Prognosis of unexpected positive intraoperative cultures in arthroplasty revision: A large multicenter cohort.

BACKGROUND: The positive-intraoperative-cultures-type prosthetic joint infection (PIOC-PJI) is considered when surgical cultures yield microorganisms in presumed aseptic arthroplasty revisions. Herein we assess the risk factors for failure in the largest cohort of PIOC-PJI patients reported to date. METHODS: A retrospective, observational, multicenter study was performed during 2007-2017. Surgeries leading to diagnose PIOC-PJI included only one-stage procedures with either complete or partial prosthesis revision. Failure was defined as recurrence caused by the same microorganism. RESULTS: 203 cases were included (age 72 years, 52% females). Coagulase-negative staphylococci (n = 125, 62%) was the main etiology, but some episodes were caused by virulent bacteria (n = 51, 25%). Prosthesis complete and partial revision was performed in 93 (46%) and 110 (54%) cases, respectively. After a median of 3.4 years, failure occurred in 17 episodes (8.4%, 95%CI 5.3-13.1). Partial revision was an independent predictor of failure (HR 3.63; 95%CI 1.03-12.8), adjusted for gram-negative bacilli (GNB) infection (HR 2.68; 95%CI 0.91-7.89) and chronic renal impairment (HR 2.40; 95%CI 0.90-6.44). Treatment with biofilm-active antibiotics (rifampin/fluoroquinolones) had a favorable impact on infections caused by staphylococci and GNB. CONCLUSION: Overall prognosis of PIOC-PJI is good, but close follow-up is required in cases of partial revision and in infections caused by GNB.

How to Handle Concomitant Asymptomatic Prosthetic Joints During an Episode of Hematogenous Periprosthetic Joint Infection, a Multicenter Analysis.

BACKGROUND: Prosthetic joints are at risk of becoming infected during an episode of bacteremia, especially during Staphylocococcus aureus bacteremia. However, it is unclear how often asymptomatic periprosthetic joint infection (PJI) occurs, and whether additional diagnostics should be considered. METHODS: In this multicenter study, we retrospectively analyzed a cohort of patients with a late acute (hematogenous) PJI between 2005-2015 who had concomitant prosthetic joints in situ. Patients without at least 1 year of follow-up were excluded. RESULTS: We included 91 patients with a hematogenous PJI and 108 concomitant prosthetic joints. The incident PJI was most frequently caused by Staphylococcus aureus (43%), followed by streptococci (26%) and Gram-negative rods (18%). Of 108 concomitant prosthetic joints, 13 were symptomatic, of which 10 were subsequently diagnosed as a second PJI. Of the 95 asymptomatic prosthetic joints, 1 PJI developed during the follow-up period and was classified as a "missed" PJI at the time of bacteremia with S. aureus (1.1%). Infected prosthetic joints were younger than the noninfected ones in 67% of cases, and prosthetic knees were affected more often than prosthetic hips (78%). CONCLUSIONS: During an episode of hematogenous PJI, concomitant asymptomatic prosthetic joints have a very low risk of being infected, and additional diagnostic work-up for these joints is not necessary.

Genotypic and Phenotypic Characteristics of Staphylococcus aureus Prosthetic Joint Infections: Insight on the Pathogenesis and Prognosis of a Multicenter Prospective Cohort.

BACKGROUND: Staphylococcus aureus is the leading cause of prosthetic joint infection (PJI). Beyond the antibiogram, little attention has been paid to the influence of deep microbiological characteristics on patient prognosis. Our aim was to investigate whether microbiological genotypic and phenotypic features have a significant influence on infection pathogenesis and patient outcome. METHODS: A prospective multicenter study was performed, including all S. aureus PJIs (2016-2017). Clinical data and phenotypic (agr functionality, ß-hemolysis, biofilm formation) and genotypic characteristics of the strains were collected. Biofilm susceptibility to antimicrobials was investigated (minimal biofilm eradication concentration [MBEC] assay). RESULTS: Eighty-eight patients (39.8% men, age 74.7 ±â€…14.1 years) were included. Forty-five had early postoperative infections (EPIs), 21 had chronic infections (CPIs), and 19 had hematogenous infections (HIs). Twenty (22.7%) were caused by methicillin-resistant S. aureus. High genotypic diversity was observed, including 16 clonal complexes (CCs), with CC5 being the most frequent (30.7%). agr activity was greater in EPI than CPI (55.6% vs 28.6%; P = .041). Strains causing EPI were phenotypically and genotypically similar, regardless of symptom duration. Treatment failure (36.5%) occurred less frequently among cases treated with implant removal. In cases treated with debridement and implant retention, there were fewer failures among those who received combination therapy with rifampin. No genotypic or phenotypic characteristics predicted failure, except vancomycin minimal inhibitory concentration ≥1.5 mg/L (23.1% failure vs 3.4%; P = .044). MBEC50 was >128 mg/L for all antibiotics tested and showed no association with prognosis. CONCLUSIONS: S. aureus with different genotypic backgrounds is capable of causing PJI, showing slight differences in clinical presentation and pathogenesis. No major microbiological characteristics were observed to influence the outcome, including MBEC.

Diagnostic accuracy of portable chest radiograph in mechanically ventilated patients when compared with autopsy findings.

PURPOSE: Evaluate diagnostic accuracy of portable chest radiograph in mechanically ventilated patients taking autopsy findings as the gold standard and the interobserver agreement among intensivists and radiologists. MATERIALS AND METHODS: Retrospective study of 422 patients over 22 years who died in the ICU, underwent an autopsy, and had at least one portable chest radiograph 72 h prior to death. Two intensivists and two radiologists independently read each chest radiograph. Sensitivity, specificity, positive and negative likelihood ratios were evaluated. Overall performance metrics accuracy between intensivists and radiologists were compared using a generalized estimating equation. Cohen's kappa coefficient was used to evaluate the interobserver agreement with the following values: <0.20:poor, 0.21-0.40:fair, 0.41-0.60:moderate, 0.61-0.80:good, 0.81-1.00:excellent. RESULTS: Overall sensitivity and specificity for pneumonia was 24% and 91% respectively. Overall sensitivity and specificity for ARDS was 68% and 74% respectively. Sensitivity for pneumonia was higher among radiologists (p < 0,05). Specificity for ADRS was higher among radiologists (p < 0,05). Good interobserver agreement among radiologists and poor correlation between intensivists was found. CONCLUSIONS: Chest radiographs has a moderate specificity for ARDS and a high specificity for pneumonia, with limited sensitivity in both entities. Interobserver agreement of portable chest radiograph in the mechanically ventilated patients is higher between radiologists than intensivists.

Lower Success Rate of Débridement and Implant Retention in Late Acute versus Early Acute Periprosthetic Joint Infection Caused by Staphylococcus spp. Results from a Matched Cohort Study.

BACKGROUND: Surgical débridement, antibiotics and implant retention (DAIR) is currently recommended by international guidelines for both early acute (postsurgical) and late acute (hematogenous) periprosthetic joint infections (PJIs). However, due to a different pathogenesis of infection, a different treatment strategy may be needed. QUESTIONS/PURPOSES: (1) Compared with early acute PJIs, are late acute PJIs associated with a higher risk of DAIR failure? (2) When stratified by microorganism, is the higher risk of failure in late acute PJI associated with Staphylocococcus aureus infection? (3) When analyzing patients with S. aureus infection, what factors are independently associated with DAIR failure? METHODS: In this multicenter observational study, early acute and late acute PJIs treated with DAIR were retrospectively evaluated and matched according to treating center, year of diagnosis, and infection-causing microorganism. If multiple matches were available, the early acute PJI diagnosed closest to the late acute PJI was selected. A total of 132 pairs were included. Treatment success was defined as a retained implant during follow-up without the need for antibiotic suppressive therapy. RESULTS: Late acute PJIs had a lower treatment success (46% [60 of 132]) compared with early acute PJIs (76% [100 of 132]), OR 3.9 [95% CI 2.3 to 6.6]; p < 0.001), but the lower treatment success of late acute PJIs was only observed when caused by Staphylococcus spp (S. aureus: 34% versus 75%; p < 0.001; coagulase-negative staphylococci: 46% versus 88%; p = 0.013, respectively). On multivariable analysis, late acute PJI was the only independent factor associated with an unsuccessful DAIR when caused by S. aureus (OR 4.52 [95% CI 1.79 to 11.41]; p < 0.001). CONCLUSIONS: Although DAIR seems to be a successful therapeutic strategy in the management of early acute PJI, its use in late acute PJI should be reconsidered when caused by Staphylococcus spp. Our results advocate the importance of isolating the causative microorganism before surgery. LEVEL OF EVIDENCE: Level III, therapeutic study.

The utility of multiparametric flow cytometry in the detection of primary effusion lymphoma (PEL).

Primary effusion lymphoma (PEL) is a rare B cell lymphoproliferative disorder that arises predominantly in body cavities causing malignant effusions. The incidence of PEL is very low, accounting for approximately 4% of all HIV-associated non-Hodgkin lymphomas. PEL has also been described in elderly patients and after solid-organ transplantation. It is associated in all cases with human herpes virus 8 (HHV8). We describe a case of PEL in a 88-year-old HIV-negative woman who presented with progressive dyspnea and moderate right-sided pleural effusion without significant lymphadenopathies or other effusions. The cytological study of the pleural fluid revealed a dense proliferation of large plasmablastic cells. A six-color multiparametric flow cytometry immunophenotyping study was carried out, and revealed 45% of large in size and high cellular complexity cells positive for CD45 (dim), CD38, CD138, CD30 and HLA-DR; and negative for CD19, CD20, cytoplasmatic CD79a, surface and cytoplasmic light chains Kappa and Lambda, CD3, CD4, CD5, CD7, CD8, CD28, CD56, CD81, and CD117. In situ hybridization for EBV-encoded smalI RNA was negative and immunohistochemistry for Kaposi sarcoma herpesvirus (HHV8) confirmed the diagnosis of PEL. Our results confirm that flow cytometry bring useful data in the diagnosis of large-cell lymphomas involving body cavities. © 2018 International Clinical Cytometry Society.

Clinical outcome and risk factors for failure in late acute prosthetic joint infections treated with debridement and implant retention.

OBJECTIVES: Debridement, antibiotics and implant retention (DAIR) is the recommended treatment for all acute prosthetic joint infections (PJI), but its efficacy in patients with late acute (LA) PJI is not well described. METHODS: Patients diagnosed with LA PJI between 2005 and 2015 were retrospectively evaluated. LA PJI was defined as the development of acute symptoms (≤ 3 weeks) occurring ≥ 3 months after arthroplasty. Failure was defined as: (i) the need for implant removal, (ii) infection related death, (iii) the need for suppressive antibiotic therapy and/or (iv) relapse or reinfection during follow-up. RESULTS: 340 patients from 27 centers were included. The overall failure rate was 45.0% (153/340). Failure was dominated by Staphylococcus aureus PJI (54.7%, 76/139). Significant independent preoperative risk factors for failure according to the multivariate analysis were: fracture as indication for the prosthesis (odds ratio (OR) 5.4), rheumatoid arthritis (OR 5.1), age above 80 years (OR 2.6), male gender (OR 2.0) and C-reactive protein > 150 mg/L (OR 2.0). Exchanging the mobile components during DAIR was the strongest predictor for treatment success (OR 0.35). CONCLUSION: LA PJIs have a high failure rate. Treatment strategies should be individualized according to patients' age, comorbidity, clinical presentation and microorganism causing the infection.

Autopsy-detected diagnostic errors over time in the intensive care unit.

We evaluate the evolution over time of discrepancies between clinical diagnoses and postmortem findings in critically ill patients and assess the factors associated with these discrepancies. We conducted a prospective study of all consecutive patients who underwent autopsy in a medical-surgical intensive care unit (ICU) between January 2008 and December 2015. Among 7655 patients admitted to our ICU, 671 (8.8%) died. Clinical autopsy was performed in 215 (32%) patients. Major missed diagnoses were noted in 38 patients (17.7%). Eighteen patients (8.4%) had class I discrepancies, and 20 patients (9.3%) had class II discrepancies. The most frequently missed diagnoses were invasive aspergillosis, intestinal ischemia, myocardial infarction, cancer, and intra-abdominal abscesses. We did not find a statistically significant correlation between any premortem factor, including age, sex, severity of illness, length of hospital stay before ICU admission, length of ICU stay before death, duration of mechanical ventilation, or admitting unit, and the level of agreement between clinical and pathological diagnosis. In the last decades, the discrepancies between clinical and autopsy diagnoses persisted despite advances in medical skills and technology. Specific clinical entities such as invasive aspergillosis, mesenteric ischemia, myocardial infarction, intra-abdominal abscesses, and neoplastic diseases remain a diagnostic challenge in critically ill patients. Clinical level of diagnostic certainty does not increase with specific premortem characteristics.

Cervical cancer screening cotesting with cytology and MRNA HPV E6/E7 yields high rates of CIN2+ lesions in young women.

BACKGROUND: European guidelines recommend primary HPV testing for cervical cancer screening. However, the starting age remains to be defined, with an undecided window between 30 and 35 years. This pilot study compares the effectiveness of primary HPV testing to that of cytology for the detection of high-grade (CIN2+) lesions stratified by age. METHODS: Cotesting with LBC cytology and APTIMA® HPV (AHPV) was performed in 5053 women aged 25-65 in an opportunistic screening program in Madrid. AHPV-positive cases were referred to colposcopy and genotyped for HPV16 and 18/45 (AHPV-GT). Results were analyzed stratified in four age groups. RESULTS: 454 cases (9.0%) were AHPV-positive. Women under 35 had a 30.2% CIN2+ rate, compared to 21.9% and 20.4% for women aged 35-44 or 45-54. There was a significant increase (P < .05) in the rate of CIN2+ in AHPV-GT-positive women when compared to that for other HPV types (AHPV-other), being 43.3% versus 15.7%. AHPV-GT-positive women under 35 had significantly higher rates of CIN2+ lesions than any other age-group. The sensitivity of cytology for cervical CIN2+ in APHV-positive women was 60.6%. All 4 carcinomas, including one AHPV-negative endometrial adenocarcinoma, had abnormal cytology. All cervical CIN2+ lesions biopsied were AHPV-positive. CONCLUSIONS: Aptima HPV shows a significantly higher sensitivity for cervical CIN2+ lesions than cytology alone. Unexpectedly, AHPV-positive women under 35 had the highest incidence of CIN2+ lesions, particularly when they are HPV16/18/45-positive. Reconsidering HPV primary screening before the recommended age of 35 is warranted.

The Not-So-Good Prognosis of Streptococcal Periprosthetic Joint Infection Managed by Implant Retention: The Results of a Large Multicenter Study.

BACKGROUND.: Streptococci are not an infrequent cause of periprosthetic joint infection (PJI). Management by debridement, antibiotics, and implant retention (DAIR) is thought to produce a good prognosis, but little is known about the real likelihood of success. METHODS.: A retrospective, observational, multicenter, international study was performed during 2003-2012. Eligible patients had a streptococcal PJI that was managed with DAIR. The primary endpoint was failure, defined as death related to infection, relapse/persistence of infection, or the need for salvage therapy. RESULTS.: Overall, 462 cases were included (median age 72 years, 50% men). The most frequent species was Streptococcus agalactiae (34%), and 52% of all cases were hematogenous. Antibiotic treatment was primarily using ß-lactams, and 37% of patients received rifampin. Outcomes were evaluable in 444 patients: failure occurred in 187 (42.1%; 95% confidence interval, 37.5%-46.7%) after a median of 62 days from debridement; patients without failure were followed up for a median of 802 days. Independent predictors (hazard ratios) of failure were rheumatoid arthritis (2.36), late post-surgical infection (2.20), and bacteremia (1.69). Independent predictors of success were exchange of removable components (0.60), early use of rifampin (0.98 per day of treatment within the first 30 days), and long treatments (≥21 days) with ß-lactams, either as monotherapy (0.48) or in combination with rifampin (0.34). CONCLUSIONS.: This is the largest series to our knowledge of streptococcal PJI managed by DAIR, showing a worse prognosis than previously reported. The beneficial effects of exchanging the removable components and of ß-lactams are confirmed and maybe also a potential benefit from adding rifampin.

Metástasis hepáticas secundarias a cáncer adenoide quístico de mama: una evolución poco frecuente / Hepatic metastasis due to adenoid cystic breast cancer: an uncommon progression

No disponible

Skin spread from an intracranial glioblastoma: case report and review of the literature.

Extracranial metastases secondary to intracranial neoplasm are extremely rare. The incidence of extraneural metastases of brain tumours is estimated to be less than 0.4%. The authors report a case of postoperative intracranial glioblastoma spreading to the skin in an adult patient. In this case, the radiological images and surgical findings suggest that the potential dissemination mechanism is as a result of infiltration through the surgical wound site. The primary tumour-upon coming into contact with the dura and the skin-mimicked the characteristics of both tissues. This case supports the theory of risk of spread through the durotomy site, although this phenomenon is extremely rare. Both the specific pathogenic mechanisms as well as the ideal and effective management have not been established yet and require further investigation.

Accuracy of clinical definitions of ventilator-associated pneumonia: comparison with autopsy findings.

METHODS: We studied patients requiring mechanical ventilation for more than 48 hours who died in the intensive care unit and whose bodies were autopsied. We evaluated 3 clinical definitions of ventilator-associated pneumonia: loose definition, defined as chest radiograph infiltrates and 2 of 3 clinical criteria (leukocytosis, fever, purulent respiratory secretions); rigorous definition, defined as chest radiograph infiltrates and all of the clinical criteria; and a clinical pulmonary infection score higher than 6 points. Sensitivity, specificity, and likelihood ratios were calculated by using pathology pattern as criterion standard. RESULTS: One hundred forty-two (56%) of the 253 patients included had histological criteria of pneumonia. Patients who met the clinical criteria of ventilator-associated pneumonia were 163 (64%) for the loose definition, 32 (13%) for the rigorous definition, and 109 (43%) for the clinical pulmonary infection score. The operative indexes (sensitivity and specificity) of each definition were as follows: loose definition, 64.8% and 36%; rigorous definition, 91% and 15.5%; and clinical pulmonary infection score higher than 6, 45.8% and 60.4%. The addition of microbiological data to the clinical definitions increased the specificity and decreased the sensitivity but not significantly. CONCLUSIONS: Accuracy of 3 commonly used clinical definitions of ventilator-associated pneumonia was poor taking the autopsy findings as reference standard.

[Obstructive jaundice caused by duodenal amyloidosis succesfully treated with surgery]. / Ictericia obstructiva. Inicio clínico de una amiloidosis duodenal tratada quirúrgicamente.

We present a case of obstructive jaundice due to duodenal amyloidosis presenting as a bulbar pseudotumor (amyloidoma). The duodenal and biliary obstruction were treated by double bypass, hepatojejunostomy and gastroenterostomy. Our case suggests that surgical palliative treatment may be effective, and that anastomosis is probably safe, allowing the patient a good quality of life.

Ictericia obstructiva. Inicio clínico de una amiloidosis duodenal tratada quirúrgicamente / Obstructive jaundice caused by duodenal amyloidosis succesfully treated with surgery

Presentamos un caso clínico de amiloidosis duodenal que se inició como seudotumor (amiloidoma) de localización bulbar, produciendo ictericia obstructiva. Su tratamiento fue quirúrgico, mediante doble derivación biliodigestiva. Esta técnica fue segura y permitió la paliación de la enfermedad con buena calidad de vida

We present a case of obstructive jaundice due to duodenal amyloidosis presenting as a bulbar pseudotumor (amyloidoma). The duodenal and biliary obstruction were treated by double bypass, hepatojejunostomy and gastroenterostomy. Our case suggests that surgical palliative treatment may be effective, and that anastomosis is probably safe, allowing the patient a good quality of life

[Intestinal linitis plastica: late metastasis from gastric signet ring cell adenocarcinoma]. / Linitis plástica intestinal: metástasis tardía de adenocarcinoma gástrico en anillo de sello.

Linitis plastica is a malignant disease that usually occurs in the stomach, although it can affect any segment of the alimentary tract. Typically, this entity shows slow progression and insidious clinical course. We present the case of a patient with a previous diagnosis of signet ring cell cancer of the stomach that had been treated with curative intent 12 years before the clinical onset of small and large bowel linitis plastica. The diagnosis was obtained as an incidental pathological finding after urgent surgery for intestinal obstruction. No gastric mass was found. Linitis plastica should be considered in the differential diagnosis of patients with symptoms of obstruction after resection of a gastric carcinoma, especially if there are macroscopic surgical findings of circumferential narrowing. A long interval after diagnosis and treatment of the primary disease does not allow malignancy to be ruled out.

Linitis plástica intestinal: metástasis tardía de adenocarcinoma gástrico en anillo de sello / Intestinal linitis plastica: late metastasis from gastric signet ring cell adenocarcinoma

La linitis plástica es una entidad maligna típica de tumores gástricos, aunque puede afectar a cualquier segmento del tubo digestivo. Característicamente presenta progresión lenta y clínica insidiosa. Se presenta el caso de un paciente con antecedente de adenocarcinoma gástrico con células en anillo de sello, diagnosticado y tratado con intención curativa 12 años antes del inicio clínico de una linitis plástica de intestino delgado e intestino grueso. El diagnóstico fue obtenido como hallazgo anatomopatológico casual tras cirugía urgente de obstrucción intestinal. No se encontró masa gástrica. La linitis plástica debe ser tenida en cuenta entre los diagnósticos diferenciales, en pacientes intervenidos previamente de neoplasias malignas de estómago que presentan cuadros obstructivos, sobre todo ante hallazgos operatorios macroscópicos de estenosis circunferencial. El largo tiempo de evolución transcurrido desde el diagnóstico y el tratamiento de la enfermedad primaria no permite descartar la naturaleza maligna de la lesión (AU)

Linitis plastica is a malignant disease that usually occurs in the stomach, although it can affect any segment of the alimentary tract. Typically, this entity shows slow progression and insidious clinical course. We present the case of a patient with a previous diagnosis of signet ring cell cancer of the stomach that had been treated with curative intent 12 years before the clinical onset of small and large bowel linitis plastica. The diagnosis was obtained as an incidental pathological finding after urgent surgery for intestinal obstruction. No gastric mass was found. Linitis plastica should be considered in the differential diagnosis of patients with symptoms of obstruction after resection of a gastric carcinoma, especially if there are macroscopic surgical findings of circumferential narrowing. A long interval after diagnosis and treatment of the primary disease does not allow malignancy to be ruled out (AU)

Hallazgos citomorfológicos del mesotelioma papilar bien diferenciado. A propósito de un caso y revisión de la literatura / Cytopatology findings of well-differentiated papillary mesothelioma. A case report and review

El mesotelioma papilar bien diferenciado es una variantede mesotelioma de bajo potencial maligno, que ocurrepredominantemente en el peritoneo de mujeres jóvenes, sinhistoria de exposición a asbestos, siendo un hallazgo casualen laparotomías por otros motivos. La ausencia de manifestacionesclínicas explica la escasez de publicaciones quehagan referencia a los hallazgos citológicos.Es importante conocer esta entidad a fin de diferenciarladel mesotelioma maligno agresivo y no confundirla conun proceso reactivo mesotelial.Presentamos el caso de un varón con ascitis persistentey múltiples nódulos peritoneales, haciendo hincapié en loshallazgos citomorfológicos, y en los problemas de diagnósticodiferencial

Well-Differentiated Papillary Mesothelioma (WDPM)is a low-grade distinct subtype of malignant mesothelioma,predominantly affecting the peritoneum of young women,with no history of asbestos exposure and which is foundincidentally in laparatomies for other indications. There arefew cytological references in the literature as clinical featuresare considered unimportant.It’s important to differentiate WDPM from malignantmesothelioma and not to be confused with mesothelial reaction.A case report of a man with persistent ascitis andmany peritoneal nodules is presented with special attentionto cytological findings and the differential diagnosisproblems

Fine-needle aspiration cytology of chondroblastoma of soft parts: case report and differential diagnosis with other soft tissue tumors.

Chondroblastoma is a benign tumor arising in the epiphysis of long bones. The extraskeletal presentation is most unusual. We report the first cytological description of a soft tissue chondroblastoma. It was a subcutaneous mass in the leg of a 62-yr-old man. Fine-needle aspiration (FNA) rendered a highly cellular material with grouped and single polygonal or round cells with a uniform, sometimes eccentric nucleus. Microvacuolated cytoplasm and hemosiderin pigment were frequent findings. There were rare nuclear grooves and mitoses. A metachromatic, focally calcified stroma was present, occasionally surrounding the cells. There were also numerous multinucleated osteoclast-like giant cells. Histological evaluation was diagnostic of chondroblastoma. The tumor was locally aggressive. A review of other soft tissue masses with similar cytological findings is included in the discussion. FNA cytology is very helpful in the diagnosis of soft tissue chondroblastoma, but additional studies may be necessary for a definitive diagnosis.