Covid-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant.

BACKGROUND: A rapid increase in coronavirus disease 2019 (Covid-19) cases due to the omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 in highly vaccinated populations has aroused concerns about the effectiveness of current vaccines. METHODS: We used a test-negative case-control design to estimate vaccine effectiveness against symptomatic disease caused by the omicron and delta (B.1.617.2) variants in England. Vaccine effectiveness was calculated after primary immunization with two doses of BNT162b2 (Pfizer-BioNTech), ChAdOx1 nCoV-19 (AstraZeneca), or mRNA-1273 (Moderna) vaccine and after a booster dose of BNT162b2, ChAdOx1 nCoV-19, or mRNA-1273. RESULTS: Between November 27, 2021, and January 12, 2022, a total of 886,774 eligible persons infected with the omicron variant, 204,154 eligible persons infected with the delta variant, and 1,572,621 eligible test-negative controls were identified. At all time points investigated and for all combinations of primary course and booster vaccines, vaccine effectiveness against symptomatic disease was higher for the delta variant than for the omicron variant. No effect against the omicron variant was noted from 20 weeks after two ChAdOx1 nCoV-19 doses, whereas vaccine effectiveness after two BNT162b2 doses was 65.5% (95% confidence interval [CI], 63.9 to 67.0) at 2 to 4 weeks, dropping to 8.8% (95% CI, 7.0 to 10.5) at 25 or more weeks. Among ChAdOx1 nCoV-19 primary course recipients, vaccine effectiveness increased to 62.4% (95% CI, 61.8 to 63.0) at 2 to 4 weeks after a BNT162b2 booster before decreasing to 39.6% (95% CI, 38.0 to 41.1) at 10 or more weeks. Among BNT162b2 primary course recipients, vaccine effectiveness increased to 67.2% (95% CI, 66.5 to 67.8) at 2 to 4 weeks after a BNT162b2 booster before declining to 45.7% (95% CI, 44.7 to 46.7) at 10 or more weeks. Vaccine effectiveness after a ChAdOx1 nCoV-19 primary course increased to 70.1% (95% CI, 69.5 to 70.7) at 2 to 4 weeks after an mRNA-1273 booster and decreased to 60.9% (95% CI, 59.7 to 62.1) at 5 to 9 weeks. After a BNT162b2 primary course, the mRNA-1273 booster increased vaccine effectiveness to 73.9% (95% CI, 73.1 to 74.6) at 2 to 4 weeks; vaccine effectiveness fell to 64.4% (95% CI, 62.6 to 66.1) at 5 to 9 weeks. CONCLUSIONS: Primary immunization with two doses of ChAdOx1 nCoV-19 or BNT162b2 vaccine provided limited protection against symptomatic disease caused by the omicron variant. A BNT162b2 or mRNA-1273 booster after either the ChAdOx1 nCoV-19 or BNT162b2 primary course substantially increased protection, but that protection waned over time. (Funded by the U.K. Health Security Agency.).

Comparative transmission of SARS-CoV-2 Omicron (B.1.1.529) and Delta (B.1.617.2) variants and the impact of vaccination: national cohort study, England.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (B.1.1.529) rapidly replaced Delta (B.1.617.2) to become dominant in England. Our study assessed differences in transmission between Omicron and Delta using two independent data sources and methods. Omicron and Delta cases were identified through genomic sequencing, genotyping and S-gene target failure in England from 5-11 December 2021. Secondary attack rates for named contacts were calculated in household and non-household settings using contact tracing data, while household clustering was identified using national surveillance data. Logistic regression models were applied to control for factors associated with transmission for both methods. For contact tracing data, higher secondary attack rates for Omicron vs. Delta were identified in households (15.0% vs. 10.8%) and non-households (8.2% vs. 3.7%). For both variants, in household settings, onward transmission was reduced from cases and named contacts who had three doses of vaccine compared to two, but this effect was less pronounced for Omicron (adjusted risk ratio, aRR 0.78 and 0.88) than Delta (aRR 0.62 and 0.68). In non-household settings, a similar reduction was observed only in contacts who had three doses vs. two doses for both Delta (aRR 0.51) and Omicron (aRR 0.76). For national surveillance data, the risk of household clustering, was increased 3.5-fold for Omicron compared to Delta (aRR 3.54 (3.29-3.81)). Our study identified increased risk of onward transmission of Omicron, consistent with its successful global displacement of Delta. We identified a reduced effectiveness of vaccination in lowering risk of transmission, a likely contributor for the rapid propagation of Omicron.

Classification of Lapses in Smokers Attempting to Stop: A Supervised Machine Learning Approach Using Data From a Popular Smoking Cessation Smartphone App.

INTRODUCTION: Smoking lapses after the quit date often lead to full relapse. To inform the development of real time, tailored lapse prevention support, we used observational data from a popular smoking cessation app to develop supervised machine learning algorithms to distinguish lapse from non-lapse reports. AIMS AND METHODS: We used data from app users with ≥20 unprompted data entries, which included information about craving severity, mood, activity, social context, and lapse incidence. A series of group-level supervised machine learning algorithms (eg, Random Forest, XGBoost) were trained and tested. Their ability to classify lapses for out-of-sample (1) observations and (2) individuals were evaluated. Next, a series of individual-level and hybrid algorithms were trained and tested. RESULTS: Participants (N = 791) provided 37 002 data entries (7.6% lapses). The best-performing group-level algorithm had an area under the receiver operating characteristic curve (AUC) of 0.969 (95% confidence interval [CI] = 0.961 to 0.978). Its ability to classify lapses for out-of-sample individuals ranged from poor to excellent (AUC = 0.482-1.000). Individual-level algorithms could be constructed for 39/791 participants with sufficient data, with a median AUC of 0.938 (range: 0.518-1.000). Hybrid algorithms could be constructed for 184/791 participants and had a median AUC of 0.825 (range: 0.375-1.000). CONCLUSIONS: Using unprompted app data appeared feasible for constructing a high-performing group-level lapse classification algorithm but its performance was variable when applied to unseen individuals. Algorithms trained on each individual's dataset, in addition to hybrid algorithms trained on the group plus a proportion of each individual's data, had improved performance but could only be constructed for a minority of participants. IMPLICATIONS: This study used routinely collected data from a popular smartphone app to train and test a series of supervised machine learning algorithms to distinguish lapse from non-lapse events. Although a high-performing group-level algorithm was developed, it had variable performance when applied to new, unseen individuals. Individual-level and hybrid algorithms had somewhat greater performance but could not be constructed for all participants because of the lack of variability in the outcome measure. Triangulation of results with those from a prompted study design is recommended prior to intervention development, with real-world lapse prediction likely requiring a balance between unprompted and prompted app data.

Improved Uranium Particle Analysis by SIMS using O3 - Primary Ions.

We have investigated the use of negative molecular oxygen primary ion beams (i.e., O2 - and O3 -) to determine the benefits of using such beams for uranium particle SIMS analyses. Typically, O- is the most practical negative primary ion species from the conventional duoplasmatron ion source for both age dating and uranium isotopic analysis of particles. Newer RF plasma ion sources make it possible to use O2 - and O3 - due to higher brightness and primary ion fluence, and the increased abundance of molecular species in the plasma relative to the duoplasmatron. We have determined that by using an O3 - beam, the ionization yield can be increased by a factor of approximately two over an O- beam, up to 4.7%, a substantial improvement that positively impacts measurement precision and detection limits. We also investigated the effect of the molecular oxygen beams on uranium isotope mass fractionation and the Th/U relative sensitivity factor for SIMS analyses in comparison to O- beams. We found that O3 - reduced instrumental mass fractionation and matrix/substrate effects relative to the other negative ion beams. Particle measurements using O3 - were improved compared to conventional O- beam analyses due to higher yields, smaller corrections, and reduced substrate effects.

Community transmission of monkeypox in the United Kingdom, April to May 2022.

Between 7 and 25 May, 86 monkeypox cases were confirmed in the United Kingdom (UK). Only one case is known to have travelled to a monkeypox virus (MPXV) endemic country. Seventy-nine cases with information were male and 66 reported being gay, bisexual, or other men who have sex with men. This is the first reported sustained MPXV transmission in the UK, with human-to-human transmission through close contacts, including in sexual networks. Improving case ascertainment and onward-transmission preventive measures are ongoing.

Enhancing epidemiological surveillance of the emergence of the SARS-CoV-2 Omicron variant using spike gene target failure data, England, 15 November to 31 December 2021.

When SARS-CoV-2 Omicron emerged in 2021, S gene target failure enabled differentiation between Omicron and the dominant Delta variant. In England, where S gene target surveillance (SGTS) was already established, this led to rapid identification (within ca 3 days of sample collection) of possible Omicron cases, alongside real-time surveillance and modelling of Omicron growth. SGTS was key to public health action (including case identification and incident management), and we share applied insights on how and when to use SGTS.

The niche of One Health approaches in Lassa fever surveillance and control.

Lassa fever (LF), a zoonotic illness, represents a public health burden in West African countries where the Lassa virus (LASV) circulates among rodents. Human exposure hinges significantly on LASV ecology, which is in turn shaped by various parameters such as weather seasonality and even virus and rodent-host genetics. Furthermore, human behaviour, despite playing a key role in the zoonotic nature of the disease, critically affects either the spread or control of human-to-human transmission. Previous estimations on LF burden date from the 80s and it is unclear how the population expansion and the improvement on diagnostics and surveillance methods have affected such predictions. Although recent data have contributed to the awareness of epidemics, the real impact of LF in West African communities will only be possible with the intensification of interdisciplinary efforts in research and public health approaches. This review discusses the causes and consequences of LF from a One Health perspective, and how the application of this concept can improve the surveillance and control of this disease in West Africa.

Passengers' destinations from China: low risk of Novel Coronavirus (2019-nCoV) transmission into Africa and South America.

Novel Coronavirus (2019-nCoV [SARS-COV-2]) was detected in humans during the last week of December 2019 at Wuhan city in China, and caused 24 554 cases in 27 countries and territories as of 5 February 2020. The objective of this study was to estimate the risk of transmission of 2019-nCoV through human passenger air flight from four major cities of China (Wuhan, Beijing, Shanghai and Guangzhou) to the passengers' destination countries. We extracted the weekly simulated passengers' end destination data for the period of 1-31 January 2020 from FLIRT, an online air travel dataset that uses information from 800 airlines to show the direct flight and passengers' end destination. We estimated a risk index of 2019-nCoV transmission based on the number of travellers to destination countries, weighted by the number of confirmed cases of the departed city reported by the World Health Organization (WHO). We ranked each country based on the risk index in four quantiles (4th quantile being the highest risk and 1st quantile being the lowest risk). During the period, 388 287 passengers were destined for 1297 airports in 168 countries or territories across the world. The risk index of 2019-nCoV among the countries had a very high correlation with the WHO-reported confirmed cases (0.97). According to our risk score classification, of the countries that reported at least one Coronavirus-infected pneumonia (COVID-19) case as of 5 February 2020, 24 countries were in the 4th quantile of the risk index, two in the 3rd quantile, one in the 2nd quantile and none in the 1st quantile. Outside China, countries with a higher risk of 2019-nCoV transmission are Thailand, Cambodia, Malaysia, Canada and the USA, all of which reported at least one case. In pan-Europe, UK, France, Russia, Germany and Italy; in North America, USA and Canada; in Oceania, Australia had high risk, all of them reported at least one case. In Africa and South America, the risk of transmission is very low with Ethiopia, South Africa, Egypt, Mauritius and Brazil showing a similar risk of transmission compared to the risk of any of the countries where at least one case is detected. The risk of transmission on 31 January 2020 was very high in neighbouring Asian countries, followed by Europe (UK, France, Russia and Germany), Oceania (Australia) and North America (USA and Canada). Increased public health response including early case recognition, isolation of identified case, contract tracing and targeted airport screening, public awareness and vigilance of health workers will help mitigate the force of further spread to naïve countries.

Advances in age-dating of individual uranium particles by large geometry secondary ion mass spectrometry.

We present the ability to conduct single micrometer-sized uranium particle age-dating measurements on particles that are younger, smaller, and less enriched in 235U content than previously reported. Specifically, we use large geometry secondary ion mass spectrometry (LG-SIMS) to precisely measure the 230Th/234U radiochronometer, combined with a systematic treatment of relevant parameters such as particle size, enrichment, and age, to achieve this development. We describe the necessary requirements for instrument background, interference rejection, abundance sensitivity, and other instrumental conditions that allow for this advance in single-particle uranium age-dating. We introduce the use of statistics developed by Feldman and Cousins to generate 95% confidence intervals in particle age, even when 230Th daughter ions are not detected. For particles where counts are limited and are of identical isotopic signatures, we provide an option for aggregating individual measurements of single particles to reduce measurement uncertainty, as if the measurement had been performed on one larger particle. The methodology is validated on a range of certified reference materials and 'real-world' samples, ranging in age from 15 to 60 years, and on individual particles ranging in equivalent size from 0.6 to 6.8 micrometers. Additionally, we provide model age calculations for particles ranging in size from 1.0 to 3.0 micrometers across enrichments ranging from natural uranium to highly-enriched uranium and on ages ranging from 0 to 60 years. Experimental results compare well with the predicted model ages, providing realistic guidance for expectations of single micrometer-sized uranium particle age-dating measurements. The age-dating capabilities described herein are directly relevant to the International Atomic Energy Agency (IAEA) and its mission to safeguard nuclear materials and monitor member state nuclear programs.

D-dopachrome tautomerase in adipose tissue inflammation and wound repair.

D-dopachrome tautomerase (D-DT/MIF-2) is a member of the macrophage migration inhibitory factor (MIF) cytokine superfamily, and a close structural homolog of MIF. MIF and D-DT have been reported to be involved in obesity, but there is little known about the regulation of D-DT in adipose tissue inflammation and wound healing. Subcutaneous adipose tissue was collected from 54 healthy donors and 28 donors with acutely inflamed wounds undergoing wound debridement. In addition, epididymal fat pads of mice were injected with lipopolysaccharide to study receptor expression and cell migration in vivo. D-DT protein levels and mRNA expression were significantly decreased in subcutaneous adipose tissue adjacent to acutely inflamed wounds. D-DT improved fibroblast viability and increased proliferation in vitro. While D-DT alone did not have a significant effect on in vitro fibroblast wound healing, simultaneous addition of neutralizing MIF antibody resulted in a significant improvement of fibroblast wound healing. Interestingly, expression of the MIF and D-DT receptor CD74 was down-regulated while the MIF receptors CXCR2 and CXCR4 were up-regulated primarily on macrophages indicating that the MIF-CXCR2/4 axis may promote recruitment of inflammatory cells into adipose tissue. Our results describe a reciprocal role of D-DT to MIF in inflamed adipose tissue, and indicate that D-DT may be beneficial in wound repair by improving fibroblast survival and proliferation.

Spata7 is a retinal ciliopathy gene critical for correct RPGRIP1 localization and protein trafficking in the retina.

Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are severe hereditary diseases that causes visual impairment in infants and children. SPATA7 has recently been identified as the LCA3 and juvenile RP gene in humans, whose function in the retina remains elusive. Here, we show that SPATA7 localizes at the primary cilium of cells and at the connecting cilium (CC) of photoreceptor cells, indicating that SPATA7 is a ciliary protein. In addition, SPATA7 directly interacts with the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1), a key connecting cilium protein that has also been linked to LCA. In the retina of Spata7 null mutant mice, a substantial reduction of RPGRIP1 levels at the CC of photoreceptor cells is observed, suggesting that SPATA7 is required for the stable assembly and localization of the ciliary RPGRIP1 protein complex. Furthermore, our results pinpoint a role of this complex in protein trafficking across the CC to the outer segments, as we identified that rhodopsin accumulates in the inner segments and around the nucleus of photoreceptors. This accumulation then likely triggers the apoptosis of rod photoreceptors that was observed. Loss of Spata7 function in mice indeed results in a juvenile RP-like phenotype, characterized by progressive degeneration of photoreceptor cells and a strongly decreased light response. Together, these results indicate that SPATA7 functions as a key member of a retinal ciliopathy-associated protein complex, and that apoptosis of rod photoreceptor cells triggered by protein mislocalization is likely the mechanism of disease progression in LCA3/ juvenile RP patients.

Sensitive and non-invasive assessment of hepatocellular iron using a novel room-temperature susceptometer.

BACKGROUND & AIMS: Liver iron accumulates in various chronic liver diseases where it is an independent factor for survival and carcinogenesis. We tested a novel room-temperature susceptometer (RTS) to non-invasively assess liver iron concentration (LIC). METHODS: Two hundred and sixty-four patients with or without signs of iron overload or liver disease were prospectively enrolled. Thirty-five patients underwent liver biopsy with semiquantitative iron determination (Prussian Blue staining), atomic absorption spectroscopy (AAS, n=33), or magnetic resonance imaging (MRI, n=15). RESULTS: In vitro studies demonstrated a highly linear (r2=0.998) association between RTS-signal and iron concentration, with a detection limit of 0.3mM. Using an optimized algorithm, accounting for the skin-to-liver capsule distance, valid measurements could be obtained in 84% of cases. LIC-RTS showed a significant correlation with LIC-AAS (r=0.74, p<0.001), LIC-MRI (r=0.64, p<0.001) and hepatocellular iron (r=0.58, p<0.01), but not with macrophage iron (r=0.32, p=0.30). Normal LIC-RTS was 1.4mg/g dry weight. Besides hereditary and transfusional iron overload, LIC-RTS was also significantly elevated in patients with alcoholic liver disease. The areas under the receiver operating characteristic curve (AUROC) for grade 1, 2 and 3 hepatocellular iron overload were 0.72, 0.89 and 0.97, respectively, with cut-off values of 2.0, 4.0 and 5.0mg/g dry weight. Notably, the positive and negative predictive values, sensitivity, specificity and accuracy of severe hepatic iron overload (HIO) (grade ≥2) detection, were equal to AAS and superior to all serum iron markers. Depletion of hepatic iron could be efficiently monitored upon phlebotomy. CONCLUSIONS: RTS allows for the rapid and non-invasive measurement of LIC. In comparison to MRI, it could be a cost-effective bedside method for LIC screening. Lay summary: Novel room-temperature susceptometer (RTS) allows for the rapid, sensitive, and non-invasive measurement of liver iron concentration. In comparison to MRI, it could be a cost-effective bedside method for liver iron concentration screening.

New bone post-processing tools in forensic imaging: a multi-reader feasibility study to evaluate detection time and diagnostic accuracy in rib fracture assessment.

PURPOSE: The aim of this multi-reader feasibility study was to evaluate new post-processing CT imaging tools in rib fracture assessment of forensic cases by analyzing detection time and diagnostic accuracy. MATERIALS AND METHODS: Thirty autopsy cases (20 with and 10 without rib fractures in autopsy) were randomly selected and included in this study. All cases received a native whole body CT scan prior to the autopsy procedure, which included dissection and careful evaluation of each rib. In addition to standard transverse sections (modality A), CT images were subjected to a reconstruction algorithm to compute axial labelling of the ribs (modality B) as well as "unfolding" visualizations of the rib cage (modality C, "eagle tool"). Three radiologists with different clinical and forensic experience who were blinded to autopsy results evaluated all cases in a random manner of modality and case. RESULTS: Rib fracture assessment of each reader was evaluated compared to autopsy and a CT consensus read as radiologic reference. A detailed evaluation of relevant test parameters revealed a better accordance to the CT consensus read as to the autopsy. Modality C was the significantly quickest rib fracture detection modality despite slightly reduced statistic test parameters compared to modalities A and B. CONCLUSION: Modern CT post-processing software is able to shorten reading time and to increase sensitivity and specificity compared to standard autopsy alone. The eagle tool as an easy to use tool is suited for an initial rib fracture screening prior to autopsy and can therefore be beneficial for forensic pathologists.

Measurement of uranium-236 in particles by secondary ion mass spectrometry.

The determination of the relative isotopic abundance by secondary ion mass spectrometry of 236U in uranium-containing material is complicated by the presence of 235U1H+ ions at the same nominal mass as the uranium isotopic peak. The net intensity of the 236U signal is usually determined by a peak-stripping procedure, whereby the 235U1H+ contribution is obtained by applying the 238U1H+/238U+ ratio to the 235U+ signal. The subtraction of one signal from another has consequences for the uncertainty of the final 236U abundance determination that may be especially significant when the amount of sample is limited, as is the case with small uranium particles that are of great interest for nuclear safeguards. We have developed a model based on Poisson counting statistics to determine the effects of various parameters on the uncertainty of the 236U abundance, including uranium enrichment level, hydride-to-parent ratio, uranium mass consumed during analysis, single versus multichannel counting, and sample substrate composition. The model predictions have been successfully tested against experimental measurements of uranium oxide particles of both 3% and 90% enrichment in 235U.

Histogram analysis of iodine maps from dual energy computed tomography for monitoring targeted therapy of melanoma patients.

AIM: Iodine quantification with dual energy computed tomography (DECT) enables quantitative assessment of contrast medium uptake. Our purpose was to investigate patterns of enhancement under BRAF inhibitor therapy by performing histogram analyses (HAs) of iodine maps. MATERIALS & METHODS: A total of 11 stage IV melanoma patients (32 metastases) underwent DECT at baseline and at least one follow up. Iodine uptake and HAs including maximum HU value (MAX), mean HU value (MEAN) and standard deviation (STD) was calculated. RESULTS: For BRAF-responders MEAN, MAX and STD decreased significantly (p < 0.05). Nonresponder showed increasing MAX and STD for six out of seven lesions, while MEAN and Iodine uptake decreased (four) and increased (three). CONCLUSION: HA based on DECT enables a quantitative and functional criterion and contributes to accurate response assessment for promising targeted therapies.

Genetic ablation of Pals1 in retinal progenitor cells models the retinal pathology of Leber congenital amaurosis.

Mutation of the polarity gene Crumbs homolog 1 (CRB1) is responsible for >10% of Leber congenital amaurosis (LCA) cases worldwide; LCA is characterized by early-onset degenerative retinal dystrophy. The role of CRB1 in LCA8 pathogenesis remains elusive since Crb1 mouse mutants, including a null allele, have failed to mimic the early-onset of LCA, most likely due to functional compensation by closely related genes encoding Crb2 and Crb3. Crb proteins form an evolutionarily conserved, apical polarity complex with the scaffolding protein associated with lin-seven 1 (Pals1), also known as MAGUK p55 subfamily member 5 (MPP5). Pals1 and Crbs are functionally inter-dependent in establishing and maintaining epithelial polarity. Pals1 is a single gene in the mouse and human genomes; therefore, we ablated Pals1 to establish a mouse genetic model mimicking human LCA. In our study, the deletion of Pals1 leads to the disruption of the apical localization of Crb proteins in retinal progenitors and the adult retina, validating their mutual interaction. Remarkably, the Pals1 mutant mouse exhibits the critical features of LCA such as early visual impairment as assessed by electroretinogram, disorganization of lamination and apical junctions and retinal degeneration. Our data uncover the indispensible role of Pals1 in retinal development, likely involving the maintenance of retinal polarity and survival of retinal neurons, thus providing the basis for the pathologic mechanisms of LCA8.

Recent developments of dual-energy CT in oncology.

UNLABELLED: Dual-energy computed tomography (DECT) can amply contribute to support oncological imaging: the DECT technique offers promising clinical applications in oncological imaging for tumour detection and characterisation while concurrently reducing the radiation dose. Fast image acquisition at two different X-ray energies enables the determination of tissue- or material-specific features, the calculation of virtual unenhanced images and the quantification of contrast medium uptake; thus, tissue can be characterised and subsequently monitored for any changes during treatment. DECT is already widely used, but its potential in the context of oncological imaging has not been fully exploited yet. The technology is the subject of ongoing innovation and increasingly with respect to its clinical potential, particularly in oncology. This review highlights recent state-of-the-art DECT techniques with a strong emphasis on ongoing DECT developments relevant to oncologic imaging, and then focuses on clinical DECT applications, especially its prospective uses in areas of oncological imaging. KEY POINTS: • Dual-energy CT (DECT) offers fast, robust, quantitative and functional whole-body imaging. • DECT provides improved tumour detection and more detailed tissue differentiation and characterisation. • DECT affords therapy monitoring with complementary information and reduced radiation dose. • The use of DECT in oncology is of increasing clinical importance. • The potential of DECT in oncology has not been fully exploited yet.

Gene therapy prevents photoreceptor death and preserves retinal function in a Bardet-Biedl syndrome mouse model.

Patients with Bardet-Biedl syndrome (BBS) experience severe retinal degeneration as a result of impaired photoreceptor transport processes that are not yet fully understood. To date, there is no effective treatment for BBS-associated retinal degeneration, and blindness is imminent by the second decade of life. Here we report the development of an adeno-associated viral (AAV) vector that rescues rhodopsin mislocalization, maintains nearly normal-appearing rod outer segments, and prevents photoreceptor death in the Bbs4-null mouse model. Analysis of the electroretinogram a-wave indicates that rescued rod cells are functionally indistinguishable from wild-type rods. These results demonstrate that gene therapy can prevent retinal degeneration in a mammalian BBS model.

Supervised machine learning to predict smoking lapses from Ecological Momentary Assessments and sensor data: Implications for just-in-time adaptive intervention development.

Specific moments of lapse among smokers attempting to quit often lead to full relapse, which highlights a need for interventions that target lapses before they might occur, such as just-in-time adaptive interventions (JITAIs). To inform the decision points and tailoring variables of a lapse prevention JITAI, we trained and tested supervised machine learning algorithms that use Ecological Momentary Assessments (EMAs) and wearable sensor data of potential lapse triggers and lapse incidence. We aimed to identify a best-performing and feasible algorithm to take forwards in a JITAI. For 10 days, adult smokers attempting to quit were asked to complete 16 hourly EMAs/day assessing cravings, mood, activity, social context, physical context, and lapse incidence, and to wear a Fitbit Charge 4 during waking hours to passively collect data on steps and heart rate. A series of group-level supervised machine learning algorithms (e.g., Random Forest, XGBoost) were trained and tested, without and with the sensor data. Their ability to predict lapses for out-of-sample (i) observations and (ii) individuals were evaluated. Next, a series of individual-level and hybrid (i.e., group- and individual-level) algorithms were trained and tested. Participants (N = 38) responded to 6,124 EMAs (with 6.9% of responses reporting a lapse). Without sensor data, the best-performing group-level algorithm had an area under the receiver operating characteristic curve (AUC) of 0.899 (95% CI = 0.871-0.928). Its ability to classify lapses for out-of-sample individuals ranged from poor to excellent (AUCper person = 0.524-0.994; median AUC = 0.639). 15/38 participants had adequate data for individual-level algorithms to be constructed, with a median AUC of 0.855 (range: 0.451-1.000). Hybrid algorithms could be constructed for 25/38 participants, with a median AUC of 0.692 (range: 0.523 to 0.998). With sensor data, the best-performing group-level algorithm had an AUC of 0.952 (95% CI = 0.933-0.970). Its ability to classify lapses for out-of-sample individuals ranged from poor to excellent (AUCper person = 0.494-0.979; median AUC = 0.745). 11/30 participants had adequate data for individual-level algorithms to be constructed, with a median AUC of 0.983 (range: 0.549-1.000). Hybrid algorithms could be constructed for 20/30 participants, with a median AUC of 0.772 (range: 0.444 to 0.968). In conclusion, high-performing group-level lapse prediction algorithms without and with sensor data had variable performance when applied to out-of-sample individuals. Individual-level and hybrid algorithms could be constructed for a limited number of individuals but had improved performance, particularly when incorporating sensor data for participants with sufficient wear time. Feasibility constraints and the need to balance multiple success criteria in the JITAI development and implementation process are discussed.