Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma.

BACKGROUND: Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy. PATIENTS AND METHODS: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined. RESULTS: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%). CONCLUSIONS: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.

Correlation of age-of-onset of Atopic Dermatitis with Filaggrin loss-of-function variant status.

The genetic background of Atopic Dermatitis (AD) with chronic pruritus is complex. Filaggrin (FLG) is an essential gene in the epidermal barrier formation s. Loss-of-function (LOF) variants in FLG associated with skin barrier dysfunction constitute the most well-known genetic risk factor for AD. In this study, we focused on the frequency and effect of FLG loss-of-function variants in association with self-reported age-of-onset of AD. The dataset consisted of 386 whole-genome sequencing (WGS) samples. We observe a significant association between FLG LOF status and age-of-onset, with earlier age of onset of AD observed in the FLG LOF carrier group (p-value 0.0003, Wilcoxon two-sample test). We first tested this on the two most prevalent FLG variants. Interestingly, the effect is even stronger when considering all detected FLG LOF variants. Having two or more FLG LOF variants associates with the onset of AD at 2 years of age. In this study, we have shown enrichment of rare variants in the EDC region in cases compared with controls. Age-of-onset analysis shows not only the effect of the FLG and likely EDC variants in terms of the heightened risk of AD, but foremost enables to predict early-onset, lending further credence to the penetrance and causative effect of the identified variants. Understanding the genetic background and risk of early-onset is suggestive of skin barrier dysfunction etiology of AD with chronic pruritus.

Deregulation of kinase signaling and lymphoid development in EBF1-PDGFRB ALL leukemogenesis.

The chimeric fusion oncogene early B-cell factor 1-platelet-derived growth factor receptor-ß (EBF1-PDGFRB) is a recurrent lesion observed in Philadelphia-like B-acute lymphoblastic leukemia (B-ALL) and is associated with particularly poor prognosis. While it is understood that this fusion activates tyrosine kinase signaling, the mechanisms of transformation and importance of perturbation of EBF1 activity remain unknown. EBF1 is a nuclear transcription factor required for normal B-lineage specification, commitment and development. Conversely, PDGFRB is a receptor tyrosine kinase that is normally repressed in lymphocytes, yet PDGFRB remains a common fusion partner in leukemias. Here, we demonstrate that the EBF1-PDGFRB fusion results in loss of EBF1 function, multimerization and autophosphorylation of the fusion protein, activation of signal transducer and activator of transcription 5 (STAT5) signaling and gain of interleukin-7 (IL-7)-independent cell proliferation. Deregulation and loss of EBF1 function is critically dependent on the nuclear export activity of the transmembrane (TM) domain of PDGFRB. Deletion of the TM domain partially rescues EBF1 function and restores IL-7 dependence, without requiring kinase inhibition. Moreover, we demonstrate that EBF1-PDGFRB synergizes with loss of IKAROS function in a fully penetrant B-ALL in vivo. Thus, we establish that EBF1-PDGFRB is sufficient to drive leukemogenesis through TM-dependent loss of transcription factor function, increased proliferation and synergy with additional genetic insults including loss of IKAROS function.

Postmortem examination (2016-2017) of weanling and older horses for the presence of select species of endoparasites: Gasterophilus spp., Anoplocephala spp. and Strongylus spp. in specific anatomical sites.

Parasite infections are more quantifiable postmortem than antemortem in horses. Thus a study was carried out examining dead horses for specific parasite species. Most of the weanling and older horses submitted to the University of Kentucky Veterinary Diagnostic Laboratory (UKVDL) for postmortem examination between November 22, 2016 and March 23, 2017 were examined for certain species of internal parasites. The stomach and duodenum from 69 horses were examined for bots (Gasterophilus spp.). Combined data for both Thoroughbred and non-Thoroughbred (16 other than Thoroughbred breeds/mixed breeds) horses revealed that the prevalence of Gasterophilus intestinalis was 19% (n=12) with 2nd instars (x̄ 8.5) and 39% (n=27) with 3rd instars (x̄ 90). The prevalence of Gasterophilus nasalis was 1.5% (n=1) for 2nd instars (x̄ 1) and 7% (n=5) for 3rd instars (x̄ 25). A few third instar G. intestinalis placed in 10% formalin showed slight movement at over two hundred hours later. The cecum and about 25cm of the terminal part of the ileum were examined from 139 horses for tapeworms (Anoplocephala spp.) and large strongyles (Strongylus spp.). The prevalence of A. perfoliata was 44% (n=62) and the average number of specimens per infected horse was 92.5. Strongylus vulgaris and Strongylus edentatus were not found in the gut of any horse.

Megacolon tóxico en una paciente con colitis seudomembranosa / Toxic megacolon in a patient with colitis pseudomembranous

La colitis seudomembranosa es una patología relacionada con el uso de antibióticos. En raras ocasiones, evoluciona a megacolon tóxico que podría requerir resolución quirúrgica. Comunicamos el caso de una mujer de 22 años, que recibió amoxicilina/ácido clavulánico unos días antes de la consulta. Presentó diarrea, fiebre y vómitos. Radiografía y tomografía computarizada de abdomen: distensión de colon derecho >6 cm. Toxina para Clostridium: positiva. Comienza con el tratamiento médico y requiere cirugía por megacolon tóxico. El megacolon tóxico es una complicación infrecuente de la colitis seudomembranosa. Es rara en pacientes jóvenes y sin comorbilidades. Se llega al diagnóstico mediante los criterios de Jalan. La tasa de mortalidad se aproxima al 70%. Se debe mantener alto nivel de alerta ante signos de toxicidad sistémica y la dilatación colónica es diagnóstica de la entidad. El uso indiscriminado de antibióticos constituye un serio factor de riesgo.(AU)

Pseudomembranous colitis is a condition associated with the use of antibiotics. On rare occasions, it evolves to toxic megacolon which may require surgical resolution. We report the case of a 22-year-old woman who received amoxicillin/clavulanic acid a few days before the consultation. She referred diarrhea, fever and vomiting. Radiography and computed tomography of abdomen: distension of the right colon >6 cm. Clostridium toxin: positive. Medical treatment is administered and surgery is needed for toxic megacolon. Toxic megacolon is an infrequent complication of pseudomembranous colitis. It is rare in young patients without comorbidities. The diagnosis is reached using the Jalan criteria. The mortality rate approaches 70%. A high level of alertness should be maintained for signs of systemic toxicity and colonic dilation is diagnostic of the entity. Indiscriminate use of antibiotics is a serious risk factor.(AU)

An investigation of the genetic basis of increased susceptibility to neutralization by anti-fusion glycoprotein antibody arising on passage of human respiratory syncytial virus in cell culture.

Human respiratory syncytial virus isolates have previously been shown to exhibit resistance to neutralization by anti-fusion glycoprotein antibodies that is lost on passage in cell culture. Early passage resistant and late passage susceptible stocks of two virus isolates from different epidemics were cloned by plaque purification. Early passage stocks of both isolates yielded predominantly neutralization resistant clones while late passage stocks yielded predominantly susceptible clones. On further characterization of resistant and susceptible clones, resistant virus yields were lower and they were relatively resistant to both neutralization and fusion inhibition by anti-F murine monoclonal antibodies and were also resistant to neutralization by human sera and by Palivizumab. The full genome of resistant and susceptible clones from one of the isolates was sequenced. Four differences, confirmed by sequencing sister clones, were found between resistant and susceptible clones, one in each of the SH, G, F, and L genes.

3D computational imaging with single-pixel detectors.

Computational imaging enables retrieval of the spatial information of an object with the use of single-pixel detectors. By projecting a series of known random patterns and measuring the backscattered intensity, it is possible to reconstruct a two-dimensional (2D) image. We used several single-pixel detectors in different locations to capture the 3D form of an object. From each detector we derived a 2D image that appeared to be illuminated from a different direction, even though only a single digital projector was used for illumination. From the shading of the images, the surface gradients could be derived and the 3D object reconstructed. We compare our result to that obtained from a stereophotogrammetric system using multiple cameras. Our simplified approach to 3D imaging can readily be extended to nonvisible wavebands.

Radiological localizing techniques in adrenal tumors.

The characterisation of adrenal lesions is a common radiological dilemma. Incidental adrenal lesions are commonly detected with computed tomography (CT), and lesion characterisation is critical. The prevalence of incidental adrenal lesions has been reported to be 2.3% at autopsy and 0.5-2% with abdominal CT. Such lesions are likely to be seen with increasing frequency given the expanding use of radiological imaging in clinical practice. Although the majority of adrenal lesions are benign, in patients with an extra-adrenal primary cancer the probability of an adrenal mass being a metastasis is 52%. Unfortunately, there may be significant overlap between the imaging appearances of benign lesions such as lipid-poor adenomas and malignant lesions, particularly metastases and small adrenal carcinomas. This review highlights recent advances in radiological imaging of adrenal lesions and we discuss the relative merits of CT and magnetic resonance imaging to aid the identification of benign and malignant adrenal lesions and their roles, in combination with biochemical and clinical data, in recognizing common pathologies such as adrenal adenoma, phaeochromocytoma, carcinoma and metastases. We also discuss the radiological characteristics of rarer adrenal lesions including lymphoma, neuroblastic tumours (neuroblastoma, ganglioneuroblastoma, and ganglioneuroma), lipomatous tumours (myelolipoma, angiolipoma, teratoma, lipoma and liposarcoma), in addition to hemangioma, hemangiosarcoma and leiomyosarcoma.

Relationship between the endophyte Embellisia spp. and the toxic alkaloid swainsonine in major locoweed species (Astragalus and Oxytropis).

Locoweeds (Astragalus and Oxytropis spp. that contain the toxic alkaloid swainsonine) cause widespread poisoning of livestock on western rangelands. There are 354 species of Astragalus and 22 species of Oxytropis in the US and Canada. Recently, a fungal endophyte, Embellisia spp., was isolated from Astragalus and Oxytropis spp. and shown to produce swainsonine. We conducted a survey of the major locoweeds from areas where locoweed poisoning has occurred to verify the presence of the endophyte and to relate endophyte infection with swainsonine concentrations. Species found to contain the fungal endophyte and produce substantial amounts of swainsonine were A. wootoni, A. pubentissimus, A. mollissimus, A. lentiginosus, and O. sericea. Astragalus species generally had higher concentrations of swainsonine than Oxytropis. Swainsonine was not detected in A. alpinus, A. cibarius, A. coltonii, A. filipes, or O. campestris. The endophyte could not be cultured from A. mollissimus var. thompsonii or A. amphioxys, but was detected by polymerase chain reaction, and only 30% of these samples contained trace levels of swainsonine. Further research is necessary to determine if the endophyte is able to colonize these and other species of Astragalus and Oxytropis and determine environmental influences on its growth and synthesis of swainsonine.

Early carotid surgery in acute stroke: a multicentre randomised pilot study.

BACKGROUND: Standard practice has been to delay carotid endarterectomy (CEA) for 2 months following acute stroke to avoid a perceived risk of cerebral haemorrhage. We investigated whether early CEA reduces early recurrent stroke and improves outcome in partial anterior circulation infarction (PACI). METHODS: Patients with PACI and a Barthel score of >18 before stroke underwent carotid duplex and CT imaging within 7 days of stroke. Forty consenting patients fit for surgery with greater than 70% ipsilateral carotid stenosis were randomised, 19 to 'early' (within 24 h) and 21 to 'delayed' surgery (at 8 weeks). Modified Rankin and Barthel scores were recorded at 1 week, 2 months, 6 and 12 months. RESULTS: Rankin scores improved more rapidly following 'early' surgery to a score of 1 (0-4) at 2 and 6 months compared with 2.5 and 2 (1-4), respectively, for delayed surgery (p < 0.05). Barthel scores were also significantly improved following 'early' CEA at 7 days but both groups reached a median score of 20 by 2 months. Four 'delayed' and 3 'early' patients suffered extension or recurrence of neurological deficits with 1 death in each group. CONCLUSIONS: Early CEA within 7 days of ischaemic stroke improved functional outcome with earlier hospital discharge. A large multicentre study is needed to exclude the possibility that 'early' CEA increases the risk of cerebral haemorrhage or death.

Big brother is watching you--the ethical implications of electronic surveillance measures in the elderly with dementia and in adults with learning difficulties.

Electronic surveillance has insidiously seeped into the fabric of society with little public debate about its moral implications. Perceived by some as a sinister Orwellian tool of repression and social control, the new technologies offer comfort and security to others; a benevolent parental watchful eye. Nervousness at being watched has been replaced increasingly by nervousness if we're not. These technologies are now becoming widely available to health care professionals who have had little opportunity to consider their ethical and moral ramifications. Electronic tagging and tracking devices may be seen as away of creating a more secure environment for vulnerable individuals such as the elderly with dementia or people with learning disabilities. However, the proponents of surveillance devices have met with considerable resistance and opposition,from those who perceive it as contrary to human dignity and freedom, with its connotations of criminal surveillance. In addition, they cite increased opportunity for abuse through, for example, the withdrawal of staff and financial resources from the care of people with complex needs. Implementing these technologies, therefore, has ethical implications for human rights and civil liberties. Optional alternatives to long-term and/or restrictive care, in the context of the practical difficulties involved in caring for those who represent a risk to themselves from wandering, demands rigorous exploration of pragmatic questions of morality, with reference to risk versus benefit strategies. Like reproductive cloning techniques, the mere existence of surveillance technologies is morally neutral. Rather it is the use (in this instance that of health and social care settings) to which it is put which has the potential for good or bad.

Comparative analysis of the Cosmed Quark b2 and K4b2 gas analysis systems during submaximal exercise.

AIM: The purpose of this study was to compare the Cosmed K4b2 portable gas analysis system with the Cosmed Quark b2 metabolic cart. METHODS: Twenty-one subjects attended one testing session that consisted of duplicate measurements of gas volumes and concentrations using both Cosmed gas analysis systems at 3 treadmill work rates; 1) 80m x min(-1), 0% grade, 2) 80m x min(-1), 5% grade, and 3) 80m x min(-1), 10% grade. Subjects walked for 3 min at each rate with one of the gas analysis systems attached to the facemask. The order of the procedures was randomized so that one system was used during both phases (1st or 2nd) of each work rate. RESULTS: The results indicated that oxygen consumption (VO2) was significantly higher in the K4b2 compared to the Quark at 80m x min(-1), 0% grade (14.3+/-1.2 vs 13.6+/-1.2ml x kg(-1) x min(-1), respectively), (p<0.01). The fractional concentration of oxygen in expired air was also significantly lower in the K4b2 at 80 m x min(-1), 0% grade and 80 m x min(-1), 10% grade (p<0.05). There were no significant differences between systems for minute ventilation or carbon dioxide production. Despite the small mean bias in mean VO2 values (0.5-1.0ml x kg-1 x min(-1) higher) in the K4b2, all individual values were within the limits of agreement (mean difference+/-2 SD) as determined by the Bland-Altman technique. CONCLUSION: The findings show a minimal bias in respiratory and metabolic parameters during bi-pedal locomotor activities at low to moderate exercise intensities in the two gas analysis systems.

Expression of uracil DNA glycosylase (UDG) does not affect cellular sensitivity to thymidylate synthase (TS) inhibition.

Uracil DNA glycosylase (UDG) is a base excision repair enzyme responsible for the removal of uracil present in DNA after cytosine deamination or misincorporation during replication. Inhibition of thymidylate synthase (TS), an important target for cancer chemotherapy, leads to deoxythymidine triphosphate (dTTP) pool depletion and elevation of deoxyuridine monophosphate (dUMP) pools which may also result in the accumulation of deoxyuridine triphosphate (dUTP). Large quantities of dUTP are believed to overwhelm the pyrophosphatase dUTPase, leading to misincorporation of uracil into DNA. Uracil is removed from DNA by uracil DNA glycosylase (UDG) resulting in an abasic site, but since the ratio dUTP:dTTP may remain high during continuing TS inhibition uracil can become re-incorporated into DNA causing a futile cycle eventually leading to DNA damage and cell death. This study has used isogenic cell lines differing in their expression of UDG to investigate the role of this enzyme in sensitivity to the specific TS inhibitors, ZD9331 and raltitrexed. The study showed that although increased expression and activity of UDG may lead to increased cell growth inhibition after TS inhibition over the first 24 h of treatment (measured using 3-(4,5-dimethyl (thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), probably due to increased damage to single-stranded DNA, the level of enzyme expression does not affect cell viability or cell death (measured using clonogenic assay, cell counting of attached/detached cells and cleavage of both poly ADP-ribose polymerase (PARP) and caspase 3). Increased expression and activity of UDG did not affect sensitivity to TS inhibition at later time points (up to 72 h treatment). Therefore UDG does not appear to play a major role in the response to TS inhibition, at least in the model used, and the results suggest that other determinants of response previously investigated, such as TS and dUTPase, may be more important for the response to TS inhibition.

Distribution of locoweed toxin swainsonine in populations of Oxytropis lambertii.

Oxytropis lambertii has been considered to be one of the major locoweeds responsible for livestock poisoning on rangelands, but there has been much confusion as to its taxonomic identity. The objective of this study was to conduct a field survey of several populations of each of the three varieties [var. lambertii Pursh; var higelovii A. Gray; var. articulata (E. Greene) Barneby] to document the presence or absence of the locoweed toxin, swainsonine. Swainsonine was found at detectable levels (>0.001% dry weight) in only five populations of var. higelovii in the southwest portion of its distribution in southern Utah, Arizona, and southwestern New Mexico, USA. No swainsonine was detected in populations in the northeast areas of its distribution (eastern Utah, Colorado, northeastern New Mexico, USA). The other varieties, articulata and lambertii, also did not contain swainsonine. It is suspected that a plant fungal endophyte may be responsible for the high variability in swainsonine content in populations of O. lambertii.

Complementary and alternative groups contemplate the need for effectiveness, safety and cost-effectiveness research.

OBJECTIVE: To examine the views of complementary and alternative medicine (CAM) groups on the need to demonstrate the effectiveness, safety and cost-effectiveness of their therapies and practices. DESIGN: Qualitative interviews were conducted with 22 representatives of three CAM groups (chiropractic, homeopathy and Reiki). Qualitative content analysis was used to identify similarities and differences among and across groups. SETTING: Ontario, Canada. RESULTS: There were striking differences in the views of the three sets of respondents. The chiropractors agreed that it was essential for their group to provide scientific evidence that their interventions work, are safe and cost-effective. The leaders of the homeopathic group were divided on these points and the Reiki respondents showed virtually no interest in undertaking such research. CONCLUSIONS: CAM groups that are more formally organized are most likely to recognize the importance of scientific research on their practices and therapies.

A randomised trial comparing cytomegalovirus antigenemia assay vs screening bronchoscopy for the early detection and prevention of disease in allogeneic bone marrow and peripheral blood stem cell transplant recipients.

Preemptive antiviral therapy is often employed for CMV prevention following allogeneic BMT. Two common strategies are a screening bronchoscopy for CMV post-BMT or regular CMV antigenemia testing with ganciclovir administration for a positive result. In a randomised trial, we prospectively compared the efficacy of these two preemptive strategies. Consecutive patients were randomised to either a bronchoscopy for CMV on day 35 post BMT or weekly CMV antigenemia testing. If the bronchoscopy was positive for CMV, patients received preemptive ganciclovir for 8-10 weeks. If the antigenemia was positive for CMV, patients received a minimum of 2 weeks of preemptive ganciclovir. The primary endpoint was the development of active CMV disease. One hundred and eighteen allogeneic BMT patients were enrolled (60 in the antigenemia arm and 58 in the bronchoscopy arm). The two groups were comparable with respect to baseline demographic data, underlying disease, conditioning regimen, and immunosuppression. Active CMV disease developed in 7/58 (12.1%) patients in the bronchoscopy arm vs 1/60 patients (1.7%) in the CMV antigenemia arm (P = 0.022). Based on the screening test, 13.8% of patients received preemptive ganciclovir in the bronchoscopy arm vs 48.3% of patients in the antigenemia arm (P < 0.001). There was no significant difference in the rate of graft-versus-host disease, bacteremia, invasive fungal infections or mortality between the two groups. Preemptive therapy based on regular CMV antigenemia monitoring is superior to screening bronchoscopy for the prevention of CMV disease after allogeneic BMT.