Epidemiology, resistant pathogens, and causes of early death in cases of bloodstream infection in patients with hematological malignancies from 2012-2019

Purpose:To investigate the epidemiology,causative pathogen antibiotic susceptibility,and mortality risk factors of bloodstream infection(BSI)in patients with hematological malignancies(HMs).Methods:Single-center retrospective analysis of BSI cases in patients with HMs in a Chinese tertiary hospital from 2012-2019.Results:Among 17,796 analyzed admissions,508 BSI episodes(2.9%;95%confidence interval:2.6%-3.2%)were identified.Of 522 resulting isolates,326(62.5%)were Gram-negative,173(33.1%)were Gram-positive.The BSI incidence among patients with different HMs(severe aplastic anemia:6.7%;acute leukemia:6.2%;myelodysplastic syndrome:3.2%;multiple myeloma:1.3%;and lymphoma:1.0%)differed significantly(p<0.001).The BSI incidence was significantly higher in the hematopoietic stem cell transplantation(HSCT)group(10.2%)than in the non-HSCT group(2.5%;p<0.001).Escherichia coli(30.7%,160/522)was the most common pathogen,followed by Coagulase-negative staphylococci(19.4%,101/522)and Klebsiella pneumoniae(10.0%,52/522).,The rates of imipenem resistance for E.coli,K.pneumoniae,Pseudomonas aeruginosa,and Acinetobacter baumannii were 6.4%,15.0%,27.8%,and 79.0%,respectively.All the Gram-positive pathogens were linezolid susceptible.Three vancomycin-resistant Enterococcus species were isolated.The overall 14-day mortality was 9.8%(95%confidence interval:7.2%-12.4%).A multivariate analysis showed that HM subtype severe aplastic anemia,A.baumannii,and malignancy non-remission were independent 14-day mortality risk factors.Conclusions:Gram-negative bacteria were the most common pathogens,with E.coli as the predominant strain,causing BSIs in HM patients.A carbapenem-resistant A.baumanni with a high mortality rate in HM patients made empirical antimicrobial choice a highly challenging issue.

Hepatoprotective drugs for prevention of liver injury resulting from anti-tuberculosis treatment:A meta-analysis of cohort studies

Background:The incidence of liver injury caused by anti-tuberculous(TB)drugs is very high.However,owing to a lack of sufficient evidence,preventive use of hepatoprotective drugs is not yet recommended.Therefore,we aimed to assess the protective effect of hepatoprotective drugs for anti-TB drug-induced liver injury.Methods:We conducted a literature search in China Biology Medicine disc,China National Knowledge Infras-tructure,WanFang,Chinese Scientific and Technological Journal,PubMed,Cochrane Library,Web of Science,and Embase.We performed meta-analysis using R 4.0 and Review Manager 5.3 software.Results:A total of 18 studies involving 3589 patients from 2 groups were included.Use of hepatoprotective drugs contributed to a lower incidence of liver injury as compared with conventional anti-TB treatment alone(relative risk[RR]=0.39,95%confidence interval[CI]:0.28-0.53,p<0.001).In subgroup analysis,significant protective effects were noted for mild liver injury(RR=0.30,95%CI 0.15-0.58),moderate(or severe)liver injury(RR=0.35,95%CI 0.19-0.65),and liver injury within 2-4 weeks(RR=0.37,95%CI 0.19-0.71).We also found a statistically significant difference in the incidence of drug withdrawal(RR=0.58,95%CI 0.34-0.97,p=0.040).Conclusions:Our results demonstrate that hepatoprotective drugs are effective in preventing liver injury in pa-tients receiving anti-TB treatment,to some extent.

Atypical miller-fisher syndrome after COVID-19 and sleeve gastrectomy:Contribution of neurochemical markers to early diagnosis

Background:The coronavirus disease 2019(COVID-19)pandemic,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),began in late 2019.More recently,there have been sporadic case reports on devel-opment of Miller-Fisher Syndrome,a rare variant of Guillain-BarréSyndrome in COVID-19 patients.Case report:We reported herein the case of a French young women presenting with ophtalmoplegia,cerebellar ataxia,and universal areflexia following a bariatric surgery(sleeve gastrectomy).A concomitant COVID-19 diagnosis was retained based on microbiological testing.The patient was successfully treated after high-dose intravenous thiamine,but areflexia persisted.Underlying COVID-19 related Miller-Fisher Syndrome was established on physical examination and confirmed by pathologic neurophysiological findings and elevated level of phosphorylated neurofilament heavy chain protein in cerebrospinal fluid analysis.Conclusions:Guillain-BarréSyndrome and its variants after SARS-CoV-2 infection are extremely rare.The mea-surement of phosphorylated neurofilament heavy chain protein should be considered as an easy tool to detect an early affection of the peripheral nervous system.

Association between Hepatitis B virus and gastric cancer:A systematic review and meta-analysis

An increasing number of studies are suggesting that hepatitis B virus(HBV)infection may be associated with an increased risk of not only hepatocellular carcinoma but also gastric cancer(GC).Whether HBV infection can be a risk factor for GC remains to be explored.In this study,we systematically searched for all eligible literature in 7 databases(China National Knowledge Infrastructure,WanFang,China Science and Technology Journal,PubMed,Cochrane Library,Web of Science and Embase).Eligible studies were required to have a case-control or cohort design.Sixteen studies were included and a meta-analysis was performed using Stata version 17.0.The quality of the included studies was assessed using the Newcastle-Ottawa Scale.The association between HBV infection and risk of GC was quantified by calculating the odds ratio and 95%confidence interval.The proportion of high-quality studies was 87.5%(14/16).The risk of GC was higher when HBV infection was present than when it was not(combined odds ratio 1.29,95%confidence interval 1.16-1.44;I^(2)=62.7%,p<0.001).The results of subgroup analyses were consistent with the main results.In conclusion,this systematic review and meta-analysis identified a positive association between HBV infection and an increased risk of GC.

Bacille-Calmette-Guerin modulates human macrophage and dendritic cell response to SARS-CoV-2 S-glycoprotein

Background:Given that epidemiological evidence suggests a potential protective role for Bacille-Calmette-Guerin against COVID-19,we aimed to explore whether pre-exposure of human monocyte-derived macrophages and dendritic cells to BCG could modulate their response to SARS-CoV-2 S-glycoprotein.Methods:Dual THP-1 cells containing 2 reporter plasmids for transcription factors NF-κB,and IRF were differ-entiated into macrophages over 3 days using phorbol 12-myristate 13-acetate,or into dendritic cells over 6 days using commercial monocyte-dencritic cell differentiation media and matured with recombinant tumor necrosis factor-α.Cells were exposed to BCG for 24 h and then stimulated with SARS-CoV-2 S-glycoprotein for 24 hours.Results:Pre-exposure of human macrophages and DCs to BCG increased IRF and NF-kb activation in response to the SARS-CoV-2 S-glycoprotein.Conclusions:Our results showed that pre-exposure of both types of cells to BCG exhibited an increase in inflam-matory transcription factors upon stimulation with S-glycoprotein.BCG-induced trained immunity may be an important tool for reducing susceptibility to SARS-CoV-2 infection and severity of COVID-19.Our findings help in the design of future BCG-based therapeutic approaches in the treatment of diseases caused by viral infections.

Correlation between human gut microbiome and diseases

Human gut microbiome is a major source of human bacterial population and a significant contribution to both positive and harmful effects.Due to its involvement in a variety of interactions,gut microorganisms have a great impact on our health throughout our lives.The impact of gut microbial population is been studied intensively in last two decades.Extensive literature survey focusing developments in the field were searched in English language Electronic Databases like PubMed,Google Scholar,Pubag,Google books,and Research Gate were mostly used to understand the role of human gut mirobiome and its role in different human diseases.Gut microbiome in healthy subjects differs from those who suffer from diseases.Type 2 diabetes,obesity,non-alcoholic liver disease,and cardiometabolic diseases have all been linked to dysbiosis of the gut microbiota.Pathogenesis of many disorders is also linked to changes in gut microbiota.Other diseases like cancer,arithritis,autism,depression,anxiety,sleep disorder,HIV,hypertension,and gout are also related to gut microbiota dysbiosis.We focus in this review on recent studies looking into the link between gut microbiome dysbiosis and disease etiology.Research on how gut microbiota affects host metabolism has been changed in past decades from descriptive analyses to high throughput integrative omics data analysis such as metagenomics and metabolomics.Identification of molecular mechanisms behind reported associations is been carried out in human,animals,and cells for measure of host physiology and mechanics.Still many the mechanisms are not completely understood.

Photo timeline of localized cutaneous leishmaniasis,Colombia

Dear Editor,New World cutaneous leishmaniasis is a vector-borne neglected tropical disease caused by infection with protozoan parasites of the genus Leishmania;most of them included in the subgenus Viannia,which are transmitted by the bites of infected female phlebotomine sandflies[1].In Colombia L.panamensis and L.braziliensis are the most frequent species associated with cutaneous leishmaniasis[2].The spectrum of New World cutaneous leishmaniasis includes single or multiple,localized,cutaneous ulcers;diffuse cutaneous leishmaniasis;disseminated cutaneous leishmaniasis;and mucosal leishmaniasis[3].

Epidemiology, clinical characteristics, and treatment of severe fever with thrombocytopenia syndrome

Severe fever with thrombocytopenia syndrome(SFTS)is an emerging tick-borne infectious disease caused by a novel phlebovirus(SFTS virus,SFTSV)in the family Phenuiviridae of the order Bunyavirales.The disease causes a wide spectrum of clinical signs and symptoms,ranging from mild febrile disease accompanied by thrombocy-topenia and/or leukocytopenia to hemorrhagic fever,encephalitis,multiple organ failure,and death.SFTS was first identified in China and was subsequently reported in South Korea and Japan.The case-fatality rate ranges from 2.7%to 45.7%.Older age has been consistently shown to be the most important predictor of adverse disease outcomes.Older age exacerbates disease mainly through dysregulation of host immune cells and uncontrolled inflammatory responses.Tick-to-human transmission is the primary route of human infection with SFTSV,and Haemaphysalis longicornis is the primary tick vector of SFTSV.Despite its high case-fatality rate,vaccines and an-tiviral therapies for SFTS are not currently available.The therapeutic efficacies of several antiviral agents against SFTSV are currently being evaluated.Ribavirin was initially identified as a potential antiviral therapy for SFTS but was subsequently found to inefficiently improve disease outcomes,especially among patients with high viral loads.Favipiravir(T705)decreased both time to clinical improvement and mortality when administered early in patients with low viral loads.Anti-inflammatory agents including corticosteroids have been proposed to play therapeutic roles.However,the efficacy of other therapeutic modalities,such as convalescent plasma,is not yet clear.

Evaluation of the diagnostic performance of a commercial molecular assay for the screening of suspected monkeypox cases in Sri Lanka

Background:The main objective of the present study was to compare the diagnostic performance of the commercial LightMix Modular Monkeypox Virus(MPXV)qPCR(TIB Molbiol,Germany)assay with the in-house non-variola orthopox/monkeypox generic real-time PCR assay(ICMR-NIV,Pune)for the screening of(MPXV)cases at Medical Research Institute(MRI)in Sri Lanka.Furthermore,clinical and sociodemographic data of suspected/confirmed cases received at MRI for the MPXV screening were also analyzed.Methods:The diagnostic performance of the commercial LightMix Modular MPXV qPCR assay with the in-house nonvariola orthopox/monkeypox generic real-time PCR assay for the screening of suspected MXPV cases was evaluated using standard methods with minor modifications.Socio-demographic and clinical profiles of suspected and confirmed MPXV cases were also analyzed.Results:The commercial LightMix Modular MPXV assay was able to detect MPXV with 100%sensitivity and specificity with non-variola orthopox/monkeypox generic rtPCR assay.During the period of study,from the total of 25 samples tested,only 2 were MPXV-positive(males).The most common symptoms of suspected MPXV cases were lesions or rashes(92%).Conclusions:With the continually increasing number of cases,access to MPXV testing should be made more widely available.The commercial LightMix Modular MPXV(TIB Molbiol)qPCR assay offers comparable performance to the non-variola orthopox/monkeypox generic real time PCR assay for MPXV detection during the present outbreak.

Mpox reinfection:A rapid systematic review of case reports

Background:Mpox re-emerged worldwide with the multi-country outbreaks that occurred in May 2022,threat-ening the public health of human beings.Methods:This rapid systematic review summarized mpox reinfection cases documented.Electronic databases(PubMed,MedRxiv,and Social Science Research Network)were searched without time limitation,using the key-words“mpox,”“monkeypox,”&“reinfection,”“reoccur,”“reoccurrence,”“episode,”and“relapse”.All laboratory-confirmed cases of mpox reinfection published in the literature were included in this study.Results:A total of seven publications(nine cases)from Africa,Europe,and South America were included.All mpox reinfection cases were male,with a median age of 36;88.89%of cases had unprotected sexual behaviors with other males before each illness episode.The average onset interval between the two episodes was about 4 months.Perianal lesions and lymphadenopathy were major symptoms in both episodes,and no differences in clinical severity were reported between the two episodes.The mean duration of the two episodes was approximately 22 days and 13 days,respectively;which the mean duration of the second episode was shorter than the first infection(t=2.17,p=0.0487).Sexually transmitted infections were commonly concurrent among most cases,accounting for 55.6%and 77.8%in the two episodes,respectively.Full vaccination against mpox was rare among reinfection cases.Conclusion:A second infection is possible even in a short period.Reinforcing monitoring,reducing high-risk behaviors,and heightening health education regarding mpox for high-risk populations are crucial to limit mpox spread,including persons with a history of mpox infection.

The presence of foci of Rickettsia conorii infection in China

China is not considered as an endemic area of Rickettsia conorii,so there is no routine clinical way to diagnose this infection.This study aims to determine whether 2 febrile patients who had a tick bite in East China were indeed infected with R.conorii.The citrate synthase gene(gltA)was amplified with universal rickettsial primers by real-time fluorescent PCR from the patients’blood samples.Nested PCR was used to amplify the outer membrane protein A gene(ompA)for positive specimens.PCR products were further identified and analyzed through nucleic acid sequencing.Positive amplification of the gltA and ompA genes was found in both patients.The nucleotide sequences(303 bp)of the ompA gene of the 2 patients had high homology(99%)with the R.conorii Indian tick typhus strain in GenBank.A more than 4-fold increase in IgG against R.conorii provided supportive evidence of SFG Rickettsia infection.And the rapid recovery after doxycycline treatment also supported a rickettsial cause for the disease.Physicians in East China should be aware of human infections with R.conorii.PCR-based diagnostic methods offer a rapid and precise way to diagnose rickettsiosis,improving patient identification and management.

Global trends in COVID-19

The pandemic COVID-19 is certainly one of the most severe infectious diseases in human history.In the last 2 years,the COVID-19 pandemic has caused over 418.6 million confirmed cases and 5.8 million deaths world-wide.Young people make up the majority of all infected COVID-19 cases,but the mortality rate is relatively lower compared to older age groups.Currently,about 55.04%individuals have been fully vaccinated rapidly approaching to herd immunity globally.The challenge is that new SARS-CoV-2 variants with potential to evade immunity from natural infection or vaccine continue to emerge.Breakthrough infections have occurred in both SARS-CoV-2 naturally infected and vaccinated individuals,but breakthrough infections tended to exhibit mild or asymptomatic symptoms and lower mortality rates.Therefore,immunity from natural infection or vaccination can reduce SARS-CoV-2 pathogenicity,but neither can completely prevent SARS-CoV-2 infection/reinfection.Fortunately,the morbidity and mortality of COVID-19 continue to decline.The 7-day average cumulative case fatality of COVID-19 has decreased from 12.3%on the February 25,2020,to 0.27%on January 09,2022,which could be related to a decreased SARS-CoV-2 variant virulence,vaccine immunization,and/or better treatment of patients.In conclusion,elimination of SARS-CoV-2 in the world could be impossible or at least an arduous task with a long way to go.The best strategy to prevent COVID-19 pandemic is to expand inoculation rate of effective vaccines.As the population reaches herd immunity,the mortality rate of COVID-19 may continue to decrease,and COVID-19 could eventually become another common cold.

A review of SARS-CoV-2 variants and vaccines:Viral properties,mutations,vaccine efficacy,and safety

The severe acute respiratory syndrome coronavirus disease 2 instigated by coronavirus disease of 2019(COVID-19)has delivered an unfathomable obstruction that has touched all sectors worldwide.Despite new vaccine tech-nologies and mass administration of booster doses,the virus persists,and unknown the ending of the pandemic for new variants and sub-variants.Moreover,whether leaning on home medications or using plant extracts is suf-ficient often to combat the virus has generated tremendous interest in the scientific fraternity.Different databases including PubMed,Scopus,Web of Science,and Google Scholar used to find published articles linked with related topics.Currently,COVID-19 third and fourth shots of vaccines are progressively administered worldwide,where some countries trail others by a significant margin.Many proteins related to viral activity have changed,possibly boosting the virus infectivity and making antibodies ineffective.This study will reminisce the viral genome,as-sociated pathways for viral protein functions,variants,and their mutations.The current,comprehensive review will also provide information on vaccine technologies developed by several biotech companies and the efficacy of their doses,costs including boosters on a mass level.As no vaccine is working to protect fully against all the variants,the new proactive vaccine research needs to be conducted based on all variants,their sub-lineage,and mutations.

Development of a rapid neutralizing antibody test for SARS-CoV-2 and its application for neutralizing antibody screening and vaccinated serum testing

Background:Since the outbreak of coronavirus disease(COVID-19),the high infection rate and mutation fre-quency of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent,have contributed to the ongoing global pandemic.Vaccination has become the most effective means of controlling COVID-19.Tra-ditional neutralizing tests of sera are complex and labor-intensive,therefore,a rapid test for detecting neutralizing antibodies and antibody status post-immunization is needed.Methods:Based on the fact that antibodies exhibit neutralizing activity by blocking the binding of the S protein receptor-binding domain(S-RBD)to ACE2,we developed a rapid neutralizing antibody test,ACE2-Block-ELISA.To evaluate the sensitivity and specificity,we used 54 positive and 84 negative serum samples.We also tested the neutralizing activities of monoclonal antibodies(mAbs)and 214 sera samples from healthy individuals im-munized with the inactivated SARS-CoV-2 vaccine.Results:The sensitivity and specificity of the ACE2-Block ELISA were 96.3%and 100%,respectively.For neu-tralizing mAb screening,ch-2C5 was selected for its ability to block the ACE2-S-RBD interaction.A plaque assay confirmed that ch-2C5 neutralized SARS-CoV-2,with NT 50 values of 4.19,10.63,and 1.074μg/mL against the SARS-CoV-2 original strain,and the Beta and Delta variants,respectively.For the immunized sera samples,the neutralizing positive rate dropped from 82.14%to 32.16%within 4 months post-vaccination.Conclusions:This study developed and validated an ACE2-Block-ELISA to test the neutralizing activities of an-tibodies.As a rapid,inexpensive and easy-to-perform method,this ACE2-Block-ELISA has potential applications in rapid neutralizing mAb screening and SARS-CoV-2 vaccine evaluation.

Ocular tuberculosis associated with Epstein-Barr virus myelitis: A case report

Ocular tuberculosis(OTB)is a chronic eye infection caused by Mycobacterium tuberculosis.Some cases of myelitis are associated with Epstein-Barr virus(EBV),with 1-5%of EBV infections leading to neurologic complications.We describe a 34-year-old Iranian woman with OTB and EBV coinfection.Despite initial success with anti-TB agents,the disease progressed,necessitating enucleation.Mycobacterium tuberculosis was detected by a tuberculin coagulation test,and EBV was confirmed via polymerase chain reaction.MRI showed plaques in the spinal cord and brain.The patient was treated with anti-TB and antiretroviral agents.Recognizing TB in the differential diagnosis of EBV myelitis is crucial.

Diagnosing and reintegrating traceability of infectious diseases via metagenomic next-generation sequencing:Study of a severe case of Rickettsia japonica infection

Background:In this study,we present a case of Japanese spotted fever(JSF)caused by Rickettsia japonica and use this case to investigate the process of diagnosing and reintegrating traceability of infectious diseases via metagenomic next-generation sequencing(mNGS).Methods:From data relating to epidemiological history,clinical and laboratory examinations,and mNGS se-quencing,a diagnosis of severe JSF was concluded.Results:A detailed field epidemiological investigation discovered parasitic Haemaphysalis longicornis from a host animal(dog)in the domicile of the patient,within which R.japonica was detected,along with a diverse array of other potentially pathogenic microorganisms that could cause other infectious diseases.Conclusion:The mNGS provided an efficient method to diagnose JSF infection.This methodology could also be applied to field epidemiological investigations to establish the traceability of infectious diseases.

The role of SARS-COV-2 infection in promoting abnormal immune response and sepsis:A comparison between SARS-COV-2-related sepsis and sepsis from other causes

Background:COVID-19 caused by SARS-CoV-2 virus is characterized by respiratory compromise and immune system involvement,even leading to serious disorders,such as cytokine storm.Methods:We then conducted a literature review on the topic of sepsis and covid-19,and in parallel conducted an experimental study on the histological finding of patients who died from SARS-Covid 19 infection and a control group.Results:Sepsis associated with covid-19 infection has some similarities and differences from that from other causes.Conclusion:In this paper the complex interplay between the 2 disorders was discussed,focusing on the similarities and on the effect that one could have on the other.A preliminary experimental section that demonstrates the multisystemic involvement in subjects who die from SARS-CoV-2 is also proposed.

Neurodevelopment from 0 to 24 months in normocephalic children,in utero exposed to Zika virus in 2016:A cohort study

Zika virus(ZIKV)is a neurotropic arbovirus almost exclusively transmitted by the bite of Aedes species mosquitoes[1].An outbreak of ZIKV infection was first confirmed in Northeast of Brazil,early 2015.The prevalence of micro-cephaly in 15 states of Brazil with laboratory-confirmed ZIKV transmission significantly exceeded that in four states without confirmed ZIKV transmission[2].

Viremia and clinical manifestations in acute febrile patients of Chikungunya infection during the 2016 CHIKV outbreak in Delhi,India

Background:Chikungunya virus(CHIKV)is an infectious agent that caused several outbreaks among different countries and affected approximately 1.3 million Indian populations.It is transmitted by Aedes mosquito–either A.albopictus or A.aegypti.Generally,the clinical manifestations of CHIKV infection involve high-grade fever,joint pain,skin rashes,headache,and myalgia.The present study aims to investigate the relationship between the CHIKV virus load and clinical symptoms of the CHIKV infection so that better patient management can be done in the background of the CHIKV outbreak as there is no licensed anti-viral drug and approved vaccines available against CHIKV.Methods:CHIKV RTPCR positive samples(n=18)(Acute febrile patients having D.O.F≤7 days)were taken for the quantification of CHIKV viremia by Real-Time PCR.Clinical features of the febrile patients were recorded during the collection of blood samples.Results:The log mean virus load of 18 RT-PCR-positive samples was 1.3×10^(6) copies/mL(1.21×10^(3)–2.33×10^(8) copies/mL).Among the observed clinical features,the log mean virus load(CHIKV)of the patients without skin rash is higher than in the patients with skin rash(6.61 vs.5.5,P=0.0435).Conclusion:The conclusion of the study was that the patients with skin rashes had lower viral load and those without skin rashes had higher viral load.

The liver-to-spleen ratio is a risk factor predicting oxygen demand in COVID-19 patients

Background:We aimed to investigate risk factors predicting oxygen demand in COVID-19 patients.Methods:Patients admitted to Shizuoka General Hospital with COVID-19 from August 2020 to August 2021 were included.First,we divided patients into groups with and without oxygen demand.Then,we compared patients’clinical characteristics and laboratory and radiological findings to determine factors predicting oxygen demand.Results:One hundred seventy patients with COVID-19(aged 58±15 years,57 females)were enrolled.Common comorbidities were cardiovascular diseases(47.6%),diabetes mellitus(28.8%),and dyslipidemia(26.5%).Elder age,higher body mass index,cardiovascular diseases,diabetes mellitus,lower lymphocyte count,albumin,hep-atic attenuation value,and the liver-to-spleen ratio(L/S),higher D-dimer,aspartate aminotransferase,lactate dehydrogenase,troponin-T,C-reactive protein,KL-6,chest and abdominal circumference,and visceral fat were found in patients with oxygen demand.According to the multivariate logistic regression analysis,L/S,lympho-cyte count,D-dimer,and abdominal circumference under the diaphragm were independent risk factors predicting oxygen demand in COVID-19 patients.Conclusions:On admission,L/S,lymphocyte count,D-dimer,and abdominal circumference were predictive factors for oxygen demand.These factors may help in the appropriate triage of COVID-19 patients in the decision to admit them to the hospital.