Clinical manifestations,diagnosis and long-term prognosis of adult autoimmune enteropathy:Experience from Peking Union Medical College Hospital

BACKGROUND Autoimmune enteropathy(AIE)is a rare disease whose diagnosis and long-term prognosis remain challenging,especially for adult AIE patients.AIM To improve overall understanding of this disease’s diagnosis and prognosis.METHODS We retrospectively analyzed the clinical,endoscopic and histopathological characteristics and prognoses of 16 adult AIE patients in our tertiary medical center between 2011 and 2023,whose diagnosis was based on the 2007 diagnostic criteria.RESULTS Diarrhea in AIE patients was characterized by secretory diarrhea.The common endoscopic manifestations were edema,villous blunting and mucosal hyperemia in the duodenum and ileum.Villous blunting(100%),deep crypt lymphocytic infiltration(67%),apoptotic bodies(50%),and mild intraepithelial lymphocytosis(69%)were observed in the duodenal biopsies.Moreover,there were other remarkable abnormalities,including reduced or absent goblet cells(duodenum 94%,ileum 62%),reduced or absent Paneth cells(duodenum 94%,ileum 69%)and neutrophil infiltration(duodenum 100%,ileum 69%).Our patients also fulfilled the 2018 diagnostic criteria but did not match the 2022 diagnostic criteria due to undetectable anti-enterocyte antibodies.All patients received glucocorticoid therapy as the initial medication,of which 14/16 patients achieved a clinical response in 5(IQR:3-20)days.Immunosuppressants were administered to 9 patients with indications of steroid dependence(6/9),steroid refractory status(2/9),or intensified maintenance medication(1/9).During the median of 20.5 months of followup,2 patients died from multiple organ failure,and 1 was diagnosed with non-Hodgkin’s lymphoma.The cumulative relapse-free survival rates were 62.5%,55.6%and 37.0%at 6 months,12 months and 48 months,respectively.CONCLUSION Certain histopathological findings,including a decrease or disappearance of goblet and Paneth cells in intestinal biopsies,might be potential diagnostic criteria for adult AIE.The long-term prognosis is still unsatisfactory despite corticosteroid and immunosuppressant medications,which highlights the need for early diagnosis and novel medications.

Pathogenesis,clinical manifestations,diagnosis,and treatment progress of achalasia of cardia

Achalasia cardia,type of esophageal dynamic disorder,is a relatively rare primary motor esophageal disease characterized by the functional loss of plexus ganglion cells in the distal esophagus and lower esophageal sphincter.Loss of function of the distal and lower esophageal sphincter ganglion cells is the main cause of achalasia cardia,and is more likely to occur in the elderly.Histological changes in the esophageal mucosa are considered pathogenic;however,studies have found that inflammation and genetic changes at the molecular level may also cause achalasia cardia,resulting in dysphagia,reflux,aspiration,retrosternal pain,and weight loss.Currently,the treatment options for achalasia focus on reducing the resting pressure of the lower esophageal sphincter,helping to empty the esophagus and relieve symptoms.Treatment measures include botulinum toxin injection,inflatable dilation,stent insertion,and surgical myotomy(open or laparoscopic).Surgical procedures are often subject to controversy owing to concerns about safety and effectiveness,particularly in older patients.Herein,we review clinical epidemiological and experimental data to determine the prevalence,pathogenesis,clinical presentation,diagnostic criteria,and treatment options for achalasia to support its clinical management.

Review of risk factors,clinical manifestations,rapid diagnosis,and emergency treatment of neonatal perioperative pneumothorax

Perioperative neonatal pneumothorax(NP)is rare but very fatal.Most of the surgeries and treatments in the neonatal period are time-limited or emergent,and there are often some risk factors for pneumothorax before surgery.Physicians,surgeons and anesthesiologists need to identify possible risk factors for pneumothorax before surgery in preterm babies,patients receiving mechanical ventilation and those with underlying lung disease.The clinical presentation of NP is nonspecific,and patients may rapidly develop life-threatening complications if not promptly diagnosed and managed.This review highlights recent progress in the identification of risk factors,clinical manifestations,diagnosis and management of NP during the perioperative period.

Clinical manifestations and outcomes of ocular sarcoidosis in Saudi Arabia

Dear Sir,We write to report on the clinical manifestations and outcomes of ocular sarcoidosis in patients presenting to uveitis referral centers in the Kingdom of Saudi Arabia.This is the first report focused solely on ocular sarcoidosis from this country.

Clinical manifestations of patients with chronic pancreatitis

BACKGROUND: Recent advances in molecular and genomic technologies and pancreatic imaging techniques provided some insights into genetic, environmental, immunologic, and pathobiological factors for chronic pancreatitis (CP). This study was undertaken to investigate the clinical manifestations of patients with chronic pancreatitis at our hospital. METHODS: The data of the patients with CP who had been treated at our hospital between 1997 and 2004 were analyzed. RESULTS: The major symptoms of the patients with CP were abdominal pain, dyspepsia, loss of weight, diabetes mellitus, pancreatic pseudocyst, steatorrhea, and calcification. Biliary diseases were found to be the first cause of CP in this study; but alcohol abuse was the major cause of CP in men and biliary diseases were the first etiological factors for CP in women. The etiological difference of constituent ratio between men and women was related to alcohol comsumption (P<0.01). CONCLUSIONS: During the past 8 years, biliary diseases have been the major etiological factors for CP, but their constituent ratio is decreasing, and the constituent ratio of alcohol abuse is increasing gradually. Alcohol tends to replace biliary diseases as the primary etiological factor for CP.

Infected aortic and iliac aneurysms:Clinical manifestations in the emergency departments of two hospitals in southern Taiwan,China

BACKGROUND: Accurate diagnosis of infected aortic and iliac aneurysms is often delayed, hampering timely treatment and potentially resulting in a fatal consequence. The aim of this study was to discover useful clinical features that can help physicians to identify these patients.METHODS: We reviewed the discharge notes from two hospitals and identifi ed all patients who had a diagnosis of infected aneurysms of the thoracoabdominal aorta and iliac arteries between July 2009 and December 2013. Eighteen patients, aged from 41 to 93, were reviewed. Only 6 patients were diagnosed accurately in their fi rst visit to our ED.RESULTS: Most patients had at least one underlying illness, and it took 1 to 30(9.9±6.5) days for physicians to diagnose their infected aneurysm. Localized pain and fever were the two most commonly presented symptoms. The majority(92%) of isolated microorganisms were gram-negative bacilli, including Salmonella spp, Klebsiella pneumoniae, and Escherichia coli. Two of the 3 patients who underwent non-operative therapy died, and all of the patients who underwent a combination of medical and operative therapies survived.CONCLUSION: We suggest that physicians liberally use computed tomography scans on patients with unknown causes of pain and inflammatory processes. A combination of surgical and medical treatments is indicated for all patients with infected aortic and iliac aneurysms.

Clinical manifestations of respiratory syncytial virus infection and the risk of wheezing and recurrent wheezing illness:a systematic review and meta‑analysis

Background Respiratory syncytial virus(RSV)infection in infants is a global health priority.We aimed to investigate the common manifestations of RSV infection by age group and human development index(HDI)level and to assess its association with the development of wheezing and recurrent wheezing illness.Methods We searched the literature published between January 1,2010 and June 2,2022 in seven databases.Outcomes included common manifestations and long-term respiratory outcomes of RSV infection in children.Random-and fixed-effect models were used to estimate the effect size and their 95%confidence intervals.Subgroup analysis was conducted by age and HDI levels.This review was registered in PROSPERO(CRD42022379401).Results The meta-analysis included 47 studies.The top five manifestations were cough(92%),nasal congestion(58%),rhinorrhea(53%),shortness of breath(50%),and dyspnea(47%).The clinical symptoms were most severe in infants.In our analysis,compared to very high and high HDI countries,fewer studies in medium HDI countries reported related manifestations,and no study in low HDI countries reported that.The RSV-infected infants were more likely to develop wheezing than the non-infected infants[odds ratio(OR),3.12;95%CI,2.59–3.76]and had a higher risk of developing wheezing illnesses after recovery(OR,2.60;95%CI,2.51–2.70).Conclusions Cough and shortness of breath are common manifestations of RSV infection.More attention should be given to infants and areas with low HDI levels.The current findings confirm an association between RSV infection and wheezing or recurrent wheezing illness.

Autoimmune pancreatitis with different clinical manifestations and imaging findings:a series of three cases

Autoimmune pancreatitis(AIP)is a rare and emerging immune-mediated pancreatitis.The involvement of the pancreas with lymph-oplasmacytic infiltration and fibrosis on histology is the most common features and has been well studied in the literature.It is characterized by a nonspecific presentation that mimics a malignant process.The purpose of this report is to explore the different clinical and paraclinical aspects of this disease,as well as the challenges posed by its management.The series are made up of three different cases of patients with elevated serum IgG4 levels and pancreatic changes.The first case initially revealed cholestatic jaundice with extrahepatic and intrahepatic cholangitis,and ultrasound reflected multiple occupying changes in the pancreas.The elevated serum IgG4 level was brilliant.Patient improved under the influence of corticosteroids.The second case was clinically asymptomatic,just found weight loss.Magnetic resonance revealed a round mass in the head of the pancreas and was considered as a neuroendocrine tumor.The patient showed slightly elevated serum IgG4 level,but was sensitive to hormone therapy.The third case concerned epigastric pain and enlarged lymph nodes.It was initially diagnosed as pancreatic cancer with distant metastasis,but also finally resolved by corticosteroid treatment.The clinical presentation of AIP is heterogeneous,as evidenced by our three clinical cases.Further observational and interventional studies are needed to better identify and manage this disease.

Liver dysfunction on admission worsens clinical manifestations and outcomes of coronavirus disease 2019

Background:Liver dysfunction was common in coronavirus disease 2019(COVID-19),but its association with clinical features and poor prognosis has not been fully delineated.Our study aimed to determine the role of liver dysfunction in COVID-19 and understand the predictors for worse outcomes in patients with liver injury.Methods:We conducted this multicenter,retrospective study in five designated hospitals for COVID-19 manage-ment.Laboratory-confirmed COVID-19 patients were enrolled and classified into the normal live function group and liver dysfunction group according to liver enzymes,bilirubin,and albumin on admission,respectively.Data of baseline,clinical manifestations,and outcomes were collected and compared in the paired groups.Results:Of the 649 included COVID-19 patients,200(30.8%),69(10.6%),and 267(41.1%)patients had elevated liver enzymes,increased bilirubin,and low-level albumin,respectively.Fever,cough,and dyspnea were the most common symptoms and showed an increased proportion in the liver dysfunction group.Compared with patients in the normal liver function group,patients with liver dysfunction manifested decreased lymphocytes,higher level of leukocytes,neutrophils,inflammatory indicators,and cytokines,as well as more severe impairment in kidney function and myocardium.They were more likely to show bilateral involvement and more pulmonary lobes involved according to chest images.With increased proportion of patients who developed severe/critical conditions and needed mechanical ventilation and systemic glucocorticoid therapy,patients with liver dysfunc-tion on admission showed significantly higher in-hospital mortality.Moreover,cardiac troponin I≥1.5 ng/mL was identified as an independent mortality predictor in the elevated liver enzymes group.Conclusion:Patients with liver dysfunction on admission had worse clinical manifestation,and resulted in higher rate of severe/critical type,receiving mechanical ventilation and in-hospital mortality.

Clinical Characteristics,Diagnosis,and Therapeutics of COVID-19:A Review

The novel severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)that suddenly emerged at the end of December 2019 and caused coronavirus disease 2019(COVID-19)continues to afflict humanity,not only seriously affecting healthcare systems but also leading to global social and economic imbalances.As of August 2022,there were approximately 580 million confirmed cases of COVID-19 and approximately 6.4 million confirmed deaths due to this disease.The data are sufficient to highlight the seriousness of SARS-CoV-2 infection.Although most patients with COVID-19 present primarily with respiratory symptoms,an increasing number of extrapulmonary systemic symptoms and manifestations have been associated with COVID-19.Since the outbreak of COVID-19,much has been learned about the disease and its causative agent.Therefore,great effort has been aimed at developing treatments and drug interventions to treat and reduce the incidence of COVID-19.In this narrative review,we provide a brief overview of the epidemiology,mechanisms,clinical manifestations,diagnosis,and therapeutics of COVID-19.

Hepatic manifestations of coronavirus disease 2019 infection:Clinical and laboratory perspective

The novel coronavirus disease 2019(COVID-19)pandemic,caused by severe acute respiratory syndrome coronavirus 2,has become a global challenge of unprecedented nature since December 2019.Although most patients with COVID-19 exhibit mild clinical manifestations and upper respiratory tract involvement,in approximately 5%-10%of patients,the disease is severe and involves multiple organs,leading to multi-organ dysfunction and failure.The liver and gastrointestinal tract are also frequently involved in COVID-19.In the context of liver involvement in patients with COVID-19,many key aspects need to be addressed in both native and transplanted organs.This review focuses on the clinical presentations and laboratory abnormalities of liver function tests in patients with COVID-19 with no prior liver disease,patients with pre-existing liver diseases and liver transplant recipients.A brief overview of the history of COVID-19 and etiopathogenesis of the liver injury will also be described as a prelude to better understanding the above aspects.

Clinical features,radiological imaging,and treatment strategies of nonmetallic intraorbital foreign bodies:a retrospective analysis

AIM:To provide comprehensive data on nonmetallic intraorbital foreign bodies(IOFBs)by summarizing and analyzing material types,clinical manifestations,imaging features,and treatment strategies.METHODS:Totally 28 nonmetallic IOFB cases treated at Shengjing Hospital of China Medical University from 2012 to 2020 were retrospectively reviewed.The types of foreign bodies,clinical features,imaging manifestations,and treatment outcomes were analyzed.RESULTS:Among all cases,67.8%(19/28)of the foreign bodies were organic.The top three entrances were the upper eyelid skin(7/28),lower fornix conjunctiva(6/28),and lower eyelid skin(4/28).In most cases(11/28,39.3%),foreign bodies remained in the medial orbits.The major clinical manifestations included eyelid redness and swelling(20/28,71.4%),conjunctival congestion and edema(17/28,60.7%),and ophthalmoptosis(15/28,53.6%).Infection was the main complication,which occurred in 57.1%(16/28)of all cases.Computerized tomography(CT)values differed for different foreign bodies and varied in the different periods after injury.The plant-and grease-derived foreign bodies and the surrounding pus cysts showed different signals on magnetic resonance imaging(MRI).The prognosis varied with different foreign body types,surgery timing,and intraoperative management.CONCLUSION:The majority of nonmetallic IOFBs are organic and often remain in the superior,medial,and inferior areas of the orbit.Clinical manifestations vary owing to their different textures.CT and MRI facilitate the identification of foreign body materials.Plant-derived foreign bodies should be completely removed,and surgical treatment is a complicated process.

Analysis of clinical manifestations and treatment in 26 children with fibrodysplasia ossificans progressiva in China

Background Fibrodysplasia ossificans progressiva(FOP)is a rare and disabling heritable connective tissue disease that is difficult to treat.This study seeks to explore the clinical characteristics,clinical manifestations,treatment and prognosis of FOP to provide a clinical basis for its early diagnosis and treatment.Methods Twenty-six children with FOP were retrospectively analyzed in terms of their onset,clinical manifestations,auxiliary examinations and treatment.Results Among the 26 cases,the youngest age of manifestation of mass was 8 days after birth,and the average age was 3 years and 2 months.The peak age was 2-5 years old.Inflammatory mass and toe-finger deformity are the main early clinical manifestations of the disease.These inflammatory masses often lead to hard osteogenic deposits that initially mainly involve the central axis,such as the neck(22/26,84.6%),back(20/26,76.9%),and head(13/26,50%).Toe-finger deformity mainly manifests as symmetrical great toe deformity,or short and deformed thumb and little finger.The diagnosis of FOP requires typical clinical manifestations or ACVR1 gene detection.The main therapeutic drugs for FOP include glucocorticoids and non-steroidal anti-inflammatory drugs.Although not compliant with the recommended medical management of FOP,in our clinical practice children with uncontrollable illness could be treated using a variety of immunosuppressive agents in combination.Conclusions FOP is a rare autosomal dominant heritable disease.The main clinical manifestations observed in this study were recurrent inflammatory mass and toe-finger deformity.If the diagnosis and treatment are not performed in a timely manner,serious complications are likely to affect the prognosis.Therefore,early diagnosis and active treatment should be performed.

Rectus sheath hematoma combined with COVID-19:A case report

BACKGROUND Rectus sheath hematoma(RSH)is uncommon,and because people have limited knowledge about it,it is difficult to recognize the symptoms in time,often delaying optimal treatment.CASE SUMMARY Herein,we report a case of a 77-year-old female with RSH.The patient was treated at our hospital for coronavirus disease 2019.Anticoagulant treatment was administered during this period because of thrombosis.On the 8th d of treatment,the patient complained of abdominal pain.Ultrasonography revealed a solid cystic mass in the pelvic cavity.An emergency laparotomy was performed,and a huge hematoma was found in the deep layer of the rectus abdominis muscle.We used anticoagulants with caution based on the patient’s condition.CONCLUSION Optimal management of patients with RSH s depends on timely diagnosis and when to reintroduce anticoagulants.

Ambispective epidemiological observational study of varicella-zoster virus infection: An 18 year-single-center Bulgarian experience

BACKGROUND Varicella(chickenpox)and herpes zoster(shingles)are outcomes of varicella-zoster virus(VZV)infection,and understanding their incidence trends is vital for public health planning.AIM To conduct an ambispective epidemiological study by analyzing the main epidemiological characteristics of VZV infection during an 18 year-period(2000-2018).METHODS We used descriptive and epidemiological methods to characterize chickenpox in Bulgaria,the city of Plovdiv and the region for a period of 18 years(2000-2018).RESULTS The average incidence of varicella-zoster infection for the period 2000–2018 in the Plovdiv region was estimated at 449.58‰.The highest relative share of the infection was assessed in the month of January at 13.6%,and the lowest in the months of August and September at 2.9%(both months).The age group most affected by the infection was 1-4 years,followed by 5-9 years.This corresponds to the so-called"pro-epidemic population"-a phenomenon typical for airborne infections,confirming their mass impact on the perpetuation of VZV infection.CONCLUSION Our findings reveal significant insights into VZV epidemiology,including age-specific incidence rates,clinical manifestations,and vaccination impact.This comprehensive analysis contributes to the broader understanding of VZV infec-tion dynamics and may inform evidence-based preventive measures.

Clinical and molecular research of neuroacanthocytosis

Neuroacanthocytosis is an autosomal recessive or dominant inherited disease characterized by widespread, non-specific nervous system symptoms, or spiculated ＂acanthocytic＂ red blood cells. The clinical manifestations typically involve chorea and dystonia, or a range of other movement disorders. Psychiatric and cognitive symptoms may also be present. The two core neuroacanthocytosis syndromes, in which acanthocytosis is atypical, are autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome. Acanthocytes are found in a smaller proportion of patients with Huntington＇s disease-like 2 and pantothenate kinase-associated neurodegeneration. Because the clinical manifestations are diverse and complicated, in this review we present features of inheritance, age of onset, neuroimaging and laboratory findings, as well as the spectrum of central and peripheral neurological abnormalities and extraneuronal involvement to help distinguish the four specific syndromes.

Clinical Characteristics, Imaging Findings and Surgical Outcomes of Chiari Malformation Type I in Pediatric and Adult Patients

A growing number of children and adolescents are being diagnosed as Chiari malformation type I （CM- I ） for behavioral disorders, developmental delay, seizures, or abnormal orpharyngeal function. The aim of this study was to compare the clinical characteristics, imaging findings and surgical outcomes of CM- I in pediatric and adult patients. Between January 2014 and June 2017, 84 patients with CM- I underwent surgical treatment in our department. We divided the patients into two groups： pediatric group （n=l 1, age 〈18 years） and adult group （n=73, age 〉18 years）. Data on clinical characteristics, imaging findings, surgical outcomes, and prognosis were retrospectively reviewed and compared between these two groups. For clinical presentation, scoliosis （36.4%） and developmental delay （36.4%） were more common in pediatric patients, whereas, sensory disturbance （58.9%） and motor weakness （41. 1%） were more common in adult patients. Imaging findings showed that the incidence of hydrocephalus and craniovertebral junctional abnormalities was significantly higher in pediatric group than in adult group （P〈0.05）. Compared to adult group, pediatric group showed a better improvement or resolution of syrinx and tonsillar herniation after surgical treatments （P〈0.05）. The total Chicago Chiari Outcome Scale （CCOS） score in pediatric patients at the last follow- up was significantly higher than that in adult patients （P=0.002）. In conclusion, the clinical characteristics and imaging findings appeared to be different in pediatric and adult patients with CM- I. The surgical outcomes of pediatric patients were shown to be significantly better than those of adult patients.

Clinical Analysis of 84 Cases of Erythrodermic Psoriasis and 121 Cases of Other Types of Erythroderma from 2010–2015

Erythroderma with complicated etiology is one of the severe skin diseases and has high mortality, of which the incidence was 0.5‰–1.5‰ in skin diseases. Erythrodermic psoriasis（EP） is the commonest type of erythroderma. In addition, there are drug-induced erythroderma, erythroderma secondary to preexisting dermatoses, malignancy-related erythroderma, and idiopathic erythroderma of unknown etiology. Erythroderma of different etiologies has various clinical manifestations, resulting in relevant curative effects and outcomes. In this article, we retrospectively investigated 205 erythroderma patients about clinical symptoms, auxiliary examination and treatments, and evaluated the efficacy and prognosis. There were 84 cases of EP among 205 patients, 10 cases of erythroderma caused by specific drugs, 77 cases of erythroderma secondary to preexisting dermatoses（excluding psoriasis）, 7 cases of erythroderma patients suffering from malignancy and 27 cases with unknown causes. We concluded that the etiology of male patients in different age groups had significant difference. The incidence of EP was the highest among all types. The EP was commonly accompanied with hypoproteinemia, and changed into psoriasis vulgaris after treatment. Drug-induced erythroderma was commonly accompanied with fever, and mostly cured by systematic steroid therapy. For erythroderma secondary to preexisting dermatoses, the original dermatoses must be actively treated to achieve a satisfying prognosis. Erythroderma with malignancy or unknown causes had long-term duration, poor response to the treatment, and high potential to relapse. Therefore, clarifying the etiology, providing an appropiate and individual regimen, and regular follow-up are crucial for the successful treatment of erythroderma with unknown causes.

The value of toxicological analysis in acute poisoning patients with uncertain exposure histories:a retrospective and descriptive study from an institute of poisoning

BACKGROUND:In clinical practice,some patients might not be able or unwilling to provide a thorough history of medication and poison exposure.The aim of this study was to use toxicological analysis to examine the clinical characteristics of patients with acute poisoning whose exposure history was uncertain from a toxicological analysis perspective.METHODS:This was a retrospective and descriptive study from an institute of poisoning.Patient registration information and test reports spanning the period from April 1,2020 to March 31,2022,were obtained.Patients with uncertain exposure histories and who underwent toxicological analysis were included.Clinical manifestations and categories of toxics were analyzed.RESULTS:Among the 195 patients with positive toxicological analysis results,the main causes of uncertain exposure history was disturbance of consciousness(62.6%),unawareness(23.6%)and unwillingness or lack of cooperation(13.8%).The predominant clinical manifestations were disturbed consciousness(62.6%),followed by vomiting and nausea(14.4%)and liver function abnormalities(8.7%).A comparison of clinical manifestations between patients with positive and negative(n=99)toxicological analyses results revealed significantly different proportions of disturbances in consciousness(63%vs.21%),dizziness(1.5%vs.5.1%),multi-organ failure(1.5%vs.7.1%),and local pain(0 vs 4%).The main categories of substances involved were psychiatric medications(23.1%),sedatives(20.5%),insecticides(13.8%),and herbicides(12.8%).CONCLUSION:The clinical manifestations of acute poisoning in patients with an uncertain exposure history are diverse and nonspecific,and toxicological analysis plays a pivotal role in the diagnosis and differential diagnosis of such patients.

Guidelines for the standardized diagnosis and treatment of non-specific orbital inflammation(2024)

Non-specific orbital inflammation(NSOI)is a noninfectious orbital inflammation.Although it is often considered the most common diagnosis in orbital biopsies,it is an exclusionary diagnosis that requires ruling out systemic disease or other possible causes.Its characteristics include acute orbital signs and symptoms,including pain,proptosis,periorbital edema,chemosis,diplopia,and visual impairment.The clinical manifestations and histological findings of NSOI are heterogeneous,without specific diagnostic criteria or treatment guidelines,which poses significant challenges for diagnosis and treatment.This guideline provides a detailed description of the definition,classification,diagnosis,and treatment of NSOI.