make a diagnosis with confidence. Recently, contrast-enhanced ultrasonography for diagnosis in various fields has been reported. However, to our knowledge, there has been no report of this method being used to diagnose torsion of the appendix testis or epididymis. The purpose of this study was to retrospectively examine contrast-enhanced ultrasonographic findings in torsion of the appendix testis or epididymis. METHODS: Patients who underwent contrast-enhanced ultrasonography for torsion of the appendix testis or epididymis at our institution between April 2010 and April 2023 were enrolled in this study (n = 12). Contrast-enhanced ultrasonography findings of the affected appendage and the testis parenchyma were examined retrospectively. RESULTS: The parenchyma of the testes was notably enhanced in all the cases. However, 9 of the 12 cases showed that the appendage with torsion was not enhanced at all. In the remaining three cases, only slight enhancement was seen. Nevertheless, it was notably less than that of the parenchyma of the testis. CONCLUSION: Our findings indicated that contrast-enhanced ultrasonography may be an easy and reliable method for diagnosing torsion of the appendix testis or epididymis.

Contrast-enhanced ultrasound findings in testicular torsion and non-testicular torsion.

PURPOSE: Testicular torsion requires emergency surgery; thus, prompt and correct diagnosis is very important. Ultrasound with color Doppler is usually the first-choice modality for diagnosis; however, skill and experience are required for confident diagnosis. Recently, contrast-enhanced ultrasound for the diagnosis of testicular torsion has been reported, but there have been only a few reports. This study aimed to compare contrast-enhanced ultrasound findings in cases of testicular torsion and non-testicular torsion. METHODS: Patients who underwent contrast-enhanced ultrasound for acute scrotum at our institution between April 2010 and January 2023 were divided into testicular torsion (n = 17) and non-testicular torsion (n = 16) groups. The respective contrast-enhanced ultrasound findings were retrospectively examined and compared. RESULTS: In 16 out of 17 cases of testicular torsion, the parenchyma of the affected testis was not enhanced. In the remaining case, reduced contrast enhancement was observed; however, it was still notably less than that observed on the unaffected testis. On the other hand, in all cases of non-testicular torsion (n = 16), the parenchyma of the affected testis was notably enhanced. CONCLUSION: Contrast-enhanced ultrasound is considered an easy and accurate method for diagnosing testicular torsion.

Dienogest Use for Recurrent Pyosalpinx as a Long-Term Complication of Cloacal Exstrophy: A Case Report.

BACKGROUND: Cloacal exstrophy (CE) is a rare congenital disease that requires multiple surgeries for complex gastrointestinal and genitourinary anomalies. Long-term complications are not uncommon; however, they are poorly reported. Pyosalpinx is sometimes encountered during CE management in adolescents and young adults. CASE: A 28-year-old woman with a history of CE presented with fever, lower abdominal pain, and vomiting and was diagnosed with left pyosalpinx. Computed tomography-guided drainage and intravenous antibiotic administration were successful; however, she had 2 readmissions for recurrent pyosalpinx 1 week after discharge and again 4 months later. She was administered Dienogest, a synthetic progestin, to prevent recurrent pyosalpinx and had no recurrence for 8 months. SUMMARY AND CONCLUSION: Dienogest is a conservative treatment choice for preventing the recurrence of pyosalpinx for patients with CE.

Differences in Fentanyl Requirements in Terminally Ill Cancer Patients.

Cancer pain is a significant issue in terminally ill cancer patients (TICPs). The fentanyl patch (FP) is used extensively for treating cancer pain, but FP requirements vary between patients. We aimed to identify determinants of FP requirements in TICPs and propose effective pain relief using a FP. In a retrospective chart review, we investigated cancer patients admitted to our hospital from April 2012 to July 2015 and used FP until death. The time course of FP use in TICPs until death was examined. The primary endpoint was the final dose of FP use (FDFP). In total, 79 patients were included the analysis. FDFP was inversely correlated with age (R= -0.262, p = 0.20; Spearman test). FDFP tended to be higher in males than in females and was significantly higher in patients with pancreatic cancer than in patients without pancreatic cancer (p = 0.017; Welch's test). FP adjustments were more frequent in the last 60 days of life in patients with pancreatic cancer than in patients with other malignancies (P for interaction = 0.002; mixed effect model). In conclusion, younger age, and pancreatic cancer were associated with higher FP requirements in TICPs. TICPs with pancreatic cancer required more frequent FP adjustment near death.

Antiviral medications for mild-to-moderate COVID-19 in Japan: a gap of timing between clinical trials and real-world scenarios in a fast-changing pandemic.

The rapid spread of a novel type of coronavirus infection, coronavirus disease 2019 (COVID-19) has made it difficult to implement the results of clinical trials in real-world situations. After the emergence of the Omicron variant and messenger RNA vaccine, a combination of less virulent but more contagious viruses and more people with protective immunity has resulted in a larger number of patients with less severe, mild-to-moderate COVID-19. Many patients with severe conditions did not have extensive viral pneumonia frequently seen in the "pre-Omicron" era but had serious complications due to aggravation of underlying comorbidities or secondary bacterial infections. Most clinical trials for new antiviral drugs were conducted in the "pre-Omicron" period based on a different set of background patient characteristics than the ones seen in the Omicron period. Understanding situational differences due to the gap in the timing between clinical trials and the practical use of drugs for COVID-19 will assist in developing an effective treatment strategy in real-world practice. In this seminar, we reviewed antiviral treatments for mild-to-moderate COVID-19 from the viewpoint of the difference in patient backgrounds between clinical trials and real-world studies, focusing on drugs currently used in Japan.

Evening rather than morning increased physical activity alters the microbiota in mice and is associated with increased body temperature and sympathetic nervous system activation.

Voluntary training and food modulate the fecal microbiota in humans and mice. Although there are some reports of the timing effects of voluntary training and feeding on metabolism, the timing effects of these factors on microbiota have not been investigated. Therefore, we investigated the effects of the timing of voluntary training and feeding on the gut microbiota. The ICR mice were housed under conditions with an early (in the morning) or late (evening) active phase of increased physical activity. Furthermore, to investigate why voluntary training affects the gut microbiota, mice were housed in a cold environment and received propranolol administration with increased physical activity. After that, we collected cecal contents and feces and measured cecal pH. Short-chain fatty acids (SCFA) were measured from cecal contents. Microbiota was determined using sequencing of the V3-V4 region of the 16S rDNA gene. This study found that increased evening physical activity rather than morning activity decreases cecal pH, increases SCFA, and changes the microbiota. It is especially important that increased evening physical activity is induced under the post-prandial voluntary training condition. Also, we found that cold room housing, sympathetic blockade, or both suppressed the increased physical activity-induced changes in cecal pH, SCFA, and microbiota. Allobaculum responded to increased physical activity through body temperature increases and sympathetic activation. Post-prandial increased physical activity, rather than pre-prandial increased physical activity by evening voluntary wheel training, altered the microbiota composition, which may be related to the increase in body temperature and sympathetic nervous system activation.

Very Early Increased Platelet Count within a Week after Initiation of High-Dose Dexamethasone Treatment Is Associated with Long-Term Response in Newly Diagnosed Immune Thrombocytopenia Patients.

To evaluate the long-term efficacy of high-dose dexamethasone (HD-DXM) treatment for immune thrombocytopenia (ITP), we retrospectively analysed 36 newly diagnosed ITP patients treated with HD-DXM as a first-line treatment. An initial response was obtained in 23 (63.9%) patients, including 11 with a complete response (CR) and 12 with a partial response (PR). Six months after HD-DXM treatment, 26 of 33 (78.8%) evaluable patients achieved objective responses, including 18 CR and 8 PR. Among 13 patients without initial response, very early increased platelet count within a week (VEIP) was observed in 7 patients, 5 (71.4%) of whom achieved a response at 6 months. In 29 patients who had available platelet count within a week, patients showing VEIP revealed longer survival than those who did not (p = 0.026). HD-DXM was an effective treatment for newly diagnosed ITP patients. VEIP after HD-DXM treatment initiation was associated with a long-term objective response in newly diagnosed ITP patients.

Discovery of New Potent anti-MERS CoV Fusion Inhibitors.

Middle East respiratory syndrome coronavirus (MERS-CoV), capable of zoonotic transmission, has been associated with emerging viral pneumonia in humans. In this study, a set of highly potent peptides were designed to prevent MERS-CoV fusion through competition with heptad repeat domain 2 (HR2) at its HR1 binding site. We designed eleven peptides with stronger estimated HR1 binding affinities than the wild-type peptide to prevent viral fusion with the cell membrane. Eight peptides showed strong inhibition of spike-mediated MERS-CoV cell-cell fusion with IC50 values in the nanomolar range (0.25-2.3 µM). Peptides #4-6 inhibited 95-98.3% of MERS-CoV plaque formation. Notably, peptide four showed strong inhibition of MERS-CoV plaques formation with EC50 = 0.302 µM. All peptides demonstrated safe profiles without cytotoxicity up to a concentration of 10 µM, and this cellular safety, combined with their anti-MERS-CoV antiviral activity, indicate all peptides can be regarded as potential promising antiviral agents.

Successful Rituximab Treatment in Thrombotic Thrombocytopenic Purpura Patients Complicated by Other Autoimmune Disorders: Two Case Reports.

We herein report two cases of thrombotic thrombocytopenic purpura (TTP) complicated by other autoimmune disorders, autoimmune hepatitis and immune thrombocytopenia, respectively. In both cases, corticosteroids were continuously administered for the treatment of preceding autoimmune disorders. However, a sufficient objective response for TTP was not obtained by plasma exchange and corticosteroid treatment. Once a week rituximab (375 mg/m2) treatment for 4 times was initiated within 2 weeks from the diagnosis. Both patients achieved a sufficient response, and have never had any recurrence as of the last follow-up dates. The early introduction of rituximab could be an effective treatment option in TTP patients complicated with other autoimmune disorders.

The Combined Effects of Magnesium Oxide and Inulin on Intestinal Microbiota and Cecal Short-Chain Fatty Acids.

Constipation is a common condition that occurs in many people worldwide. While magnesium oxide (MgO) is often used as the first-line drug for chronic constipation in Japan, dietary fiber intake is also recommended. Dietary fiber is fermented by microbiota to produce short-chain fatty acids (SCFAs). SCFAs are involved in regulating systemic physiological functions and circadian rhythm. We examined the effect of combining MgO and the water-soluble dietary fiber, inulin, on cecal SCFA concentration and microbiota in mice. We also examined the MgO administration timing effect on cecal SCFAs. The cecal SCFA concentrations were measured by gas chromatography, and the microbiota was determined using next-generation sequencing. Inulin intake decreased cecal pH and increased cecal SCFA concentrations while combining MgO increased the cecal pH lowered by inulin and decreased the cecal SCFA concentrations elevated by inulin. When inulin and MgO were combined, significant changes in the microbiota composition were observed compared with inulin alone. The MgO effect on the cecal acetic acid concentration was less when administered at ZT12 than at ZT0. In conclusion, this study suggests that MgO affects cecal SCFA and microbiota during inulin feeding, and the effect on acetic acid concentration is time-dependent.

Differences in the effects of organisational climate on burnout according to nurses' level of experience.

AIM: To elucidate the orientation of burnout prevention in line with the experience level of nurses by examining the impact of organisational climate on burnout by nursing experience level. BACKGROUND: While the relationship between a nurse and the organisation where they work changes depending on the nurse's experience level, there is a dearth of research that takes into account the nursing experience level in exploring the relationship between organisational climate and burnout. METHOD: A cross-sectional questionnaire survey was conducted with 1,102 nurses. Nursing experience was divided into six levels. Two scales for organisational climate and the Maslach burnout inventory were used. RESULTS: There were effects between the organisational climate and exhaustion/depersonalization, depending on the experience level. Novices with low scores for head nurses' considerations towards staff felt the highest level of emotional exhaustion. For advanced beginners, a sense of control significantly determined emotional exhaustion. CONCLUSIONS: There was a difference in the relationship between organisational climate and burnout in experience level, suggesting different intervention directions. IMPLICATIONS FOR NURSING MANAGEMENT: There is a direction of intervention suitable for each experience level, suggesting the need to respond to each accordingly.

The Antimalarial Compound Atovaquone Inhibits Zika and Dengue Virus Infection by Blocking E Protein-Mediated Membrane Fusion.

Flaviviruses bear class II fusion proteins as their envelope (E) proteins. Here, we describe the development of an in vitro quantitative mosquito-cell-based membrane-fusion assay for the E protein using dual split proteins (DSPs). The assay does not involve the use of live viruses and allows the analysis of a membrane-fusion step independent of other events in the viral lifecycle, such as endocytosis. The progress of membrane fusion can be monitored continuously by measuring the activities of Renilla luciferase derived from the reassociation of DSPs during cell fusion. We optimized the assay to screen an FDA-approved drug library for a potential membrane fusion inhibitor using the E protein of Zika virus. Screening results identified atovaquone, which was previously described as an antimalarial agent. Atovaquone potently blocked the in vitro Zika virus infection of mammalian cells with an IC90 of 2.1 µM. Furthermore, four distinct serotypes of dengue virus were also inhibited by atovaquone with IC90 values of 1.6-2.5 µM, which is a range below the average blood concentration of atovaquone after its oral administration in humans. These findings make atovaquone a likely candidate drug to treat illnesses caused by Zika as well as dengue viruses. Additionally, the DSP assay is useful to study the mechanism of membrane fusion in Flaviviruses.

Combinatorial Effects of Soluble, Insoluble, and Organic Extracts from Jerusalem Artichokes on Gut Microbiota in Mice.

Jerusalem artichokes contain high amounts of inulin, which is a prebiotic that supports digestive health, as well as a variety of insoluble fibers and caffeoylquinic acid. The individual impact of these components on gut microbiota is well known; however, the combinatorial effects are less clear. In this investigation, we fractionated Jerusalem artichokes into three parts (water-soluble extract, insoluble extract, and organic extract) and powdered them. Mice were fed a high-fat diet that included one or more of these extracts for 10 days, and then their cecal pH, cecal short-chain fatty acids (SCFAs), and fecal microbiota were evaluated. The combination of the water-soluble and organic extract decreased cecal pH and increased the concentration of SCFAs and led to dynamic changes in the composition of the gut microbiota. These results demonstrate that both the water-soluble and organic extracts in Jerusalem artichokes are bioactive substances that are capable of changing SCFA production and the composition of gut microbiota. Powdered Jerusalem artichokes, rather than inulin supplements, may be superior for promoting a healthy gut.

AI approach of cycle-consistent generative adversarial networks to synthesize PET images to train computer-aided diagnosis algorithm for dementia.

OBJECTIVE: An artificial intelligence (AI)-based algorithm typically requires a considerable amount of training data; however, few training images are available for dementia with Lewy bodies and frontotemporal lobar degeneration. Therefore, this study aims to present the potential of cycle-consistent generative adversarial networks (CycleGAN) to obtain enough number of training images for AI-based computer-aided diagnosis (CAD) algorithms for diagnosing dementia. METHODS: We trained CycleGAN using 43 amyloid-negative and 45 positive images in slice-by-slice. RESULTS: The CycleGAN can be used to synthesize reasonable amyloid-positive images, and the continuity of slices was preserved. DISCUSSION: Our results show that CycleGAN has the potential to generate a sufficient number of training images for CAD of dementia.

Small Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Fusion by Targeting Cavities on Heptad Repeat Trimers.

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a newly emerging viral disease with fatal outcomes. However, no MERS-CoV-specific treatment is commercially available. Given the absence of previous structure-based drug discovery studies targeting MERS-CoV fusion proteins, this set of compounds is considered the first generation of MERS-CoV small molecule fusion inhibitors. After a virtual screening campaign of 1.56 million compounds followed by cell-cell fusion assay and MERS-CoV plaques inhibition assay, three new compounds were identified. Compound numbers 22, 73, and 74 showed IC50 values of 12.6, 21.8, and 11.12 µM, respectively, and were most effective at the onset of spike-receptor interactions. The compounds exhibited safe profiles against Human embryonic kidney cells 293 at a concentration of 20 µM with no observed toxicity in Vero cells at 10 µM. The experimental results are accompanied with predicted favorable pharmacokinetic descriptors and drug-likeness parameters. In conclusion, this study provides the first generation of MERS-CoV fusion inhibitors with potencies in the low micromolar range.

Three-dimensional microanatomy of human nipple visualized by X-ray dark-field computed tomography.

PURPOSE: The three-dimensional (3D) structure of the human nipple has not been fully clarified. However, its importance has increased in recent years because it has become common practice to preoperatively explore the spread of breast cancer to the nipple with needle biopsy, ductoscopy, and/or ductal lavage for nipple-sparing mastectomy. Here, we demonstrated that X-ray dark-field computed tomography (XDFI-CT) is a powerful tool for reconstructing the 3D distribution pattern of human lactiferous ducts non-destructively, without contrast agent, and with high tissue contrast. METHODS: Nipples amputated from mastectomy specimens of 51 patients with breast cancer were visualized three-dimensionally by XDFI-CT. First, CT images and conventionally stained tissue sections were compared to demonstrate that XDFI-CT provides 3D anatomical information. Next, the number of ducts in the nipple and the number of ducts sharing an ostium near the tip of the nipple were measured from the volume set of XDFI-CT. Finally, the 3D distribution pattern of the ducts was determined. RESULTS: XDFI-CT can provide images almost equivalent to those of low-magnification light microscopy of conventional hematoxylin-eosin-stained histological sections. The mean number of ducts in all cases was 28.0. The total number of ducts sharing an ostium near the tip of the nipple was 525 of 1428. The 3D distribution patterns of the ducts were classified into three types that we defined as convergent (22%), straight (39%), or divergent (39%). CONCLUSIONS: XDFI-CT is useful for exploring the microanatomy of the human nipple and might be used for non-invasive nipple diagnosis in the future.

Lobar distribution of non-emphysematous gas trapping and lung hyperinflation in chronic obstructive pulmonary disease.

BACKGROUND: Lung hyperinflation in chronic obstructive pulmonary disease (COPD) is closely associated with emphysema and non-emphysematous gas trapping, termed functional small airway disease (fSAD), on inspiratory and expiratory computed tomography (CT). Because the cranial-caudal emphysema distribution affects pulmonary function and fSAD may precede emphysema on CT, we tested the hypothesis that lobar fSAD distribution would affect lung hyperinflation differently in COPD with minimal and established emphysema. METHODS: The volume percentages of fSAD and emphysema (fSAD% and Emph%) over the upper and lower lobes were measured using inspiratory and expiratory CT in 70 subjects with COPD. Subjects were divided into those with minimal and established emphysema (n = 36 and 34) using a threshold of 10% Emph% in the whole lung. RESULTS: In the minimal emphysema group, fSAD% in the upper and lower lobes was positively correlated with functional residual capacity (FRC) and residual volume to total lung capacity ratio (RV/TLC), and the correlation of fSAD% with RV/TLC was greater in the lower lobes. Conversely, in the established emphysema group, fSAD% in the upper and lower lobes was correlated with RV/TLC, but not with FRC. In multivariate analysis, fSAD% in the lower lobes, but not in the upper lobes, was associated with RV/TLC in subjects with minimal emphysema after adjusting for age, smoking status, and bronchodilator use. CONCLUSION: Non-emphysematous gas trapping in the upper and lower lobes has a distinct physiological effect, especially in COPD with minimal emphysema. This local evaluation might allow sensitive detection of changes in lung hyperinflation in COPD.