Early but reversible haemostatic changes in a-symptomatic females expressing COVID-19 antibodies.

The coronavirus, COVID-19 pandemic spread across the globe in 2020, with an initial high case mortality in those requiring intensive care treatment due to serious complication. A vaccine programme was quickly developed and currently the UK is one of highest double vaccinated and boosted countries in the world. Despite tremendous efforts by the UK, new cases of COVID-19 are still occurring, due to viral mutation. A major problem associated with COVID-19 is the large a-symptomatic spread within the population. Little investigation into the a-symptomatic population has been carried out and therefore we pose that the residual effects of a-symptomatic infection is still largely unknown. Prior to mass vaccination, a multi-phased single cohort study of IgM and IgG COVID-19 antibody prevalence and the associated haemostatic changes were assessed in a Welsh cohort of 739 participants, at three time points. Positive antibody participants with age and gender matched negative antibody controls were assessed at 0, 3 and 6 months. Antibody positive females appeared to have lower antibody responses in comparison to their a-symptomatic male counterparts. Despite this initial testing showed a unique significant increase in TRAP-6-induced platelet aggregation, prothrombin time (PT) and clot initiation time. Despite coagulation parameters beginning to return to normal at 3 months, significant decreases are observed in both haemoglobin and haematocrit levels. The production of extracellular vesicles (EV) was also determined in this study. Although the overall number of EV does not change throughout the study, at the initial 0 months' time point a significant increase in the percentage of circulating pro-coagulant platelet derived EV is seen, which does not appear to be related to the extent of platelet activation in the subject. We conclude that early, but reversible changes in haemostatic pathways within the a-symptomatic, female, antibody positive COVID-19 individuals are present. These changes may be key in identifying a period of pro-coagulative risk for a-symptomatic female patients.

3-D ocean particle tracking modeling reveals extensive vertical movement and downstream interdependence of closed areas in the northwest Atlantic.

Novel 3-D passive particle tracking experiments were performed in the northwest Atlantic to elucidate connectivity among areas closed to protect vulnerable marine ecosystems. We examined (1) the degree of vertical movement of particles released at different depths and locations; (2) the location of potential source populations for the deep-sea taxa protected by the closures; and (3) the degree of functional connectivity. A long-term oceanographic dataset (EN4) was queried to characterize the temperature and salinity regimes in each of the closed areas as a basis for interpreting recently published climate change projections. Using the Parcels Lagrangian particle tracking framework and the BNAM hydrodynamic model, we found enhanced connectivity over previously developed 2-D models and unexpected, current-driven, strong (to a maximum of about 1340 m) downward displacement at depth (450, 1000 and 2250 m), with weaker upward displacement except for the release depth of 2250 m which showed upward movement of 955 m with a drift duration of 3 months. The current velocities create down-stream interdependence among closed areas and allow redundancy to develop in some of the areas of the network, with some of the larger areas also showing retention. Source populations for sponges in the upstream closure are likely in adjacent waters of the Canadian continental shelf. Collectively this information can be used to inform management decisions related to the size and placement of these closed areas, and vertical velocity surfaces have potential for use in species distribution modeling of benthic species and habitats.

Growth of single-layer boron nitride dome-shaped nanostructures catalysed by iron clusters.

We report on the growth and formation of single-layer boron nitride dome-shaped nanostructures mediated by small iron clusters located on flakes of hexagonal boron nitride. The nanostructures were synthesized in situ at high temperature inside a transmission electron microscope while the e-beam was blanked. The formation process, typically originating at defective step-edges on the boron nitride support, was investigated using a combination of transmission electron microscopy, electron energy loss spectroscopy and computational modelling. Computational modelling showed that the domes exhibit a nanotube-like structure with flat circular caps and that their stability was comparable to that of a single boron nitride layer.

Pain fiber anesthetic reduces brainstem Fos after tooth extraction.

We recently demonstrated that pain-sensing neurons in the trigeminal system can be selectively anesthetized by co-application of QX-314 with the TRPV1 receptor agonist, capsaicin (QX cocktail). Here we examined whether this new anesthetic strategy can block the neuronal changes in the brainstem following molar tooth extraction in the rat. Adult male Sprague-Dawley rats received infiltration injection of anesthetic 10 min prior to lower molar tooth extraction. Neuronal activation was determined by immunohistochemistry for the proto-oncogene protein c-Fos in transverse sections of the trigeminal subnucleus caudalis (Sp5C). After tooth extraction, c-Fos-like immunoreactivity (Fos-LI) detected in the dorsomedial region of bilateral Sp5C was highest at 2 hrs (p < .01 vs. naïve ipsilateral) and declined to pre-injury levels by 8 hrs. Pre-administration of the QX cocktail significantly reduced to sham levels Fos-LI examined 2 hrs after tooth extraction; reduced Fos-LI was also observed with the conventional local anesthetic lidocaine. Pulpal anesthesia by infiltration injection was confirmed by inhibition of the jaw-opening reflex in response to electrical tooth pulp stimulation. Our results suggest that the QX cocktail anesthetic is effective in reducing neuronal activation following tooth extraction. Thus, a selective pain fiber 'nociceptive anesthetic' strategy may provide an effective local anesthetic option for dental patients in the clinic.

Adverse ophthalmic reaction in poppers users: case series of 'poppers maculopathy'.

BACKGROUND: Poppers are a recreational substance of abuse belonging to the alkyl nitrite family of compounds. In the United Kingdom, where they are legal to purchase but illegal to sell for human consumption, 10% of the general population have tried them. They are considered low risk to physical and mental health. Two recent case series from France demonstrated foveal pathology in individuals associated with poppers use. METHOD: A case series of seven patients presenting to four hospitals in the United Kingdom with visual impairment and maculopathy associated with inhalation of poppers. RESULTS: All patients experienced visual symptoms associated with poppers use. The majority had impaired visual acuity, central scotomata, distortion, or phosphenes. Clinical signs on fundoscopy ranged from normal foveal appearance to yellow, dome-shaped lesions at the foveola. Spectral domain optical coherence tomography (SD-OCT) showed varying degrees of disruption of the presumed inner segment/outer segment (IS/OS) junction. DISCUSSION: Although poppers have been in use for several decades, in 2007, following legislative changes, there was a change in the most commonly used compound from isobutyl nitrite to isopropyl nitrite. There were no reports of 'poppers maculopathy' before this. Poppers maculopathy may be missed if patients are not directly questioned about their use. The disruption or loss of the presumed IS/OS junction on SD-OCT are a characteristic feature. Further study of maculopathy in poppers users is now needed. Raising public awareness of the ocular risks associated with their use may be necessary.

Defects in lymphocyte subsets and serological memory persist a median of 10 years after high-dose therapy and autologous progenitor cell rescue for malignant lymphoma.

The number of survivors having undergone high-dose therapy (HDT) followed by auto-SCT continues to increase, although some of the long-term sequelae remain incompletely understood. The immunological status and quality of life of 37 HDT/auto-SCT survivors with lymphoma in continuous remission of ≥3 years were assessed alongside 14 age-matched controls. At a median follow-up of 10.5 years (range 2.2-20.2) following HDT/auto-SCT, the proportion of CD4(+) cells remained significantly reduced in patients compared with controls (median 43.4% vs 62.5%, respectively; P = < 0.001), predominantly a result of sustained reduction in the naive CD4(+) component (P < 0.001). Naive CD8(+) lymphocytes (P = 0.014) and transitional B cells (P = 0.008) were also significantly reduced, but differences in other lymphocyte subsets were not observed. Uptake of revaccination following HDT/auto-SCT was sporadic; between 11% and 33% of patients had serological titres outside the protective ranges for five of six routinely used vaccines. In the main, patients were found to have a good quality of life, although their EORTC QLQ-C30 questionnaire scores were significantly lower for the physical and social functioning domains compared with controls. Ten years after HDT/auto-SCT immunological deficits persist; to avoid excess risk of preventable disease, serological immunity should be assessed post HDT/auto-SCT followed by appropriate revaccination.

Blood feeding in juvenile Paragnathia formica (Isopoda: Gnathiidae): biochemical characterization of trypsin inhibitors, detection of anticoagulants, and molecular identification of fish hosts.

The 3 post-marsupial juvenile stages of the gnathiid isopod, Paragnathia formica, are haematophagous ectoparasites of fishes that may, in heavy infestations, cause host mortality. Protein digestion in fed stage 3 juveniles is accomplished by cysteine proteinases, but what bioactive compounds attenuate host haemostatic, inflammatory and immunological responses during feeding is unknown. Trypsin inhibitory activity and anticoagulant activity were detected in crude extracts of unfed P. formica stage 1 juveniles; fractionation of stage 1 crude extracts by ion exchange chromatography resulted in 3 preparations each displaying these bioactivities. Further characterization revealed anti-thrombin activity in 2 of these preparations, whilst the third displayed the strongest anticoagulant activity that targeted a factor of the intrinsic coagulation pathway. Three trypsin inhibitors (18 kDa, 21 kDa, and 22 kDa) were also detected using reverse zymography. In parallel, homogenates of fed stage 2 and 3 juveniles were used to identify their fish hosts by amplifying the 16S mitochondrial rDNA and 18S genomic rDNA vertebrate gene regions. Blood from at least 4 fish families had been ingested by separate individuals during feeding. This study demonstrates that trypsin inhibitors and anticoagulants are present in P. formica juveniles which could suppress host haemostatic, inflammatory and immunological responses during feeding, and that juveniles are not host specific.

Changes to colour vision on exposure to high altitude.

OBJECTIVES: Several studies have shown deterioration in colour vision at altitudes above 3,000m. These studies have been conducted in photopic (bright daylight) conditions, whereas many military operations take place in mesopic (dim light) conditions. Data suggests that the tritan colour vision axis (blue cones, TA) are more susceptible to hypoxic insult than protan axis (red cones, PA). The objective of this study was to examine colour vision at high altitude, in mesopic conditions, and using a novel method of assessment to discriminate between the tritan and protan axis. METHODS: We examined 42 eyes (21 subjects, mean age 44, range 22-71), at sea level and within 12-36 hours of exposure to 3300m. This was done in a darkened room, with refractive error correction. Colour vision was studied using ChromaTest, a software programme that analyzes colour contrast threshold (CCT) of both TA and PA. We planned to repeat CCT measurement at 4,392m, but technology failure prevented this. Non-parametric paired data was examined using the Wilcoxon signed rank test. RESULTS: There was found to be no change to either the PA (p = 0.409) or the TA (p = 0.871) upon ascent. Within the PA 16 eyes had a lower CCT at high altitude, whilst 26 were higher. In the TA 20 eyes had a lower CCT and 22 were higher. At sea level, mean CCT for PA was 4.21 (SD 2.29) TA was 7.06 (SD 1.77). At 3,300m mean CCT for PA was 4.36 (SD 2.86) and TA was 6.93 (SD 2.39). CONCLUSIONS: This experiment revealed no changes to colour vision with exposure to 3,300m. This may be below the threshold altitude for cone dysfunction, alternatively colour vision deterioration may be less significant in mesopic conditions.

Hemoproteids (Apicomplexa: Haemoproteidae) from South African tortoises (Cryptodira: Testudinidae).

Terrestrial tortoises, Chersina angulata (Schweigger, 1812), Kinixys belliana belliana Gray, 1831, K. lobatsiana Power, 1927, K. natalensis Hewitt, 1935, and Stigmochelys pardalis (Bell, 1828), both wild (n  =  84) and captive (n  =  70), were examined for hematozoans from the provinces of Gauteng, Kwazulu-Natal, North West, and Western Cape, South Africa. In Giemsa-stained blood films, 2 species of hemoproteids were identified, 1 previously described, that is, Haemoproteus testudinalis ( Laveran, 1905 ) Wenyon, 1915, the other unknown. Haemoproteus testudinalis occurred in 2/27 wild K. lobatsiana and 1/41 S. pardalis and 2/2 captive K. lobatsiana from the North West and Gauteng, respectively, whereas Haemoproteus sp. A was recorded in 1 of 3 captive K. natalensis from Kwazulu-Natal. Haemoproteus testudinalis had pale blue-stained, often vacuolated, halteridial macrogametocytes, pale pink-stained microhalterdial to halteridial microgametocytes, and dark, scattered, often bacillus-like hemozoin granules. Haemoproteus natalensis n. sp. had ameboid growth stages, blue-stained halteridial to circumnuclear macrogametocytes, purple-stained circumnuclear microgametocytes, and brownish, often clustered, pigment granules. It is recommended that Haemoproteus balazuci Dias, 1953, become a junior synonym of H. testudinalis.

Strategies for endometrial screening in the Lynch syndrome population: a patient acceptability study.

Lynch syndrome is an autosomal dominant syndrome accounting for 2-5% of all colorectal cancer. In addition, women with Lynch syndrome have a substantially increased risk of developing endometrial cancer particularly pre-menopausally when symptom detection is more difficult. Current recommendations are that screening for endometrial cancer be offered to women identified to be at risk. The aim of the study was to assess the relative patient acceptability of the available screening modalities. A survey of the perception of the associated pain or discomfort associated with different screening modalities was conducted. Transvaginal ultrasonography was associated with less discomfort than hysteroscopy or Pipelle biopsy, and would be the single test of choice for the majority. There was no significant difference between the pain scores for hysteroscopy and Pipelle biopsy. Issues relating to test acceptability specific to this population are described. Patient acceptability of screening modalities should form an integral part of studies assessing the effectiveness of endometrial screening in the Lynch syndrome population.

First record of a Kabatana sp. microsporidium infecting fish in the Atlantic Ocean.

Two-spotted goby Gobiusculus flavescens from the Swedish Gullmarsfjord regularly present subcutaneous creamy-white patches in the body musculature, associated with Kabatana sp. infection. Analysis of the 16S rRNA gene of the microsporidium showed 98.54% homology with Kabatana newberryi infecting a marine goby from California, indicating that the Swedish microsporidium is either a different strain of K. newberryi or a closely related species. This represents the first record of a Kabatana species in the Atlantic Ocean. The genetic similarity of the 2 microsporidia was paralleled by close infection phenotypes. Infected muscle fibres were swollen compared to adjacent non-infected fibres, and mature spore masses were found throughout the skeletal musculature. No xenoma formation was detected. Since G. flavescens is an established model species in behavioural ecology, the host-parasite system is ideally suited for testing how microsporidian infections affect host behaviour and fitness.

Immunological tolerance and the autoimmune response.

The discovery by McIntire and Faulk of masked autoantibodies calls into question the mechanisms of self recognition that exist in the human body. Their finding is reviewed in relation to three other facets of the interaction of humans with the foreign agencies with which they come in contact, innate immunity, microchimaerism and communicable disease-causing infections. It is concluded that the capacity to respond to foreign agencies may not primarily be defensive and that self recognition is probably an active process rather than dependent on elimination of self reactive capacity.

Minimally invasive and selective hydrodynamic gene therapy of liver segments in the pig and human.

This paper highlights our experience of the transfer of hydrodynamic gene therapy (HGT) from the large animal, the pig, into clinical practice. The modification of balloon catheters and the development of a minimally invasive technique to allow selective isolation of liver segments for HGT in the large animal and human are described. Finally, our preliminary results from a phase I clinical study of HGT for thrombopoietin (TPO) in cirrhotic patients with thrombocytopenia are discussed. Based on these provisional data, minimally invasive selective HGT of liver segments appears to be technically safe, but further work is required to optimize the efficiency of gene transfer in order to achieve clinical benefit.

Radioimmunotherapy for B-cell lymphoma: Y90 ibritumomab tiuxetan and I(131) tositumomab.

Radioimmunotherapy, targeting the CD20 antigen, in B-cell lymphoma has clearly demonstrated efficacy and tolerability over the preceding 15 years. As a result, two products are available with Food and Drug Administration approval for marketing - Y(90) ibritumomab tiuxetan and I(131) tositumomab, given as the Zevalin and Bexxar therapeutic regimens, respectively. Both demonstrate high-response rates and durability of remission in the relapsed/refractory disease setting. Data are emerging regarding their utility as initial therapy, and furthermore, they are been investigated for use sequentially with chemotherapy, and in the myeloablative setting. As yet however, how to best use these agents in the clinical disease course remains uncertain.