SARS-CoV-2-induced disruption of a vascular bed in a microphysiological system caused by type-I interferon from bronchial organoids.

Blood vessels show various COVID-19-related conditions including thrombosis and cytokine propagation. Existing in vitro blood vessel models cannot represent the consequent changes in the vascular structure or determine the initial infection site, making it difficult to evaluate how epithelial and endothelial tissues are damaged. Here, we developed a microphysiological system (MPS) that co-culture the bronchial organoids and the vascular bed to analyze infection site and interactions. In this system, virus-infected organoids caused damage in vascular structure. However, vasculature was not damaged or infected when the virus was directly introduced to vascular bed. The knockout of interferon-related genes and inhibition of the JAK/STAT pathway reduced the vascular damage, indicating the protective effect of interferon response suppression. The results demonstrate selective infection of bronchial epithelial cells and vascular damage by cytokines and also indicate the applicability of MPS to investigate how the infection influences vascular structure and functions.

Ten-Year Trends in Psychotropic Prescribing and Polypharmacy in Australian General Practice Patients with and without Dementia.

OBJECTIVE: Little research has evaluated trends in psychotropic prescribing and polypharmacy in primary care patients, especially those with dementia. We sought to examine this in Australia from 2011 to 2020 using the primary care dataset, MedicineInsight. METHODS: Ten consecutive serial cross-sectional analyses were performed to evaluate the proportion of patients aged 65 years or more, with a recorded diagnosis of dementia, who were prescribed psychotropic medications within the first six months of each year from 2011 to 2020. This proportion was compared with propensity score-matched control patients without dementia. RESULTS: Before matching, 24,701 patients (59.2% females) with, and 72,105 patients (59.2% females) without, a recorded diagnosis of dementia were included. In 2011, 42% (95% confidence interval [CI] 40.5-43.5%) of patients in the dementia group had at least one recorded prescription of a psychotropic medication, which declined to 34.2% (95% CI 33.3-35.1%; p for trend < 0.001) by 2020. However, it remained unchanged for matched controls (36% [95% CI 34.6-37.5%] in 2011 and 36.7% [95% CI 35.7-37.6%] in 2020). The greatest decline in the dementia groups by medication class was for antipsychotics (from 15.9% [95% CI 14.8-17.0%] to 8.8% [95% CI 8.2-9.4%]; p for trend < 0.001). During this period, the prevalence of psychotropic polypharmacy (use of two or more individual psychotropics) also decreased from 21.7% (95% CI 20.5-22.9%) to 18.1% (95% CI 17.4-18.9%) in the dementia groups, and slightly increased from 15.2% (95% CI 14.1-16.3%) to 16.6% (95% CI 15.9-17.3%) in the matched controls. CONCLUSIONS: The decline in psychotropic prescribing, particularly antipsychotics, in Australian primary care patients with dementia is encouraging. However, psychotropic polypharmacy still occurred in almost one in five patients with dementia at the end of the study period. Programs focused on encouraging further reductions in the use of multiple psychotropic drugs in patients with dementia are recommended, particularly in rural and remote regions.

Elucidation of the liver pathophysiology of COVID-19 patients using liver-on-a-chips.

SARS-CoV-2 induces severe organ damage not only in the lung but also in the liver, heart, kidney, and intestine. It is known that COVID-19 severity correlates with liver dysfunction, but few studies have investigated the liver pathophysiology in COVID-19 patients. Here, we elucidated liver pathophysiology in COVID-19 patients using organs-on-a-chip technology and clinical analyses. First, we developed liver-on-a-chip (LoC) which recapitulating hepatic functions around the intrahepatic bile duct and blood vessel. We found that hepatic dysfunctions, but not hepatobiliary diseases, were strongly induced by SARS-CoV-2 infection. Next, we evaluated the therapeutic effects of COVID-19 drugs to inhibit viral replication and recover hepatic dysfunctions, and found that the combination of anti-viral and immunosuppressive drugs (Remdesivir and Baricitinib) is effective to treat hepatic dysfunctions caused by SARS-CoV-2 infection. Finally, we analyzed the sera obtained from COVID-19 patients, and revealed that COVID-19 patients, who were positive for serum viral RNA, are likely to become severe and develop hepatic dysfunctions, as compared with COVID-19 patients who were negative for serum viral RNA. We succeeded in modeling the liver pathophysiology of COVID-19 patients using LoC technology and clinical samples.

Preparation of NanoMEDIC Extracellular Vesicles to Deliver CRISPR-Cas9 Ribonucleoproteins for Genomic Exon Skipping.

The CRISPR-Cas9 system has quickly become the standard tool for genome editing. To deliver this system to target cells, adeno-associated virus (AAV) vectors are commonly used. In fact, AAV vectors have been utilized to deliver the CRISPR-Cas9 system to induce genomic exon skipping and restore the dystrophin protein in various Duchenne muscular dystrophy model animals. Despite the high transduction efficiency, AAV vector-mediated delivery has several limitations, such as the packaging size, prolonged overexpression of Cas9, immunogenicity against the AAV capsid, and the risk of integrating a part of the AAV genomic sequence into the host cell. To overcome these issues, we have recently engineered a transient delivery system utilizing VSV-G pseudotyped extracellular vesicles (EVs) termed NanoMEDIC (nanomembrane-derived extracellular vesicles for the delivery of macromolecular cargo). NanoMEDIC utilizes an HIV-derived Gag protein to package Cas9 protein and gRNA into EVs. The Cas9 and Gag proteins are fused to a heterodimerizer and conditionally dimerized by the addition of an inducible chemical ligand to recruit Cas9 protein into EVs. sgRNA is packaged into EVs through an HIV-derived RNA packaging signal and is subsequently released by two self-cleaving ribozymes. Utilizing these features, NanoMEDIC can achieve highly efficient packaging of the Cas9 protein and gRNA for genome editing into a variety of target cells and in vivo. Here, we describe a step-by-step protocol, including the gRNA-expressing vector construction and large-scale NanoMEDIC production, for in vivo genome editing.

Optimized electroporation of CRISPR-Cas9/gRNA ribonucleoprotein complex for selection-free homologous recombination in human pluripotent stem cells.

Selection-free, scarless genome editing in human pluripotent stem cells (PSCs) by utilizing ribonucleoprotein (RNP) of CRISPR-Cas9 is a useful tool for a variety of applications. However, the process can be hampered by time-consuming subcloning steps and inefficient delivery of the RNP complex and ssDNA template. Here, we describe the optimized protocol to introduce a single nucleotide change or a loxP site insertion in feeder-free, xeno-free iPSCs by utilizing MaxCyte and 4D-Nucleofector electroporators. For complete details on the use and execution of this protocol, please refer to Kagita et al. (2021) and Xu et al. (2019).

Efficient ssODN-Mediated Targeting by Avoiding Cellular Inhibitory RNAs through Precomplexed CRISPR-Cas9/sgRNA Ribonucleoprotein.

Combined with CRISPR-Cas9 technology and single-stranded oligodeoxynucleotides (ssODNs), specific single-nucleotide alterations can be introduced into a targeted genomic locus in induced pluripotent stem cells (iPSCs); however, ssODN knockin frequency is low compared with deletion induction. Although several Cas9 transduction methods have been reported, the biochemical behavior of CRISPR-Cas9 nuclease in mammalian cells is yet to be explored. Here, we investigated intrinsic cellular factors that affect Cas9 cleavage activity in vitro. We found that intracellular RNA, but not DNA or protein fractions, inhibits Cas9 from binding to single guide RNA (sgRNA) and reduces the enzymatic activity. To prevent this, precomplexing Cas9 and sgRNA before delivery into cells can lead to higher genome editing activity compared with Cas9 overexpression approaches. By optimizing electroporation parameters of precomplexed ribonucleoprotein and ssODN, we achieved efficiencies of single-nucleotide correction as high as 70% and loxP insertion up to 40%. Finally, we could replace the HLA-C1 allele with the C2 allele to generate histocompatibility leukocyte antigen custom-edited iPSCs.

Effects of a Mobile App Called Quittr, Which Utilizes Premium Currency and Games Features, on Improving Engagement With Smoking Cessation Intervention: Pilot Randomized Controlled Trial.

BACKGROUND: Numerous mobile health (mHealth) apps have been developed to support smokers attempting to quit smoking. Although these apps have been reported to be successful, only modest improvements in the quit rate have been measured. It has been proposed that efforts to improve user engagement and retention may improve the quit rate further. Owing to the high cost of smoking-related disease, it is considered worthwhile to pursue even small improvements. OBJECTIVE: The aim of this study was to test a novel smartphone app that leverages premium currency strategies developed by the mobile games industry in an attempt to improve engagement and retention with a smoking cessation intervention. METHODS: We designed and developed a smoking cessation app called "Quittr" in line with previously developed smoking cessation mHealth apps. In addition to this established framework, we added a stand-alone fully featured city-building clicker-style game called "Tappy Town," and a premium virtual currency called "QuitCoins." The user earns QuitCoins for using the app in a way that contributes positively toward their quit attempt, and they can redeem these coins in Tappy Town for bonuses. To establish whether these features improved engagement and retention, we ran a 5-month randomized controlled trial where the intervention group had the full app with the extra games features, while the control group had the standard app only. Recruitment was performed via web-based advertising. Participants (N=175) had no direct contact with the researchers or other support staff. RESULTS: No significant differences in terms of engagement, retention, or smoking outcomes were found between the control and intervention groups. However, survey data indicated that the majority of the participants valued Tappy Town (10/17, 59%) and the QuitCoins rewards system (13/17, 77%). Usage data also suggested that Tappy Town was widely played and was generally appealing to users (mean total time spent in app, control group: 797 seconds vs intervention group: 3502 seconds, P<.001). Analysis of the results suggests that users in the intervention group may have been negatively affected by the aspects of the chosen design, and some theories were explored to explain this unexpected outcome. CONCLUSIONS: Although the novel features of the Quittr app failed to improve the key outcomes measured in this study, there were enough positive indications to warrant further exploration of the concept. Additional research will be required to identify and correct any design flaws that may have adversely affected our participants before a follow-up study can be completed. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Register ACTRN12617000491369; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372661&isReview=true.

Extracellular nanovesicles for packaging of CRISPR-Cas9 protein and sgRNA to induce therapeutic exon skipping.

Prolonged expression of the CRISPR-Cas9 nuclease and gRNA from viral vectors may cause off-target mutagenesis and immunogenicity. Thus, a transient delivery system is needed for therapeutic genome editing applications. Here, we develop an extracellular nanovesicle-based ribonucleoprotein delivery system named NanoMEDIC by utilizing two distinct homing mechanisms. Chemical induced dimerization recruits Cas9 protein into extracellular nanovesicles, and then a viral RNA packaging signal and two self-cleaving riboswitches tether and release sgRNA into nanovesicles. We demonstrate efficient genome editing in various hard-to-transfect cell types, including human induced pluripotent stem (iPS) cells, neurons, and myoblasts. NanoMEDIC also achieves over 90% exon skipping efficiencies in skeletal muscle cells derived from Duchenne muscular dystrophy (DMD) patient iPS cells. Finally, single intramuscular injection of NanoMEDIC induces permanent genomic exon skipping in a luciferase reporter mouse and in mdx mice, indicating its utility for in vivo genome editing therapy of DMD and beyond.

CRISPR-Cas3 induces broad and unidirectional genome editing in human cells.

Although single-component Class 2 CRISPR systems, such as type II Cas9 or type V Cas12a (Cpf1), are widely used for genome editing in eukaryotic cells, the application of multi-component Class 1 CRISPR has been less developed. Here we demonstrate that type I-E CRISPR mediates distinct DNA cleavage activity in human cells. Notably, Cas3, which possesses helicase and nuclease activity, predominantly triggered several thousand base pair deletions upstream of the 5'-ARG protospacer adjacent motif (PAM), without prominent off-target activity. This Cas3-mediated directional and broad DNA degradation can be used to introduce functional gene knockouts and knock-ins. As an example of potential therapeutic applications, we show Cas3-mediated exon-skipping of the Duchenne muscular dystrophy (DMD) gene in patient-induced pluripotent stem cells (iPSCs). These findings broaden our understanding of the Class 1 CRISPR system, which may serve as a unique genome editing tool in eukaryotic cells distinct from the Class 2 CRISPR system.

Targeted Disruption of HLA Genes via CRISPR-Cas9 Generates iPSCs with Enhanced Immune Compatibility.

Induced pluripotent stem cells (iPSCs) have strong potential in regenerative medicine applications; however, immune rejection caused by HLA mismatching is a concern. B2M gene knockout and HLA-homozygous iPSC stocks can address this issue, but the former approach may induce NK cell activity and fail to present antigens, and it is challenging to recruit rare donors for the latter method. Here, we show two genome-editing strategies for making immunocompatible donor iPSCs. First, we generated HLA pseudo-homozygous iPSCs with allele-specific editing of HLA heterozygous iPSCs. Second, we generated HLA-C-retained iPSCs by disrupting both HLA-A and -B alleles to suppress the NK cell response while maintaining antigen presentation. HLA-C-retained iPSCs could evade T cells and NK cells in vitro and in vivo. We estimated that 12 lines of HLA-C-retained iPSCs combined with HLA-class II knockout are immunologically compatible with >90% of the world's population, greatly facilitating iPSC-based regenerative medicine applications.

More action needed: Psychotropic prescribing in Australian residential aged care.

OBJECTIVE: For at least two decades, concerns have been raised about inappropriate psychotropic prescribing in Australian residential aged care facilities, due to their modest therapeutic benefit and increased risk of falls and mortality. To date, the majority of prevalence data has been collected in Sydney exclusively and it is not known if recent initiatives to promote appropriate psychotropic prescribing have impacted utilisation. Thus, we aimed to comprehensively analyse psychotropic use in a large national sample of residential aged care facility residents. METHOD: A cross-sectional, retrospective cohort study of residents from 150 residential aged care facilities distributed nationally during April 2014-October 2015. Antipsychotic, anxiolytic/hypnotic and antidepressant utilisation was assessed, along with anticonvulsant and anti-dementia drug use. Negative binomial regression analysis was used to examine variation in psychotropic use. RESULTS: Full psychotropic prescribing data was available from 11,368 residents. Nearly two-thirds (61%) were taking psychotropic agents regularly, with over 41% prescribed antidepressants, 22% antipsychotics and 22% of residents taking benzodiazepines. Over 30% and 11% were charted for 'prn' (as required) benzodiazepines and antipsychotics, respectively. More than 16% of the residents were taking sedating antidepressants, predominantly mirtazapine. South Australian residents were more likely to be taking benzodiazepines ( p < 0.05) and residents from New South Wales/Australian Capital Territory less likely to be taking them ( p < 0.01), after adjustment for rurality and size of residential aged care facility. Residents located in New South Wales/Australian Capital Territory were also significantly less likely to take antidepressants ( p < 0.01), as were residents from outer regional residential aged care facilities ( p < 0.01). Antipsychotic use was not associated with State, rurality or residential aged care facility size. CONCLUSION: Regular antipsychotic use appears to have decreased in residential aged care facilities but benzodiazepine prevalence is higher, particularly in South Australian residential aged care facilities. Sedating antidepressant and 'prn' psychotropic prescribing is widespread. Effective interventions to reduce the continued reliance on psychotropic management, in conjunction with active promotion of non-pharmacological strategies, are urgently required.

Efficient mRNA delivery system utilizing chimeric VSVG-L7Ae virus-like particles.

The delivery of mRNA is advantageous over DNA delivery as it is transient and does not carry the risk of genomic DNA integration. However, there are currently few efficient mRNA delivery options available, especially for hard-to-transfect cell types, and thus new delivery methods are needed. To this end, we have established a novel mRNA delivery system utilizing chimeric virus-like particles (VLPs). We generated a novel VLP by fusing protein G of Vesicular stomatitis virus (VSV-G) with a ribosomal protein L7Ae of Archeoglobus fulgidus. This system allowed the efficient delivery of EGFP mRNA which was independent from the presence of BoxC/D motif in the mRNA sequence. Our VSVG-L7Ae VLP system demonstrated high transduction efficacy in hard-to-transfect cell lines, such as human induced pluripotent stem cells (iPS cells) and monocytes. In summary, this platform may serve as an efficient and transient transgene delivery tool for an mRNA of interest.

RedUSe: reducing antipsychotic and benzodiazepine prescribing in residential aged care facilities.

OBJECTIVE: To assess the impact of a multi-strategic, interdisciplinary intervention on antipsychotic and benzodiazepine prescribing in residential aged care facilities (RACFs). Design, setting: Prospective, longitudinal intervention in Australian RACFs, April 2014 - March 2016. PARTICIPANTS: 150 RACFs (with 12 157 residents) comprised the main participant group; two further groups were consultant pharmacists (staff education) and community pharmacies (prescribing data). Data for all RACF residents, excluding residents receiving respite or end-stage palliative care, were included. INTERVENTION: A multi-strategic program comprising psychotropic medication audit and feedback, staff education, and interdisciplinary case review at baseline and 3 months; final audit at 6 months. MAIN OUTCOME MEASURE: Mean prevalence of regular antipsychotic and benzodiazepine prescribing at baseline, and at 3 and 6 months. Secondary measures: chlorpromazine and diazepam equivalent doses/day/resident; proportions of residents for whom drug was ceased or the dose reduced; prevalence of antidepressant and prn (as required) psychotropic prescribing (to detect any substitution practice). RESULTS: During the 6-month intervention, the proportion of residents prescribed antipsychotics declined by 13% (from 21.6% [95% CI, 20.4-22.9%] to 18.9% [95% CI, 17.7-20.1%]), and that of residents regularly prescribed benzodiazepines by 21% (from 22.2% [95% CI, 21.0-23.5%] to 17.6% [95% CI, 16.5-18.7]; each, P < 0.001). Mean chlorpromazine equivalent dose declined from 22.9 mg/resident/day (95% CI, 19.8-26.0) to 20.2 mg/resident/day (95% CI, 17.5-22.9; P < 0.001); mean diazepam equivalent dose declined from 1.4 mg/resident/day (95% CI, 1.3-1.5) to 1.1 mg/resident/day (95% CI, 0.9-1.2; P < 0.001). For 39% of residents prescribed antipsychotics and benzodiazepines at baseline, these agents had been ceased or their doses reduced by 6 months. There was no substitution by sedating antidepressants or prn prescribing of other psychotropic agents. CONCLUSIONS: The RedUSe program achieved significant reductions in the proportions of RACF residents prescribed antipsychotics and benzodiazepines. TRIAL REGISTRATION: Australian New Zealand Clinical Trials, ACTRN12617001257358.

Patients' Experience of Living with Cancer-associated thrombosis in Spain (PELICANOS).

INTRODUCTION: The previously reported Patients' Experience of LIving with CANcer-associated thrombosis (PELICAN) identified several areas of unmet clinical and support need for cancer patients diagnosed with venous thromboembolism (VTE) in the UK. It is not known whether such experiences are restricted to one particular country's healthcare system and culture. We therefore undertook an evaluation of patients' experience of cancer-associated thrombosis (CAT) within a Spanish setting. METHODS: Twenty consecutive Spanish patients with CAT were interviewed about their experiences of living with CAT as per the previous PELICAN study. Where possible, spouses were interviewed in conjunction. Semi-structured interviews were audio recorded, transcribed and translated into English. Transcripts were coded using Nvivo software and data were analysed using framework analysis. A pragmatic approach was undertaken to allow explication of the potential cultural and operational differences that were not apparent in the UK dataset. RESULTS: Several commonalities between the UK and Spanish patients were identified including the traumatic nature of the experience, the need for information and adaptive behaviors through ritualisation. Within the major themes lay new themes as follows. (1) The traumatic experience of CAT impacted on the family dynamic with respect to discussions within the family unit and support needs of individuals other than the patient. It also had a profound impact on the patient's concept of self with increased awareness of their mortality and seriousness of the cancer. (2) The need for information extended to the family as well as the patients. This was needed at the point of CAT diagnosis as well as an opportunity to later address unanswered questions. (3) Adaptive behaviors were common with similar ritualisations seen in the UK patients. CONCLUSION: The distress experienced by patients with CAT is not isolated to the UK alone but is similar in Spanish patients as well. The patient information provided regarding LMWH injections is important, but there is a need to for patients and their families to be given additional information about CAT itself and future prognosis. CAT also has a profound impact on the patient's family who has similar support needs. It appears that there are several commonalities between UK and Spanish patients, as well as specific local issues. This study justifies expansion of the sampling to other countries.

Site-specific randomization of the endogenous genome by a regulatable CRISPR-Cas9 piggyBac system in human cells.

Randomized mutagenesis at an endogenous chromosomal locus is a promising approach for protein engineering, functional assessment of regulatory elements, and modeling genetic variations. In mammalian cells, however, it is challenging to perform site-specific single-nucleotide substitution with single-stranded oligodeoxynucleotide (ssODN) donor templates due to insufficient homologous recombination and the infeasibility of positive selection. Here, we developed a DNA transposon based CRISPR-Cas9 regulated transcription and nuclear shuttling (CRONUS) system that enables the stable transduction of CRISPR-Cas9/sgRNA in broad cell types, but avoids undesired genome cleavage in the absence two chemical inducing molecules. Highly efficient single nucleotide alterations induced randomization of desired codons (up to 4 codons) at a defined genomic locus in various human cell lines, including human iPS cells. Thus, CRONUS provides a novel platform for modeling diseases and genetic variations.

An Internet-Based Method for Extracting Nursing Home Resident Sedative Medication Data From Pharmacy Packing Systems: Descriptive Evaluation.

BACKGROUND: Inappropriate use of sedating medication has been reported in nursing homes for several decades. The Reducing Use of Sedatives (RedUSe) project was designed to address this issue through a combination of audit, feedback, staff education, and medication review. The project significantly reduced sedative use in a controlled trial of 25 Tasmanian nursing homes. To expand the project to 150 nursing homes across Australia, an improved and scalable method of data collection was required. This paper describes and evaluates a method for remotely extracting, transforming, and validating electronic resident and medication data from community pharmacies supplying medications to nursing homes. OBJECTIVE: The aim of this study was to develop and evaluate an electronic method for extracting and enriching data on psychotropic medication use in nursing homes, on a national scale. METHODS: An application uploaded resident details and medication data from computerized medication packing systems in the pharmacies supplying participating nursing homes. The server converted medication codes used by the packing systems to Australian Medicines Terminology coding and subsequently to Anatomical Therapeutic Chemical (ATC) codes for grouping. Medications of interest, in this case antipsychotics and benzodiazepines, were automatically identified and quantified during the upload. This data was then validated on the Web by project staff and a "champion nurse" at the participating home. RESULTS: Of participating nursing homes, 94.6% (142/150) had resident and medication records uploaded. Facilitating an upload for one pharmacy took an average of 15 min. A total of 17,722 resident profiles were extracted, representing 95.6% (17,722/18,537) of the homes' residents. For these, 546,535 medication records were extracted, of which, 28,053 were identified as antipsychotics or benzodiazepines. Of these, 8.17% (2291/28,053) were modified during validation and verification stages, and 4.75% (1398/29,451) were added. The champion nurse required a mean of 33 min website interaction to verify data, compared with 60 min for manual data entry. CONCLUSIONS: The results show that the electronic data collection process is accurate: 95.25% (28,053/29,451) of sedative medications being taken by residents were identified and, of those, 91.83% (25,762/28,053) were correct without any manual intervention. The process worked effectively for nearly all homes. Although the pharmacy packing systems contain some invalid patient records, and data is sometimes incorrectly recorded, validation steps can overcome these problems and provide sufficiently accurate data for the purposes of reporting medication use in individual nursing homes.

Cellular Reprogramming, Genome Editing, and Alternative CRISPR Cas9 Technologies for Precise Gene Therapy of Duchenne Muscular Dystrophy.

In the past decade, the development of two innovative technologies, namely, induced pluripotent stem cells (iPSCs) and the CRISPR Cas9 system, has enabled researchers to model diseases derived from patient cells and precisely edit DNA sequences of interest, respectively. In particular, Duchenne muscular dystrophy (DMD) has been an exemplary monogenic disease model for combining these technologies to demonstrate that genome editing can correct genetic mutations in DMD patient-derived iPSCs. DMD is an X-linked genetic disorder caused by mutations that disrupt the open reading frame of the dystrophin gene, which plays a critical role in stabilizing muscle cells during contraction and relaxation. The CRISPR Cas9 system has been shown to be capable of targeting the dystrophin gene and rescuing its expression in in vitro patient-derived iPSCs and in vivo DMD mouse models. In this review, we highlight recent advances made using the CRISPR Cas9 system to correct genetic mutations and discuss how emerging CRISPR technologies and iPSCs in a combined platform can play a role in bringing a therapy for DMD closer to the clinic.

Quittr: The Design of a Video Game to Support Smoking Cessation.

BACKGROUND: Smoking is recognized as the largest, single, preventable cause of death and disease in the developed world. While the majority of smokers report wanting to quit, and many try each year, smokers find it difficult to maintain long-term abstinence. Behavioral support, such as education, advice, goal-setting, and encouragement, is known to be beneficial in improving the likelihood of succeeding in a quit attempt, but it remains difficult to effectively deliver this behavioral support and keep the patient engaged with the process for a sufficient duration. In an attempt to solve this, there have been numerous mobile apps developed, yet engagement and retention have remained key challenges that limit the potential effectiveness of these interventions. Video games have been clearly linked with the effective delivery of health interventions, due to their capacity to increase motivation and engagement of players. OBJECTIVE: The objective of this study is to describe the design and development of a smartphone app that is theory-driven, and which incorporates gaming characteristics in order to promote engagement with content, and thereby help smokers to quit. METHODS: Game design and development was informed by a taxonomy of motivational affordances for meaningful gamified and persuasive technologies. This taxonomy describes a set of design components that is grounded in well-established psychological theories on motivation. RESULTS: This paper reports on the design and development process of Quittr, a mobile app, describing how game design principles, game mechanics, and game elements can be used to embed education and support content, such that the app actually requires the user to access and engage with relevant educational content. The next stage of this research is to conduct a randomized controlled trial to determine whether the additional incentivization game features offer any value in terms of the key metrics of engagement-how much content users are consuming, how many days users are persisting with using the app, and what proportion of users successfully abstain from smoking for 28 days, based on user-reported data and verified against a biochemical baseline using cotinine tests. CONCLUSIONS: We describe a novel, and theoretically-informed mobile app design approach that has a broad range of potential applications. By using the virtual currency approach, we remove the need for the game to comprehensively integrate the healthy activity as part of its actual play mechanics. This opens up the potential for a wide variety of health problems to be tackled through games where no obvious play mechanic presents itself. The implications of this app are that similar approaches may be of benefit in areas such as managing chronic conditions (diabetes, heart disease, etc), treating substance abuse (alcohol, illicit drugs, etc), diet and exercise, eating disorders (anorexia, bulimia, and binge eating), and various phobias.

Antiretroviral adherence and treatment outcomes among adult Ethiopian patients.

Developing appropriate strategies to sustain optimal medication adherence among the increasing number of HIV-positive patients taking antiretroviral therapy (ART) in sub-Saharan Africa is a major challenge. The objective of this study was to determine patient, regimen, disease, patient-provider, and healthcare-related factors associated with adherence with ART over a one-year period, and assess the impact of adherence on treatment outcomes. We performed a prospective, observational study among 246 patients who were initiated on ART in Ethiopia. Of 172 who completed follow-up, 130 (75.6%) had ≥95% adherence. In the multivariate analyses, a higher baseline BMI (OR, 1.2; 95% CI 1.0, 1.4) and use of reminder devices (OR, 9.1; 95% CI 2.0, 41.6) remained positively associated with adherence, while a higher HIV symptom and adverse drug reaction distress score was an independent negative predictor of adherence (OR, 0.90; 95% CI 0.9, 1.0) CD4 count increase was significantly higher in the adherent patients compared to non-adherent patients at 12 months (159 cells/µL [interquartile range (IQR), 72-324 cells/µL] vs. 132 cells/µL [IQR, 43-190 cells/µL]; p = 0.026). Our findings indicate that interventions aimed at improving adherence and thereby treatment outcomes in patients initiated on ART should promote the use of reminder devices, and monitor HIV symptoms and adverse reaction distress and nutritional status.

Perspectives of Genome-Editing Technologies for HIV Therapy.

BACKGROUND: Current HIV antiretroviral therapies potently suppress virus replication and prevent patients from progressing to AIDS but are unable to completely eliminate HIV due to the existence of dormant viral reservoirs which threaten to reemerge at anytime. Recently, genome-editing technologies that can recognize specific DNA sequences, including viral DNA, are being touted as promising tools for curing HIV, owing to their specificity, ease of use, and ability to be custom designed. CONCLUSION: Here, we introduce several novel strategies aimed at eradicating HIV proviruses with state-of-the-art genome-editing technologies and discuss perspectives of these approaches for curing HIV.