Simplified risk stratification in early cholecystectomy for acute cholecystitis based on age: A report from an institution with zero mortality.

BACKGROUND/PURPOSE: The existing risk stratification for early cholecystectomy in patients with acute cholecystitis (AC) is complex. This study aims to establish a simpler risk assessment for surgical complications after cholecystectomy based on age group. METHODS: This single-center retrospective observational study enrolled 350 patients diagnosed with AC who underwent early cholecystectomy within 72 h of diagnosis from 2013 to 2021. Patients were divided into three subgroups based on age: young (<65 years), elderly (65-79 years), and very elderly (≥80 years). Since no mortality was observed, risk factors for the Clavien-Dindo (CD) grade ≥ II complications were identified within the entire cohort and in each subgroup. RESULTS: There were 120 young, 130 elderly, and 100 very elderly patients. The overall prevalence of complications with CD grade ≥ II was 11.1%. Age and Tokyo Guidelines 18 (TG18) severity were independent risk factors for surgical complications in the whole cohort. Subgroup analysis revealed that there was no independent risk factor in the young group. Meanwhile, age and poor physical status were independent risk factors in the elderly group, and TG18 severity in the very elderly group. CONCLUSION: Evaluation of only age, physical status, and TG18 severity may be sufficient for risk stratification of surgical complications of AC.

Effects of message order and active participation on vaccine risk communication.

BACKGROUND: "Message order" and "active participation" could be effective as risk communication methods. "Anticipated regret" (AR) has also been recognized as affecting risk perception and vaccine uptake in vaccination risk communication. We aimed to evaluate the effects of message order and active participation and the interactions between these two interventions on AR for vaccination. METHODS: We conducted a 2 (message order: positive-negative or negative-positive) × 2 (message calendar: with or without planning) factorial design study among 81 study participants. The effects of message order and active participation of mothers, using a message calendar, were evaluated on mothers' decision-making regarding vaccination with Haemophilus influenzae type b vaccine and pneumococcal conjugate vaccine for their children. Participants completed questionnaires to evaluate the AR of infection if unvaccinated (anticipated regret of inaction) and of side effects if vaccinated (anticipated regret of action, ARA) twice: immediately after interventions and 1 month later. RESULTS: An interaction between message order and active participation was significant with regard to anticipated regret of inaction immediately after interventions (P = 0.01), but this effect disappeared 1 month after interventions. The message order showed no main effect with regard to ARA. However, the main effect of active participation was marginally significant with regard to ARA 1 month after intervention (P = 0.09); AR over vaccine side effects was lower when vaccination was planned than in the condition without planning. CONCLUSIONS: The effect of message order was hardly detectable in a clinical setting. However, active participation induced by planning may affect AR. Further studies are needed to evaluate the effect of active participation in decision-making for vaccination.

Challenges to neonatal care in Cambodia amid the COVID-19 pandemic.

Since mid-February, 2020, coronavirus disease-2019 (COVID-19) has been spreading in Cambodia and, as of April 9, 2020, the Ministry of Health has identified 119 polymerase chain reaction (PCR)-positive cases. However, the PCR test is available in only two specialized institutes in the capital city Phnom Penh; therefore, exact and adequate identification of the cases remains still limited. Many vulnerable newborn infants have been admitted to the neonatal care unit (NCU) at the National Maternal and Child Health Center in Phnom Penh. Although the staff have implemented strict infection prevention and control measures, formidable gaps in neonatal care between Cambodia and Japan exist. Due to the shortages in professional workforce, one family member of sick newborn(s) should stay for 24 hours in the NCU to care for the baby. This situation, however, may lead to several errors, including hospital-acquired infection. It is crucial not only to make all efforts to prevent infections but also to strengthen the professional healthcare workforce instead of relying on task sharing with family members.

Analysis of spinal muscular atrophy-like patients by targeted resequencing.

BACKGROUND: Several effective therapies have been developed for spinal muscular atrophy (SMA), but there are multiple diseases that show SMA-like symptoms, necessitating efficient differential genetic diagnostic methods. Advancements in next-generation sequencing (NGS) technology have facilitated the successful diagnosis of many undiagnosed genetic diseases. Here, we applied NGS along with conventional methods for the molecular diagnosis of undiagnosed patients with lower motor neuron (LMN) symptoms who were initially suspected to have SMA. METHODS: We enrolled 157 patients with LMN symptoms who visited the Institute of Medical Genetics, Tokyo Women's Medical University, between 2005 and 2016. We excluded 86 patients diagnosed with SMA after confirming the causative SMN1 gene deletion or variants. Finally, we examined 12 undiagnosed patients from eight families by targeted resequencing using NGS. Variants were selected on the basis of literature search and databases, and mutations in a gene where loss of function is a known mechanism of disease were considered as pathogenic. Candidate variants were validated by Sanger sequencing. RESULTS: We detected novel variants for three patients from two families. Patients 1 and 2 (siblings) showed compound heterozygous TTN variants (c.6621delG, p.W2207Cfs*28 and c.23718T>A, p.F7906L), while patient 3 displayed compound heterozygous KIF1A variants of (c.3871C>T, p.R1291C and c.3898G>A, p.V1300M). CONCLUSIONS: We detected appropriate variants using our approach of obtaining candidate pathogenic variants by targeted resequencing through NGS and narrowed down the variants in light of patient clinical symptoms. We successfully identified novel causative variants in three undiagnosed patients, which indicated the effectiveness of our approach.

Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway.

Pancreas transcription factor 1 subunit alpha (PTF1A) is one of the key regulators in pancreatogenesis. In adults, it transcribes digestive enzymes, but its other functions remain largely unknown. Recent conditional knockout studies using Ptf1aCreER/floxed heterozygous mouse models have found PTF1A contributes to the identity maintenance of acinar cells and prevents tumorigenesis caused by the oncogenic gene Kras. However, Ptf1a heterozygote is known to behave differently from homozygote. To elucidate the effects of Ptf1a homozygous loss, we prepared Elastase-CreERTM; Ptf1afloxed/floxed mice and found that homozygous Ptf1a deletion in adult acinar cells causes severe apoptosis. Electron microscopy revealed endoplasmic reticulum (ER) stress, a known cause of unfolded protein responses (UPR). We confirmed that UPR was upregulated by the activating transcription factor 6 (ATF6) and protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK) pathways, but not the inositol requiring enzyme 1 (IRE1) pathway. Furthermore, we detected the expression of CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP), a pro-apoptotic factor, indicating the apoptosis was induced through UPR. Our homozygous model helps clarify the role PTF1A has on the homeostasis and pathogenesis of exocrine pancreas in mice.

Congenital Cytomegalovirus Pneumonitis and Treatment Response Evaluation Using Viral Load during Ganciclovir Therapy: a Case Report.

Cytomegalovirus (CMV) is the most common cause of congenital infection. Pneumonitis is considered to be a rare manifestation although congenital CMV infection presents with various non-specific findings. Ganciclovir and valganciclovir are beneficial for improving neurodevelopmental sequelae and hearing outcomes of congenital CMV infection; however, treatment response evaluation is not well reported. We report a female case of congenital CMV infection presenting with pneumonitis, meningoencephalitis, and chorioretinitis. She was treated with intravenous ganciclovir for 6 weeks, and clinical features improved. Measurement of the CMV genome load by real-time polymerase chain reaction assay was performed during treatment. After the administration of ganciclovir, the CMV genome was not detected in the blood and levels decreased gradually in the urine. Physicians should consider the possibility of congenital CMV infection in neonates who present with respiratory distress. Furthermore, measurement of the CMV genome load in blood and urine may be useful for evaluating treatment response.

Liver-specific Prox1 inactivation causes hepatic injury and glucose intolerance in mice.

Previous reports have revealed that Prospero-related homeobox 1 (Prox1) is required for the migration and differentiation of hepatoblasts during embryonic liver formation. However, the role of Prox1 in adults remains to be elucidated. We created liver-specific Prox1 knockout mice to verify the role of Prox1 in adult hepatocytes. The mutant mice exhibit hepatic injury and a nonobese, insulin-resistant diabetic phenotype in vivo. Hepatocyte injury is observed predominantly in the perivenous region and is characterized by the formation of vacuoles and emergence of round-shaped mitochondria, suggesting that the effect of Prox1 on the maintenance of adult hepatocytes is region dependent. Furthermore, glycolysis is suppressed, and both oxidative phosphorylation and autophagy are upregulated in the livers of Prox1 knockout mice, indicating that Prox1 has a role in regulating energy homeostasis in hepatocytes.

Short- and long-term outcomes after pancreaticoduodenectomy following total gastorectomy: Report of case series and literature review.

PURPOSE: Pancreaticoduodenectomy (PD) following gastrectomy (TG) should be considered challenging even currently although its procedure and clinical value have been being standardized. Short- and long-term outcomes as well as standard reconstruction method following these procedures remain unclear. In order to clarify these issues, we reviewed worldwide English literature and 4 of our own cases of PD for patients with previous TG. METHODS: Clinicopathological variables of 11 cases of PD for patients with previous TG were evaluated. Seven of these 11 were abstracted from a review of worldwide English literature and 4 of 11 were our own cases. RESULTS: 3 cases was reconstructed using Y-limb made in previous TG and afferent loop syndrome (ALS) was observed in 2 of 3, in these cases whereas no cases of ALS were found in cases reconstructed using newly-made Y-limb. In cases where PD was indicated for cancer, early cancer death, defined as death related to cancer recurrence observed within 2 years after PD, was observed in 6 of 9 cases. Notably in cases of pancreatic cancer recurrent cancer was diagnosed within 1year after PD in 5 of 7 cases and 4 of these patients died of pancreatic cancer soon after recurrence. CONCLUSION: In cases of PD following TG, previously-made Y-limb should not be used for reconstruction following PD because of probable cause of previously-made Y-limb for ALS. Long-term outcomes of PD after TG seemed unsatisfactory notably in cases of pancreatic cancer and thus application of PD for patients with previous TG should be carefully decided until reasonable explanation for this dismal outcome is obtained.

High Plasma Concentrations of Zidovudine (AZT) Do Not Parallel Intracellular Concentrations of AZT-Triphosphates in Infants During Prevention of Mother-to-Child HIV-1 Transmission.

OBJECTIVES: Zidovudine (AZT) is mainly used to prevent mother-to-child HIV-1 transmission (PMTCT). Despite serious concerns on AZT-associated toxicity, there is little information on pharmacokinetics of intracellular AZT metabolites in infants. METHODS: We conducted a prospective study in 31 HIV-uninfected infants who received AZT for PMTCT. Blood samples were obtained from 14 infants on postdelivery days (PDD) 1, 7, 14, and 28 and from 17 infants at 0 and 4 hours after dosing on PDD-1. Plasma AZT concentrations (pAZT) and intracellular concentrations of AZT-monophosphate (icAZT-MP), diphosphate (icAZT-DP), and triphosphate (icAZT-TP) were determined. RESULTS: Plasma AZT and icAZT-MP concentrations were 2713 nmol/L and 79 fmol/10 cells in PDD-1, but decreased to 1437 nmol/L and 31 fmol/10 cells by PDD-28 (P = 0.02 and P = 0.07 for all PDDs, respectively), whereas those of icAZT-DP and icAZT-TP remained low throughout the sampling period (P = 0.29 and P = 0.61 for all PDDs, respectively) There were no differences in icAZT-TP between infants of the 2 mg/kg 4 times a day dose and 4 mg/kg twice daily dose (P = 0.25), whereas pAZT and icAZT-MP levels were higher in the latter (P < 0.01 and <0.01, respectively). The pAZT and icAZT-MP significantly increased from 0 to 4 hours after dosing (P < 0.001 and <0.001, respectively), whereas icAZT-DP, icAZT-TP levels were not changed (P = 0.41 and 0.33, respectively). CONCLUSIONS: The level of icAZT-TP did not change with age, time, or a single dose despite the wide range of pAZT concentration. A safer dosage needs to be determined because high pAZT levels do not parallel those of icAZT-TP.

Republication: Two Premature Neonates of Congenital Syphilis with Severe Clinical Manifestations.

Congenital syphilis (CS) is a public health burden in both developing and developed countries. We report two cases of CS in premature neonates with severe clinical manifestations; Patient 1 (gestational age 31 weeks, birth weight 1423 g) had disseminated idiopathic coagulation (DIC) while Patient 2 (gestational age 34 weeks and 6 days, birth weight 2299 g) had refractory syphilitic meningitis. Their mothers were single and had neither received antenatal care nor undergone syphilis screening. Both neonates were delivered via an emergency cesarean section and had birth asphyxia and transient tachypnea of newborn. Physical examination revealed massive hepatosplenomegaly. Laboratory testing of maternal and neonatal blood showed increased rapid plasma reagin (RPR) titer and positive Treponema pallidum hemagglutination assay. Diagnosis of CS was further supported by a positive IgM fluorescent treponemal antibody absorption test and large amounts of T. pallidum spirochetes detected in the placenta. Each neonate was initially treated with ampicillin and cefotaxime for early bacterial sepsis/meningitis that coexisted with CS. Patient 1 received fresh frozen plasma and antithrombin III to treat DIC. Patient 2 experienced a relapse of CS during initial antibiotic treatment, necessitating parenteral penicillin G. Treatment was effective in both neonates, as shown by reductions in RPR. Monitoring of growth and neurological development through to age 4 showed no evidence of apparent delay or complications. Without adequate antenatal care and maternal screening tests for infection, CS is difficult for non-specialists to diagnose at birth, because the clinical manifestations are similar to those of neonatal sepsis and meningitis. Ampicillin was insufficient for treating CS and penicillin G was necessary.

An hour-specific transcutaneous bilirubin nomogram for Mongolian neonates.

UNLABELLED: Transcutaneous bilirubin (TcB) nomograms have been developed for different populations. However, the TcB level, rate of rise and peak varies among countries and ethnicities. The aim of this study was to establish an hour-specific TcB nomogram for healthy term and late preterm Mongolian neonates during the first 144 h after birth. A total of 5084 TcB measurements from 1297 healthy neonates (gestational age ≥35 weeks, birth weight ≥2000 g) were obtained from October 2012 to October 2013. All measurements were performed using the Jaundice Meter, the JM-103 at 6 to 144 postnatal hours. Mongolian infants had the following characteristics: 27.1 % were delivered by cesarean section, 17.8 % had a birth weight >4000 g, and >90 % were being breastfed. TcB percentiles for each designated time point were calculated for the development of an hour-specific nomogram. TcB levels increased most rapidly in the first 24 h and less rapidly from 24 to 78 h, reaching a plateau after 78 h for the 50th percentile. TcB levels of Mongolian neonates for each time point were higher than those of previous studies. CONCLUSION: The higher values of the TcB nomogram for Mongolian neonates may be due to their Asian ethnicity and exclusive breastfeeding. WHAT IS KNOWN: • TcB nomograms for neonatal jaundice screening have been established for many countries and ethnicities. The pattern of the TcB nomogram varies by country and ethnicity. What is New: • A TcB nomogram for neonates of Mongolian ethnicity at 6-144 postnatal hours was created and it had higher values than those in previous studies.

Impact of Sox9 dosage and Hes1-mediated Notch signaling in controlling the plasticity of adult pancreatic duct cells in mice.

In the adult pancreas, there has been a long-standing dispute as to whether stem/precursor populations that retain plasticity to differentiate into endocrine or acinar cell types exist in ducts. We previously reported that adult Sox9-expressing duct cells are sufficiently plastic to supply new acinar cells in Sox9-IRES-CreERT2 knock-in mice. In the present study, using Sox9-IRES-CreERT2 knock-in mice as a model, we aimed to analyze how plasticity is controlled in adult ducts. Adult duct cells in these mice express less Sox9 than do wild-type mice but Hes1 equally. Acinar cell differentiation was accelerated by Hes1 inactivation, but suppressed by NICD induction in adult Sox9-expressing cells. Quantitative analyses showed that Sox9 expression increased with the induction of NICD but did not change with Hes1 inactivation, suggesting that Notch regulates Hes1 and Sox9 in parallel. Taken together, these findings suggest that Hes1-mediated Notch activity determines the plasticity of adult pancreatic duct cells and that there may exist a dosage requirement of Sox9 for keeping the duct cell identity in the adult pancreas. In contrast to the extended capability of acinar cell differentiation by Hes1 inactivation, we obtained no evidence of islet neogenesis from Hes1-depleted duct cells in physiological or PDL-induced injured conditions.

Validation of a transcutaneous bilirubin meter in Mongolian neonates: comparison with total serum bilirubin.

BACKGROUND: Neonatal hyperbilirubinemia, especially kernicterus, can be prevented by screening for neonatal jaundice. The transcutaneous bilirubin (TcB) meter is a non-invasive medical device for screening neonates. The study aimed to investigate the validity of a TcB meter in a resource-limited setting such as Mongolia. METHODS: Term and late preterm neonates from the National Center for Maternal and Child Health of Ulaanbaatar in Mongolia who met the inclusion criteria (gestational age ≥35 weeks, birth weight ≥2000 g, postnatal age ≤ 1 month) were enrolled in the study. We used a TcB meter, JM-103 to screen for neonatal jaundice. TcB measurements at the infant's forehead and midsternum were performed within 3 h of obtaining samples for total serum bilirubin (TSB) measurement. We analyzed the correlation between TcB measurements and TSB measurements to validate the meter. RESULTS: A total of 47 term and six late preterm neonates were included in the study. TcB measured by the meter at both the forehead and the midsternum showed a strong correlation with TSB measured in the laboratory. The correlation equations were TSB = 1.409+0.8655 × TcB (R2=0.78871) at the forehead, and TSB = 0.7555+0.8974 × TcB (R2=0.78488) at the midsternum. Bland-Altman plots and the Bradley-Blackwood test showed no significant differences between the two methods at all measured ranges of bilirubin. The mean areas under the curves of TcB at the forehead and midsternum at three TSB levels (>10 mg/dL, >13 mg/dL, >15 mg/dL) of TcB were greater than 0.9, and all had high sensitivity and specificity. CONCLUSIONS: This study established the validity of the JM-103 meter as a screening tool for neonatal jaundice in term and late preterm infants in Mongolia. Future studies are needed, including the establishment of a TcB hour-specific nomogram, for more effective clinical practice to prevent severe hyperbilirubinemia.

Associations of maternal and neonatal serum trace element concentrations with neonatal birth weight.

BACKGROUND: Trace elements play important nutritional roles in neonates. Our objective was to examine whether there are differences in maternal/neonatal serum trace element concentrations between mature infants and premature infants. METHODS: During 2012, 44 infants born at National Center for Global Health and Medicine, Tokyo, Japan, were enrolled. Serum samples were collected to measure serum iron, zinc, copper, and selenium concentrations 5 days after birth. Maternal serum samples were obtained before delivery and cord blood was taken at delivery to measure the same trace elements. We compared the results between term group whose birth weight were ≥2500 g and gestational age were ≥37 weeks and premature group whose birth weight were <2500 g or gestational age were <37 weeks. Variables significantly different between two groups were included in linear regression models to identify significant predictors of birth weight. Values of P<0.05 were considered statistically significant. RESULTS: Serum selenium concentrations were lower in premature group than in term group (43.3±7.0 µg/L vs. 52.0±8.9 µg/L, P = 0.001). Maternal serum selenium concentrations were also significantly lower in the mothers of premature group than in the mothers of term group (79.3±19.3 µg/L vs. 94.1±18.1 µg/L, P = 0.032). There were no significant differences in neonatal or maternal iron, zinc, or copper concentrations between two groups. Multivariate linear regression analysis showed that, except for gestational age, only maternal serum selenium was significantly associated with birth weight (P = 0.015). CONCLUSIONS: Serum selenium concentrations were lower in premature group and their mothers compared with the term group. The maternal serum selenium concentration was positively correlated with birth weight. These results suggest that maternal serum selenium concentration may influence neonatal birth weight.

A Japanese neonatal case of glucose-6-phosphate dehydrogenase deficiency presenting as severe jaundice and hemolytic anemia without apparent trigger.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is rare among Japanese ethnicity although it is known as one of the most common hereditary disorders of erythrocytes, causing intravascular hemolysis. It is well-known that G6PD deficiency may cause hemolysis even in the neonatal period. However, most cases are asymptomatic, and the frequency of severe anemia is low. FINDINGS: We describe a Japanese male neonatal case of G6PD deficiency presenting as severe, persistent indirect hyperbilirubinemia on day 2 and hemolytic anemia. He was born to non-consanguineous Japanese parents without any family history. We could not find any triggers that could have induced hemolysis during pregnancy. CONCLUSIONS: This case encouraged us to investigate G6PD deficiency as a differential diagnosis of severe neonatal jaundice and hemolytic anemia despite the low prevalence in Japan.

Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine.

The liver and exocrine pancreas share a common structure, with functioning units (hepatic plates and pancreatic acini) connected to the ductal tree. Here we show that Sox9 is expressed throughout the biliary and pancreatic ductal epithelia, which are connected to the intestinal stem-cell zone. Cre-based lineage tracing showed that adult intestinal cells, hepatocytes and pancreatic acinar cells are supplied physiologically from Sox9-expressing progenitors. Combination of lineage analysis and hepatic injury experiments showed involvement of Sox9-positive precursors in liver regeneration. Embryonic pancreatic Sox9-expressing cells differentiate into all types of mature cells, but their capacity for endocrine differentiation diminishes shortly after birth, when endocrine cells detach from the epithelial lining of the ducts and form the islets of Langerhans. We observed a developmental switch in the hepatic progenitor cell type from Sox9-negative to Sox9-positive progenitors as the biliary tree develops. These results suggest interdependence between the structure and homeostasis of endodermal organs, with Sox9 expression being linked to progenitor status.