Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy.

Research into the disequilibrium of microglial phenotypes has become an area of intense focus in neurodegenerative disease as a potential mechanism that contributes to chronic neuroinflammation and neuronal loss in Parkinson's disease (PD). There is growing evidence that neuroinflammation accompanies and may promote progression of alpha-synuclein (Asyn)-induced nigral dopaminergic (DA) degeneration. From a therapeutic perspective, development of immunomodulatory strategies that dampen overproduction of pro-inflammatory cytokines from chronically activated immune cells and induce a pro-phagocytic phenotype is expected to promote Asyn removal and protect vulnerable neurons. Cannabinoid receptor-2 (CB2) is highly expressed on activated microglia and peripheral immune cells, is upregulated in the substantia nigra of individuals with PD and in mouse models of nigral degeneration. Furthermore, modulation of CB2 protects against rotenone-induced nigral degeneration; however, CB2 has not been pharmacologically and selectively targeted in an Asyn model of PD. Here, we report that 7 weeks of peripheral administration of CB2 inverse agonist SMM-189 reduced phosphorylated (pSer129) alpha-synuclein in the substantia nigra compared to vehicle treatment. Additionally, SMM-189 delayed Asyn-induced immune cell infiltration into the brain as determined by flow cytometry, increased CD68 protein expression, and elevated wound-healing-immune-mediator gene expression. Additionally, peripheral immune cells increased wound-healing non-classical monocytes and decreased pro-inflammatory classical monocytes. In vitro analysis of RAW264.7 macrophages treated with lipopolysaccharide (LPS) and SMM-189 revealed increased phagocytosis as measured by the uptake of fluorescence of pHrodo E. coli bioparticles. Together, results suggest that targeting CB2 with SMM-189 skews immune cell function toward a phagocytic phenotype and reduces toxic aggregated species of Asyn. Our novel findings demonstrate that CB2 may be a target to modulate inflammatory and immune responses in proteinopathies.

High tibial osteotomy combined with cartilage restoration: A systematic review of clinical outcomes and prognostic factors.

Background: Focal chondral defects are often treated with cartilage restoration procedures. Malalignment often accompanies chondral defects. High tibial osteotomy (HTO), classically utilized to treat uni-compartmental knee osteoarthritis, corrects malalignment. HTO combined with cartilage restoration procedures can treat uni-compartmental osteoarthritis and focal chondral defects. Purpose: To assess outcomes of combined HTO and cartilage restoration procedures and review prognostic factors that may assist in preoperative planning and patient counseling. Study design: Systematic Review of published literature. Methods: A systematic review of PubMed and Scopus was performed following PRISMA guidelines. Thirty-four papers were included in qualitative considerations. Results: Thirty-four papers that reported the combined outcome of HTO and cartilage repair were included. Twenty of the 34 included papers reported prognostic factors that affected the success or failure of combined HTO and cartilage repair surgery for focal articular defect and uni-compartmental knee osteoarthritis. Cartilage repair techniques that were combined with HTO and included in this review are bone marrow stimulation, allograft transplantation, osteochondral autograft transplantation, autologous chondrocyte implantation, and mesenchymal stem cell implantation. Conclusions: HTO with adjunctive cartilage repair procedures improve clinical outcome scores and restore alignment in patients with medial compartment osteoarthritis and isolated focal chondral defects. HTO with adjunctive cartilage procedures produces optimal results in younger, non-obese patients with focal chondral defects and varus malalignment, without significant lateral compartment and patellofemoral involvement.

Advancing gender inclusivity for Two-Spirit, trans, nonbinary and other gender-diverse blood and plasma donors.

BACKGROUND AND OBJECTIVES: Two-Spirit, trans, nonbinary and other gender-diverse (2STGD) donors face challenges in donation. While many blood operators aim to address these challenges, to date, no empirical study with these donors has been conducted to guide their efforts. This paper reports 2STGD donors' views on a two-step approach asking donors their gender and sex assigned at birth (SAAB), and expanding gender options in donor registration. MATERIALS AND METHODS: A qualitative community-based study was conducted with 2STGD donors (n = 85) in Canada. Semi-structured, in-depth interviews were conducted from July to October 2022, audio-recorded and transcribed. Data were analysed using a thematic analytic framework. RESULTS: Participants were divided on their views of a two-step approach asking gender and SAAB. Themes underlying views in favour of this approach included the following: demonstrating validation and visibility, and treating 2STGD donors and cisgender donors alike. Themes underlying views not in favour or uncertain included potential for harm, compromising physical safety, and invalidation. All participants were in favour of expanding gender options if blood operators must know donors' gender. CONCLUSION: Results indicate that a two-step approach for all donors is not recommended unless the blood operator must know both a donor's gender and SAAB to ensure donor and/or recipient safety. Gender options should be expanded beyond binary options. Ongoing research and evidence synthesis are needed to determine how best to apply donor safety measures to nonbinary donors.

The effects of COVID-19 on cognitive performance in a community-based cohort: a COVID symptom study biobank prospective cohort study.

Background: Cognitive impairment has been reported after many types of infection, including SARS-CoV-2. Whether deficits following SARS-CoV-2 improve over time is unclear. Studies to date have focused on hospitalised individuals with up to a year follow-up. The presence, magnitude, persistence and correlations of effects in community-based cases remain relatively unexplored. Methods: Cognitive performance (working memory, attention, reasoning, motor control) was assessed in a prospective cohort study of participants from the United Kingdom COVID Symptom Study Biobank between July 12, 2021 and August 27, 2021 (Round 1), and between April 28, 2022 and June 21, 2022 (Round 2). Participants, recruited from the COVID Symptom Study smartphone app, comprised individuals with and without SARS-CoV-2 infection and varying symptom duration. Effects of COVID-19 exposures on cognitive accuracy and reaction time scores were estimated using multivariable ordinary least squares linear regression models weighted for inverse probability of participation, adjusting for potential confounders and mediators. The role of ongoing symptoms after COVID-19 infection was examined stratifying for self-perceived recovery. Longitudinal analysis assessed change in cognitive performance between rounds. Findings: 3335 individuals completed Round 1, of whom 1768 also completed Round 2. At Round 1, individuals with previous positive SARS-CoV-2 tests had lower cognitive accuracy (N = 1737, ß = -0.14 standard deviations, SDs, 95% confidence intervals, CI: -0.21, -0.07) than negative controls. Deficits were largest for positive individuals with ≥12 weeks of symptoms (N = 495, ß = -0.22 SDs, 95% CI: -0.35, -0.09). Effects were comparable to hospital presentation during illness (N = 281, ß = -0.31 SDs, 95% CI: -0.44, -0.18), and 10 years age difference (60-70 years vs. 50-60 years, ß = -0.21 SDs, 95% CI: -0.30, -0.13) in the whole study population. Stratification by self-reported recovery revealed that deficits were only detectable in SARS-CoV-2 positive individuals who did not feel recovered from COVID-19, whereas individuals who reported full recovery showed no deficits. Longitudinal analysis showed no evidence of cognitive change over time, suggesting that cognitive deficits for affected individuals persisted at almost 2 years since initial infection. Interpretation: Cognitive deficits following SARS-CoV-2 infection were detectable nearly two years post infection, and largest for individuals with longer symptom durations, ongoing symptoms, and/or more severe infection. However, no such deficits were detected in individuals who reported full recovery from COVID-19. Further work is needed to monitor and develop understanding of recovery mechanisms for those with ongoing symptoms. Funding: Chronic Disease Research Foundation, Wellcome Trust, National Institute for Health and Care Research, Medical Research Council, British Heart Foundation, Alzheimer's Society, European Union, COVID-19 Driver Relief Fund, French National Research Agency.

Successful Return to Sport and Daily Activities After Suture Augmentation of Both the Anterior Talofibular Ligament and Calcaneofibular Ligament.

Purpose: To evaluate the return to sport and daily activities in addition to clinical outcomes after modification of the Brostöm repair, specifically using suture augmentation for concomitant fixation of both the anterior talofibular ligament and calcaneofibular ligament. Methods: Patients who had grade III ankle sprains and lateral ankle instability, all of whom failed supervised conservative management, were included. Patients underwent a modified Broström procedure consisting of suture augmentation for both the anterior talofibular ligament and calcaneofibular ligament. For clinical outcome evaluation, Foot and Ankle Ability Measure (FAAM) and Karlsson-Peterson Scoring System for Ankle Function questionnaires coupled with questions regarding time of return to sport and level of sports activity were used. Results: Thirty-one patients were included. The differences in preoperative and postoperative FAAM scores for both the Activities of Daily Living subscale and Sports subscale were significant (P < .001). The FAAM Activities of Daily Living score improved from an average of 46.06 preoperatively to 77.49 postoperatively (P < .001, 99% confidence interval, 26.4-36.4). The FAAM Sports score improved from an average of 4 preoperatively to 19.31 postoperatively (P < .001, 99% confidence interval, 11.6-19.0). For the Karlsson-Peterson Scoring System for Ankle Function, the surveyed population reported a mean of 82.74 points out of 100 post-op (standard deviation 20.14). The mean time to return to sport activity was 5.72 months. Mean follow-up time was 24.12 months. Conclusions: This variant Broström procedure with suture anchors and augmentation of both the anterior talofibular ligament and calcaneofibular ligament was effective in helping patients return to their preinjury functionality level in both daily life and sports activity. Level of Clinical Evidence: Level IV, therapeutic case series.

Southern Alaska as a source of atmospheric mineral dust and ice-nucleating particles.

Ice-nucleating particles (INPs) influence cloud radiative properties and climate; however, INP sources and concentrations are poorly constrained, particularly in high-latitude regions. Southern Alaska is a known source of high-latitude dust, but its contribution to atmospheric mineral dust and INP concentrations has not been quantified. We show that glacial dust collected in southern Alaska is an effective ice-nucleating material under conditions relevant for mixed-phase clouds and is more active than low-latitude dust because of a biological component that enhances its activity. We use dispersion modeling to show that this source contributes to the regional INP population and that the dust emitted is transported over a broad area of North America, reaching altitudes where it could cause cloud glaciation. Our results highlight the importance of quantifying emissions and ice-nucleating characteristics of high-latitude dusts and suggest that the ice-nucleating ability of emitted dust in these regions should be represented in models using different parametrizations to low-latitude dust.

Accuracy of radiographic techniques in detection of the calcaneofibular ligament calcaneal insertion for lateral ankle ligament complex surgery.

BACKGROUND: Grade III ankle sprains that fail conservative treatment can require surgical management. Anatomic procedures have been shown to properly restore joint mechanics, and precise localization of insertion sites of the lateral ankle complex ligaments can be determined through radiographic techniques. Ideally, radiographic techniques that are easily reproducible intraoperatively will lead to a consistently well-placed CFL reconstruction in lateral ankle ligament surgery. PURPOSE: To determine the most accurate method to locate the calcaneofibular ligament (CFL) insertion radiographically. METHODS: MRIs of 25 ankles were utilized to identify the "true" insertion of the CFL. Distances between the true insertion and three bony landmarks were measured. Three proposed methods (Best, Lopes, and Taser) for determining the CFL insertion were applied to lateral ankle radiographs. X and Y coordinate distances were measured from the insertion found on each proposed method to the three bony landmarks: the most superior point of the postero-superior surface of the calcaneus, the posterior most aspect of the sinus tarsi, and the distal tip of the fibula. X and Y distances were compared to the true insertion found on MRI. All measurements were made using a picture archiving and communication system. The average, standard deviation, minimum, and maximum were obtained. Statistical analysis was performed using repeated measures ANOVA, and a post hoc analysis was performed with the Bonferroni test. RESULTS: The Best and Taser techniques were found to be closest to the true CFL insertion when combining X and Y distances. For distance in the X direction, there was no significant difference between techniques (P = 0.264). For distance in the Y direction, there was a significant difference between techniques (P = 0.015). For distance in the combined XY direction, there was a significant difference between techniques (P = 0.001). The CFL insertion as determined by the Best method was significantly closer to the true insertion compared to the Lopes method in the Y (P = 0.042) and XY (P = 0.004) directions. The CFL insertion as determined by the Taser method was significantly closer to the true insertion compared to the Lopes method in the XY direction (P = 0.017). There was no significant difference between the Best and Taser methods. CONCLUSION: If the Best and Taser techniques can be readily used in the operating room, they would likely prove the most reliable for finding the true CFL insertion.

Profiling post-COVID-19 condition across different variants of SARS-CoV-2: a prospective longitudinal study in unvaccinated wild-type, unvaccinated alpha-variant, and vaccinated delta-variant populations.

BACKGROUND: Self-reported symptom studies rapidly increased understanding of SARS-CoV-2 during the COVID-19 pandemic and enabled monitoring of long-term effects of COVID-19 outside hospital settings. Post-COVID-19 condition presents as heterogeneous profiles, which need characterisation to enable personalised patient care. We aimed to describe post-COVID-19 condition profiles by viral variant and vaccination status. METHODS: In this prospective longitudinal cohort study, we analysed data from UK-based adults (aged 18-100 years) who regularly provided health reports via the Covid Symptom Study smartphone app between March 24, 2020, and Dec 8, 2021. We included participants who reported feeling physically normal for at least 30 days before testing positive for SARS-CoV-2 who subsequently developed long COVID (ie, symptoms lasting longer than 28 days from the date of the initial positive test). We separately defined post-COVID-19 condition as symptoms that persisted for at least 84 days after the initial positive test. We did unsupervised clustering analysis of time-series data to identify distinct symptom profiles for vaccinated and unvaccinated people with post-COVID-19 condition after infection with the wild-type, alpha (B.1.1.7), or delta (B.1.617.2 and AY.x) variants of SARS-CoV-2. Clusters were then characterised on the basis of symptom prevalence, duration, demography, and previous comorbidities. We also used an additional testing sample with additional data from the Covid Symptom Study Biobank (collected between October, 2020, and April, 2021) to investigate the effects of the identified symptom clusters of post-COVID-19 condition on the lives of affected people. FINDINGS: We included 9804 people from the COVID Symptom Study with long COVID, 1513 (15%) of whom developed post-COVID-19 condition. Sample sizes were sufficient only for analyses of the unvaccinated wild-type, unvaccinated alpha variant, and vaccinated delta variant groups. We identified distinct profiles of symptoms for post-COVID-19 condition within and across variants: four endotypes were identified for infections due to the wild-type variant (in unvaccinated people), seven for the alpha variant (in unvaccinated people), and five for the delta variant (in vaccinated people). Across all variants, we identified a cardiorespiratory cluster of symptoms, a central neurological cluster, and a multi-organ systemic inflammatory cluster. These three main clusers were confirmed in a testing sample. Gastrointestinal symptoms clustered in no more than two specific phenotypes per viral variant. INTERPRETATION: Our unsupervised analysis identified different profiles of post-COVID-19 condition, characterised by differing symptom combinations, durations, and functional outcomes. Our classification could be useful for understanding the distinct mechanisms of post-COVID-19 condition, as well as for identification of subgroups of individuals who might be at risk of prolonged debilitation. FUNDING: UK Government Department of Health and Social Care, Chronic Disease Research Foundation, The Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value-Based Healthcare, UK National Institute for Health Research, UK Medical Research Council, British Heart Foundation, UK Alzheimer's Society, and ZOE.

A highly active mineral-based ice nucleating agent supports in situ cell cryopreservation in a high throughput format.

Cryopreservation of biological matter in microlitre scale volumes of liquid would be useful for a range of applications. At present, it is challenging because small volumes of water tend to supercool, and deep supercooling is known to lead to poor post-thaw cell viability. Here, we show that a mineral ice nucleator can almost eliminate supercooling in 100 µl liquid volumes during cryopreservation. This strategy of eliminating supercooling greatly enhances cell viability relative to cryopreservation protocols with uncontrolled ice nucleation. Using infrared thermography, we demonstrate a direct relationship between the extent of supercooling and post-thaw cell viability. Using a mineral nucleator delivery system, we open the door to the routine cryopreservation of mammalian cells in multiwell plates for applications such as high throughput toxicology testing of pharmaceutical products and regenerative medicine.

Opening wedge high tibial osteotomy for medial compartment knee osteoarthritis: Planning and improving outcomes: Case series and literature review.

Background: Opening wedge high tibial osteotomy (OWHTO) is a safe surgical procedure to treat medial compartmental osteoarthritis caused by a varus deformity. Over-correction of this varus deformity can lead to lateral compartment over-loading. In our study, we planned our correction by using the mechanical axis deviation (MAD). Purpose: The purpose of this study is to evaluate the clinical and radiological results of OWHTO based on planning using the MAD measurements. Study Design: Retrospective Case Series. Methods: 14 patients with Kellgren- Lawrence classification (KL) grade 3 or above underwent OWHTO, with plans to have the mechanical axis pass through 5-15 mm lateral to the center of the tibial plateau. Pre-operative and post-operative radiographic measurements were made and compared using the student t-test. SF-36 scores were obtained for clinical performance. Results: Our patients experienced MAD from 25.9 mm medial to the center of the tibial plateau pre-operatively to 12.7 mm lateral to the center of the plateau post-operatively. The mean change in MAD was 38.7 mm (p < 0.0001). The accuracy of our correction compared to the planned MAD was 98.3%. The mechanical axis angle shifted from 7.35° of varus to 3.5° of valgus (p < 0.0001). All patients had post-operative alignments of 1-6° of valgus, with 11 of out the 14 patients with alignments less than 5° of valgus, preventing over-loading of the lateral compartment. Conclusion: Using MAD measurements is an accurate planning method for OWHTO that corrects varus deformity without over-loading the lateral compartment, and leads to improved clinical outcomes.

Post-vaccination infection rates and modification of COVID-19 symptoms in vaccinated UK school-aged children and adolescents: A prospective longitudinal cohort study.

Background: We aimed to explore the effectiveness of one-dose BNT162b2 vaccination upon SARS-CoV-2 infection, its effect on COVID-19 presentation, and post-vaccination symptoms in children and adolescents (CA) in the UK during periods of Delta and Omicron variant predominance. Methods: In this prospective longitudinal cohort study, we analysed data from 115,775 CA aged 12-17 years, proxy-reported through the Covid Symptom Study (CSS) smartphone application. We calculated post-vaccination infection risk after one dose of BNT162b2, and described the illness profile of CA with post-vaccination SARS-CoV-2 infection, compared to unvaccinated CA, and post-vaccination side-effects. Findings: Between August 5, 2021 and February 14, 2022, 25,971 UK CA aged 12-17 years received one dose of BNT162b2 vaccine. The probability of testing positive for infection diverged soon after vaccination, and was lower in CA with prior SARS-CoV-2 infection. Vaccination reduced proxy-reported infection risk (-80·4% (95% CI -0·82 -0·78) and -53·7% (95% CI -0·62 -0·43) at 14-30 days with Delta and Omicron variants respectively, and -61·5% (95% CI -0·74 -0·44) and -63·7% (95% CI -0·68 -0.59) after 61-90 days). Vaccinated CA who contracted SARS-CoV-2 during the Delta period had milder disease than unvaccinated CA; during the Omicron period this was only evident in children aged 12-15 years. Overall disease profile was similar in both vaccinated and unvaccinated CA. Post-vaccination local side-effects were common, systemic side-effects were uncommon, and both resolved within few days (3 days in most cases). Interpretation: One dose of BNT162b2 vaccine reduced risk of SARS-CoV-2 infection for at least 90 days in CA aged 12-17 years. Vaccine protection varied for SARS-CoV-2 variant type (lower for Omicron than Delta variant), and was enhanced by pre-vaccination SARS-CoV-2 infection. Severity of COVID-19 presentation after vaccination was generally milder, although unvaccinated CA also had generally mild disease. Overall, vaccination was well-tolerated. Funding: UK Government Department of Health and Social Care, Chronic Disease Research Foundation, The Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value Based Healthcare, UK National Institute for Health Research, UK Medical Research Council, British Heart Foundation and Alzheimer's Society, and ZOE Limited.

Highly Active Ice-Nucleating Particles at the Summer North Pole.

The amount of ice versus supercooled water in clouds is important for their radiative properties and role in climate feedbacks. Hence, knowledge of the concentration of ice-nucleating particles (INPs) is needed. Generally, the concentrations of INPs are found to be very low in remote marine locations allowing cloud water to persist in a supercooled state. We had expected the concentrations of INPs at the North Pole to be very low given the distance from open ocean and terrestrial sources coupled with effective wet scavenging processes. Here we show that during summer 2018 (August and September) high concentrations of biological INPs (active at >-20°C) were sporadically present at the North Pole. In fact, INP concentrations were sometimes as high as those recorded at mid-latitude locations strongly impacted by highly active biological INPs, in strong contrast to the Southern Ocean. Furthermore, using a balloon borne sampler we demonstrated that INP concentrations were often different at the surface versus higher in the boundary layer where clouds form. Back trajectory analysis suggests strong sources of INPs near the Russian coast, possibly associated with wind-driven sea spray production, whereas the pack ice, open leads, and the marginal ice zone were not sources of highly active INPs. These findings suggest that primary ice production, and therefore Arctic climate, is sensitive to transport from locations such as the Russian coast that are already experiencing marked climate change.

Cutaneous manifestations of SARS-CoV-2 infection during the Delta and Omicron waves in 348 691 UK users of the UK ZOE COVID Study app.

BACKGROUND: Symptoms of SARS-CoV-2 infection have differed during the different waves of the pandemic but little is known about how cutaneous manifestations have changed. OBJECTIVES: To investigate the diagnostic value, frequency and duration of cutaneous manifestations of SARS-CoV-2 infection and to explore their variations between the Delta and Omicron waves of the pandemic. METHODS: In this retrospective study, we used self-reported data from 348 691 UK users of the ZOE COVID Study app, matched 1 : 1 for age, sex, vaccination status and self-reported eczema diagnosis between the Delta and Omicron waves, to assess the diagnostic value, frequency and duration of five cutaneous manifestations of SARS-CoV-2 infection (acral, burning, erythematopapular and urticarial rash, and unusual hair loss), and how these changed between waves. We also investigated whether vaccination had any effect on symptom frequency. RESULTS: We show a significant association between any cutaneous manifestations and a positive SARS-CoV-2 test result, with a diagnostic value higher in the Delta compared with the Omicron wave (odds ratio 2·29, 95% confidence interval 2·22-2·36, P < 0·001; and odds ratio 1·29, 95% confidence interval 1·26-1·33, P < 0·001, respectively). Cutaneous manifestations were also more common with Delta vs. Omicron (17·6% vs. 11·4%, respectively) and had a longer duration. During both waves, cutaneous symptoms clustered with other frequent symptoms and rarely (in < 2% of the users) as first or only clinical sign of SARS-CoV-2 infection. Finally, we observed that vaccinated and unvaccinated users showed similar odds of presenting with a cutaneous manifestation, apart from burning rash, where the odds were lower in vaccinated users. CONCLUSIONS: Cutaneous manifestations are predictive of SARS-CoV-2 infection, and their frequency and duration have changed with different variants. Therefore, we advocate for their inclusion in the list of clinically relevant COVID-19 symptoms and suggest that their monitoring could help identify new variants. What is already known about this topic? Several studies during the wildtype COVID-19 wave reported that patients presented with common skin-related symptoms. It has been observed that COVID-19 symptoms differ among variants. No study has focused on how skin-related symptoms have changed across different variants. What does this study add? We showed, in a community-based retrospective study including over 348 000 individuals, that the presence of cutaneous symptoms is predictive of SARS-CoV-2 infection during the Delta and Omicron waves and that this diagnostic value, along with symptom frequency and duration, differs between variants. We showed that infected vaccinated and unvaccinated individuals reported similar skin-related symptoms during the Delta and Omicron waves, with only burning rashes being less common after vaccination.

COVID-19 due to the B.1.617.2 (Delta) variant compared to B.1.1.7 (Alpha) variant of SARS-CoV-2: a prospective observational cohort study.

The Delta (B.1.617.2) variant was the predominant UK circulating SARS-CoV-2 strain between May and December 2021. How Delta infection compares with previous variants is unknown. This prospective observational cohort study assessed symptomatic adults participating in the app-based COVID Symptom Study who tested positive for SARS-CoV-2 from May 26 to July 1, 2021 (Delta overwhelmingly the predominant circulating UK variant), compared (1:1, age- and sex-matched) with individuals presenting from December 28, 2020 to May 6, 2021 (Alpha (B.1.1.7) the predominant variant). We assessed illness (symptoms, duration, presentation to hospital) during Alpha- and Delta-predominant timeframes; and transmission, reinfection, and vaccine effectiveness during the Delta-predominant period. 3581 individuals (aged 18 to 100 years) from each timeframe were assessed. The seven most frequent symptoms were common to both variants. Within the first 28 days of illness, some symptoms were more common with Delta versus Alpha infection (including fever, sore throat, and headache) and some vice versa (dyspnoea). Symptom burden in the first week was higher with Delta versus Alpha infection; however, the odds of any given symptom lasting ≥ 7 days was either lower or unchanged. Illness duration ≥ 28 days was lower with Delta versus Alpha infection, though unchanged in unvaccinated individuals. Hospitalisation for COVID-19 was unchanged. The Delta variant appeared more (1.49) transmissible than Alpha. Re-infections were low in all UK regions. Vaccination markedly reduced the risk of Delta infection (by 69-84%). We conclude that COVID-19 from Delta or Alpha infections is similar. The Delta variant is more transmissible than Alpha; however, current vaccines showed good efficacy against disease. This research framework can be useful for future comparisons with new emerging variants.

Illness Characteristics of COVID-19 in Children Infected with the SARS-CoV-2 Delta Variant.

BACKGROUND: The Delta (B.1.617.2) SARS-CoV-2 variant was the predominant UK circulating strain between May and November 2021. We investigated whether COVID-19 from Delta infection differed from infection with previous variants in children. METHODS: Through the prospective COVID Symptom Study, 109,626 UK school-aged children were proxy-reported between 28 December 2020 and 8 July 2021. We selected all symptomatic children who tested positive for SARS-CoV-2 and were proxy-reported at least weekly, within two timeframes: 28 December 2020 to 6 May 2021 (Alpha (B.1.1.7), the main UK circulating variant) and 26 May to 8 July 2021 (Delta, the main UK circulating variant), with all children unvaccinated (as per national policy at the time). We assessed illness profiles (symptom prevalence, duration, and burden), hospital presentation, and presence of long (≥28 day) illness, and calculated odds ratios for symptoms presenting within the first 28 days of illness. RESULTS: 694 (276 younger (5-11 years), 418 older (12-17 years)) symptomatic children tested positive for SARS-CoV-2 with Alpha infection and 706 (227 younger and 479 older) children with Delta infection. Median illness duration was short with either variant (overall cohort: 5 days (IQR 2-9.75) with Alpha, 5 days (IQR 2-9) with Delta). The seven most prevalent symptoms were common to both variants. Symptom burden over the first 28 days was slightly greater with Delta compared with Alpha infection (in younger children, 3 (IQR 2-5) symptoms with Alpha, 4 (IQR 2-7) with Delta; in older children, 5 (IQR 3-8) symptoms with Alpha, 6 (IQR 3-9) with Delta infection ). The odds of presenting several symptoms were higher with Delta than Alpha infection, including headache and fever. Few children presented to hospital, and long illness duration was uncommon, with either variant. CONCLUSIONS: COVID-19 in UK school-aged children due to SARS-CoV-2 Delta strain B.1.617.2 resembles illness due to the Alpha variant B.1.1.7., with short duration and similar symptom burden.

Volcanic ash ice nucleation activity is variably reduced by aging in water and sulfuric acid: the effects of leaching, dissolution, and precipitation.

Volcanic ash nucleates ice when immersed in supercooled water droplets, giving it the potential to influence weather and climate from local to global scales. This ice nucleation activity (INA) is likely derived from a subset of the crystalline mineral phases in the ash. The INA of other mineral-based dusts can change when exposed to various gaseous and aqueous chemical species, many of which also interact with volcanic ash in the eruption plume and atmosphere. However, the effects of aqueous chemical aging on the INA of volcanic ash have not been explored. We show that the INA of two mineralogically distinct ash samples from Fuego and Astroni volcanoes is variably reduced following immersion in water or aqueous sulfuric acid for minutes to days. Aging in water decreases the INA of both ash samples by up to two orders of magnitude, possibly due to a reduction in surface crystallinity and cation availability accompanying leaching. Aging in sulfuric acid leads to minimal loss of INA for Fuego ash, which is proposed to reflect a quasi-equilibrium between leaching that removes ice-active sites and dissolution that reveals or creates new sites on the pyroxene phases present. Conversely, exposure to sulfuric acid reduces the INA of Astroni ash by one to two orders of magnitude, potentially through selective dissolution of ice-active sites associated with surface microtextures on some K-feldspar phases. Analysis of dissolved element concentrations in the aged ash leachates shows supersaturation of certain mineral species which could have precipitated and altered the INA of the ash. These results highlight the key role that leaching, dissolution, and precipitation likely play in the aqueous aging of volcanic ash with respect to its INA. Finally, we discuss the implications for understanding the nature and reactivity of ice-active sites on volcanic ash and its role in influencing cloud properties in the atmosphere.

Individual Factors Including Age, BMI, and Heritable Factors Underlie Temperature Variation in Sickness and in Health: An Observational, Multi-cohort Study.

BACKGROUND: Aging affects immunity, potentially altering fever response to infection. We assess effects of biological variables on basal temperature, and during COVID-19 infection, proposing an updated temperature threshold for older adults ≥65 years. METHODS: Participants were from 4 cohorts: 1 089 unaffected adult TwinsUK volunteers; 520 adults with emergency admission to a London hospital with RT-PCR confirmed SARS-CoV-2 infection; 757 adults with emergency admission to a Birmingham hospital with RT-PCR confirmed SARS-CoV-2 infection and 3 972 adult community-based COVID Symptom Study participants self-reporting a positive RT-PCR test. Heritability was assessed using saturated and univariate ACE models; mixed-effect and multivariable linear regression examined associations between temperature, age, sex, and body mass index (BMI); multivariable logistic regression examined associations between fever (≥37.8°C) and age; receiver operating characteristic (ROC) analysis was used to identify temperature threshold for adults ≥ 65 years. RESULTS: Among unaffected volunteers, lower BMI (p = .001), and increasing age (p < .001) was associated with lower basal temperature. Basal temperature showed a heritability of 47% (95% confidence interval 18%-57%). In COVID-19+ participants, increasing age was associated with lower temperatures in Birmingham and community-based cohorts (p < .001). For each additional year of age, participants were 1% less likely to demonstrate a fever ≥37.8°C (OR 0.99; p < .001). Combining healthy and COVID-19+ participants, a temperature of 37.4°C in adults ≥65 years had similar sensitivity and specificity to 37.8°C in adults <65 years for discriminating infection. CONCLUSIONS: Aging affects temperature in health and acute infection, with significant heritability, indicating genetic factors contribute to temperature regulation. Our observations suggest a lower threshold (37.4°C/97.3°F) for identifying fever in older adults ≥65 years.

Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study.

BACKGROUND: COVID-19 vaccines show excellent efficacy in clinical trials and effectiveness in real-world data, but some people still become infected with SARS-CoV-2 after vaccination. This study aimed to identify risk factors for post-vaccination SARS-CoV-2 infection and describe the characteristics of post-vaccination illness. METHODS: This prospective, community-based, nested, case-control study used self-reported data (eg, on demographics, geographical location, health risk factors, and COVID-19 test results, symptoms, and vaccinations) from UK-based, adult (≥18 years) users of the COVID Symptom Study mobile phone app. For the risk factor analysis, cases had received a first or second dose of a COVID-19 vaccine between Dec 8, 2020, and July 4, 2021; had either a positive COVID-19 test at least 14 days after their first vaccination (but before their second; cases 1) or a positive test at least 7 days after their second vaccination (cases 2); and had no positive test before vaccination. Two control groups were selected (who also had not tested positive for SARS-CoV-2 before vaccination): users reporting a negative test at least 14 days after their first vaccination but before their second (controls 1) and users reporting a negative test at least 7 days after their second vaccination (controls 2). Controls 1 and controls 2 were matched (1:1) with cases 1 and cases 2, respectively, by the date of the post-vaccination test, health-care worker status, and sex. In the disease profile analysis, we sub-selected participants from cases 1 and cases 2 who had used the app for at least 14 consecutive days after testing positive for SARS-CoV-2 (cases 3 and cases 4, respectively). Controls 3 and controls 4 were unvaccinated participants reporting a positive SARS-CoV-2 test who had used the app for at least 14 consecutive days after the test, and were matched (1:1) with cases 3 and 4, respectively, by the date of the positive test, health-care worker status, sex, body-mass index (BMI), and age. We used univariate logistic regression models (adjusted for age, BMI, and sex) to analyse the associations between risk factors and post-vaccination infection, and the associations of individual symptoms, overall disease duration, and disease severity with vaccination status. FINDINGS: Between Dec 8, 2020, and July 4, 2021, 1 240 009 COVID Symptom Study app users reported a first vaccine dose, of whom 6030 (0·5%) subsequently tested positive for SARS-CoV-2 (cases 1), and 971 504 reported a second dose, of whom 2370 (0·2%) subsequently tested positive for SARS-CoV-2 (cases 2). In the risk factor analysis, frailty was associated with post-vaccination infection in older adults (≥60 years) after their first vaccine dose (odds ratio [OR] 1·93, 95% CI 1·50-2·48; p<0·0001), and individuals living in highly deprived areas had increased odds of post-vaccination infection following their first vaccine dose (OR 1·11, 95% CI 1·01-1·23; p=0·039). Individuals without obesity (BMI <30 kg/m2) had lower odds of infection following their first vaccine dose (OR 0·84, 95% CI 0·75-0·94; p=0·0030). For the disease profile analysis, 3825 users from cases 1 were included in cases 3 and 906 users from cases 2 were included in cases 4. Vaccination (compared with no vaccination) was associated with reduced odds of hospitalisation or having more than five symptoms in the first week of illness following the first or second dose, and long-duration (≥28 days) symptoms following the second dose. Almost all symptoms were reported less frequently in infected vaccinated individuals than in infected unvaccinated individuals, and vaccinated participants were more likely to be completely asymptomatic, especially if they were 60 years or older. INTERPRETATION: To minimise SARS-CoV-2 infection, at-risk populations must be targeted in efforts to boost vaccine effectiveness and infection control measures. Our findings might support caution around relaxing physical distancing and other personal protective measures in the post-vaccination era, particularly around frail older adults and individuals living in more deprived areas, even if these individuals are vaccinated, and might have implications for strategies such as booster vaccinations. FUNDING: ZOE, the UK Government Department of Health and Social Care, the Wellcome Trust, the UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging and Artificial Intelligence Centre for Value Based Healthcare, the UK National Institute for Health Research, the UK Medical Research Council, the British Heart Foundation, and the Alzheimer's Society.