The use of colposcopy for triage in HPV-positive women aged 65 years and older.

PURPOSE: Persistent high-risk HPV infection is associated with an elevated risk for prevalent CIN II + despite normal cytology (NILM). Our study aims to evaluate the clinical relevance of a persistent high-risk HPV infection without cytologic changes in women aged ≥ 65 and to determine the role of colposcopy for triage in these cases. METHODS: 211 patients aged ≥ 65 with persistent HPV infection and normal cytology (NILM) who presented for colposcopy at five certified centers between January 2021 and April 2022 were included in the study. Colposcopic findings, HPV subtypes, when available, histology and p16/Ki67 staining were assessed as well as individual risk factors such as smoking and previous HPV-related surgery. RESULTS: 87.7% (185/211) of the included women had a type 3 transformation zone. In 83.4% (176/211), a biopsy was taken [thereof 163 endocervical curettages (ECC)]. In 35/211 women (16.6%), sampling was not possible during colposcopy due to an inaccessible cervix, pain during examination or obliteration of the cervical canal. Out of these, 6 women received a diagnostic excision. CIN II + was detected in 10.6% of all histologies (excisional or biopsy) (20/182). 50% of the women with a CIN II + where HPV 16 positive. Taking only the women diagnosed with CIN III or AIS into account, (n = 12) 75% were HPV 16 positive. Interestingly, 80% of the women with CIN II + had an abnormal cytology when repeatedly taken during colposcopy, vice versa an endocervical lesion was diagnosed in 53% of women with abnormal repeat cytology (27/51). CONCLUSION: The prevalence of CIN II + in women is ≥ 65 with persistent hr HPV infection but NILM cytology is similar to that in younger women. However, more than 85% of the women have a type 3 transformation zone. Colposcopy is, therefore, not helpful to diagnose the women who need treatment in this age group.

Pelvic lymphadenectomy in vulvar cancer and its impact on prognosis and outcome.

BACKGROUND: The value of pelvic lymphadenectomy (LAE) has been subject of discussions since the 1980s. This is mainly due to the fact that the relation between lymph node involvement of the groin and pelvis is poorly understood and therewith the need for pelvic treatment in general. PATIENTS AND METHODS: N = 514 patients with primary vulvar squamous cell cancer (VSCC) FIGO stage ≥ IB were treated at the University Medical Center Hamburg-Eppendorf between 1996 and 2018. In this analysis, patients with pelvic LAE (n = 21) were analyzed with regard to prognosis and the relation of groin and pelvic lymph node involvement. RESULTS: The majority had T1b/T2 tumors (n = 15, 78.9%) with a median diameter of 40 mm (11-110 mm). 17/21 patients showed positive inguinal nodes. Pelvic nodal involvement without groin metastases was not observed. 6/17 node-positive patients with positive groin nodes also had pelvic nodal metastases (35.3%; median number of affected pelvic nodes 2.5 (1-8)). These 6 patients were highly node positive with median 4.5 (2-9) affected groin nodes. With regard to the metastatic spread between groins and pelvis, no contralateral spread was observed. Five recurrences were observed after a median follow-up of 33.5 months. No pelvic recurrences were observed in the pelvic nodal positive group. Patients with pelvic metastasis at first diagnosis had a median progression-free survival of only 9.9 months and overall-survival of 31.1 months. CONCLUSION: A relevant risk for pelvic nodal involvement only seems to be present in highly node-positive disease, therefore pelvic staging (and radiotherapy) is probably unnecessary in the majority of patients with node-positive VSCC.

Population Pharmacokinetics of Unbound and Total Teicoplanin in Critically Ill Pediatric Patients.

BACKGROUND AND OBJECTIVES: Teicoplanin is a highly protein-bound antibiotic, increasingly used to treat serious Gram-positive infections in critically ill children. Maturational and pathophysiological intensive care unit-related changes often lead to altered pharmacokinetics. In this study, the objectives were to develop a pediatric population-pharmacokinetic model of unbound and total teicoplanin concentrations, to investigate the impact of plasma albumin levels and renal function on teicoplanin pharmacokinetics, and to evaluate the efficacy of the current weight-based dosing regimen. METHODS: An observational pharmacokinetic study was performed and blood samples were collected for quantification of unbound and total concentrations of teicoplanin after the first dose and in assumed steady-state conditions. A population-pharmacokinetic analysis was conducted using a standard sequential approach and Monte Carlo simulations were performed for a probability of target attainment analysis using previously published pharmacokinetic-pharmacodynamic targets. RESULTS: A two-compartment model with allometric scaling of pharmacokinetic parameters and non-linear plasma protein binding best described the data. Neither the inclusion of albumin nor the renal function significantly improved the model and no other covariates were supported for inclusion in the final model. The probability of target attainment analysis showed that the standard dosing regimen does not satisfactory attain the majority of the proposed targets. CONCLUSIONS: We successfully characterized the pharmacokinetics of unbound and total teicoplanin in critically ill pediatric patients. The highly variable unbound fraction of teicoplanin could not be predicted using albumin levels, which may support the use of therapeutic drug monitoring of unbound concentrations. Poor target attainment was shown for the most commonly used dosing regimen, regardless of the pharmacokinetic-pharmacodynamic target evaluated.

Completion of radical hysterectomy does not improve survival of patients with cervical cancer and intraoperatively detected lymph node involvement: ABRAX international retrospective cohort study.

BACKGROUND: The management of cervical cancer patients with intraoperative detection of lymph node involvement remains controversial. Since all these patients are referred for (chemo)radiation after the surgery, the key decision is whether radical hysterectomy should be completed as originally planned, taking into account an additional morbidity associated with extensive surgical dissection prior to adjuvant treatment. The ABRAX study investigated whether completing a radical uterine procedure is associated with an improved oncological outcome of such patients. PATIENTS AND METHODS: We performed retrospective analyses of 515 cervical cancer patients (51 institutions, 19 countries) who were referred for primary curative surgery between 2005 and 2015 (stage IA-IIB, common tumour types) in whom lymph node involvement was detected intraoperatively. Patients were stratified according to whether the planned uterine surgery was completed (COMPL group, N = 361) or abandoned (ABAND group, N = 154) to compare progression-free survival. Definitive chemoradiation was given to 92.9% patients in the ABAND group and adjuvant (chemo)radiation or chemotherapy to 91.4% of patients in the COMPL group. RESULTS: The risks of recurrence (hazard ratio [HR] 1.154, 95% confidence intervals [CI] 0.799-1.666, P = 0.45), pelvic recurrence (HR 0.836, 95% CI 0.458-1.523, P = 0.56), or death (HR 1.064, 95% CI 0.690-1.641, P = 0.78) were not significantly different between the two groups. No subgroup showed a survival benefit from completing radical hysterectomy. Disease-free survival reached 74% (381/515), with a median follow-up of 58 months. Prognostic factors were balanced between the two groups. FIGO stage and number of pelvic lymph nodes involved were significant prognostic factors in the whole study cohort. CONCLUSION: We showed that the completion of radical hysterectomy does not improve survival in patients with intraoperatively detected lymph node involvement, regardless of tumour size or histological type. If lymph node involvement is confirmed intraoperatively, abandoning uterine radical procedure should be considered, and the patient should be referred for definitive chemoradiation. CLINICAL TRIALS IDENTIFIER: NCT04037124.

MicroRNA expression profiling of porcine mammary epithelial cells after challenge with Escherichia coli in vitro.

BACKGROUND: Coliform mastitis is a symptom of postpartum dysgalactia syndrome (PDS), a multifactorial infectious disease of sows. Our previous study showed gene expression profile change after bacterial challenge of porcine mammary epithelial cells (PMECs). These mRNA expression changes may be regulated through microRNAs (miRNAs) which play critical roles in biological processes. Therefore, miRNA expression profile was investigated in PMECs. RESULTS: PMECs were isolated from three lactating sows and challenged with heat-inactivated potential mastitis-causing pathogen Escherichia coli (E. coli) for 3 h and 24 h, in vitro. At 3 h post-challenge with E. coli, target gene prediction identified a critical role of miRNAs in regulation of host immune responses and homeostasis of PMECs mediated by affecting pathways including cytokine binding (miR-202, miR-3277, miR-4903); IL-10/PPAR signaling (miR-3277, miR-4317, miR-548); and NF-ĸB/TNFR2 signaling (miR-202, miR-2262, miR-885-3p). Target genes of miRNAs in PMECs at 24 h were significantly enriched in pathways associated with interferon signaling (miR-210, miR-23a, miR-1736) and protein ubiquitination (miR-125, miR-128, miR-1280). CONCLUSIONS: This study provides first large-scale miRNA expression profiles and their predicted target genes in PMECs after contact with a potential mastitis-causing E. coli strain. Both, highly conserved miRNAs known from other species as well as novel miRNAs were identified in PMECs, representing candidate predictive biomarkers for PDS. Time-dependent pathogen clearance suggests an important role of PMECs in inflammatory response of the first cellular barrier of the porcine mammary gland.

Serological evidence for the circulation of flaviviruses in seabird populations of the western Indian Ocean.

Birds play a central role in the epidemiology of several flaviviruses of concern for public and veterinary health. Seabirds represent the most abundant and widespread avifauna in the western Indian Ocean and may play an important role as host reservoirs and spreaders of arthropod-borne pathogens such as flaviviruses. We report the results of a serological investigation based on blood samples collected from nine seabird species from seven islands in the Indian Ocean. Using a commercial competitive enzyme-linked immunosorbent assay directed against the prototypic West Nile flavivirus, antibodies against flaviviruses were detected in the serum of 47 of the 855 seabirds tested. They were detected in bird samples from three islands and from four bird species. Seroneutralization tests on adults and chicks suggested that great frigatebirds (Fregata minor) from Europa were infected by West Nile virus during their non-breeding period, and that Usutu virus probably circulated within bird colonies on Tromelin and on Juan de Nova. Real-time polymerase chain reactions performed on bird blood samples did not yield positive results precluding the genetic characterization of flavivirus using RNA sequencing. Our findings stress the need to further investigate flavivirus infections in arthropod vectors present in seabird colonies.

Is S-Adenosyl Methionine (SAMe) for Depression Only Effective in Males? A Re-Analysis of Data from a Randomized Clinical Trial.

OBJECTIVE: The aim of this study was to examine whether gender differences may have affected treatment response to S-adenosyl methionine (SAMe) in a recent failed randomized clinical trial (RCT) for adults with major depressive disorder. METHODS: Data from a 2-site, 12-week, double-blind RCT (n=189) assessing the efficacy of SAMe vs. placebo and a comparator selective serotonin reuptake inhibitor (escitalopram) were subjected to post-hoc analyses to evaluate effects of patient gender on treatment response. RESULTS: When assessing the efficacy outcomes within each gender separately, SAMe was superior to placebo among males (n=51), but not among females (n=62). Males showed a significant reduction of depression severity from baseline to study endpoint on the 17-item Hamilton Depression Rating Scale (4.3 point difference; p=0.034; d=0.95), while females did not show significant change. This finding emerged despite equivalence on baseline measures of depression severity between the gender groups. CONCLUSION: RESULTS of this secondary data analysis suggest that gender might impact the antidepressant efficacy of SAMe, with greater therapeutic effect found in males. The underlying mechanism is still relatively unknown. Further work is needed to replicate this observation in independent samples.Clinicaltrials.gov identifier: NCT00101452.

In vitro optical detection of simulated blood pulse in a human tooth pulp model.

OBJECTIVE: Noninvasive optical methods such as photoplethysmography, established for blood pulse detection in organs, have been proposed for vitality testing of human dental pulp. However, no information is available on the mechanism of action in a closed pulp chamber and on the impairing influence of other than pulpal blood flow sources. Therefore, the aim of the present in vitro study was to develop a device for the optical detection of pulpal blood pulse and to investigate the influence of different parameters (including gingival blood flow [GBF] simulation) on the derived signals. MATERIALS AND METHODS: Air, Millipore water, human erythrocyte suspensions (HES), non-particulate hemoglobin suspension (NPHS), and lysed hemoglobin suspension (LHES) were pulsed through a flexible (silicone) or a rigid (glass) tube placed within an extracted human molar in a tooth-gingiva model. HES was additionally pulsed through a rigid tube around the tooth, simulating GBF alone or combined with the flow through the tooth by two separate peristaltic pumps. Light from high-power light-emitting diodes (625 nm (red) and 940 nm (infrared [IR]); Golden Dragon, Osram, Germany) was introduced to the coronal/buccal part of the tooth, and the signal amplitude [∆U, in volts] of transmitted light was detected by a sensor at the opposite side of the tooth. Signal processing was carried out by means of a newly developed blood pulse detector. Finally, experiments were repeated with the application of rubber dam (blue, purple, pink, and black), aluminum foil, and black antistatic plastic foil. Nonparametric statistical analysis was applied (n = 5; α = 0.05). RESULTS: Signals were obtained for HES and LHES, but not with air, Millipore water, or NPHS. Using a flexible tube, signals for HES were higher for IR compared to red light, whereas for the rigid tube, the signals were significantly higher for red light than for IR. In general, significantly less signal amplitude was recorded for HES with the rigid glass tube than with the flexible tube, but it was still enough to be detected. ∆U from gingiva compared to tooth was significantly lower for red light and higher for IR. Shielding the gingiva was effective for 940 nm light and negligible for 625 nm light. CONCLUSIONS: Pulpal blood pulse can be optically detected in a rigid environment such as a pulp chamber, but GBF may interfere with the signal and the shielding effect of the rubber dam depends on the light wavelength used. CLINICAL RELEVANCE: The optically based recording of blood pulse may be a suitable method for pulp vitality testing, if improvements in the differentiation between different sources of blood pulse are possible.

Meso-Rex shunt using deep femoral vein conduit: first report.

The Meso-Rex shunt (MRS) procedure was first described in 1992 by de VILLE et al. for the treatment of extrahepatic portal vein obstruction (EHPVO) in paediatric liver transplant patients. This technique provides more physiological relief of portal hypertension compared to the porto-systemic shunts, which can lead to long-term complications such as hyperammonaemia and hepato-pulmonary syndrome. Different conduits as autologous and cryopreserved veins or prosthetic grafts have been previously reported. We present herein the first case of a MRS using the autologous deep femoral vein in a 17-year-old female patient affected by EHPVO from unknown reasons.

Near-fatal betaxolol self-poisoning treated with percutaneous extracorporeal life support.

We present a case of successful treatment of near-fatal beta-blocker self-poisoning but requiring extracorporeal circulatory support with severe complications. A 38-year-old woman ingested a mixture of tablets including betaxolol (5.32 g). Despite intensive treatment with fluid, dobutamine, isoprenaline, epinephrine, nor-epinephrine and glucagon, sustained cardiogenic shock occurred with almost complete hypokinesia of the left ventricular 14 h later. Therefore, a cardiac support was performed with a percutaneous cardiopulmonary bypass device at bedside. We review the literature with emphasis on both the best time to start this technique and its complications.

Cardio protective effect of glucose-insulin infusion on acute digoxin toxicity in rat.

UNLABELLED: We recently observed a case of digoxin and insulin self-poisoning without cardiac repercussion. We raised the hypothesis that insulin may have a cardio-protective effect in case of digoxin toxicity. We have therefore evaluated the effect of glucose-insulin infusion on mortality and ECG abnormalities during acute digoxin toxicity in rats. Before and after a hyperinsulinemia-euglycemia clamp, rats in glucose-insulin-digoxin (GID) group (n=10) received an intravenous infusion of 12ml/h or 2,5ml/h digoxin (0.25mg/ml) respectively until death occured. Animals receiving digoxin or saline solution intravenously served as control (n=10). ECG recording was performed in all animals over the entire period. Serum insulin and digoxin concentrations were measured by ELISA method after digoxin administration. When digoxin was administered after the clamp, all animals in GID group were alive, whereas 80% of animals in the digoxin group were dead (p<0.001) after 30min. The administration of Digoxin provoked rapid death of rats in the digoxin group in 15+/-12min whereas in GID group the survival period was significantly increased to 38+/-3min (p<0.001). Twenty minutes after digoxin administration, P waves disappeared for 78% of animals in digoxin group while they were present in all rats of GID group (p<0.001). Animal death occurred after a digoxin infusion volume of 7.7+/-0.6ml and 3.0+/-2.4ml in GID and digoxin group respectively (p<0.001). Five minutes after digoxin administration, potassium plasmatic level increased significantly in digoxin group as compared to GID group: 7.1+/-2mmol/l versus 4.4+/-0.4mmol/l (p<0.001). When digoxin was infused before the clamp, 40% of animals in GID group were alive after 180min and the other 60% died after 137+/-40min whereas death of rats in the digoxin group occurred within 80+/-10min (p<0.001). The death of animals was preceded by the P waves disappearing. Thirty minutes after digoxin administration, the potassium plasmatic level increased significantly in the digoxin group as compared to the GID group: 6.9+/-0.5mmol/l versus 4.9+/-0.3mmol/l (p<0.001). At the time of death, both volume of digoxin infusion and serum digoxin concentration were increased in GID group as compared to digoxin group: 5.7+/-1.6ml versus 3.3+/-0.4ml (p<0.001) and 10.7+/-8.3mg/l versus 8.5+/-4.6mg/l. CONCLUSION: Glucose-insulin infusion delayed the abnormalities in cardiac conduction and improved rat survival after acute digoxin toxicity. These results suggest a cardioprotective effect of insulin in case of acute digoxin toxicity.

Mutually dependent secretion of proteins required for mycobacterial virulence.

The ESX-1 locus is a region critical for full virulence in Mycobacterium tuberculosis, which encodes two secreted proteins as well as other genes involved in their secretion. The mechanism of secretion of the two proteins, ESAT-6 and CFP-10, and their function remain unknown. Using proteomic methods to search for additional proteins secreted by the ESX-1 locus, we discovered that a protein encoded by a chromosomally unlinked gene, espA, is also secreted by strains that contain the ESX-1 locus but not by strains with ESX-1 deletions. Mutations in individual ESX-1 genes, including those that encode ESAT-6 and CFP-10, were found to block EspA secretion. Surprisingly, mutants that lack espA reciprocally failed to secrete ESAT-6 and CFP-10 and were as attenuated as ESX-1 mutants in virulence assays. The results indicate that secretion of these proteins, which are each critical for virulence of pathogenic mycobacteria, is mutually dependent. The results further suggest that discerning the nature of the interaction and the structure of macromolecular complexes will provide insights into both an alternative mechanism of protein secretion and mycobacterial virulence.

[Spontaneous anaerobic osteomyelitis with necrotizing fasciitis of femur: two reasons for the use of hyperbaric oxygenotherapy]. / Ostéomyélite auguë gazogène non traumatique associée à une myonécrose de la cuisse: deux raisons d'utiliser l'oxygénothérapie hyperbare.

This is a case report of a 50-year-old male patient who had septic shock with anaerobic bacterial septicaemia coming from a spontaneous left femoral osteomyelitis. The combined treatment with antibiotics, surgery and hyperbaric oxygenotherapy restored normal mobility of the lower limb. Two years later, there was no recurrence. Despite many efforts the aetiology of the disease is unknown. The authors, discuss the relevance of hyperbaric oxygenotherapy in such cases.

An experimental ecotoxicological study and its application to the behavioural study of organic mercury (CH3HgCl) in the environment: influence of temperature and pH.

Laboratory experiments were carried out to study the influence of temperature (24, 28 and 30 degrees C) and pH (1-10) on organic mercury (CH3HgCl) transfer and accumulation in an experimental ecotoxicological model. We followed the evolution of CH3HgCl in a basic model (water + air) by varying temperature and pH. In a second step, we completed the model by adding sediment and fish. We added CH3HgCI to water at the beginning of each experiment which was repeated at least three times. Results demonstrated that mercury was released from methylmercury into the air regardless of water pH and its concentration in the air increased with increasing pH. By contrast, in presence of sediment, almost all the mercury was fixed onto the sediment and no mercury was traced in air or in water. Interestingly, in the presence of sediment, the life span of fish under methylmercury exposure lasted longer despite their higher mercury body level content at their death. These results indicate that water is a bad exposure indicator for aquatic pollution. In case of chronic pollution, sediments, fish and aquatic plants are more appropriate indicators.

Rationales of arthroscopic shoulder stabilization.

Arthroscopic reconstruction of glenohumeral instability has become more common during the past decade. Compared with open reconstruction, which is still the gold standard in the treatment of shoulder instability, arthroscopic techniques allow for improved diagnosis of numerous intraarticular findings. This review presents an appropriate system for the arthroscopic classification of most pathological findings in patients with anterior shoulder instability. Based on the presented classification, a rationale for arthroscopic reconstruction under special conditions is given. Several operative techniques and implants are discussed and their use in certain circumstances analyzed. Special emphasis is targeted on techniques of realizing sufficient capsular shift or plication. Arthroscopic procedures remain technically demanding and require skills to address the great variety of possible situations. On the other hand, arthroscopic techniques in shoulder reconstruction benefit patients by avoiding the morbidity of open surgery. However, the surgeon must be prepared to address numerous conditions beyond a mere Bankart lesion, especially those involving capsular laxity, rotator interval lesions, and SLAP (superior labrum lesions from anterior to posterior) lesions. Nowadays, considering all the new technical possibilities of arthroscopic shoulder reconstruction including capsular shift procedures, most cases of anterior shoulder instability are suitable for arthroscopic reconstruction. Further studies are necessary to validate the continued efficacy of arthroscopic stabilization.

Fatal allergic vasculitis associated with celecoxib.

We report on the occurrence of a rare and as yet unforseeable adverse reaction to treatment with celecoxib, a cyclooxygenase-2 (COX-2) selective, non-steroidal, anti-inflammatory drug. A previously healthy adult suffered fatal acute multiple organ failure presumably after diffuse allergic vasculitis with diffuse necrotic purpura. Although no conclusive proof is available, such a reaction could have been triggered by at least one of two mechanisms: an allergic reaction linked to the chemical structure of celecoxib; or an interaction of the drug with synthesis of endothelial eiconasoids leading to an imbalance between vasoactive end products, resulting in widespread rise to local thrombosis.

Treatment of acute methanol poisoning with fomepizole.

OBJECTIVE: To assess the efficacy and safety of fomepizole, a competitive alcohol dehydrogenase inhibitor, in methanol poisoning and to test the hypothesis that fomepizole obviates the need for hemodialysis in selected patients. DESIGN AND SETTING: Retrospective clinical study in three intensive care units in university-affiliated teaching hospitals. PATIENTS: All methanol-poisoned patients admitted to these ICUs and treated with fomepizole from 1987-1999 (n=14). MEASUREMENTS AND RESULTS: The median plasma methanol concentration was 50 mg/dl (range 4-146), anion gap 22.1 mmol/l (11.8-42.2), arterial pH 7.34 (7.11-7.51), and bicarbonate 17.5 mmol/l (3.0-25.0). Patients received oral or intravenous fomepizole until blood methanol was undetectable. The median cumulative dose was 1250 mg (500-6000); the median number of twice daily doses was 2 (1-16). Four patients underwent hemodialysis for visual impairment present on admission. Four patients with plasma methanol concentrations of 50 mg/dl or higher and treated without hemodialysis recovered fully. Patients without pretreatment visual disturbances recovered, with no sequelae in any case. There were no deaths. Fomepizole was safe and well tolerated, even in the case of prolonged treatment. Analysis of methanol toxicokinetics in five patients demonstrated that fomepizole was effective in blocking methanol's toxic metabolism. CONCLUSIONS: Fomepizole appears safe and effective in the treatment of methanol-poisoned patients. If our results are confirmed in prospective analyses, hemodialysis may prove unnecessary in patients presenting without visual impairment or severe acidosis.

Care of the potential pediatric organ donor.

Although all of this information may create the impression that caring for a potential organ donor is an exceedingly complex task, in the authors' experience, this often is not true, and much energy can--and should--be devoted to the care of the bereaved family. Of crucial importance are the early recognition of brain death and the consequent radical switch of the treatment goal from preservation of the patient's brain and life to preservation of organs for the lives of others. Care for the donor is the natural extension of care for a critically ill or injured patient. During the foregoing discussion, the authors had to stress the absence of sound evidence on many points. Because many reports originate from transplant centers dedicated to a specific organ, gaining a comprehensive view on management options in the ICU further is hampered. Thus, this situation leaves another field in which investigations originating from pediatric intensivists could provide evidence urgently needed to make optimal choices. The next decade should see the thyroid hormone controversy solved by at least one controlled prospective study and the differential applicability of inotropic, vasoactive, or fluid-centered strategies. It seems self-evident that only graft survival and related parameters can form adequate endpoints for future studies.