Prediction and observation of an antiferromagnetic topological insulator.

Magnetic topological insulators are narrow-gap semiconductor materials that combine non-trivial band topology and magnetic order1. Unlike their nonmagnetic counterparts, magnetic topological insulators may have some of the surfaces gapped, which enables a number of exotic phenomena that have potential applications in spintronics1, such as the quantum anomalous Hall effect2 and chiral Majorana fermions3. So far, magnetic topological insulators have only been created by means of doping nonmagnetic topological insulators with 3d transition-metal elements; however, such an approach leads to strongly inhomogeneous magnetic4 and electronic5 properties of these materials, restricting the observation of important effects to very low temperatures2,3. An intrinsic magnetic topological insulator-a stoichiometric well ordered magnetic compound-could be an ideal solution to these problems, but no such material has been observed so far. Here we predict by ab initio calculations and further confirm using various experimental techniques the realization of an antiferromagnetic topological insulator in the layered van der Waals compound MnBi2Te4. The antiferromagnetic ordering  that MnBi2Te4  shows makes it invariant with respect to the combination of the time-reversal and primitive-lattice translation symmetries, giving rise to a ℤ2 topological classification; ℤ2 = 1 for MnBi2Te4, confirming its topologically nontrivial nature. Our experiments indicate that the symmetry-breaking (0001) surface of MnBi2Te4 exhibits a large bandgap in the topological surface state. We expect this property to eventually enable the observation of a number of fundamental phenomena, among them quantized magnetoelectric coupling6-8 and axion electrodynamics9,10. Other exotic phenomena could become accessible at much higher temperatures than those reached so far, such as the quantum anomalous Hall effect2 and chiral Majorana fermions3.

Immune related endonucleases and GTPases are not associated with tumor response in patients with advanced non-small cell lung cancer treated with checkpoint inhibitors.

Immune related endonucleases have recently been described as potential therapeutic targets and predictors of response to treatment with immune checkpoint inhibitors (ICI). The aim is to evaluate the association between the expression of 5 biomarkers involved in the immune response (CD73, CD39, VISTA, Arl4d and Cytohesin-3) in parallel with the more common ICI-predictive markers, PD-L1 expression and Tumor Mutation Burden (TMB) with response to ICI therapy in an advanced non-small cell lung cancer (NSCLC) cohort. METHODS: Patients with advanced NSCLC treated with ICI single agent were divided into responders and non-responders according to RECIST v1.1 and duration of response (DOR) criteria. Immunohistochemistry was performed on pretreatment tumor tissue samples for PD-L1, CD73, CD39, VISTA, Arl4d, and Cytohesin-3 expression. TMB was estimated with NEOplus v2 RUO (NEO New Oncology GmbH) hybrid capture next generation sequencing assay. Resistance mutations in STK11/KEAP1 and positive predictive mutations in ARID1A/POLE were also evaluated. RESULTS: Included were 56 patients who were treated with ICI single agent. The median progression-free and overall survival for the whole cohort was 3.0 (95% CI, 2.4-3.6) and 15 (95% CI, 9.7-20.2) months, respectively. The distribution of CD73 in tumor cells and CD39, VISTA, Arl4d and Cytohesin-3 expression in immune cells were not different between responders and non-responders. Also, PD-L1 and TMB were not predictive for response. The frequency of STK11, KEAP1 and ARID1A mutations was low and only observed in the non-responder group. CONCLUSION: Separate and combined expression of 5 biomarkers involved in the immune response (CD73, CD39, VISTA, Arl4d, and Cytohesin-3) was not associated with response in our cohort of advanced NSCLC patients receiving single agent ICI. To confirm our findings the analysis of independent larger cohorts is warranted.

A multi-institutional randomized controlled trial comparing first-generation transrectal high-resolution micro-ultrasound with conventional frequency transrectal ultrasound for prostate biopsy.

Objectives: To study high-frequency 29 MHz transrectal side-fire micro-ultrasound (micro-US) for the detection of clinically significant prostate cancer (csPCa) on prostate biopsy, and validate an image interpretation protocol for micro-US imaging of the prostate. Materials and methods: A prospective randomized clinical trial was performed where 1676 men with indications for prostate biopsy and without known prostate cancer were randomized 1:1 to micro-US vs conventional end-fire ultrasound (conv-US) transrectal-guided prostate biopsy across five sites in North America. The trial was split into two phases, before and after training on a micro-US image interpretation protocol that was developed during the trial using data from the pre-training micro-US arm. Investigators received a standardized training program mid-trial, and the post-training micro-US data were used to examine the training effect. Results: Detection of csPCa (the primary outcome) was no better with the first-generation micro-US system than with conv-US in the overall population (34.6% vs 36.6%, respectively, P = .21). Data from the first portion of the trial were, however, used to develop an image interpretation protocol termed PRI-MUS in order to address the lack of understanding of the appearance of cancer under micro-US. Micro-US sensitivity in the post-training group improved to 60.8% from 24.6% (P < .01), while specificity decreased (from 84.2% to 63.2%). Detection of csPCa in the micro-US arm increased by 7% after training (32% to 39%, P < .03), but training instituted mid-trial did not affect the overall results of the comparison between arms. Conclusion: Micro-US provided no clear benefit over conv-US for the detection of csPCa at biopsy. However, it became evident during the trial that training and increasing experience with this novel technology improved the performance of this first-generation system.

Prevalence of Acanthamoeba and other naked amoebae in South Florida domestic water.

The purpose was to identify the prevalence of naked amoebae in tap water in south Florida to ascertain the risk of amoebal infections of the cornea in contact lens wearers. Over the course of a 2-year period, water samples were collected from sites throughout Broward, Palm Beach, and Dade counties, Florida. The presence of amoebae in samples was based on an enrichment cultivation method appropriate for Acanthamoeba. Amoebae were identified using diagnostic features discernable by light microscopy. A total of 283 water samples were processed and amoebae were noted in 80 of these. Acanthamoeba were found on 8 occasions (2.8%). The genera Hartmannella and Vahlkampfia, rarely involved in keratitis cases, were found in 3.5% and 2.8% of samples, respectively. A total of 19 different naked amoebae were recorded and amoebae (regardless of genus) were present in 19.4% of all samples. Previous surveys in England and Korea have shown that acanthamoebae are found in 15 to 30% of tap water samples in the home and have been associated with corneal infection in contact lens wearers. The incidence of acanthamoebae infection in the USA (2.8%) has been found to be lower than that in the UK and it has been postulated that this is related to the lack of a storage water tank in the roof loft space. However, the level of treatment of municipal water is clearly not effective at killing amoebal cysts (or trophozoites) as evidenced by the high occurrence of amoebae (19.4%) in this study.

Prevalence of yeasts in beach sand at three bathing beaches in South Florida.

The abundance and types of yeasts in the wet and dry sand of three recreational beaches in South Florida were determined. Samples were collected on 17 occasions between August 2001 and July 2002. After analyzing 102 sand samples, a total of 21 yeast species were identified by molecular methods. These isolates comprised four Basidiomycetes and 17 Ascomycetes and included eight species that had previously been reported from humans. The most frequently encountered yeasts were Candida tropicalis and Rhodotorula mucilaginosa. A greater diversity of species (16 species) was found in the dry sand above the high tide mark compared with the wet sand in the intertidal zone (11 species). Densities were also highest in the dry sand relative to wet sand (20-fold higher at Hobie beach, 6-fold higher at Fort Lauderdale Beach and 1.3-fold higher at Hollywood beach). There were no clear temporal patterns in the data and overall densities were greatest at the busiest bathing beach (Hobie Beach) where total yeasts averaged 37,720 cfu 100g(-1) dry sand and 1852 cfu 100 g(-1) in the wet sand. This concentration of yeast was significantly higher than populations at the less populated beaches. Fort Lauderdale beach had a mean count of 4130 cfu 100 g(-1) dry sand and 705 cfu 100g(-1) in the wet sand while the least populated beach, Hollywood Beach averaged 1945 cfu 100g(-1) dry sand and 1483 cfu 100g(-1) wet sand. While definitive statements cannot be made, high levels of yeasts may have a deleterious bearing on human health and the presence of such a diverse aggregation of species suggests that yeasts could have a role as indicators of beach health.

Anticoagulation in atrial fibrillation. Does efficacy in clinical trials translate into effectiveness in practice?

BACKGROUND: Several recent randomized clinical trials of anticoagulation in atrial fibrillation have demonstrated significant reduction in stroke rates with a small incidence of bleeding complications. The objective of this study was to determine whether the recommendations resulting from these trials have been implemented into routine practice, and if the anticoagulation control, therapeutic efficacy, and low complication rates achieved in the trials have been matched in community practice. METHODS: We analyzed the anticoagulation practices and outcomes obtained for patients in atrial fibrillation at a large staff model health maintenance organization (HMO). We reviewed the medical records of all patients in atrial fibrillation as of April 1990. We compared demographic characteristics and clinical risk factors between HMO patients and those in the clinical trials. We also compared anticoagulation monitoring, adequacy of anticoagulation control, and clinical outcomes at the HMO with those achieved in the clinical trials. RESULTS: Of 238 HMO patients in atrial fibrillation, 198 were without contraindications and therefore eligible for anticoagulation. Of these, 168 were offered anticoagulation (84.8%) and 156 were receiving anticoagulation therapy (78.8% of those eligible). The HMO patients had a greater prevalence of comorbidities than those in the clinical trials. The routine monitoring interval at the HMO was estimated at between 36.3 and 40.9 days (compared with 21 to 28 days reported in the clinical trials). The prothrombin time ratios at the HMO were in the target range on 50% of days compared with 68% of days in the clinical trials. The annual stroke and major bleeding rates in the HMO patients (1.3% and 0.6%, respectively) were not significantly different from the rates in the clinical trials (1.3% and 1.1%, respectively). The annual minor bleeding rate of 13.6% at the HMO was greater than the 7.8% to 8.4% rates in the two trials with better anticoagulation control (Boston Area Anticoagulation Trial for Atrial Fibrillation and Stroke Prevention in Atrial Fibrillation Study) but was not significantly different than the rates of 12.7% and 13.7% of the two trials with poorer anticoagulation control (Canadian Atrial Fibrillation Anticoagulation Study and Stroke Prevention in Nonrheumatic Atrial Fibrillation Study). CONCLUSIONS: Anticoagulation practices in this community setting appear to be good in that a large majority of patients were receiving anticoagulation therapy, and there were few major adverse outcomes. However, this study illustrates two common problems in attempting to apply the results of randomized clinical trials to routine practice: (1) differences between community patient populations and those on which the conclusions of clinical trials are based, and (2) less successful application of therapeutic interventions in settings other than that of a controlled clinical trial. The greater prevalence of comorbidities in the HMO patient population appears to convey a greater overall risk of thromboembolism and bleeding complications than in the clinical trials. In addition, the suboptimal anticoagulation control achieved at the HMO may increase the risks and decrease the potential benefits compared with those achieved in the clinical trials. Thus, the efficacy demonstrated in the clinical trials of anticoagulation in atrial fibrillation may not be directly translated into effectiveness in practice.

Spectroscopic probing of the acid-base properties and photosensitization of a fluorinated phthalocyanine in organic solutions and liposomes.

A perfluorinated derivative of phthalocyanine was synthesized as the free base, hexadeca-(2,2,2-trifluoroethoxy) phthalocyanine (H2F48Pc), and as a zinc complex, hexadeca-(2,2,2-trifluoroethoxy)-phthalocyaninatozinc (ZnF48Pc), and their spectroscopic and photochemical properties were studied. The absorption bands are shifted bathochromically relative to simple phthalocyanines, exhibiting the longest wavelength band near 735 nm (H2F48Pc) and 705 (ZnF48Pc). The solvatochromism of both compounds was modeled by Reichardt's ET(30) parameter and Kamlet, Abboud and Taft multiparameter approach. The former, simpler, model was found to be adequate. We found that H2F48Pc undergoes unique basic and acidic titrations in organic solvents. These titration processes are accompanied by spectral changes that are explained on the basis of the chromophore's symmetry. Singular value decomposition was employed to resolve the spectra into the contributions of the species at various stages of protonation and to obtain the equilibrium constants. Nuclear magnetic resonance spectra (1H, 19F and 13C) for the free base were obtained in a tetrahydrofurand8 solution. The carbon spectrum, taken as a function of temperature, provided evidence for the presence of a tautomerization process, which switches the two internal hydrogens between the four central nitrogen atoms. As far as we know, this is the first report of the measurement of the free energy of activation for such process (delta G = 10.6-11.4 kcal mol-1 between 217 and 330 K) for a phthalocyanine, in solution. Like most other phthalocyanines these two compounds also act as photosensitizers and as generators of singlet molecular oxygen. The absolute quantum yields (phi delta) for ZnF48Pc was 0.58 +/- 0.01 in benzene and 0.35 +/- 0.01 in lipid vesicles. H2F48Pc had lower yields, 0.16 and 0.005, respectively. Either protonation or deprotonation of the pyrrole nitrogens in H2F48Pc lowered the phi delta.

Monoclonal B-cell population mimicking lymphoma in a patient with multiple sclerosis.

BACKGROUND: Diagnosis of intraparenchymal brain lesions has usually required invasive diagnostic procedures, because too few cells are shed into cerebrospinal fluid to permit cytologic diagnosis. Polymerase chain reaction technology makes it possible to identify cell populations that are present at a much lower frequency than traditional techniques. CASE REPORT: A young woman presented with multiple brain lesions raised the question of primary central nervous system lymphoma. Polymerase chain reaction analysis of cerebrospinal fluid showed evidence of a monoclonal B-cell population heightening suspicion of lymphoma. Brain biopsy showed acute demyelination most consistent with multiple sclerosis. CONCLUSION: Although T-cell restriction has been demonstrated in multiple sclerosis lesions, the finding of a monoclonal B-cell population was unexpected and to our knowledge has not been previously reported. This case emphasizes that monoclonality is not always indicative of a neoplastic process, particularly in the central nervous system.

Effect of open and laparoscopic surgery on cellular immunity in a swine model.

Immune suppression associated with trauma has been demonstrated to be proportional to the magnitude of injury. Laparoscopic surgery has been shown to produce a diminished stress response compared to open surgery. Postoperative immune function, specifically cellular immunity, may be better preserved after laparoscopic surgery compared to open surgery. The aim of this study was to examine the effect of open versus laparoscopic surgery on cellular immunity in a swine model. Twenty domestic female pigs were randomly selected for laparoscopic cholecystectomy (LC) or open cholecystectomy (OC). Cellular immune functions were evaluated with delayed-type hypersensitivity (DTH) skin test and serial phytohemoagglutinin (PHA)-induced T-cell proliferation of the peripheral blood. There was a significant reduction in PHA-induced T-cell proliferation in both LC and OC groups on days 1 and 3 compared to preoperative values (p < 0.05). The reduction of mitogen-induced T-cell proliferation after LC was significantly less than after OC on day 1 (p = 0.03). The mean DTH reaction was 29.7 +/- 3.7 mm2 in the LC group compared to 13.9 +/- 1.2 mm2 in the OC group (p < 0.001). There was no difference in postoperative white blood count values between the two groups. Suppression of cellular immunity occurred after both LC and OC. The magnitude and duration of impaired cellular immunity after laparoscopic surgery was less than after open surgery as measured by T-cell proliferation and DTH response.

Congenital spleen thinning mimicking a space-occupying lesion.

By splenic imaging, a large focal defect was demonstrated in a symptomatic South American immigrant with simultaneous parasitic infestation of strongyloidiasis and entamebiasis. The CT scan also was thought to be abnormal. Pathologic findings reported a variation in splenic configuration. Unusual splenic configuration should be considered in the differential diagnosis of abnormal scans.

Computerized blood-flow analysis in osteochondritis dissecans.

A retrospective review of static images and computerized blood flow studies (CBFS) in patients with osteochondritis dissecans (OCD) suggests that CBFS maybe useful in following the clinical course of this disease.

A nationwide survey of financing health-related services for special education students.

The Individuals with Disability Education Act (IDEA) requires state educational systems to provide school-based, health related services (RS). This survey determined the financing arrangements used by states for health-related services for school-aged children with disabilities. A survey was sent to directors of special education, Medicaid, and public health departments in each of the 50 states. Financial patterns for RS were sought at the state level for children ages 3-21 with disabilities for the 1993-1994 school year, the most recent year for which complete financial data were available. Univariate analyses probed the relationship between systems' variables and the extent of Medicaid usage by local education agencies. Respondents reported that schools tapped traditional health resources to supplement educational dollars in paying for related services in schools. Medicaid was by far the most common source with 29 states reporting established mechanisms for recouping Medicaid dollars and 10 states reporting phase-in activities. Seventeen states reported that departments of public health played some role in administration, training, and demonstrations, but only six states provided specific dollars for related services through the department. Use of private insurance was reported sporadically with only one state indicating a specific state-level program. Correlates of increased Medicaid usage were presence of interagency agreements (IAAs) (OR 11.1, p = 0.002), having specific personnel for school-based medical assistance (OR 17.7, p = 0.001), and utilizing school nursing services as a Medicaid optional service (OR 4.2, p = 0.048).

Measurement of faecal cortisol metabolites in cats and dogs: a non-invasive method for evaluating adrenocortical function.

The aim of this comparative study was to gain more information about the metabolism and excretion of glucocorticoids in cats and dogs in order to establish non-invasive methods for evaluating stressful conditions. Therefore, in a first experiment, [14C]cortisol was administered intravenously to 8 animals (two of each sex and species). Over a period of 6 days, faeces and urine were collected immediately after spontaneous defecation and urination. Marked species differences were found, as cats mainly excreted cortisol in the faeces (82% +/- 4% of the total recovered radioactivity), whereas in dogs only a small portion was found there (23% +/- 4%). The highest urinary radioactivity was observed after 9 +/- 3 h in cats and 3 +/- 1 h in dogs. Peak concentrations in the faeces occurred after 22 +/- 6 h in cats and after 24 +/- 4 h in dogs. Most of the radioactivity was not extractable with diethyl ether, indicating that the metabolites excreted in urine and faeces were mainly of the conjugated or polar unconjugated types. This was confirmed by RP-HPLC, which also revealed marked differences between cats and dogs concerning the metabolites formed. In addition, the immunoreactivity of the metabolites was tested in cortisol, corticosterone and 11-oxoaetiocholanolone EIAs. The latter, measuring 11,17-dioxoandrostanes (11,17-DOA) detected the highest quantities of immunoreactive metabolites in cats, but not in dogs. In a second experiment, the adrenal cortex of both species was stimulated by ACTH and, three weeks later, suppressed by dexamethasone. In this study, only faeces were collected over a period of 7 days. In both species, inter-animal variability in the basal and maximal/minimal faecal cortisol metabolite concentrations and the time course was observed. The 11-oxoaetiocholanolone EIA in cats and the cortisol EIA in dogs proved best suited for monitoring changes in adrenocortical activity. ACTH injections resulted in an increase above baseline values of 355%, (median) in 11,17-DOA concentrations in cats and of 702% in the concentrations of cortisol equivalents in dogs by about 25 h and 22 h (median) after injection, respectively. Minimal concentrations after dexamethasone administration were about 17% in cats and 31% in dogs (in relation to baseline values) and were reached in 66 h and 72 h, respectively. It was concluded that measuring cortisol metabolites in faeces should be a useful non-invasive tool for monitoring stress in carnivores.

Post-streptococcal uveitis.

BACKGROUND: We report additional evidence supporting the association between the occurrence of bilateral nongranulomatous uveitis and previous infection by group A streptococci--i.e., post-streptococcal syndrome. METHODS: As shown through a series of case reports, physical examination and laboratory blood analysis--including antistreptolysin O (ASO) antibody titer--were ordered due to a recent history of sore throat and presence of nongranulomatous bilateral anterior uveitis. RESULTS: Serological laboratory testing revealed elevated ASO antibody titer. The etiology of the uveitis was attributed to streptococcal infection. Bilateral uveitis responded to topical corticosteroids. Systemic antibiotic treatment was used to treat possible post-streptococcal syndrome sequelae with resolution of symptoms. CONCLUSION: Uveitis should be considered a possible manifestation of post-streptococcal syndrome. ASO antibody quantification should be included in the serologic testing performed in evaluating the cause of seemingly idiopathic bilateral nongranulomatous anterior uveitis associated with signs and symptoms that suggest previous streptococcal infection.

[Effect of vaccination on fecal cortisol metabolites in cats and dogs]. / Einfluss der Impfung auf die Konzentration von Kortisolmetaboliten im Kot von Fleischfressern.

The aim of this study was to apply a cortisol metabolite determination in the faeces of cats and dogs for monitoring disturbances. In this experiment faeces from every spontaneous defecation of 10 cats and 10 dogs (5 of each sex) were collected starting from one day before until two days after the yearly vaccination. Concentrations of 11,17-dioxoandrostanes (cat) and cortisol equivalents (dog) were determined by enzyme immunoassay (EIA). Faecal cortisol metabolites increased and reached peak concentrations (median: 412% in cats and 417% in dogs, respectively above baseline values) in one of the next two samples following the vaccination. This indicated an activation of the adrenocortex, the degree to which the different parts (physical and psychological components) of the whole vaccination procedure contributed to it was not evaluated. From this experiment we conclude that measuring cortisol metabolites in the faeces is a non-invasive method to monitor stressful conditions in cats and dogs and thus is a valuable tool for evaluating animal welfare.

Repeated exclusive enteral nutrition in the treatment of paediatric Crohn's disease: predictors of efficacy and outcome.

BACKGROUND: Exclusive enteral nutrition (EEN) induces remission and mucosal healing in children with active Crohn's disease (CD). AIM: To compare short- and long-term outcomes of the first vs. second courses of EEN, and to identify predictors of sustained remission. METHODS: Retrospective single centre analysis of all patients with CD (6-18 years) treated with EEN over 7.5 years. Patients were excluded if exposed to anti-TNFα or corticosteroids 3 months prior to EEN. Data included disease phenotype, activity, NOD2 genotype, laboratory indices and anthropometrics. Remission and relapse were defined by mathematically weighted Paediatric Crohn's Disease Activity Index (wPCDAI) with 1-year follow-up. RESULTS: Of 94 patients treated with EEN, 52 fulfilled inclusion criteria (31 male, mean age 13.2 years). Azathioprine was started within the first month in 33/52 patients; 26/52 received a second EEN course. First compared to second EEN revealed higher wPCDAI at start (59 vs. 40, P < 0.0001), tended to higher remission rates after 3 months (92% vs. 77%, n.s.), but showed comparable 1-year relapse rates (67% vs. 70%, median time 231 vs. 145 days, n.s.). Disease activity, weight gain and inflammatory markers showed better improvement with first EEN. Faecal calprotectin >200 µg/g during EEN was associated with shorter remission (median time 157 vs. 287 days, n.s.). Certain NOD2 genotypes were related to higher relapse rates (92% R702W or G908R vs. 50% 1007fs vs. 60% wild-type, P < 0.01). CONCLUSIONS: Exclusive enteral nutrition induces remission in active Crohn's disease, but efficacy tends to decrease with the second course. Despite early azathioprine use, 1-year relapse rates are high, but may be related to NOD2 genotype.