Nationwide Longitudinal Annual Survey of HIV/AIDS Referral Hospitals in Japan From 1999 to 2021: Trend in Non-AIDS-defining Cancers Among Individuals Infected With HIV-1.

BACKGROUND: Non-AIDS-defining cancers (NADCs) in patients infected with HIV have recently attracted attention because of the improved survival of this patient population. To obtain accurate data, a longitudinal study is warranted for the nationwide surveillance of the current status and national trend of NADCs in patients infected with HIV in Japan. SETTING: An annual nationwide surveillance of NADCs in patients infected with HIV-1 in Japan from 1999 to 2021. METHODS: An annual questionnaire was sent to 378 HIV/AIDS referral hospitals across Japan to collect data (clusters of differentiation 4-positive lymphocytes, time of onset, outcomes, and antiretroviral therapy status) of patients diagnosed with any of the NADCs between 1999 and 2021. RESULTS: The response and case-capture rates for the questionnaires in 2021 were 37.8% and 81.2%, respectively. The number of reported NADC cases subsequently increased since the beginning of this study. Evaluation of the case counts of NADCs demonstrated a high incidence of lung, colorectal, gastric, and liver cancers as the top 4 cancers. Pancreatic cancer (0.63), lung cancer (0.49), and leukemia (0.49) had the highest mortality rates among the NADCs. Trends of NADCs regarding transmission routes were maintained over the years in male individuals who have sex with male individuals compared with heterosexual male individuals and female individuals. CONCLUSIONS: We demonstrated an increasing trend in the incidence of NADCs over a period of 23 years in Japan. The current data highlighted the importance of raising awareness regarding cancer management for patients infected with HIV in Japan.

Two cases of Clostridium ramosum bacteremia with intestinal perforation: The antimicrobial susceptibility of clinical strains.

Clostridium ramosum is one of the obligate anaerobes that constitute the intestinal microbiota, and one of the rare Clostridia. With Clostridium ramosum, very few data have been reported to investigate antimicrobial susceptibility for clinical isolates that have caused bacteremia. Here, we report two cases of Clostridium ramosum bacteremia. The first case was a 54-year-old Japanese man with taking 20mg hydrocortisone for hypopituitarism. He presented to the emergency department for an unknown cause cardiopulmonary arrest. At the hospital day 36, he had fever and a drop in blood pressure. Abdomen computed tomography (CT) revealed free air around the ascending colon, we diagnosed with intestinal perforation, and peritonitis. Blood culture revealed Clostridium ramosum. We administered conservative management by 6-week of antibiotic treatment. The second case was a 78-year-old Japanese man with no significant medical history. He was referred to our hospital with fever and abdominal pain. Abdomen CT revealed perforated appendicitis, and blood cultures revealed Clostridium ramosum. We performed emergency surgery, and administered one-week course of antibiotic treatment. This report demonstrates two cases of Clostridium ramosum bacteremia with intestinal perforation, and the antimicrobial susceptibility of each clinical strain. For the future, it is necessary to accumulate data on the susceptibility of clinical isolates in order to find an appropriate treatment.

Discrepant Antigen-specific Antibody Responses Causing SARS-CoV-2 Persistence in a Patient Receiving B-cell-targeted Therapy with Rituximab.

A 73-year-old man previously treated with rituximab for his mucosa-associated lymphoid tissue lymphoma suffered a suboptimal humoral immune response against an acquired SARS-CoV-2 infection. A detailed serological description revealed discrepant antigen-specific humoral immune responses. The titer of spike-targeting, "viral-neutralizing" antibodies remained below the detection level, in contrast to the anti-nucleocapsid, "binding" antibody response, which was comparable in both magnitude and kinetics. Accordingly, viral neutralizability and clearance was delayed, leading to prolonged RNAemia and persistent pneumonia. The present case highlights the need to closely monitor this unique population of recipients of B-cell-targeted therapies for their neutralizing antibody responses against SARS-CoV-2.

Nationwide surveillance of AIDS-defining illnesses among HIV patients in Japan from 1995 to 2017.

OBJECTIVES: The accurate prevalence of acquired immunodeficiency syndrome (AIDS)-defining illnesses (ADIs) in human immunodeficiency virus (HIV)-infected patients has not been well investigated. Hence, a longitudinal nationwide surveillance study analyzing the current status and national trend of opportunistic complications in HIV-infected patients in Japan is warranted. METHODS: A nationwide surveillance of opportunistic complications in HIV-infected patients from 1995 to 2017 in Japan was conducted. An annual questionnaire was sent to 383 HIV/AIDS referral hospitals across Japan to collect information (CD4+ lymphocyte count, time of onset, outcome, and antiretroviral therapy [ART] status) of patients diagnosed with any of 23 ADIs between 1995 and 2017. RESULTS: The response and case capture rates of the questionnaires in 2017 were 53% and 76%, respectively. The number of reported cases of opportunistic complications peaked in 2011 and subsequently declined. Pneumocystis pneumonia (38.7%), cytomegalovirus infection (13.6%), and candidiasis (12.8%) were associated with the cumulative incidence of ADIs between 1995 and 2017. The mortality rate in HIV-infected patients with opportunistic complications substantially decreased to 3.6% in 2017. The mortality rate was significantly higher in HIV patients who received ART within 14 days of diagnosis of complications than in those who received ART 15 days after diagnosis (13.0% vs. 3.2%, p < 0.01). CONCLUSIONS: We have demonstrated a 23-year trend of a newly diagnosed AIDS status in Japan with high accuracy. The current data reveal the importance of Pneumocystis pneumonia as a first-onset illness and that early initiation of ART results in poor outcomes in HIV patients in Japan.

Risk factors for acute kidney injury in vancomycin and piperacillin/tazobactam combination therapy: A retrospective study.

INTRODUCTION: Combined use of vancomycin (VCM) and piperacillin/tazobactam (PIPC/TAZ) has been reported to increase the incidence of acute kidney injury (AKI). However, the risk factors associated with AKI after VCM and PIPC/TAZ (VPT) administration have not yet been identified. Therefore, we retrospectively assessed patients treated with VPT to investigate the risk factors for AKI development. METHODS: The study involved patients who were treated with VPT from January 1, 2016 to March 31, 2020. The patients were divided into the AKI or non-AKI group. The clinical characteristics of patients and antimicrobial therapy were compared between the groups. Their association with AKI risk was evaluated using multivariate logistic regression analysis. RESULTS: In total, 182 patients were included, with 118 in the non-AKI group and 64 in the AKI group. Therefore, the incidence of AKI was 35.2 %. The initiation of VPT combination therapy on the same day and concomitant use of vasopressors were associated with an increased risk of AKI (odds ratio [OR] 2.55, 95 % confidential interval [CI] 1.20-5.44 and OR 3.22, 95 % CI 1.31-7.89, respectively). CONCLUSION: Our findings suggest that the concomitant use of vasopressors and initiating VPT combination therapy on the same day are likely risk factors for AKI development.

Isoniazid-induced Immune Thrombocytopenia.

Drug-induced thrombocytopenia occurs through immune-mediated platelet destruction, and its management is challenging during tuberculosis treatment. Although rifampicin is the most common drug causing thrombocytopenia, isoniazid can also cause thrombocytopenia. We herein report a 75-year-old man who developed thrombocytopenia during tuberculosis treatment. Platelet-associated immunoglobulin G and a drug-induced lymphocyte stimulation test for isoniazid were positive; no other causes of thrombocytopenia were identified. The patient was diagnosed with isoniazid-induced immune thrombocytopenia, and the platelet count normalized after isoniazid discontinuation. We describe the immunological mechanism of thrombocytosis due to isoniazid, an uncommon cause of thrombocytopenia that physicians should be aware exists.

Risk factor analysis for piperacillin-tazobactam-resistant Enterobacter spp. bacteremia at a tertiary hospital.

This study aimed to analyze the risk factors for piperacillin-tazobactam (TZP1)-resistant Enterobacter spp. bacteremia. The medical records of 111 patients with Enterobacter spp. bacteremia divided into a TZP-susceptible group (minimum inhibitory concentrations [MICs2] ≤16 µg/mL) and TZP-resistant group (MICs >16 µg/mL) were retrospectively reviewed. The male-to-female ratio, age, underlying disease, and infection site did not differ between the 2 groups. Multivariate analysis revealed that the independent predictor associated with TZP-resistant Enterobacter spp. bacteremia was the previous usage of third-generation cephalosporins (P = 0.036). In conclusion, TZP administration in cases of suspected Enterobacter spp. bacteremia previously treated with third-generation cephalosporin should be cautiously considered.

Corynebacterium jeikeium-induced infective endocarditis and perivalvular abscess diagnosed by 16S ribosomal RNA sequence analysis: A case report.

INTRODUCTION: Corynebacterium jeikeium normally presents on human skin, and it is often judged as contamination when it is cultured from blood. C. jeikeium can cause infective endocarditis, especially, that associated with cardiac surgery and prosthetic valvular endocarditis. CASE REPORT: A 66-year-old Japanese male patient was diagnosed with C. jeikeium-induced infective endocarditis (IE) and perivalvular abscess after a coronary artery bypass grafting and aortic valve replacement with bioprosthesis; pyogenic spondylodiscitis was also observed. Patch repair for aortic valve annulus and re-Bentall procedure with bioprosthesis was performed for IE and perivalvular abscess. The causative bacterium was confirmed as C. jeikeium on 16S ribosomal RNA sequencing of surgical sample and positive blood culture. The patient underwent six weeks of intravenous antibacterial treatment with vancomycin and an additional two weeks of oral treatment with linezolid, following which, his condition improved. Corynebacterium jeikeium can cause infective endocarditis and perivalvular abscess, which is a more severe condition than IE. CONCLUSION: 16S ribosomal RNA sequencing is useful in diagnosing bacterial species that can cause contamination, such as Corynebacterium spp.

Duration of antifungal therapy for septic pulmonary embolism caused by Candida albicans from a central venous catheter: A case report.

The treatment duration for candidemia with septic pulmonary embolism should be determined based on the clearance of fungus from the bloodstream and improvement of symptoms. The remaining lung nodules may not necessarily indicate persistent infection.

Congenital bronchial atresia complicated by a lung abscess due to Aspergillus fumigatus: a case report.

BACKGROUND: Congenital bronchial atresia is a rare pulmonary abnormality characterized by the disrupted communication between the central and the peripheral bronchus and is typically asymptomatic. Although it can be symptomatic especially when infections occur in the involved areas, fungal infections are rare complications in patients with bronchial atresia. We report a case of congenital bronchial atresia complicated by a fungal infection. CASE PRESENTATION: A 30-year-old man with no previous history of immune dysfunction was brought to a nearby hospital and diagnosed with a left lung abscess. Although antimicrobial treatment was administered, it was ineffective, and he was transferred to our hospital. Since diagnostic imaging findings and bronchoscopy suggested congenital bronchial atresia and a fungal infection, he was treated with voriconazole and surgical resection was subsequently performed. A tissue culture detected Aspergillus fumigatus and histopathological findings were compatible with bronchial atresia. After discharge, he remained well and voriconazole was discontinued 5 months after the initiation of therapy. CONCLUSION: Bronchial atresia is a rare disease that is seldom complicated by a fungal infection, which is also a rare complication; however, physicians should consider fungal infections in patients with bronchial atresia who present with infections resistant to antimicrobial treatment.

Three-year epidemiological analysis of Clostridioides difficile infection and the value of hospital-infection control measures in a tertiary-care teaching hospital in Japan using PCR-based open-reading frame typing.

INTRODUCTION: Clostridioides difficile is an important causative pathogen in antibiotic-associated colitis and nosocomial infections. This study aimed to assess immunochromatographic test results for C. difficile infection and the utility of PCR-based open-reading frame typing (POT) for potentially controlling the intra-ward transmission of C. difficile. METHODS: We conducted a molecular epidemiological analysis using POT to investigate 102 inpatients who tested positive for the C. difficile toxin using immunochromatography in a tertiary-care teaching hospital in Japan between 2016 and 2018; isolates from the patients were obtained and cultured. RESULTS: The number of POT numbers detected in 2016, 2017, and 2018 were 27 (among 34 patients), 20 (among 31 patients), and 28 (among 37 patients), respectively. During this three-year period, there were seven cases whose bacterial strains with the same POT number was identified in the same ward within 6 months. The intra-ward transmission rate was the highest in 2017 (16.1%). Intra-ward transmission was identified at a higher rate in patients whose sample cultures tested toxin-positive than in patients whose sample cultures tested toxin- and glutamate-dehydrogenase-positive via immunochromatography (16% vs. 3%, p < 0.05). CONCLUSIONS: We conclude that the use of immunochromatographic tests for C. difficile diagnosis and epidemiological analyses via POT may be helpful for evaluating intra-ward transmission of C. difficile.

Incidental finding of neurosyphilis with intracranial hemorrhage and cerebral infarction: A case report.

Syphilis has recently increased in prevalence in Japan. Neurosyphilis is a special pathological condition of syphilis well known to cause cerebral vasculitis and ischemic stroke. Neurosyphilis in the meningovascular stage rarely causes caliber irregularity of the cerebral blood vessels or cerebral hemorrhage. We describe the case of a 49-year-old Japanese man with neurosyphilis. Cerebral hemorrhage, multiple cerebral infarctions, and caliber irregularity of the cerebral blood vessels were observed, the patient underwent surgery for cerebral hemorrhage on the day of admission, all of which were suspected to be caused by syphilis. He was started on an antibacterial treatment of penicillin on the day of admission and was diagnosed with neurosyphilis the following week based on his serum and spinal fluid test results. His condition improved, and he was transferred to another hospital after 4 weeks of treatment consisting of 3 weeks of infusion treatment with benzylpenicillin followed by oral treatment with amoxicillin. To the best of our knowledge, this is a rare case of neurosyphilis in conjunction with cerebral hemorrhage and cerebral infarction. Clinicians should consider syphilis in the differential diagnosis of cerebral hemorrhage and cerebral infarction and test patients for sexually transmitted diseases, in addition to cerebrospinal fluid testing, when cerebral hemorrhage occurs with an unknown cause. This is especially pertinent when patients present with cerebral infarction or caliber irregularity of the cerebral blood vessels.

Increasing riverine heat influx triggers Arctic sea ice decline and oceanic and atmospheric warming.

Arctic river discharge increased over the last several decades, conveying heat and freshwater into the Arctic Ocean and likely affecting regional sea ice and the ocean heat budget. However, until now, there have been only limited assessments of riverine heat impacts. Here, we adopted a synthesis of a pan-Arctic sea ice-ocean model and a land surface model to quantify impacts of river heat on the Arctic sea ice and ocean heat budget. We show that river heat contributed up to 10% of the regional sea ice reduction over the Arctic shelves from 1980 to 2015. Particularly notable, this effect occurs as earlier sea ice breakup in late spring and early summer. The increasing ice-free area in the shelf seas results in a warmer ocean in summer, enhancing ocean-atmosphere energy exchange and atmospheric warming. Our findings suggest that a positive river heat-sea ice feedback nearly doubles the river heat effect.

A mouse model of rapidly progressive fatal haemorrhagic pneumonia caused by Stenotrophomonas maltophilia.

OBJECTIVES: Stenotrophomonas maltophilia causes severe haemorrhagic pneumonia with a reported mortality rate of 100%. However, currently there are no available mouse models of haemorrhagic pneumonia. In the present study, we generated a mouse model of haemorrhagic pneumonia and subjected the animals to treatment with levofloxacin and moxifloxacin to determine whether this model can be used to determine therapeutic effects. METHODS: Stenotrophomonas maltophilia was transtracheally administered to mice immunosuppressed with cyclophosphamide. We confirmed the pathological status of the S. maltophilia isolate and assessed whether the therapeutic effects of quinolone antibiotics could be studied using the model. Levofloxacin and moxifloxacin were administered to evaluate survival rate, bacterial load in the lungs and cardiac blood, as well as pathological changes in diseased lungs compared with those of the control group. RESULTS: Haemorrhagic pneumonia developed within 16-24 h after bacterial infection and was confirmed pathologically. Levofloxacin and moxifloxacin significantly improved survival rates, decreased the bacterial load in lungs and cardiac blood, and improved haemorrhagic pneumonia as indicated by pathological examination. CONCLUSIONS: We established a mouse model of rapidly progressive fatal haemorrhagic pneumonia caused by S. maltophilia that is useful for determining the therapeutic effect of various agents. We believe that this model will prove useful to further elucidate the mechanisms underlying haemorrhagic pneumonia as well as in the design and development of novel therapeutic modalities and targets.

Blood culture reports by infectious disease physicians can improve prognosis of bacteremia, including weekend-onset cases.

OBJECTIVES: Cases of positive blood cultures were previously reported by a microbiological technologist (MT) to an attending physician (AP), and the Antimicrobial Stewardship team provided medical assistance by grasping the situation at the morning meeting the next day. Since April 2018, MTs have reported positive blood cultures to an infectious disease physician (IDP), who proposes the management approach to the AP and provides weekend support. This study assessed the effectiveness of blood culture reports provided by IDPs to APs on outcomes of bacteremia, including weekend-onset cases. METHODS: Patient characteristics and prognoses before (October 2017 to March 2018) and after intervention (April to September 2018) were compared. RESULTS: The pre-intervention and post-intervention groups comprised 134 and 161 patients, respectively. Patients were more likely to be older (>65 years) in the post-intervention group (p < 0.05). There were no significant between-group differences in infection severity. The rate of de-escalation significantly increased from 38.1%-57.8% (p = 0.001). The rates of 28-day and in-hospital mortality reduced following the intervention (21.3% vs. 8.2% and 32.8% vs. 10.6%; p = 0.004 and p < 0.001, respectively). In-hospital mortality for weekend-onset cases also reduced following the intervention (33.3% vs. 12.9%, p = 0.01). Sepsis was a poor prognostic factor (OR 8.070, 95% CI 3.320-19.600, p < 0.001) and intervention was a good prognostic factor (OR 0.311, 95% CI 0.142-0.680, p = 0.003) affecting 28-day mortality in multivariate analysis. CONCLUSIONS: Changes to blood culture result reporting protocols can improve outcomes of bacteremia, including weekend-onset cases.

Detection of viral RNA in diverse body fluids in an SFTS patient with encephalopathy, gastrointestinal bleeding and pneumonia: a case report and literature review.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that commonly has a lethal course caused by the tick-borne Huaiyangshan banyang virus [former SFTS virus (SFTSV)]. The viral load in various body fluids in SFTS patients and the best infection control measure for SFTS patients have not been fully established. CASE PRESENTATION: A 79-year-old man was bitten by a tick while working in the bamboo grove in Nagasaki Prefecture in the southwest part of Japan. Due to the occurrence of impaired consciousness, he was referred to Nagasaki University Hospital for treatment. The serum sample tested positive for SFTSV-RNA in the genome amplification assay, and he was diagnosed with SFTS. Furthermore, SFTSV-RNA was detected from the tick that had bitten the patient. He was treated with multimodal therapy, including platelet transfusion, antimicrobials, antifungals, steroids, and continuous hemodiafiltration. His respiration was assisted with mechanical ventilation. On day 5, taking the day on which he was hospitalized as day 0, serum SFTSV-RNA levels reached a peak and then decreased. However, the cerebrospinal fluid collected on day 13 was positive for SFTSV-RNA. In addition, although serum SFTSV-RNA levels decreased below the detectable level on day 16, he was diagnosed with pneumonia with computed tomography. SFTSV-RNA was detected in the bronchoalveolar lavage fluid on day 21. By day 31, he recovered consciousness completely. The pneumonia improved by day 51, but SFTSV-RNA in the sputum remained positive for approximately 4 months after disease onset. Strict countermeasures against droplet/contact infection were continuously conducted. CONCLUSIONS: Even when SFTSV genome levels become undetectable in the serum of SFTS patients in the convalescent phase, the virus genome remains in body fluids and tissues. It may be possible that body fluids such as respiratory excretions become a source of infection to others; thus, careful infection control management is needed.

Clinical features and cause analysis of false positive results of Aspergillus galactomannan assay in pulmonary cryptococcosis patients.

There have been conflicting reports of false positive galactomannan assay results in patients with systemic cryptococcosis. We sought to determine the frequency of GM positivity in patients with pulmonary cryptococcosis and confirm the source of this cross-reactivity in vitro. We conducted a retrospective study to elucidate the rate of galactomannan (GM) false positivity and cause in a cohort of 29 patients with pulmonary cryptococcal disease. The production of GM cross-reacting substances by clinical isolates and laboratory isolates of C. neoformans was tested in vitro. The mean serum GM index (Platelia Aspergillus) in patients with pulmonary cryptococcosis was 1.06, with 16 (55.2%) of patients having values above the positive cutoff value of 0.5. GM index values significantly decreased after treatment of cryptococcosis. There was no significant correlation between galactomannan and cryptococcal glucuronoxylomannan antigen (Eiken Latex test) results. Culture supernatants from clinical isolates and wild-type C. neoformans did not react in the GM assay; however, growth in the presence of 6% sodium chloride induced the production of cross-reacting GM antigens in culture supernatants from clinical isolates, wild type and a glucuronoxylomannan-deficient mutant of C. neoformans, but not in culture supernatants from a galactoxylomannan-deficient strain. Our results support the cross-reactivity of cryptococcal galactoxylomannan with the serum GM assay in vitro and in patients with pulmonary cryptococcal infection.

Examination of cryptococcal glucuronoxylomannan antigen in bronchoalveolar lavage fluid for diagnosing pulmonary cryptococcosis in HIV-negative patients.

We clarified the performance of a cryptococcal glucuronoxylomannan (GXM) antigen test using bronchoalveolar lavage fluid (BALF) samples, in an HIV-negative Japanese population. Between March 2008 and December 2014, we examined cryptococcal GXM antigens in both serum and BALF specimens from 429 cases at Nagasaki University hospital. The diagnoses, underlying diseases, chest computed tomography findings, and cryptococcal GXM antigen test results were retrospectively investigated. Twenty-three patients were confirmed to have pulmonary cryptococcosis, another six were clinically diagnosed with cryptococcosis because they were seropositive for the GXM antigen, and five possible cryptococcosis cases had BALF samples that were positive for the GXM antigen and serum samples that were negative. The test's sensitivities for detecting cryptococcal GXM antigens in serum and BALF samples, for confirmed cases, were 73.9% and 82.6%, respectively, and their respective specificities were 98.5% and 97.8%. Three of the five putative patients with cryptococcosis were treated with antifungal agents; the pulmonary lesions decreased in size in all treated patients. Both the BALF and serum GXM antigen titers showed positive correlations with the lesion sizes; however, the serum antigen titers showed a higher correlation (r = 0.490, P = .0033) than did the BALF titres (r = 0.312, P = .0724). The rate of GXM-positive BALF samples was higher than the rate for serum samples, especially for patients with pulmonary lesion diameters ≤25 mm. Testing for the presence of the cryptococcal GXM antigen in BALF specimens might contribute to the early diagnosis of pulmonary cryptococcosis.

Pulmonary Actinomycosis Mimicking Pulmonary Aspergilloma and a Brief Review of the Literature.

Pulmonary actinomycosis is a rare pulmonary infection that often exhibits unspecific symptoms and radiological findings. We herein report a case of pulmonary actinomycosis that mimicked pulmonary aspergilloma in an immunocompetent patient.

Comparative efficacies of daptomycin, vancomycin, and linezolid in experimental enterococcal peritonitis.

Enterococci have become increasingly important pathogens for nosocomial infection (e.g. bacteremia, intra-abdominal infection, endocarditis, etc.), related to their intrinsic resistance to many antibiotics. Although the in vitro susceptibility of daptomycin (DAP) against Enterococci is well established, the Food and Drug Administration has only approved its use for complicated skin and skin structure infections induced by Enterococcus faecalis. In this study we evaluated the potential therapeutic application of DAP in a murine model of enterococcal experimental peritonitis. Mice were injected intraperitoneally with 4 × 1010 colony-forming units of Enterococcus faecium. DAP alone, DAP combined with ampicillin, vancomycin, or linezolid were administered 2 h after enterococcal inoculation and examined the survival, viable bacteria counts, the level of KC/CXCL1 in the peritoneal fluid. The viable bacteria counts in the peritoneal fluid of the DAP- or DAP plus ampicillin-treated groups were decreased significantly compared to those of the vancomycin- and linezolid-treated groups (P < 0.05) at 6 and 12 h after the inoculation of Enterococcus. The level of neutrophil chemoattractants KC in the peritoneal fluid at 12 h after enterococcal inoculation was significantly decreased in the DAP plus ampicillin-treated group (P < 0.05). In addition DAP showed the inhibitory effect of enterococcal biofilm formation dose-dependently by a microtiter biofilm assay. These results indicate that DAP, particularly with ß-lactams, is a possible alternative agent to treat severe enterococcal infection such as peritonitis.