Pelvic floor dysfunction after vaginal delivery: MOODS-a prospective study.

INTRODUCTION AND HYPOTHESIS: Labor is a known risk factor for pelvic floor dysfunction (PFD); however, the impact of operative vaginal delivery (OVD), particularly spatulas, remains unclear. The aim of this study was to compare postpartum PFD symptoms in women undergoing spontaneous vaginal delivery (SVD) and those undergoing OVD. METHODS: An observational prospective study (MOODS: Maternal-neonatal Outcomes in Operative Vaginal Delivery) was enrolled at Hospital de Braga from February to October 2018. All singleton term OVD (Thierry spatulas and vacuum extractor) and a convenience SVD sample were recruited, in a 2:1 ratio. To assess PFD symptoms Pelvic Floor Distress Inventory-20 (PFDI-20) was applied at 3, 6, and 12 months postpartum. The questionnaire is divided into three subscales: Urinary (UDI), Colorectal-Anal (CRADI), and Pelvic Organ Prolapse Distress Inventory (POPDI). RESULTS: Of the 304 women recruited, 207 were included, 34.3% with SVD and 65.7% with OVD. Thierry spatulas were used in 53.7% of women undergoing OVD. Frequency of nulliparous (p < 0.001), episiotomy (p < 0.001), neuraxial anesthesia (p < 0.001), postpartum pain (p = 0.001) and occiput-posterior fetal position (p < 0.001) were significantly higher in OVD. Second phase of labor duration was longer in OVD (p = 0.001). At 3 months postpartum, women undergoing OVD and spatula-assisted delivery had higher UDI score, POPDI score, and global score, with no differences at 6 months and 1 year. After controlling for confounding variables, OVD and spatulas were still associated with greater POPDI scores at 3 months postpartum. CONCLUSIONS: Operative vaginal delivery, particularly with spatulas, seems to be associated with a higher prevalence of early PFD symptoms, mainly regarding pelvic organ prolapse.

Colonic Kaposi's sarcoma as the first clinical manifestation of undiagnosed HIV.

A 52-year-old male, without significant past medical history, is referred for new onset constipation, hematochezia and significant weight loss. Blood tests were unremarkable. A colonoscopy was performed, showing reddish, hematocystic and friable mucosa in a circumferential pattern in the rectum, with similar patches throughout the whole colon, one of them infiltrating the ileocecal valve. Biopsies were obtained and revealed spindle cell proliferation immunoreactive for CD34 and herpesvirus 8 (HHV-8), compatible with Kaposi's sarcoma (KS). HIV serologies were subsequently done, with a positive result, the patient then reporting previous heterosexual unprotected sexual activities. He was started on highly active antiretroviral therapy (HAART) and chemotherapy with liposomal doxorubicin, with a favorable outcome to this date. KS is a low-grade tumor of the vascular endothelium that requires infection with HHV-8. HIV-related KS is more commonly diagnosed in homosexual males with uncontrolled HIV infection and is associated with a variable clinical course. The gastrointestinal tract is involved in up to 51% of patients, but since the majority is clinically silent (70%), visceral involvement is probably underestimated. The treatment goal is symptomatic relief, and may range from HAART alone to a combination with systemic chemotherapy, depending on disease extent. We present this case given its endoscopic exuberance, with biopsies showing an HIV-defining condition, in a patient unaware of his diagnosis.

The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells.

OBJECTIVE: Cancer stem cells (CSCs) represent the root of many solid cancers including pancreatic ductal adenocarcinoma, are highly chemoresistant and represent the cellular source for disease relapse. However the mechanisms involved in these processes still need to be fully elucidated. Understanding the mechanisms implicated in chemoresistance and metastasis of pancreatic cancer is critical to improving patient outcomes. DESIGN: Micro-RNA (miRNA) expression analyses were performed to identify functionally defining epigenetic signatures in pancreatic CSC-enriched sphere-derived cells and gemcitabine-resistant pancreatic CSCs. RESULTS: We found the miR-17-92 cluster to be downregulated in chemoresistant CSCs versus non-CSCs and demonstrate its crucial relevance for CSC biology. In particular, overexpression of miR-17-92 reduced CSC self-renewal capacity, in vivo tumourigenicity and chemoresistance by targeting multiple NODAL/ACTIVIN/TGF-ß1 signalling cascade members as well as directly inhibiting the downstream targets p21, p57 and TBX3. Overexpression of miR-17-92 translated into increased CSC proliferation and their eventual exhaustion via downregulation of p21 and p57. Finally, the translational impact of our findings could be confirmed in preclinical models for pancreatic cancer. CONCLUSIONS: Our findings therefore identify the miR-17-92 cluster as a functionally determining family of miRNAs in CSCs, and highlight the putative potential of developing modulators of this cluster to overcome drug resistance in pancreatic CSCs.

Nicotine promotes initiation and progression of KRAS-induced pancreatic cancer via Gata6-dependent dedifferentiation of acinar cells in mice.

BACKGROUND & AIMS: Although smoking is a leading risk factor for pancreatic ductal adenocarcinoma (PDAC), little is known about the mechanisms by which smoking promotes initiation or progression of PDAC. METHODS: We studied the effects of nicotine administration on pancreatic cancer development in Kras(+/LSLG12Vgeo);Elas-tTA/tetO-Cre (Ela-KRAS) mice, Kras(+/LSLG12D);Trp53+/LSLR172H;Pdx-1-Cre (KPC) mice (which express constitutively active forms of KRAS), and C57/B6 mice. Mice were given nicotine for up to 86 weeks to produce blood levels comparable with those of intermediate smokers. Pancreatic tissues were collected and analyzed by immunohistochemistry and reverse transcriptase polymerase chain reaction; cells were isolated and assayed for colony and sphere formation and gene expression. The effects of nicotine were also evaluated in primary pancreatic acinar cells isolated from wild-type, nAChR7a(-/-), Trp53(-/-), and Gata6(-/-);Trp53(-/-) mice. We also analyzed primary PDAC cells that overexpressed GATA6 from lentiviral expression vectors. RESULTS: Administration of nicotine accelerated transformation of pancreatic cells and tumor formation in Ela-KRAS and KPC mice. Nicotine induced dedifferentiation of acinar cells by activating AKT-ERK-MYC signaling; this led to inhibition of Gata6 promoter activity, loss of GATA6 protein, and subsequent loss of acinar differentiation and hyperactivation of oncogenic KRAS. Nicotine also promoted aggressiveness of established tumors as well as the epithelial-mesenchymal transition, increasing numbers of circulating cancer cells and their dissemination to the liver, compared with mice not exposed to nicotine. Nicotine induced pancreatic cells to acquire gene expression patterns and functional characteristics of cancer stem cells. These effects were markedly attenuated in K-Ras(+/LSL-G12D);Trp53(+/LSLR172H);Pdx-1-Cre mice given metformin. Metformin prevented nicotine-induced pancreatic carcinogenesis and tumor growth by up-regulating GATA6 and promoting differentiation toward an acinar cell program. CONCLUSIONS: In mice, nicotine promotes pancreatic carcinogenesis and tumor development via down-regulation of Gata6 to induce acinar cell dedifferentiation.

Thromboembolic risk in atrial fibrillation: association between left atrium mechanics and risk scores. A study based on 3D wall-motion tracking technology.

BACKGROUND/OBJECTIVES: Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with a significantly high risk of stroke and systemic embolism. The aim of our study was to assess the association between left atrium (LA) mechanics measured by 3D wall-motion tracking (3DWMT) technology and the most common thromboembolic risk scores (CHADS2, CHA2DS2-VASc). METHODS: A total of 101 consecutive patients with permanent AF referred were included. Conventional bidimensional (2D) LA parameters, and LA mechanics by means of 3DWMT were studied. Association between LA 2D and 3DWMT parameters and both risk scores was evaluated as well as its correlation with every component of the score individually. RESULTS: Mean age was 78 ± 10 years. Mean CHADS2 was 2.7 ± 1.3 and mean CHA2DS2-VASc was 4.4 ± 1.7. Values of 2D and 3DWTM LA parameters were: 2D area 26.4 ± 9.7 cm(2) , 2D volume index 49.4 ± 10.1 mL/m(2) , 3DWMT left atrial emptying fraction (LAEF) 15.9 ± 8.4%, longitudinal strain 9.1 ± 4.5% and area strain 14.9 ± 8.8%. Linear regression analysis showed statistically significant correlation between LA longitudinal strain and LAEF with CHADS2 and CHA2DS2-VASc scores. For each 10% variation in longitudinal strain, CHADS2 and CHA2DS2-VASc scores change in 0.7 and 0.8 points, respectively. CONCLUSIONS: Left atrial longitudinal strain and emptying fraction assessed by 3D WMT technology have correlation with both CHADS2 and CHA2DS2-VASc scores. Each 10% of variation in longitudinal strain represents a 0.7 and 0.8 points change in those risk scores. LA mechanics evaluation might provide additional value to risk scores and could be considered to be a predictor of stroke in patients with AF.

Early versus late cardiac magnetic resonance in the diagnosis of myocardial infarction with non-obstructive coronary arteries.

INTRODUCTION AND OBJECTIVES: Myocardial infarction with non-obstructive coronary arteries (MINOCA) is responsible for about 10% of all acute myocardial infarctions (AMI). Therapeutic strategies and prognosis depend on the underlying etiology, and a multimodal approach is essential. The objectives of this study were to characterize the group of patients diagnosed with MINOCA and to valuate the diagnostic yield of cardiovascular magnetic resonance (CMR). METHODS: This was a retrospective, observational, and analytical study, including 516 patients admitted for a non-ST-elevation MI and with no significant coronary disease on coronary angiography between January 2016 and September 2021. RESULTS: After the inclusion criteria, 163 patients remained of the 516 admitted to the study. They were divided into four groups based on the CMR results: MINOCA (n=51), Takotsubo syndrome (n=37), myocarditis (n=33), and without diagnosis (n=42). Most patients diagnosed with MINOCA were female with a mean age of 61.06±13.83 years. CMR identified the diagnosis in 74.2% of patients admitted for suspected acute MI, in which coronary angiography showed the absence of significant obstructions. The median time between hospital admission and CMR was significantly shorter in the groups that had a diagnosis compared with the group with no diagnosis (p=0.038), with a significant increase in diagnostic profitability if CMR was performed up to 14 days after admission (p=0.022). There were no deaths of cardiovascular etiology during the follow-up period. CONCLUSIONS: CMR was fundamental as it identified the diagnosis in three out of four patients; it should be performed in the first 14 days.

A simple and easy technique to overcome anatomic challenges of transradial access in STEMI patients.

BACKGROUND: Transradial access (TRA) is associated with fewer access-related complications, earlier discharge and lower mortality than transfemoral access (TFA), being the preferred route to perform primary percutaneous coronary interventions (PPCIs) in STEMI patients. However, the radial artery is smaller, more superficial and thinner than the femoral artery, which may make PPCIs difficult. PURPOSE: This study describes a practical solution to overcome several of the anatomical difficulties during the TRA, demonstrating its outcomes during clinical practice. METHODS: The authors reviewed the clinical records of 1510 STEMI patients who underwent PPCIs over seven years. Of these, 95 (6.3%) patients experienced problems in advancing a 6F guiding catheter and underwent to STR technique. This technique consists in the use of a longer 5Fr STR flush catheter, which can be used as a "child" type rapid exchange catheter inside the 6Fr guiding catheter, adopting a 5-in-6 Fr technique and creating a smooth distal tip transition of the 6Fr guiding catheter. RESULTS: In 89/95 patients (93.7%), this new technique was successful. The majority of these patients were female (51; 53.7%) and the mean age was 67 ± 14.3 years. The mean reperfusion time since arrival at the catheterization laboratory with STR technique was 24.5 ± 9.9 min, being statistically shorter than when a crossover to TFA was used (29.3 ± 9.5 min; p < 0.017). PPCIs were successfully completed in all different coronary arteries, without complications related to the procedure. CONCLUSIONS: The STR technique is a simple and useful approach that allowed more successful passage of guiding catheters through difficult TRA, allowing a reduction of crossover to TFA in this study to 2.4 %, which translates into a shorter reperfusion time.

Evidence of ongoing replication in a human immunodeficiency virus type 1 persistently infected cell line.

Human immunodeficiency virus type 1 (HIV-1) persistently infected cell lines are characterized by the continuous viral production without cytopathic effect. However, it is not completely clear if this production is contributed only by viral transcription or also by new cycles of viral replication. We studied an HIV-1 persistently infected cell line, designated H61-D, providing evidence of new replication cycles as sustained by: (i) a decrease in viral production, measured by p24 protein, after treatment of the culture with 3'-azydo-3'-deoxythymydine; (ii) detection of new integration events in the course of cell culture, and (iii) finding of two-long-terminal repeat circles in the cells. H61-D cells were not infected by cell-free virus, but infection was possible by co-culture with another productive-infected cell line. In conclusion, ongoing viral replication is taking place in H61-D persistent cells and new infections are mediated by a cell-to-cell spread mechanism.

A case of esophageal squamous cell carcinoma with positive HPV 11.

HPV (human pappiloma virus) infection is an etiologic risk factor for esophageal carcinoma with several studies supporting its carcinogenic role. The main strains are HPV16 and 18 and the less frequent strains 11, 6, 31 and 36. We report the case of a 58 year old male, smoker, admitted to our hospital for progressive dysphagia. Previous endoscopies and biopsies were compatible with a hyperkeratotic esophagus, negative for dysplasia. Second endoscopy showed a hyperkeratotic, verrucous, esophagus with two circumferential stenosis which were dilated with TTS (Through the Scope) balloon. Biopsies revealed multiple squamous cell abnormalities, negative for dysplasia and positive for HPV 11. Symptoms recurred, and he was submitted to another upper gastrointestinal endoscopy with dilation of the stenosis and esophageal stent placement. Two months later, esophagectomy was performed, and the histopathological analysis revealed a squamous cell carcinoma of the esophagus (T2, N0, M0, G1). The patient died after surgery due to acute respiratory distress syndrome.

Ischemic rupture of the anterolateral papillary muscle.

We describe the case of a 59-year-old man who presented with chest pain and ST-segment elevation in the inferior leads, R>S in V1 and ST depression in the anterior leads due to proximal occlusion of the first obtuse marginal. Primary coronary angioplasty and stenting of this artery were performed. Twelve hours later the patient became hemodynamically unstable and severe mitral regurgitation due to rupture of one of the heads of the anterolateral papillary muscle was diagnosed. Emergency surgery was performed (papillary muscle head reimplantation, mitral annuloplasty with a rigid ring, tricuspid annuloplasty and coronary artery bypass grafting). On surgical inspection, it was observed that the detached muscle head had become trapped in the left ventricle by a secondary cord attached to the other head. This case is unusual in presenting two uncommon features of ischemic papillary muscle: rupture of the anterolateral muscle in myocardial infarction involving the inferoposterior walls, and the fact that the ruptured muscle head did not prolapse because it had become trapped in the left ventricle by secondary cord attachment.

[A rare cause of pericardial disease]. / Causa rara de doença pericárdica.

Among cardiovascular diseases, pericardial disease has specific characteristics. Its etiology, diagnosis and medical management are not as well understood as in coronary and valvular heart disease. In most cases, its cause is benign, although the proportion decreases with more severe clinical presentation. The authors present the case of a 35-year-old man with no relevant past medical history, who went to the emergency department with what appeared to be an idiopathic case of acute pericarditis. However, over the following five months, there was an unfavorable evolution to constrictive pericarditis, requiring pericardiectomy. The final diagnosis was only made following surgery - a rare case of a primary pericardial tumor, a mesothelioma.

Stress Cardiomyopathy as a Complication of SARS-CoV-2 Infection.

The worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in early 2020 led to the coronavirus disease 2019 (COVID-19) pandemic. Acute lung diseases, such as COVID-19 pneumonia, can trigger stress cardiomyopathy, raising concerns about potential cardiovascular complications related to these diseases. The current case involved a 72-year-old man with SARS-CoV-2 infection who was experiencing dyspnea, desaturation, and oppressive retrosternal chest pain. On his admission to the hospital, an electrocardiogram demonstrated sinus tachycardia, negative T waves in leads V4-V6, and slight ST-segment elevation in the same precordial leads. The patient also had an increased troponin I value and worsening of his baseline respiratory failure, which required starting noninvasive ventilation. The echocardiogram showed moderately depressed left ventricular systolic function and apical ballooning. The echocardiographic changes resolved during hospitalization without directed therapeutic intervention. We diagnosed Takotsubo syndrome associated with SARS-CoV-2 infection; however, the pathophysiological disruption remains to be clarified.

Atrial cardiopathy in young adults with embolic stroke of undetermined source: a myocardial deformation imaging analysis.

BACKGROUND: Atrial cardiopathy (AC) has emerged as a potential pathological thrombogenic atrial substract of embolic stroke of undetermined source (ESUS), even in the absence of atrial fibrillation. Left atrium (LA) myocardial deformation analysis may be of value as a subclinical marker of AC and a predictor of ESUS. AIMS: To compare LA mechanical function between ESUS cases and age and sex-matched controls. METHODS: A single-center analytical study with case-control design was performed. Case group was composed by young patients admitted in the Neurology department from January 2017 to June 2021. Control group was composed by age and sex matched controls recruited from the community. All participants performed echocardiogram and a smaller sample underwent cardiac magnetic resonance. RESULTS: We recruited 31 ESUS patients aged between 18 and 65 years and 31 age and sex matched controls. ESUS patients had a significantly higher prevalence of cardiovascular risk factors and patent foramen ovale (PFO). The prevalence of AC was not different between groups. Echocardiogram parameters, including strain analysis, were similar between groups, except for LA appendage (LAA) ostium variation which was significantly lower in ESUS patients (absolute: 6.5vs8.7mm, p<0.001; relative: 44.5%vs53.4%, p=0.002). After exclusion of patients with PFO, all the results were statistically similar. Regarding cardiac magnetic resonance analysis, there were no statistically significant differences between groups. CONCLUSION: This study shows that in our population atria cardiopathy and atrial function was not associated with ESUS.LAA structural and functional abnormalities may play a major role. The role of LAA in ESUS warrants further studies.

Syncope in the athlete - Minor changes, major diagnosis!

We report the case of a 17-year-old athlete who resorted to the emergency department for palpitations and dizziness while exercising. He mentioned two exercise-associated episodes of syncope in the last six months. He was tachycardic and hypotensive. The electrocardiogram showed regular wide complex tachycardia, left bundle branch block morphology with superior axis restored to sinus rhythm after electrical cardioversion. In sinus rhythm, it showed T-wave inversion in V1-V5. Transthoracic echocardiography revealed mild dilation and dysfunction of the right ventricle (RV) with global hypocontractility. Cardiac magnetic resonance (CMR) revealed a RV end diastolic volume indexed to body surface area of 180 ml/m2, global hypokinesia and RV dyssynchrony, subepicardial late enhancement in the distal septum and in the middle segment of the inferoseptal wall. The patient underwent a genetic study which showed a mutation in the gene that encodes the desmocolin-2 protein (DSC-2), which is involved in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC). According to the modified Task Force Criteria for this diagnosis, the patient presented four major criteria for ARVC. Thus, a subcutaneous cardioverter was implanted, and the patient was followed up at the cardiology department. Arrhythmogenic right ventricular cardiomyopathy diagnosis is based on structural, functional, electrophysiological and genetic criteria reflecting underlying histological changes. This case depicts the essential characteristics for disease recognition.

A case of esophageal complication in epidermolysis bulhosa simplex.

UNLABELLED: It is well known the involvement of the gastrointestinal tract in Epidermolysis Bulhosa (EB) and its consequences on both nutrition and growth. We present a case of a young girl with EB diagnosed soon after birth, admitted to our emergency room with food impactation. The endoscopy revealed a double barrel esophagus. No medical or surgical therapy was started and after 2 months of enteric feeding, spontaneous resolution was observed at endoscopy. Skin biopsy was compatible with EB Simplex. According to the literature EB Simplex is the subtype the least associated with GI tract involvement, presenting with dysphagia in only 2% of the patients, and with the lowest cumulative risk of esophageal stricturing. CONCLUSION: We present an unusual case of EB simplex involvement of the esophagus with spontaneous resolution of a false lumen, with clinical improvement of the patient.

Infective endocarditis: Epidemiology and prognosis.

INTRODUCTION: Infective endocarditis (IE) is associated with high morbidity and mortality, despite advances in diagnosis and treatment. OBJECTIVE: To assess changes in the epidemiological profile of IE, to perform a time-trend analysis and to define short-term and long-term prognostic predictors of IE. METHODS: Retrospective analysis of 173 patients admitted with a diagnosis of IE to a Portuguese level II Hospital between January 1998 and December 2013. The patients were divided into two groups according to the period of occurrence of the IE episode (1998-2007 vs. 2008-2013). The clinical event studied was the occurrence of death or the need for urgent surgery during hospitalization, and death in the follow-up period. Independent predictors of short-term and long-term prognosis were identified. RESULTS: In the first portion of the study, IE occurred in younger individuals, often drug addicts, users of intravenous drugs and with gastrointestinal disease, human immunodeficiency virus and hepatitis B infection. In the second portion of the study, IE occurred more frequently in individuals of an older age with concomitant cardiovascular disease; enterococcus was isolated more frequently. The independent predictors of in-hospital death or need for urgent valve surgery were septic shock and the occurrence of peri-annular complications. The independent predictors of long-term mortality were age, chronic kidney disease and IE due to multidrug-resistant microorganisms. CONCLUSION: Differences were found in the epidemiological profile of IE during the study period. Referral for valve surgery increased slightly, but mortality remained high.

Consensus document on chronic coronary syndrome assessment and risk stratification in Portugal: A position paper statement from the [Portuguese Society of Cardiology's] Working Groups on Nuclear Cardiology, Magnetic Resonance and Cardiac Computed Tomography, Echocardiography, and Exercise Physiology and Cardiac Rehabilitation. / Documento de Consenso sobre Estratificação de Risco Cardiovascular e estudo da doença coronária em Portugal: a posição dos Grupos de Estudo de Cardiologia Nuclear, Ressonância Magnética e Tomografia Computorizada Cardíaca, de Ecocardiografia e de Fisiopatologia do Esforço e Reabilitação Cardíaca.

Despite constant medical evolution, the reimbursement policy of Portuguese National Health Service (NHS) for the study and risk stratification of coronary heart disease has remained unchanged for several decades. Lack of adjustment to contemporary clinical practice has long been evident. However, the recent publication of the European Guidelines for diagnosis and treatment of chronic coronary syndromes further highlighted this gap and the urgent need for a change. Prompted by these Guidelines, the Working Group on Nuclear Cardiology, Cardiac Magnetic Resonance and Cardiac CT, the Working Group on Echocardiography and the Working Group on Stress Pathophysiology and Cardiac Rehabilitation of the Portuguese Society of Cardiology, began a process of joint reflection on the current limitations and how these recommendations could be applied in Portugal. To this end, the authors suggest that the new imaging methods (stress echocardiogram, cardiac computed tomography and cardiac magnetic resonance), should be added to exercise treadmill stress test and myocardial perfusion scintigraphy in the available exam portfolio within the Portuguese NHS. This change would allow full adoption of European guidelines and a better use of tests, according to clinical context, availability and local specificities. The adoption of clinical guidance standards, based on these assumptions, would translate into a qualitative improvement in the management of these patients and would promote an effective use of the available resources, with potential health and financial gains.

Primary Cardiac Angiosarcoma: A Rare and Fatal Diagnosis.

Primary cardiac angiosarcoma is a rare malignant neoplasm and occurs most frequently in middle-aged males. It has an aggressive nature, with highly variable clinical features, which results in delayed diagnosis and high mortality. We report a 19-year-old man presented to the ED with a three-month history of hemoptysis and one-week history of anterior chest pain. Additionally, an aortic diastolic murmur grade II/VI was found on physical examination. Thoracic CT scan revealed bilateral dispersed hypodense pulmonary nodes with peripheral halo, alveolar densification, and pericardial effusion. The transthoracic echocardiogram confirmed sizeable pericardial effusion and bicuspid aortic valve, without other significant findings. A pericardiocentesis removed 1300 mL of hemorrhagic fluid, consistent with an exudate without malignant cells. Both cardiac magnetic resonance and transesophageal echocardiogram revealed a large mass on the right atrium's anterior wall. Mass biopsy was performed, revealing malignant cardiac angiosarcoma. The biopsy of the lung lesions was compatible with lung metastasis of primary cardiac angiosarcoma. The patient was submitted to palliative chemotherapy but died 12 months after the diagnosis.