Genomic analysis of inter-hospital transmission of vancomycin-resistant Enterococcus faecium sequence type 80 isolated during an outbreak in Hiroshima, Japan.

Outbreaks caused by vancomycin-resistant enterococci that transcend jurisdictional boundaries are occurring worldwide. This study focused on a vancomycin-resistant enterococcus outbreak that occurred between 2018 and 2021 across two cities in Hiroshima, Japan. The study involved genetic and phylogenetic analyses using whole-genome sequencing of 103 isolates of vancomycin-resistant enterococci to identify the source and transmission routes of the outbreak. Phylogenetic analysis was performed using core genome multilocus sequence typing and core single-nucleotide polymorphisms; infection routes between hospitals were inferred using BadTrIP. The outbreak was caused by Enterococcus faecium sequence type (ST) 80 carrying the vanA plasmid, which was derived from strain A10290 isolated in India. Of the 103 isolates, 93 were E. faecium ST80 transmitted across hospitals. The circular vanA plasmid of the Hiroshima isolates was similar to the vanA plasmid of strain A10290 and transferred from E. faecium ST80 to other STs of E. faecium and other Enterococcus species by conjugation. The inferred transmission routes across hospitals suggest the existence of a central hospital serving as a hub, propagating vancomycin-resistant enterococci to multiple hospitals. Our study highlights the importance of early intervention at the key central hospital to prevent the spread of the infection to small medical facilities, such as nursing homes, with limited medical resources and a high number of vulnerable individuals.

Natural course of post-COVID symptoms in adults and children.

More than 200 million COVID-19 survivors have lasting symptoms after recovering, but the duration and related risk factors remain uncertain. This study focused on all 6551 patients diagnosed with COVID-19 at a medical institution in Hiroshima from March 2020 to July 2022. In November 2022, a questionnaire survey was conducted regarding post-COVID symptoms and their duration. The prevalence and duration of post-COVID symptoms were illustrated using the Kaplan-Meier method. Risk factors for symptoms lasting over 3 months and interfering with daily life were assessed via multivariate logistic regression. A total of 2421 survivors responded: 1391 adults, 1030 children, median age 34 years (IQR 9-55), 51·2% male, 36·7% hospitalized, median time from infection to the survey was 295 days (IQR 201-538). Upon their initial recovery, the prevalence of post-COVID symptoms was 78·4% in adults and 34·6% in children. Three months later, the rates were 47·6% and 10·8%. After over one year, they were 31·0% and 6·8%. Regarding symptoms interfere with daily life, 304 people (12.6%) experienced symptoms lasting for over three months, with independent risk factors including age, being female, diabetes mellitus, infection during the Delta period, and current smoking. There was no significant association between vaccination history and post-COVID symptoms.

Relationship between clinical symptom profiles and COVID-19 infection status during Delta-dominant period versus Omicron-dominant period-analysis of real-world data collected in Hiroshima Prefecture, Japan.

OBJECTIVES: The present study investigates the diagnosis and prediction of COVID-19 based on clinical symptoms, and corresponding difference between the Delta- and Omicron-dominant periods, using data collected at polymerase chain reaction (PCR) centers in Hiroshima Prefecture, Japan. METHODS: Data was collected using a J-SPEED-style COVID-19 standard data collection form. The analysis was done in two directions: calculating the likelihood ratio that clinical symptoms will manifest in "infected" versus "non-infected" individuals and calculating the diagnostic odds ratio (OR) of infection for those who have symptoms compared to those without symptoms. RESULTS: COVID-19 was more strongly associated with smell and taste disorders during the Delta-dominant period, and muscle pain during the Omicron-dominant period. An age-specific analysis of likelihood and diagnostic ORs found cold-like symptoms had the lowest ability to diagnose COVID-19, and the lowest predictability of COVID-19 with children during both periods. The likelihood and diagnostic ORs of other symptoms for COVID-19 were highest in adults and lowest in those over 65. CONCLUSION: Symptoms are an important indicator of COVID-19, but the association between specific symptoms and COVID-19 is dependent on the dominant variant of the virus.

The role of discrimination in the relation between COVID-19 sequelae, psychological distress, and work impairment in COVID-19 survivors.

Perceived discrimination and work impairment are commonly observed in COVID-19 survivors, but their relationship has not been well understood. We aimed to evaluate the role of discrimination in the development of psychological distress and work impairment in COVID-19 survivors. From April 2020 to November 2021, 309 patients were recruited at two designated COVID-19 hospitals in Japan. Participants completed a standardized questionnaire including COVID-19 sequelae, psychological distress, impairments in work performance and perceived discrimination. The majority of participants (62.5%) experienced one or more COVID-19 sequelae. Psychological distress was observed in 36.9% and work impairment in 37.9%. In multivariate logistic regression analyses, COVID-19 sequelae and discrimination were associated with both psychological distress and work impairment. Mediation analysis demonstrated that the direct effect of sequelae on work impairment was non-significant after accounting for psychological distress, suggesting that the effect of sequelae on work impairment was mainly mediated through psychological distress. These findings were replicated in a subgroup analysis limited to patients with mild COVID-19. We conclude that discrimination plays an important role in the development of psychological distress and work impairment, and that both discrimination and psychological distress should be targets of intervention in COVID-19 survivors.

Exercising the Sanger Sequencing Strategy for Variants Screening and Full-Length Genome of SARS-CoV-2 Virus during Alpha, Delta, and Omicron Outbreaks in Hiroshima.

This study aimed to exercise the Sanger sequencing strategy for screening of variants among confirmed COVID-19 cases and validate our strategy against NGS strains in Hiroshima retrieved from GISAID. A total of 660 samples from confirmed COVID-19 cases underwent screening for variants by Sanger-based partial sequencing to the targeted spike gene (nt22,735~nt23,532) using an in-house-developed primer set. The identification of variants was done by unique checkpoints of base nucleotide changes in the targeted spike gene. Moreover, we amplified one full-length genome using Sanger method and an in-house-developed primer library. Using NGS strains of the same sampling period from GISAID, a phylogenetic tree was constructed to examine the distribution pattern of variants in Hiroshima and to validate our Sanger method. The modified primer set provided 100% validation and 99.2% amplification. PANGO Lineage R.1 was detected in late in the third wave, followed by Alpha (B.1.1.7) domination in the fourth wave, Delta (B.1.617.2) domination in the fifth wave, and Omicron (B.1.1.529) domination in the sixth wave, and there was no significant difference in viral copies between variants (p = 0.09). The variants showed different transmission patterns, but the distribution of variants is consistent to that shown by the phylogenetic tree. The Sanger method also provided successful amplification of the full-length genome of the SARS-CoV-2 virus. Our Sanger sequencing strategy was useful for the screening of SASR-CoV-2 variants without the need for full-genome amplification. The modified primer set was validated to use universally, which allows an understanding of the variants' distribution in real time and provides the evidence for policy-making and the formulation or modification of preventive strategies.

Mass Screening of SARS-CoV-2 Variants using Sanger Sequencing Strategy in Hiroshima, Japan.

This study aimed to develop the feasible and effective universal screening strategy of the notable SARS-CoV-2 variants by Sanger Sequencing Strategy and then practically applied it for mass screening in Hiroshima, Japan. A total of 734 samples from COVID-19 confirmed cases in Hiroshima were screened for the notable SARS-CoV-2 variants (B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.617.1, C.37, B.1.1.529, etc.). The targeted spike region is amplified by nested RT-PCR using in-house designed primer set hCoV-Spike-A and standard amplification protocol. Additionally, randomly selected 96 samples were also amplified using primer sets hCoV-Spike-B and hCoV-Spike-C. The negative amplified samples were repeated for second attempt of amplification by volume-up protocol. Thereafter, the amplified products were assigned for Sanger sequencing using corresponding primers. The positive amplification rate of primer set hCoV-Spike-A, hCoV-Spike-B and hCoV-Spike-C were 87.3%, 83.3% and 93.8% respectively for standard protocol and increased to 99.6%, 95.8% and 96.9% after second attempt by volume-up protocol. The readiness of genome sequences was 96.9%, 100% and 100% respectively. Among 48 mutant isolates, 26 were B.1.1.7 (Alpha), 7 were E484K single mutation and the rest were other types of mutation. Moreover, 5 cluster cases with single mutation at N501S were firstly reported in Hiroshima. This study indicates the reliability and effectiveness of Sanger sequencing to screen large number of samples for the notable SARS-CoV-2 variants. Compared to the Next Generation Sequencing (NGS), our method introduces the feasible, universally applicable, and practically useful tool for identification of the emerging variants with less expensive and time consuming especially in those countries where the NGS is not practically available. Our method allows not only to identify the pre-existing variants but also to examine other rare type of mutation or newly emerged variants and is crucial for prevention and control of pandemic.

The Association between Wearing a Mask and COVID-19.

With the widespread and increasing number of cases of Coronavirus Disease (2019) globally, countries have been taking preventive measures against this pandemic. However, there is no universal agreement across cultures on whether wearing face masks are an effective physical intervention against disease transmission. We investigated the relationship between mask wearing and COVID-19 among close contacts of COVID-19 patients in the Hiroshima Prefecture, Japan. In the Hiroshima Prefecture, a COVID-19 form adapted from the reporting form, "Japanese Surveillance in Post-Extreme Emergencies and Disasters", was developed to collect data from COVID-19 patients' close contacts under active epidemiological surveillance at Public Health Centers. The relative risk of COVID-19 for mask users versus non-mask users was calculated. A total of 820 interviewees were included in the analysis and 53.3% of them responded that they wore masks. Non-mask users were infected at a rate of 16.4%, while mask users were infected at a rate of 7.1%. Those who wore masks were infected at a rate of 0.4 times that of those who did not wear masks. (RR = 0.4, 95%CI = 0.3-0.6; Adjusted RR = 0.6, 95%CI = 0.3-0.9). These findings implied that COVID-19 could be avoided to a certain degree by wearing a mask.

Molecular characterization and the mutation pattern of SARS-CoV-2 during first and second wave outbreaks in Hiroshima, Japan.

BACKGROUND: In this study, we performed molecular characterization of SARS-CoV-2 strains in Hiroshima and its mutation pattern between the first and second waves of the outbreak. METHOD: A total of 55 nasal swab samples from the first wave in Hiroshima and 13 from the second wave were examined quantitatively by RT-qPCR and qualitatively by nested PCR using specific primers. Four samples from each wave underwent next-generation sequencing and phylogenetic tree analysis including controls and all sequences retrieved in Japan from GISAID and GenBank. Subsequently, mutations were examined. RESULTS: Viral load ranged 7.85 × 101-1.42 × 108 copies/ml. Of 68 samples, one was Asian type-O, 65 were European type-GR, and 2 were undetectable. Phylogenetic tree analysis indicated that Japan was infected with various Asian strains (L, S, V, O) from January through April. By second week of March, European strains (G, GH, GR) had appeared, and GR strains became predominant after mid-March. The first case in Hiroshima was classified as Asian strain O, and the rest were GR strains. Then, second wave of GR strains appeared independently with 11-15 base mutations. Comparing the first- and second-wave GR strains, mutation rate was 1.17-1.36 × 10-3 base substitutions per site per year; in addition, amino acid changes occurred at S1361P and P3371S in ORF1a, A314V in ORF1b, and P151L in N. All seven GR strains were D614G variants with R202K and G203R mutations in N. A single-nucleotide insertion in ORF8 that causes a defect in ORF8 protein was found in one isolate (S66) from the second wave. CONCLUSION: Our findings reveal the evolutionary hierarchy of SARS-CoV-2 in Japan. The predominant D614G variants and a new form of ORF8 deletion in Hiroshima provide the clue for role of viral factor in local outbreaks of SARS-CoV-2.

High Vaccination Coverage among Children during Influenza A(H1N1)pdm09 as a Potential Factor of Herd Immunity.

The objective of this study was to identify factors related to the expansion of infection and prevention of influenza A(H1N1)pdm09. A retrospective non-randomized cohort study (from June 2009 to May 2010) on influenza A(H1N1)pdm09 was conducted in a sample of residents from Hiroshima Prefecture, Japan. The cumulative incidence of the influenza A(H1N1)pdm09 and the pandemic vaccine effectiveness (VE) were estimated. The response rate was 53.5% (178,669/333,892). Overall, the odds ratio of non-vaccinated group to vaccinated group for cumulative incidence of influenza A(H1N1)pdm09 was 2.18 (95% confidence interval (CI): 2.13-2.23) and the VE was 43.9% (CI: 42.8-44.9). The expansion of infection, indicating the power of transmission from infected person to susceptible person, was high in the 7-15 years age groups in each area. In conclusion, results from this survey suggested that schoolchildren-based vaccination rate participates in determining the level of herd immunity to influenza and children might be the drivers of influenza transmission. For future pandemic preparedness, vaccination of schoolchildren may help to prevent disease transmission during influenza outbreak.

Seasonal influenza vaccine (A/New York/39/2012) effectiveness against influenza A virus of health care workers in a long term care facility attached with the hospital, Japan, 2014/15: A cohort study.

The 2014/15 influenza season started earlier than usual, and intense activity was reflection of circulation of antigenically-drifted and vaccine-mismatched dominant A(H3N2) viruses. Although inpatients and health-care workers (HCWs) had a high influenza vaccination coverage rate well prior to the beginning of influenza season, numerous outbreaks of influenza A(H3N2) infection with fatal cases were reported in long-term care facilities (LTCFs) in Japan during 2014/15 influenza season. In January 2015, we were given opportunity to conduct outbreak investigation of influenza A at facility A (LTCF attached with hospital) in Western part of Japan. We evaluated overall and occupation-stratified influenza vaccine effectiveness (VE) among HCWs at facility A using a retrospective cohort design. Overall VE, occupation-stratified VE and adjusted VE (AVE) with 95% confidence intervals (CIs) were estimated using the following formula: (1-relative risks (RR) or 1-adjusted RR) × 100%. Overall vaccine coverage rate among HCWs was 85%. Overall VE for HCWs was 28% (95% CI: -70 to 67) and overall AVE was 3% (95% CI: -34 to 30). Although there was no severe cases, our results indicated that even with high vaccination coverage rate with appropriate vaccination timing, the VE was low for HCWs, which echoes with previously reported VE from other northern hemisphere countries. However, rehabilitation group who had high awareness against influenza as a group and carried out intensive precautions from early influenza season had no cases. We conclude that multiple preventive measures in addition to high vaccination rate is necessary for preventing influenza of HCWs working at LCTFs.

[Two cases of Mycoplasma pneumoniae bronchopneumonia diagnosed with LAMP (loop-mediated isothermal amplification) as a rapid assay].

Mycoplasma pneumoniae is one of the common pathogens of the community-acquired pneumonia in adults and children. Macrolide antibiotics are considered to be the first-choice drug for M. pneumoniae infections. However, macrolide-resistant M. pneumoniae was first detected from Japanese pediatric patients in 2000,and it has been increasing over the past decade. On the other hand, the Immunocard Mycoplasma IgM test is widely used as a rapid and easy diagnostic method for M. pneumoniae pneumonia, but false-positive or false-negative cases have been reported in adults. Therefore new methods have been developed recently. Using the LAMP assay, the results are available rapidly and accurately. We report herein on two cases of M. pneumoniae bronchopneumonia in which the LAMP assay was useful in the diagnosis and treatment.

[Epidemiology and drug susceptibility of Pseudomonas aeruginosa strains isolated in the Chugoku region of Japan. Infection Forum in the Chugoku Region].

Recently, there have been reports concerning an increased frequency of isolation of multi-drug resistant Pseudomonas aeruginosa (MDRP) strains in hospitals and other clinical settings as well as the associated risk of their hospital-acquired infections; in such a situation, it has been a major challenge to establish methods of managing and treating the infections. In order to investigate the trend of P. aeruginosa, the Infection Forum in the Chugoku Region has conducted to a multi-center collaborative study to isolate P. aeruginosa strains from sputum and urine samples collected between October 2006 and September 2008, analyzed the drug susceptibility and the pulsed-field gel electrophoresis (PFGE) patterns of each strain, and assessed epidemiologic characteristics. Of the 738 P. aeruginosa strains collected in this study, 152 (20.6%), 179 (24.3%), 47 (6.4%), and 39 (5.3%) were found to be ciprofloxacin-resistant, imipenem-resistant, amikacin-resistant, and MDRP, respectively. Among the various antimicrobial agents tested, arbekacin (ABK) revealed the strongest inhibitory effects on each drug-resistant and MDRP strain; therefore, ABK was considered as a potential candidate for future treatment of diseases caused by P. aeruginosa. The study also showed that the detection rates of MDRP varied a lot from hospital to hospital. In addition, PFGE-based cluster analyses revealed several strains isolated in the same hospital exhibited a similar PFGE pattern and the same drug susceptibility, suggesting the presence of "unique" hospital-specific strains.

[A case of germ-cell tumor of the mediastinum].

An 18-year-old man complaining of chest pain was admitted to our hospital. Contrast-enhanced chest computed tomography (CT) showed an anterior mediastinal tumor with patchy enhanced lesions in the peripheral and poorly-enhanced central areas. His serum alpha fetoprotein (AFP) level was high. FDG-PET imaging indicated intense FDG uptake in the mediastinal tumor (SUVmax was 11.2), but no other abnormal FDG uptake, including in his testes, was detected. CT-guided needle biopsy revealed necrotizing tissue, including immature cartilage-like tissue. Based on these clinical features, we diagnosed mixed-type germ cell tumor originating from the mediastinum. Bleomycin, etoposide and cisplatin combination chemotherapy was administered every 3 weeks, for 4 cycles. His serum AFP level declined during the treatment course, and the mediastinal tumor decreased in size. After 4 cycles of chemotherapy, the residual tumor was resected completely and no viable cells were detected in the resected tumor. Tumor recurrence has not been detected for more than 9 months after surgery without adjuvant chemotherapy at the time of writing.

Incidence and survival of childhood cancer cases diagnosed between 1998 and 2000 in Hiroshima City, Japan.

There have been few studies on cancer incidence and survival among children in Japan. Childhood cancer cases in Hiroshima City can be ascertained almost perfectly in terms of completeness and validity as both a population-based cancer registry and a tissue registry cover the whole area. We report here recent incidence and survival of childhood cancer in Hiroshima City. Subjects were cancer patients less than 15 years of age in Hiroshima City registered in the Hiroshima City Cancer Registry and/or the Hiroshima Prefecture Tumor Registry (tissue registry) between 1998 and 2000. Cancer incidence in Hiroshima City was calculated for 12 diagnostic groups according to the International Classification of Childhood Cancer, and compared with general incidence in Japan. Five-year survival was calculated by the Kaplan-Meier method. There were 63 children who had a cancer newly diagnosed during 1998-2000, with only one death-certificate-only case (1.6%). Age-standardized incidence rates (per million) were 144.3 for boys and 93.9 for girls. Leukemia was the most frequent (29%) among the 12 diagnostic groups. There were 13 cancer deaths during this period and five-year survival was 79% (95% Confidence Interval: 67%-87%). Childhood cancer incidence was slightly higher than that for all of Japan, but the relative distribution of patients by diagnostic group was compatible with the general pattern. Both of these observations might be due to the high quality of the tumor and tissue registries.

Pharmacokinetic-pharmacodynamic target attainment analysis of biapenem in adult patients: a dosing strategy.

BACKGROUND: A pharmacokinetic-pharmacodynamic (PK-PD) target attainment analysis to build a dosing strategy for biapenem in adult patients has not been conducted. METHODS: A total of 321 plasma concentration samples from 68 adult patients (1-6 samples per patient) were assayed biologically and chromatographically, and used for a population PK modeling and Monte Carlo simulation to assess the probability of attaining the PK-PD target (40% of the time above the minimum inhibitory concentration). RESULTS: The population PK model was based on the standard two-compartment model, and creatinine clearance (Cl(cr)) was the most significant covariate that affected the drug clearance. The Monte Carlo simulation demonstrated that the dosages up to 600 mg Q12H (0.5-h infusions) achieved a PK-PD target attainment probability of > or =90%, which varied with Cl(cr) of the patient and susceptibility of the tested bacterium; however, higher dosage with prolonged infusion time (600 mg Q8H, 3 h infusion) was required for a high probability against Pseudomonas aeruginosa and Haemophilus influenzae isolates in the case of Cl(cr) = 90 ml/min. CONCLUSION: These results provide guidance for constructing a PK-PD-based strategy for tailoring biapenem regimens in adult patients.

Increased resistance to cationic antimicrobial peptide LL-37 in methicillin-resistant strains of Staphylococcus aureus.

OBJECTIVES: The susceptibility of clinical isolates of Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), to host-derived cationic antimicrobial peptides was investigated. METHODS: We examined the susceptibility of 190 clinical strains of methicillin-susceptible S. aureus (MSSA) and 304 strains of MRSA to two different classes of cationic antimicrobial peptides: LL-37 and human beta-defensin-3 (hBD3). Out of the total 494 clinical strains, a random selection of 54 S. aureus strains was examined to establish the relationship between the net charge, or zeta potential, of each strain and its susceptibility to hBD3 or LL-37. To further confirm bacterial susceptibility to either hBD3 or LL-37, we concurrently measured: (i) percentage survival after in vitro bacterial exposure and (ii) MBCs for both MRSA and MSSA strains. RESULTS: Of the 54 randomly selected S. aureus strains, those MRSA strains resistant to LL-37 showed significantly higher zeta potentials than those susceptible to LL-37 (P < 0.05). In contrast, there was no difference in bacterial zeta potentials for MRSA strains that showed either resistance or susceptibility to hBD3. In addition, resistance to LL-37, but not to hBD3, as determined by either percentage survival or MBC, was significantly elevated in highly methicillin-resistant strains of S. aureus when compared with MSSA strains (P < 0.01). CONCLUSIONS: Clinical strains of MRSA, but not MSSA, that demonstrated an increased net charge also showed elevated resistance to LL-37, but not to hBD3.

Pharmacokinetics and pharmacodynamics of biapenem in critically ill patients under continuous venovenous hemodiafiltration.

To characterize the PK/PD of biapenem (BIPM) in critically ill patients under continuous venovenous hemodiafiltration (CVVHDF), we conducted a prospective, open-label study in nine adult CVVHDF patients with acute renal failure at the Critical Care Medical Center, Hiroshima Prefectural Hospital. Plasma and filtrate samples were obtained at six time points. The concentrations of BIPM in plasma and filtrate were determined by HPLC. PK parameters were analyzed using Monte Carlo simulation with MIC data. BIPM concentrations in the plasma and CVVHDF filtrate peaked at the end of infusion, and the values were similar. The drug clearance by CVVHDF and non-CVVHDF was 1.28 +/- 0.14 and 9.05 +/- 4.05 L/h, respectively. Monte Carlo simulation showed that the more administration times, there were the higher the probability. In conclusion, a dosing regimen of 300 mg BIPM q8h had a higher probability of therapeutic efficacy than q12h in patients with severe sepsis under CVVHDF.

High incidence of newly-developed gastroesophageal reflux disease in the Japanese community: a 6-year follow-up study.

BACKGROUND AND AIM: We conducted a community-based study to assess the incidence of newly-developed gastroesophageal reflux disease (GERD). We also analyzed the risk factors of GERD occurrence. METHODS: A total of 322 patients without acid suppression therapy (135 men, mean age: 59.8 years), who lived in the Japanese community, took a QUEST questionnaire (a self-administered questionnaire for the screening of GERD) in 1998. Blood samples were taken for the measurement of an anti-Helicobacter pylori antibody and pepsinogen (PG) I/II to assess the grade of gastric atrophy. Of these patients, 289 scored less than six points and were diagnosed as non-GERD. Two-hundred-and-forty-one patients (95 men, mean age: 67.0 years) took the QUEST questionnaire again in 2004 (after 6 years). The incidence of newly-developed GERD was analyzed. These patients were categorized into three groups based on their initial PG I/II (group A: less than three, group B: three to six, and group C: more than six). The risk factors of GERD occurrence were evaluated. RESULTS: Of the 241 non-GERD patients, 37 patients (15.4%) developed GERD after 6 years. The incidence of newly-developed GERD in group C was significantly higher than both groups A and B (group A: 3.8% [three of 79], group B: 11.8% (11/93), group C: 33.3% (26/69), P < 0.01, respectively). The prevalence of H. pylori negativity, constipation, and medication of Ca antagonists in newly-developed GERD were significantly higher than in those who did not develop GERD. [Correction added after online publication on 1 July 2007: the preceding sentence has replaced one that read 'The prevalence of H. pylori negativity, constipation, and medication of Ca antagonists in newly-developed GERD were significantly higher than in those who did develop GERD.'] CONCLUSION: The incidence of newly-developed GERD in the Japanese community was 16.5% for 6 years. The incidence of newly-developed GERD patients who scored a PG I/II over six was significantly higher than those who scored lower. H. pylori negativity, constipation, and medication of Ca antagonists might be risk factors of GERD occurrence.

Frequency scale for symptoms of gastroesophageal reflux disease predicts the need for addition of prokinetics to proton pump inhibitor therapy.

BACKGROUND AND AIM: Proton pump inhibitor (PPI) monotherapy cannot cure all cases of gastroesophageal reflux disease (GERD), and combination therapy with prokinetics and PPI achieves symptomatic improvement for some GERD patients. Few studies have been performed to predict the need for prokinetics. METHODS: Subjects were 163 patients (64 male, mean age 53.1 +/- 16.6 years) with GERD symptoms. They were evaluated using the frequency scale for the symptoms of GERD (FSSG), a GERD-specific questionnaire developed in Japan(1) and endoscopy. They were administered with rabeprazole 10 mg daily. At 12 and 24 weeks of treatment, subjects were offered a choice of four treatment regimens according to their degree of satisfaction (1, no need for further treatment; 2, opt for continued PPI treatment; 3, step-down to H2RA; 4, dissatisfied with present treatment, so opt for combination treatment with prokinetics, mosapride 5 mg tid). RESULTS: The choice of treatment after 12 weeks of treatment placed 79.1% of subjects in the satisfied group (1, 21; 2, 98; 3, 10). After 24 weeks, 98.2% of subjects were in the satisfied group. Pretreatment FSSG scores were significantly higher in the dissatisfied group (4, 17.4 +/- 1.4) than in the satisfied group (1, 12.3 +/- 1.3; 2, 12.8 +/- 0.8; 3, 10.2 +/- 1.8) (P < 0.05). CONCLUSIONS: The satisfaction rate with these treatment regimens was 98.2% at 24 weeks, suggesting that combination therapy with prokinetics was effective for patients dissatisfied with PPI monotherapy. The FSSG is a useful predictor of the necessity for combination therapy.

[Case of highly active anti-retroviral therapy-induced immune reconstitution inflammatory syndrome in AIDS-related progressive multifocal leukoencephalopathy].

A 44-year-old man presented with difficulties in gripping a ball with the left hand upon playing tennis. He developed muscle weakness involving the left limbs, as well as memory decline, with subsequent gradual worsening of such symptoms. Cranial MRI showed multiple high intensity lesions in the white matter on T2-weighted imaging and FLAIR imaging. Serologic testing was positive for HIV infection and laboratory studies revealed a CD4+T cell count of 103 cells/microl and a plasma HIV-1 RNA load of 240,000 copies/ml. Accordingly, the diagnosis of AIDS was made. Although the initial result of DNA amplification by PCR for detection of the JC virus with CSF was negative, PML was suspected because of the presence of multifocal white matter lesions. Four weeks after the commencement of highly active anti-retroviral therapy (HAART), the HIV-1 RNA load was decreased from 680,000 to 480 copies/ml, although the CD4+T cell count was unchanged. JC virus DNA became positive at the second examination. Five weeks after the commencement of HAART, general fever, disturbance of consciousness, and brain edema suddenly developed, and the patient died within two days. Histological examination of the autopsied brain revealed demyelination and reactive gliosis within the white matter and JC virus antigen was detected in oligodendrocytes, consistent with a diagnosis of PML. The most striking feature was an intense perivascular infiltration by CD8+T cells with proteinaceous fluid exudation, suggesting an occurrence of HAART-induced immune reconstitution inflammatory syndrome. Immune reconstitution inflammatory syndrome should be considered as a fatal complication of HAART in patients with AIDS-related PML.