An enterococcal phage-derived enzyme suppresses graft-versus-host disease.

Changes in the gut microbiome have pivotal roles in the pathogenesis of acute graft-versus-host disease (aGVHD) after allogenic haematopoietic cell transplantation (allo-HCT)1-6. However, effective methods for safely resolving gut dysbiosis have not yet been established. An expansion of the pathogen Enterococcus faecalis in the intestine, associated with dysbiosis, has been shown to be a risk factor for aGVHD7-10. Here we analyse the intestinal microbiome of patients with allo-HCT, and find that E. faecalis escapes elimination and proliferates in the intestine by forming biofilms, rather than by acquiring drug-resistance genes. We isolated cytolysin-positive highly pathogenic E. faecalis from faecal samples and identified an anti-E. faecalis enzyme derived from E. faecalis-specific bacteriophages by analysing bacterial whole-genome sequencing data. The antibacterial enzyme had lytic activity against the biofilm of E. faecalis in vitro and in vivo. Furthermore, in aGVHD-induced gnotobiotic mice that were colonized with E. faecalis or with patient faecal samples characterized by the domination of Enterococcus, levels of intestinal cytolysin-positive E. faecalis were decreased and survival was significantly increased in the group that was treated with the E. faecalis-specific enzyme, compared with controls. Thus, administration of a phage-derived antibacterial enzyme that is specific to biofilm-forming pathogenic E. faecalis-which is difficult to eliminate with existing antibiotics-might provide an approach to protect against aGVHD.

Association between consumption of small fish and all-cause mortality among Japanese: the Japan Multi-Institutional Collaborative Cohort Study.

OBJECTIVE: Although small fish are an important source of micronutrients, the relationship between their intake and mortality remains unclear. This study aimed to clarify the association between intake of small fish and all-cause and cause-specific mortality. DESIGN: We used the data from a cohort study in Japan. The frequency of the intake of small fish was assessed using a validated FFQ. The hazard ratio (HR) and 95 % confidence interval (CI) for all-cause and cause-specific mortality according to the frequency of the intake of small fish by sex were estimated using a Cox proportional hazard model with adjustments for covariates. SETTING: The Japan Multi-Institutional Collaborative Cohort Study. PARTICIPANTS: A total of 80 802 participants (34 555 males and 46 247 females), aged 35-69 years. RESULTS: During a mean follow-up of 9·0 years, we identified 2482 deaths including 1495 cancer-related deaths. The intake of small fish was statistically significantly and inversely associated with the risk of all-cause and cancer mortality in females. The multivariable-adjusted HR (95 % CI) in females for all-cause mortality according to the intake were 0·68 (0·55, 0·85) for intakes 1-3 times/month, 0·72 (0·57, 0·90) for 1-2 times/week and 0·69 (0·54, 0·88) for ≥ 3 times/week, compared with the rare intake. The corresponding HR (95 % CI) in females for cancer mortality were 0·72 (0·54, 0·96), 0·71 (0·53, 0·96) and 0·64 (0·46, 0·89), respectively. No statistically significant association was observed in males. CONCLUSIONS: Intake of small fish may reduce the risk of all-cause and cancer mortality in Japanese females.

[Severe neuropsychiatric disorder developing during busulfan-containing regimen for stem cell transplantation].

Here we describe two patients that required interruption of a busulfan (BU) containing conditioning regimen due to severe mental disorder before stem cell transplantation. The first patient was a 66-year-old man scheduled for unrelated peripheral blood stem cell transplantation with fludarabine/BU conditioning for myelodysplastic syndrome. He received 9.6 mg/kg BU and developed hallucinations that worsened the next day. BU was stopped on the final day, but the patient became comatose (grade 4). He recovered the next day. The second patient was a 69-year-old man scheduled for autologous peripheral blood stem cell transplantation with thiotepa (TT)/BU conditioning for cerebral nervous system relapse of mantle cell lymphoma. He received 12.8 mg/kg BU and developed hallucinations. His mental symptoms worsened on the next day, and thus administration was stopped on the second day of TT. His symptoms improved the next day. Both patients were over 65 years old, and their psychiatric symptoms worsened 1-2 days after the final dose of BU. Our findings suggest that BU may cause psychiatric disorders in elderly patients. When performing BU conditioning, it may be necessary to avoid azole antifungal medication and acetaminophen and to reduce the dose or perform therapeutic dose monitoring for elderly patients.

Paraneoplastic isolated adrenocorticotropic hormone deficiency revealed after immune checkpoint inhibitors therapy: new insights into anti-corticotroph antibody.

Introduction: A recently discovered facet of paraneoplastic adrenocorticotropic hormone (ACTH) deficiency exists in two forms: a paraneoplastic spontaneous isolated ACTH deficiency (IAD) and an immune checkpoint inhibitor (ICI)-related hypophysitis. Autoantibodies against corticotrophs, such as circulating anti-proopiomelanocortin (POMC) antibodies are considered disease markers. However, the number of identified cases was limited, implying that the characteristics of these autoantibodies are not fully understood. Methods: We investigate circulating autoimmune autoantibodies in detail through a novel case of IAD that developed as a paraneoplastic autoimmune ACTH deficiency. Results: The patient developed IAD after 25 weeks of ICI therapy for metastasis of large-cell neuroendocrine carcinoma at 69 years of age. Ectopic ACTH expression and infiltration of CD3+, CD4+, CD8+, and CD20+ lymphocytes were observed in the tumor tissues and circulating anti-POMC antibodies were detected specifically in the patient's serum. Moreover, detailed analyses of immunofluorescence staining using patient serum revealed that the recognition site of the autoantibody was ACTH25-39, which had not been identified in previous cases of paraneoplastic autoimmune ACTH deficiency. Conclusion: This case involved a combination of paraneoplastic spontaneously acquired IAD and ICI-related hypophysitis occupying the middle ground. Moreover, our study reveals new aspects of anti-POMC antibodies in patients with paraneoplastic ACTH deficiency. This report expands our understanding of the immunological landscape and provides new insights for the identification of antibodies associated with paraneoplastic autoimmune ACTH deficiency.

End-of-Life Care of Acute Myeloid Leukemia Compared with Aggressive lymphoma in Patients Who Are Eligible for Intensive Chemotherapy: An Observational Study in a Japanese Community Hospital.

Background: Patients with hematological malignancies (HMs) are reported to receive more aggressive care at the end of life (EOL) than patients with solid tumors. However, the reasons behind this occurrence are not fully understood. Objectives: To examine whether the care at EOL for HMs is mainly because of the disease characteristics or hematologists' attitudes and systems of care, we compared the EOL care of patients with acute myeloid leukemia (AML) and diffuse large B cell lymphoma (DLBCL). Design: We retrospectively analyzed the EOL care of patients with AML and DLBCL younger than 80 years who were receiving combination chemotherapy at a city hospital in Japan. Results: Fifty-nine patients with AML and 65 with DLBCL were included. Those with AML received chemotherapy more often within their last 30 days (48% vs. 19%, p < 0.001) and 14 days (37% vs. 1.5%, p < 0.001) of life, and consulted the palliative team less frequently (5.3% vs. 29%, p < 0.001). In the last 3 years, the mortality rate in hematological wards decreased from 74% to 29% in the DLBCL group, but only from 95% to 90% in the AML group. In multivariate analysis, AML (odds ratio [OR] 0.065) and death before 2018 (OR, 0.077) were significant factors associated with reduced referrals to specialized palliative teams. Conclusion: Patients with AML tend to have lesser access to specialized palliative care and fewer options for their place of death than those with DLBCL. Detailed EOL care plans are needed for these patients, considering the characteristics of the disease.

Second Primary Metachronous Malignancies Occurring in Oral Cavity of Young Adult-A Case Report.

The incidence of oral cancer in Japan is increasing. Interestingly, the number of young patients with oral cancer is also rising. A 19-year-old man with no history of smoking or drinking alcohol presented with a 20×15-mm elastic, hard, protruding mass with a white surface on the right-hand margin of the tongue. A biopsy resulted in a diagnosis of a well-differentiated squamous cell carcinoma of the tongue, for which a partial resection was subsequently performed. During regular follow-up, the patient demonstrated no clinical or imaging abnormalities until 4 years and 9 months later, when erosion was observed at the right palatoglossal arch. A malignant tumor of the right palatoglossal arch was diagnosed based on cytology and imaging findings, and total resection of the lesion performed. Histopathological examination of the resected lesion revealed a moderately differentiated squamous cell carcinoma. Epithelial dysplasia on the right-hand margin of the tongue was diagnosed 4 years and 9 months after the second surgery and was subsequently resected. The patient's condition has been favorable for 7 years since the diagnosis of the second cancer, with no noted recurrence. This case emphasizes the importance of follow-up after initial treatment, as even young people, who are likely to have to endure long-lasting consequences from treatment, can develop metachronous cancer in the oral cavity.

BACH1 Expression Is Promoted by Tank Binding Kinase 1 (TBK1) in Pancreatic Cancer Cells to Increase Iron and Reduce the Expression of E-Cadherin.

BTB and CNC homology 1 (BACH1) represses the expression of genes involved in the metabolism of iron, heme and reactive oxygen species and promotes metastasis of various cancers including pancreatic ductal adenocarcinoma (PDAC). However, it is not clear how BACH1 is regulated in PDAC cells. Knockdown of Tank binding kinase 1 (TBK1) led to reductions of BACH1 mRNA and protein amounts in AsPC-1 human PDAC cells. Gene expression analysis of PDAC cells with knockdown of TBK1 or BACH1 suggested the involvement of TBK1 and BACH1 in the regulation of iron homeostasis. Ferritin mRNA and proteins were both increased upon BACH1 knockdown in AsPC-1 cells. Flow cytometry analysis showed that AsPC-1 cells with BACH1 knockout or knockdown contained lower labile iron than control cells, suggesting that BACH1 increased labile iron by repressing the expression of ferritin genes. We further found that the expression of E-cadherin was upregulated upon the chelation of intracellular iron content. These results suggest that the TBK1-BACH1 pathway promotes cancer cell metastasis by increasing labile iron within cells.

Does Direct-to-Consumer Personal Genetic Testing Improve Gynecological Cancer Screening Uptake among Never-Screened Attendees? A Randomized Controlled Study.

The clinical impact of direct-to-consumer genetic testing (DTC-GT) on health behavior change has remained controversial. The aim of this study is to clarify the short-term effects of DTC-GT on gynecological cancer screening uptake among middle-aged never-screened Japanese women in a randomized controlled trial (RCT). A total of 144 women aged 45-50 who had never undergone gynecological cancer screening were randomly selected to receive health education (control group), or health education and DTC-GT (intervention group), at a 1:1 ratio. We compared the gynecological screening uptake during the follow-up period. Furthermore, to estimate the impact of learning of an elevated genetic cancer risk in the intervention group, we conducted an analysis dichotomized by genetic risk category. A total of 139 women completed the one-year follow-up survey (69 in the control group and 70 in the intervention group). The follow-up period did not differ between control and intervention groups (the median follow-up period was 276 days and 279 days, respectively, p = 0.746). There were 7 (9.7%) women in the control group and 10 (13.9%) in the intervention group who attended breast cancer screening (p = 0.606), and 9 (12.5%) women from both groups attended cervical cancer screening (p = 1.000). Likewise, there were no significant differences in cancer screening uptake in the analysis stratified by risk category within the intervention group. In conclusion, there was no significant effect of DTC-GT on gynecological cancer screening uptake in this RCT setting. Increasing cancer screening attendance may require a combination of well-established intervention strategies and DTC-GT. Clinical Trial Registration: UMIN-CTR Identifier, UMIN000031709.

A Case of Mandibular Cancer Involving Almost Entire Attached Gingiva.

Here we describe a rare case of mandibular cancer involving almost the entire attached gingiva in a 71-year-old man. First, marginal resection of the entire mandible was performed, followed by one-stage reconstruction comprising application of a split-thickness skin graft onto the wound. This resulted in good alveolar ridge morphology, allowing for a mandibular prosthesis to be installed soon postoperatively. Histopathological analysis revealed a well-differentiated squamous cell carcinoma extending throughout most of the resected attached gingiva, but no malignant features in the stumps. Furthermore, no infiltration into the jawbone was observed, and no vascular or lymphatic invasion or perineural infiltration. At 3 years postoperatively, the patient's clinical course has remained uneventful, with no recurrence or problems arising in the remaining mandible. The patient is also able to eat regularly using the mandibular prosthesis provided.

Case Report: Metreleptin and SGLT2 Inhibitor Combination Therapy Is Effective for Acquired Incomplete Lipodystrophy.

Childhood cancer survivors (CCSs) who have undergone bone marrow transplantation with systemic chemotherapy and whole-body irradiation often experience impaired glucose tolerance with marked insulin resistance. Incomplete acquired diabetic lipodystrophy should be considered as a late complication of bone marrow transplantation. A 24-year-old Japanese female patient with incomplete acquired lipodystrophy, a CCS of acute lymphocytic leukemia at the age of 3 years, was treated for diabetes mellitus and dyslipidemia at our hospital. Administration of multiple daily insulin injections (70 units/day), and oral administration of 500 mg/day metformin, 15 mg/day pioglitazone, and 200 mg/day bezafibrate had proven ineffective for her metabolic disorders. Subcutaneous administration of metreleptin improved her insulin resistance and hypertriglyceridemia within a month; however, it failed to maintain adequate plasma glucose levels in the long term. When oral administration of 10 mg/day empagliflozin was added to the metreleptin supplementation, her HbA1c value (National Glycohemoglobin Standardization Program) improved from 11% to 8%, which was maintained for an additional 18 months. This is the first case report of incomplete lipodystrophy that shows efficacy of a combination therapy with metreleptin and a sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of diabetes and dyslipidemia. An SGLT2 inhibitor attenuates hyperglycemia through urinary glucose excretion and has been suggested to enhance lipid catabolism in the extra-adipose tissues, especially in the liver and skeletal muscles. Furthermore, metreleptin supplementation could enhance the action of the SGLT2 inhibitor by promoting satiety and lipolysis through the central nervous system. Combination therapy with metreleptin and an SGLT2 inhibitor was suggested to recover the volume of adipose tissue, possibly through improvement of insulin resistance in the adipose tissue. This report highlights the pathophysiological mechanism of an SGLT2 inhibitor in the improvement of glucose metabolism in non-healthy lean CCSs with insulin resistance. Administration of SGLT2 inhibitor, along with metreleptin supplementation, could be a good alternative therapy for diabetic lipodystrophy observed in CCSs.

Impact of PSCA Polymorphisms on the Risk of Duodenal Ulcer.

BACKGROUND: While duodenal ulcer (DU) and gastric cancer (GC) are both H. pylori infection-related diseases, individuals with DU are known to have lower risk for GC. Many epidemiological studies have identified the PSCA rs2294008 T-allele as a risk factor of GC, while others have found an association between the rs2294008 C-allele and risk of DU and gastric ulcer (GU). Following these initial reports, however, few studies have since validated these associations. Here, we aimed to validate the association between variations in PSCA and the risk of DU/GU and evaluate its interaction with environmental factors in a Japanese population. METHODS: Six PSCA SNPs were genotyped in 584 DU cases, 925 GU cases, and 8,105 controls from the Japan Multi-Institutional Collaborative Cohort (J-MICC). Unconditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between the SNPs and risk of DU/GU. RESULTS: PSCA rs2294008 C-allele was associated with per allele OR of 1.34 (95% CI, 1.18-1.51; P = 2.28 × 10-6) for the risk of DU. This association was independent of age, sex, study site, smoking habit, drinking habit, and H. pylori status. On the other hand, we did not observe an association between the risk of GU and PSCA SNPs. CONCLUSIONS: Our study confirms an association between the PSCA rs2294008 C-allele and the risk of DU in a Japanese population.

Study Profile of the Japan Multi-institutional Collaborative Cohort (J-MICC) Study.

BACKGROUND: The Japan Multi-institutional Collaborative Cohort (J-MICC) study was launched in 2005 to examine gene-environment interactions in lifestyle-related diseases, including cancers, among the Japanese. This report describes the study design and baseline profile of the study participants. METHODS: The participants of the J-MICC Study were individuals aged 35 to 69 years enrolled from respondents to study announcements in specified regions, inhabitants attending health checkup examinations provided by local governments, visitors at health checkup centers, and first-visit patients at a cancer hospital in Japan. At the time of the baseline survey, from 2005 to 2014, we obtained comprehensive information regarding demographics, education, alcohol consumption, smoking, sleeping, exercise, food intake frequency, medication and supplement use, personal and family disease history, psychological stress, and female reproductive history and collected peripheral blood samples. RESULTS: The baseline survey included 92,610 adults (mean age: 55.2 [standard deviation, 9.4] years, 44.1% men) from 14 study regions in 12 prefectures. The participation rate was 33.5%, with participation ranging from 19.7% to 69.8% in different study regions. The largest number of participants was in the age groups of 65-69 years for men and 60-64 years for women. There were differences in body mass index, educational attainment, alcohol consumption, smoking, and sleep duration between men and women. CONCLUSIONS: The J-MICC Study collected lifestyle and clinical data and biospecimens from over 90,000 participants. This cohort is expected to be a valuable resource for the national and international scientific community in providing evidence to support longer healthy lives.

Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19.

BACKGROUND: Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known. METHODS: We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15. RESULTS: A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003). CONCLUSIONS: Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).

Masked Diabetes Insipidus Hidden by Severe Hyponatremia: A Case of Pituitary Metastasis of Lung Adenocarcinoma.

BACKGROUND Hyponatremia is an electrolyte disorder frequently encountered by clinicians. Secondary adrenal insufficiency due to pituitary metastatic tumors should be considered as an alternative diagnosis when clinicians encounter patients with lung cancer who demonstrate hyponatremia. However, masked central diabetes insipidus should also be considered to prevent critical dehydration when glucocorticoid replacement therapy will be initiated. CASE REPORT A 70-year-old man with advanced lung adenocarcinoma demonstrated high-grade hyponatremia of 122 mmol/L. Magnetic resonance imaging disclosed a metastatic pituitary tumor and endocrinological examinations confirmed panhypopituitarism, including secondary adrenal insufficiency. Hydrocortisone replacement revealed masked diabetes insipidus with elevation of serum sodium levels that reached 151 mmol/L. Desmopressin administration was required to prevent water depletion and to immediately ameliorate the hypernatremia. CONCLUSIONS This is the first case report of masked diabetes insipidus that demonstrated high-grade hyponatremia. Secondary adrenal insufficiency can mask the hypernatremia that is a typical manifestation of diabetes insipidus. Physicians should consider adrenal insufficiency and diabetes insipidus due to pituitary metastasis of advanced malignancies, even when they encounter patients with hyponatremia.

Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients.

OBJECTIVES: Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000-3000 years. METHODS: Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. RESULTS: In addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10-8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients' gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. CONCLUSIONS: Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.

Association Between Second-hand Smoke Exposure and Depressive Symptoms Among Japanese Adults: A Cross-sectional Study.

BACKGROUND: Second-hand smoke exposure has been associated with poor mental health. However, among Japanese adults, little is known about the association between second-hand smoking and depressive symptoms. We examined this association in a cross-sectional study among a Japanese general adult population sample. METHODS: Japanese adults were recruited from the Japan Multi-Institutional Collaborative Cohort Study in the Okazaki area between 2012 and 2017. Second-hand smoke exposure and smoking status were assessed using a self-administered questionnaire. Based on their frequency of exposure to second-hand smoke, non-smokers and smokers were categorized as "almost never," "sometimes," and "almost every day". Depressive symptoms were defined by a Kessler 6 score ≥5 points. We performed a multivariable Poisson regression analysis to obtain adjusted prevalence ratios (PRs) and 95% confidence intervals (CIs) for depressive symptoms. RESULTS: Overall, 5,121 participants (4,547 non-smokers and 574 smokers) were included whose mean age was 63.6 (standard deviation [SD], 10.3) years for non-smokers and 59.33 (SD, 10.2) years for smokers. The association between second-hand smoking and depressive symptoms was significant among non-smokers, but not among smokers. Among non-smokers, PRs compared with "almost never" were 1.25 (95% CI, 1.09-1.42) for "sometimes" and 1.41 (95% CI, 1.09-1.84) for "almost every day" (P for trend <0.001); among smokers, PRs compared with "almost never" were 1.30 (95% CI, 0.82-2.06) for "sometimes" and 1.44 (95% CI, 0.90-2.33) for "almost every day" (P for trend = 0.144). CONCLUSIONS: Second-hand smoking and depressive symptoms were associated among non-smokers. Our findings indicate the importance of tobacco smoke control for mental health.

A Pilot Study of Human Milk to Reduce Intestinal Inflammation After Bone Marrow Transplant.

OBJECTIVE: Human milk administration in the early peritransplant period would lower intestinal inflammation after bone marrow transplant (BMT). MATERIALS AND METHODS: Children 0-5 years undergoing BMT received either a ready-to-feed human milk preparation designed for these children (Prolacta Bioscience, Duarte, CA) or standard formula. Babies breastfeeding at the time of BMT were also enrolled on the human milk arm. Human milk was administered from day -3 until day +14 after BMT. Metagenomic shotgun sequencing and metabolomics of stool, plasma cytokines, and regenerating islet-derived 3α (REG3α) levels were measured at enrollment and day +14. Human leukocyte antigen-DR isotype (HLA-DR), CD38, and CD69 expression on T cells were evaluated at day +21. RESULTS: Forty-six children were enrolled, 32 received human milk (donor milk n = 23, breastfeeding babies n = 9), and 14 were controls who received standard feeds supervised by a BMT dietician. Twenty-four patients received at least 60% of goal human milk and were evaluable. Plasma interleukin (IL)-8 (p = 0.04), IL-10 (p = 0.02), and REG3α (p = 0.03) were decreased in the human milk cohort. Peripheral blood CD69+ CD8+ T cells were higher in controls (p = 0.01). Species abundance of Adenovirus (p = 0.00034), Escherichia coli (p = 0.0017), Cryptosporidium parvum (p = 0.0006), Dialister invisus (p = 0.01), and Pseudomonas aeruginosa (p = 0.05) from stool was higher in controls. Stool alanine, tyrosine, methionine, and the ratio of fecal alanine to choline and phosphocholine were higher in controls (p < 0.05). No difference was observed in stool propionate and butyrate levels as measures of short-chain fatty acids between the two cohorts. CONCLUSIONS: Administration of human milk resulted in decreased markers of intestinal inflammation and could be a valuable adjunct for patients after BMT.

Prognostic factors for maxillary sinus mucosal thickening following Le Fort I osteotomy: a retrospective analysis.

BACKGROUND: Le Fort I osteotomy is one of the surgical procedures now routinely and safely performed. It is possible to move the maxilla in three dimensions, but it is necessary to separate the bones around the maxillary sinus. Therefore, with surgery, maxillary sinus mucosal thickening occurs. By knowing the changes in the sinus mucosa after surgery and the factors affecting it, it is possible to better predict the outcomes of surgery and contribute to safer surgery. In this study, thickening of maxillary sinus mucosa before and after surgery in Le Fort I osteotomy was evaluated using multidetector-row computed tomography (MDCT) images, and the changes in mucosal thickening and the related factors were examined. METHODS: Using MDCT images, the maxillary sinus mucosa of 125 patients who had undergone Le Fort I osteotomy was retrospectively evaluated before surgery, 1 month after surgery, and 1 year after surgery. On the MDCT images, the maxillary sinus was judged as mucosal thickening and classified into three grades according to the proportion occupying the maxillary sinus. In the evaluation of factors related to mucosal thickening, the following eight factors were examined: sex, age, diagnosis, operating time, amount of postoperative bleeding, with/without bone graft, with/without multisegmental osteotomy, and with/without macrolide therapy after surgery. RESULTS: The mean age at the time of surgery was 25.6 ± 8 years. Of all 125 patients, 66 had bilateral thickening, 19 had unilateral thickening, and 40 had no thickening. Factors that were significantly related to mucosal thickening were the operative time for the maxilla, bone grafts, and macrolide therapy after surgery. CONCLUSIONS: Operative time for the maxilla, bone grafts, and macrolide therapy after surgery were found to be related to mucosal thickening. In addition, MDCT scanning 1 month after surgery was considered to be appropriate for evaluation of maxillary sinus mucosal thickening.

Eficacia del propofol-fentanilo comparada con propofolketamina en procedimientos dolorosos mayores en un Departamento de Emergencia Pediátrica / Efficacy of propofol-fentanyl compared with propofolketamine in significantly painful procedures in a Pediatric Emergency Department

Objetivo: Comparar la eficacia de la combinación propofol - fentanilo (P / F) con propofol - ketamina (P / K) en procedimientos dolorosos mayores en un Departamento de Emergencias Pediátricas (DEP). Diseño: Ensayo aleatorizado, controlado, abierto, con cegamiento del evaluador. Material y Métodos: Se incluyeron pacientes de 6 meses a 18 años, con una clasificación ASA menor o igual a 3, sometidos a sedación y analgesia para la realización de procedimientos dolorosos. Intervenciones: Los sujetos fueron asignados al azar para recibir propofol-fentanilo o propofol-ketamina. Se evaluaron las complicaciones. Las variables fueron: datos demográficos, tipos de procedimientos, tiempo hasta la adecuada sedación y analgesia, dosis adicionales requeridas, tiempo de recuperación y efectos adversos. Resultados: Se analizaron sesenta procedimientos (30 por grupo). No hubo diferencias en la edad, el sexo, el tipo de procedimiento, la duración de la infusión y la duración del procedimiento o el tiempo de recuperación. El tiempo para lograr la sedación (minutos) fue mayor con P / F que con P / K: 2 (1-4 rango intercuartilo) vs. 1 (rango intercuartil a 1-1). El tiempo (minutos) para lograr una analgesia adecuada con P / F fue 2 (1-5 rango intercuartilo) vs. 1 (1-1 ,25 rango intercuartilo). p <0,001. El P / F requirió más dosis adicionales, 80% frente a 43%, p <0,004, y tuvo más efectos secundarios, 46, 6% (intervalo de confianza [IC] del 95%: 70% a 100%) versus 20% (95%). % CI-2% a 59%) p <0,024. La proporción de efectos adversos graves con P/F vs P/K fue: 6% (95% CI-1,8% a 2%) versus 0% (95% CI-0 a 0%) p 0.246. Conclusiones: Concluimos que las combinaciones de Propofol / Fentanilo y Propofol/Ketamina, son eficaces en alcanzar la sedoanalgesia en procedimientos muy dolorosos y cortos. Presentando la primera combinación más efectos secundarios y requiriendo más tiempo y dosis adicionales para lograr los niveles deseados de sedoanalgesia.

Objective: To compare the efficacy of the combination of propofol - fentanyl (P / F) with propofol - ketamine (P / K) in significantly painful procedures in a Pediatric Emergency Department (PED). Design: This was a randomized, controlled, open label trial, with evaluator blinding. Materials and Methods: Patients from 6 months to 18 years were included, with an ASA classification less than or equal to 3, undergoing sedation and analgesia for significantly painful procedures. Interventions: Subjects were randomized to receive propofol-fentanyl or propofol-ketamine. Complications were evaluated. The variables were: demographic data, procedure type, time to adequate sedation and analgesia, additional doses required, recovery time and adverse effects. Results: Sixty procedures were analyzed (30 per group). There were no differences in age, sex, procedure type, duration of infusion, duration of the procedure or recovery time. The time to achieve sedation (minutes) was higher with P / F than with P / K: 2 (1-4 interquartile range) vs. 1 (interquartile range to 1-1). The time (minutes) to achieve adequate analgesia with P / F was 2 (1-5 interquartile range) vs. 1 (1-1, 25 interquartile range). p <0.001. The P / F required more additional doses, 80% vs. 43%, p <0.004, and had more side effects, 46.6% (95% confidence interval [CI]: 70% to 100%) versus 20% (95% CI-2% to 59%), p <0.024. The proportion of serious adverse effects with P / F vs P / K was: 6% (95% CI-1.8% to 2%) versus 0% (95% CI-0 to 0%), p = 0.246. Conclusions: We conclude that the combinations of Propofol / Fentanyl and Propofol / Ketamine are effective in achieving sedoanalgesia in significantly painful and short-duration procedures, with the P / F combination having more side effects and requiring more time and additional doses to achieve the desired levels of sedoanalgesia.