If is a key determinant for cardiac pacemaker activity. It is conducted by subunits of the hyperpolarization-activated cyclic nucleotide–gated (HCN) channel family, of which HCN4 is predominant in mammalian heart. Both loss-of-function and gain-of-function mutations of the HCN4 gene are associated with sinus node dysfunction in humans; however, their functional impact is not fully understood yet. Here, we sought to characterize a HCN4 V759I variant detected in a patient with a family history of sick sinus syndrome. The genomic analysis yielded a mono-allelic HCN4 V759I variant in a 49-year-old woman presenting with a family history of sick sinus syndrome. This HCN4 variant was previously classified as putatively pathogenic because genetically linked to sudden infant death syndrome and malignant epilepsy. However, detailed electrophysiological and cell biological characterization of HCN4 V759I in Xenopus laevis oocytes and embryonic rat cardiomyocytes, respectively, did not reveal any obvious abnormality. Voltage dependence and kinetics of mutant channel activation, modulation of cAMP-gating by the neuronal HCN channel auxiliary subunit PEX5R, and cell surface expression were indistinguishable from wild-type HCN4. In good agreement, the clinically likewise affected mother of the patient does not exhibit the reported HCN4 variance. HCN4 V759I resembles an innocuous genetic HCN channel variant, which is not sufficient to disturb cardiac pacemaking. Once more, our work emphasizes the importance of careful functional interpretation of genetic findings not only in the context of hereditary cardiac arrhythmias.The hyperpolarization-activated cation current  The sick sinus syndrome (SSS) is a heterogeneous group of disorders, in which the heart fails to perform adequate pacemaking function. It is of great socioeconomic relevance as it represents the most common indication for pacemaker implantation accounting for up to 50% of implant diagnoses . ClinicaIf). A further hallmark of If is its direct facilitation by cyclic nucleotides [If and is thought to contribute to the autonomic regulation of heart rate. Recent experimental evidence indicates that, besides its well-known role in generating pacemaking activity, If is required for SAN cell synchronization, impulse propagation, and resulting in regular beat-to-beat variation [If including the activation by hyperpolarization, its facilitation by cyclic nucleotides, and its ion selectivity [Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels form the ion pore conducting the cardiac pacemaker current . As its leotides . Regulatariation . Four isariation . Heterolectivity . The fouectivity .Here, we describe the case of a 49-year-old woman with a family history of SSS. The genomic analysis yielded a mono-allelic HCN4 V759I variant. The HCN4 mutation V759I had been previously classified as putatively pathogenic as it was found in cases of sudden unexpected death in epilepsy (SUDEP) and sudden infant death syndrome (SIDS) , 29, 31.The studies in human subjects were in accordance with the ethical standards in the revised version of the Declaration of Helsinki and approved by the local ethics committee (# 4869). Informed written consent was given prior to the inclusion of subjects in the study.Genomic DNA was extracted from whole blood using the QIAmp DNA Blood Mini Kit (Qiagen) following the supplier’s instructions. All HCN4 exons were amplified by PCR using intronic HCN4-specific primers , 125 ng Xenopus laevis oocytes was performed as described before [In vitro transcription and injection of cRNAs into d before . Site-did before . GenBankX. laevis oocytes were prepared using standard methods as described previously [X. laevis frogs anesthetized in ice water with 0.1% tricaine (MS-222). After surgery, frogs were allowed to recover to consciousness followed by at least 3 months of recovery without surgery. Oocyte collection was alternated between left and right ovaries with a maximum of four surgeries in one individual animal. After final surgery, the anesthetized frog was euthanized by decapitation. Twenty-four hours after surgery, stages V–IV oocytes were selected, injected with 5–15 ng cRNA per oocyte, and incubated in Barth+ 2, 2.4 NaHCO3, 0.8 MgSO4, 5 HEPES, pH 7.2), supplemented with 100 U/ml penicillin, 100 U/ml streptomycin from an antibiotic antimycotic solution (× 100) (Sigma-Aldrich) at 18 °C. After 2–7 days, transmembrane currents could be recorded using the two-electrode voltage clamp (TEVC) technique. Electrodes with a tip resistance of 0.5–1 MΩ were prepared using a DMZ-Universal micropipette puller (Zeitz Instruments) and filled with 3 M KCl. Oocytes were placed in a custom-made chamber and superfused with HCN Ringer solution . Current signals were recorded using a TEVC amplifier  coupled to a LIH8+8 computer interface (HEKA), and stored using Patchmaster v2 × 65 (HEKA). All experiments were performed at room temperature (RT). Steady-state activation curves were determined with a tail current protocol. Briefly, preconditioning voltage steps  were applied to potentials between − 20 mV and − 150 mV (10 mV increments) for a duration of 5 s before the membrane potential was stepped to − 150 mV for 2 s to elicit the tail current. Currents recorded at the tail potential were normalized to maximum, plotted versus the preconditioning potential, and fitted with a Boltzmann function. Curve fitting and further data analysis were done with Patchmaster and Fitmaster software (HEKA). Data are given as mean ± SEM.eviously , 37. ProX. laevis oocytes were performed as previously described [2 1.0; and adjusted to pH 7.2 with KOH. Macropatches were perfused with a bath solution composed of (in mM): KCl 120, HEPES 10, EGTA 10; and adjusted to pH 7.2 with KOH. For voltage-dependence of activation experiments, the bath solution was supplemented with 100 μM 3′,5′-cAMP (Sigma-Aldrich) to analyze the shift caused by cAMP. Bath solutions were applied via a 4-channel valve controlled gravity perfusion system  to the cytoplasmic side of excised membrane patches. All patch-clamp recordings were made using an Axopatch 200B amplifier  and Clampex 10.6 software . Data were digitized with a Digidata 1550B digitizer  and filtered at 5 kHz. Data were analyzed using Microsoft Excel and OriginPro . Statistical significance was calculated using the unpaired Student’s t test. All experiments were performed at room temperature (21–24 °C). Tail currents were obtained in response to 1 s voltage steps to potentials between − 60 mV and − 160 mV (increment of − 10 mV). The holding potential was 0 mV and tail currents were recorded at + 50 mV. Tail currents were normalized for each measurement and the V1/2 of conductance–voltage relationships (GVs) were determined by fitting the data to a Boltzmann equation.Inside-out macropatch clamp recordings from escribed . Briefly+ over Na+ (PK+/PNa+: 3–5) and the reported dependence of channel conductance on extracellular K+ [+/low or no Na+ to enhance signal-to-noise.Based on the weak selectivity of HCN channels for Klular K+ , 14, 34,Cardiomyocytes were prepared from hearts of E18 embryonic Wistar rats. Procedures conform to the Directive 2010/63/EU of the European Parliament and were approved by the local Animal Welfare Committee . Briefly, pregnant mother animals were euthanized by decapitation after isoflurane pre-anesthesia. E18 embryos were quickly dissected and also euthanized by decapitation. Embryonic hearts were cut into small pieces and digested with 0.05% Collagenase type 2 (Worthington) and 0.15% Trypsin. Cell suspension was filtered through a 70-μm cell strainer and cardiomyocytes were pelleted by centrifugation at 1200 rpm for 8 min. Cells were initially seeded onto gelatin-coated coverslips at a density of 60,000 cells/24-well in plating medium , 1% non-essential amino acids, 1% penicillin/streptomycin and 0.0004% β-Mercaptoethanol ). After 24 h, cells were treated with mitomycin (10 μg/ml) for 1 h in maintenance medium (plating medium with 1% FBS) and afterwards cultured in maintenance medium. The medium was replaced once daily. Cardiomyocytes were identified by the striated aspect of their actin cytoskeleton stained with AF647-conjugated phalloidin (Life Technologies).2 for 48 h, the culture medium containing the viral particles was harvested, purified, and stored at − 80 °C. For infection of cardiomyocytes, the virus was activated by 45 min incubation with chymotrypsin (0.5 mg/ml) followed by 10 min incubation with aprotinin (0.67 mg/ml).At DIV2–3, cardiomyocytes were infected with recombinant Semliki Forest Virus (SFV) for expression of wild-type or V759I variant HCN4 tagged with an extracellular hemagglutinin (HA) epitope . To thisSixteen to 20 h after viral transduction, the surface population of wild-type and variant HCN4 channels were detected by incubation of living cardiomyocytes with a mouse monoclonal anti-HA antibody  in DMEM + Glutamax for 30 min at 37 °C followed by a brief washing step in phosphate-buffered saline (PBS) and subsequent incubation with secondary goat anti-mouse antiserum conjugated to cy3  for 30 min at 37 °C. For detection of intracellular HCN4 channels, cells were fixed with 4% paraformaldehyde, permeabilized, and blocked with 10% normal goat serum in PBS containing 0.01% Triton X-100 and incubated with the mouse monoclonal anti-HA antibody (1:100) for 1 h at RT followed by incubation with goat anti-mouse antiserum conjugated to AF488 . Coverslips were mounted onto microscope slides using ProLong Gold Antifade Mountant (Life Technologies). Image acquisition and quantification of fluorescence intensities were performed as described in Milstein et al.  using a c 348 ms)). During exercise electrocardiography, the patient showed sinus rhythm and reached a maximum heart rate of 146 bpm at a maximum workload of 225 W  examination did not reveal any disturbances of cardiac depolarization or repolarization Fig.  a; the P5 W Fig. . This wa5 W Fig. .Fig. 1Dehttp://evs.gs.washington.edu/EVS/). The mutation V759I in HCN4 has been linked to cases of sudden unexpected death in epilepsy (SUDEP) and sudden infant death syndrome (SIDS) [As the patient reported a family history of SSS, we sequenced all eight exons of the HCN4 gene and identified a mono-allelic non-synonymous variant of c.2275G>A in exon 8 resulting in the single amino acid exchange of V759I in the translated protein. HCN4 V759I has been described as a rare variant in a European population at a frequency of 0.6% and in an African population at 0.1%  , 29. It e (SIDS) .The mother of the patient reported palpitations since the age of 64 without any evidence for structural heart disease. Pacemaker implantation was performed in 2014 after detection of symptomatic sinus pauses of 4 s during 24-h Holter monitoring. Pacemaker interrogation revealed predominant bradycardia at a lower intervention frequency of 60 bpm. Proportions of dual-chamber pacing were equally high due to sinus bradycardia and prolonged atrioventricular conduction time of 300 ms . No abnormalities, however, were detected in the exon sequence of her HCN4 gene.X. laevis oocytes [n = 15) and 10.44 ± 1.99 μA (n = 20) for HCN4 and HCN4 V759I, respectively). Voltage-dependence of channel activation of HCN4 V759I was indistinguishable from wild-type HCN4 with values for V1/2 of − 100.4 ± 2.0 mV  for wild-type and − 101.5 ± 1.9 mV  for mutant channels ). In line with the preserved voltage-dependence of channel activation, also the kinetics of channel activation did not differ between wild-type and HCN4 V759I  and 10.0 ± 0.9 mV (n = 8), respectively, starting from insignificantly different activation voltages prior cAMP application . As PEX5R was identified as an auxiliary subunit of HCN channel complexes in the brain [V1/2 of − 100.9 ± 1.6 mV for wild-type (n = 8), − 108.9 ± 1.2 mV for wild-type + PEX5R (n = 6), − 99.6 ± 1.2 mV for V759I channels (n = 9), and − 109.1 ± 0.9 mV for V759I + PEX5R channels (n = 10)). In good agreement with the view of PEX5R as an antagonist of channel modulation by cyclic nucleotides [Given the reported association of HCN4 V759I with SUDEP and SIDS , 29, we  oocytes  and firsels Fig. . Also, c59I Fig. . In insibed Fig. . As quanhe brain , and theleotides , co-exprThus, neither voltage-dependence, nor kinetics, nor modulation of channel activation by cyclic nucleotides are affected by the amino acid exchange V759I.Besides their biophysical gating properties, also the number of ion channels on the cell surface determines the extent of transmembrane current that can be conducted and hence their functional role. Numerous mutations have been identified in the mammalian ion channel proteome, which impair surface trafficking of channels while leaving their gating characteristics unaffected . TherefoIn the present study, a recently described genetic variant of the cardiac pacemaker channel HCN4 has been identified in a patient diagnosed with a putatively familial form of SSS. Recombinant investigation of this variant, which translates into HCN4 V759I, did not reveal any obvious defects, neither in HCN4 channel gating nor in its trafficking to the cell surface. Our observation allays a previous classification of the HCN4 V759I variant as being putatively pathogenic, which was based on genetic association studies; it therefore strongly emphasizes an imperative of functional studies for serious interpretation of genetic findings , 30.The herein reported patient presented as a typical case of idiopathic SSS without any evidence for congenital or acquired structural heart disease, metabolic disorder, or drug-induced SSS. Because of the positive family history of SAN dysfunction, we set out to sequence the patient’s HCN4 gene, coding for the primary cardiac pacemaker channel subunit in human SAN , 29. TheXenopus oocytes did not reveal any obvious abnormalities in their gating behavior. Particularly, voltage-dependence of activation, its modulation by cAMP, and its kinetics, three major determinants for channel availability in SAN impulse generation, remained unchanged in mutant compared to wild-type HCN4 channels. They were in good agreement with the biophysical properties of HCN4 reported for the same heterologous expression system [Recombinant expression of mutant channels in n system . In isoln system . In orden system  and thatn system ; we finan system . PEX5R bn system . In bothn system . Thus, aNot only the gating properties but also the number of ion channels on the cell surface eventually determine the transmembrane current at a given driving potential. In line, many channelopathies have been identified, in which the processing and trafficking of ion channel proteins are impaired . As V759X. laevis oocytes may concededly at best approximate native conditions. Albeit HCN channel family members are known to heteromerize, we did not pursue analyzing the assembly of HCN4 V759I with other HCN isoforms, as the determinants of channel tetramerization were previously localized to the N-terminus, C-linker, and CNBD domains, upstream of residue V759 [Given the available electrophysiological and cell biological readouts, we did not observe any obvious phenotype of HCN4 V759I. Despite good agreement with the mammalian secretory pathway of protein transport, despite of providing a plasma membrane phospholipid composition and canonical signal transduction pathways comparable to the mammalian system, which has enabled seminal work on ion channel processing and gating , 36, 37,due V759 , 28, 35.due V759 , 23, exidue V759 , 20, alsIn summary, we conclude that the here described genetic variant of HCN4 resulting in a missense mutation V759I of rather small physicochemical difference (Grantham score 29) is not sufficient to cause the SSS diagnosed in the index patient. Our finding that the patient’s mother also suffering from SAN dysfunction with the need for pacemaker implantation does not carry the variant HCN4 allele most convincingly supports this view. The study once more underscores the necessity of functional studies for a careful and sophisticated interpretation of genetic association, not only in the context of hereditary cardiac arrhythmias .


Binge drinkingBRFSS is an ongoing state-based, random-digit–dialed telephone survey of the noninstitutionalized U.S. adult population aged ≥18 years in all 50 states, DC, and participating U.S. territories. Information is collected on various health conditions, health practices, and risk behaviors, including alcohol use. CDC analyzed 2017 data from the 13 states and DC that administered an optional alcohol SBI module. All BRFSS respondents are asked about the timing of their last routine checkup. Those who had a checkup in the past 2 years were asked alcohol SBI module questions.Analyses were conducted to account for BRFSS’s complex sampling design. Weighted crude and age-standardized prevalence estimates of responses to alcohol SBI module questions were calculated. Estimates were stratified by demographic characteristics and selected drinking patterns. Subanalyses were performed among alcohol SBI module respondents who indicated that they had been asked at least one of three alcohol use screening–related questions in the past 2 years and who reported current binge drinking (in the past 30 days) at time of survey. Only age-standardized estimates are included in the text of this report. Wald chi-squared tests were used to determine significant within-group differences. SUDAAN  was used for analyses. Only significant differences are reported. The median cooperation rateOverall, 81.4% of module respondents indicated being asked by their health care provider about alcohol use in person or by form, 71.8% reported being asked how much they drink, and 37.8% reported being asked about binge drinking . The preAmong module respondents who were asked at least one of the alcohol use screening–related questions at a checkup in the past 2 years and reported current binge drinking (past 30 days) at time of survey, only 41.7% were advised about the harms of drinking too much at a checkup in the past 2 years, and only 20.1% were advised to reduce or quit drinking at a checkup in the past 2 years . Among mIn 2017, although 81% of U.S. adults reported being asked by their health care provider about alcohol use, only 38% reported being asked about binge drinking during a checkup in the past 2 years, based on BRFSS data from 13 states and DC. Fewer than half (42%) of module respondents who were asked about alcohol use at a checkup in the past 2 years and reported current binge drinking (past 30 days) at time of survey were advised of harmful drinking levels; almost 80% (four of five persons) received no advice to reduce their drinking (only 20% were advised to reduce their drinking). Previous overall 2014 estimates, using the BRFSS alcohol SBI module from 17 states and DC  and only by adults of legal drinking age.The findings in this report are subject to at least four limitations. First, BRFSS data are self-reported, which can result in recall and social desirability biases around the period of recall for the checkup. Second, data in this report were from 14 sites, and thus, these results cannot be used to estimate the prevalence of alcohol SBI across all states and territories. Third, although respondents indicated current binge drinking in response to a BRFSS survey question, whether they reported binge drinking to their health care provider at time of checkup in the past 2 years is unknown; many respondents reported not being asked about binge drinking at a checkup in the past 2 years. Finally, the survey median response rate was only 43.8%, which increases the possibility of response bias.Binge drinking among U.S. adults continues to be a leading preventable cause of considerable morbidity and mortality , recommended by the U.S. Preventive Services Task Force (USPSTF) for all adults in primary care, is effective in reducing binge drinking.In 2017, 81% of survey respondents were asked by their health care provider about alcohol consumption and 38% about binge drinking at a checkup in the past 2 years. Among those asked about alcohol use and who reported current binge drinking, 80% received no advice to reduce their drinking.Implementation of alcohol SBI as recommended by USPSTF, coupled with population-level evidence-based interventions, can reduce binge drinking among U.S. adults.


Location-based augmented reality (AR) games, such as Pokémon GO and Harry Potter: Wizards Unite, have been shown to have a beneficial impact on the physical activity, social connectedness, and mental health of their players. In March 2020, global social distancing measures related to the COVID-19 pandemic prompted the AR games developer Niantic Inc to implement several changes to ensure continued player engagement with Pokémon GO and Harry Potter: Wizards Unite. We sought to examine how the physical and mental well-being of players of these games were affected during the unprecedented COVID-19 restriction period as well as how their video game engagement was affected.The aims of this study were to examine the impact of COVID-19–related social restrictions on the physical and mental well-being of AR game players; to examine the impact of COVID-19–related social restrictions on the use of video games and motivations for their use; and to explore the potential role of AR games  in supporting well-being during COVID-19–related social restrictions.A mixed methods web-based self-reported survey was conducted in May 2020, during which COVID-19–related social restrictions were enforced in many countries. Participants were recruited on the web via four subreddits dedicated to Pokémon GO or Harry Potter: Wizards Unite. Data collected included quantitative data on demographics, time spent playing video games, physical activity, and mental health; qualitative data included motivations to play and the impact of video games on mental health during COVID-19 lockdown.P<.001). More than half of the participants reported poor mental health . Female gender, younger age, and reduced exercise were significant predictors of poor mental health. Participants reported a significant increase in video game play time from 16.38 hours per week on average (SD 19.12) to 20.82 hours (SD 17.49) (P<.001). Approximately three quarters of the participants  reported that playing video games had been beneficial to their mental health. The changes made to Pokémon GO and Harry Potter: Wizards Unite were very well received by players, and the players continued to use these games while exercising and to maintain social connection. In addition to seeking an escape during the pandemic and as a form of entertainment, participants reported that they used video games for emotional coping and to lower stress, relax, and alleviate mental health conditions.We report results for 2004 participants . Self-reported physical activity during COVID-19–related social restrictions significantly decreased from 7.50 hours per week on average (SD 11.12) to 6.50 hours (SD 7.81) (AR games have the potential to promote physical and mental health during the COVID-19 pandemic. Used by populations under isolation and distress, these games can improve physical and mental health by providing virtual socialization, sustained exercise, temporal routine, and mental structure. Further research is needed to explore the potential of AR games as digital behavioral interventions to maintain human well-being in the wider population. COVID-19 was first reported in Wuhan, China, on December 31, 2019 . With thAlthough web-based gaming has played a supporting role during the COVID-19 pandemic in maintaining physical distancing, concerns have been raised about encouraging video gaming ; previouFor this reason, “healthier” gaming options that promote increased physical activity and social connection ,9,10 areWith government-issued restrictions during the COVID-19 pandemic encouraging—or requiring—individuals to stay at home, playing AR games in the manner in which they were originally designed has become challenging ,16. NianAs such, our aims were (1) to examine the impact of COVID-19–related social restrictions on the physical and mental well-being of AR game players; (2) to examine the impact of COVID-19–related social restrictions on use of video games and motivations for their use; and (3) to explore the potential role of AR games  in supporting players’ well-being during COVID-19–related social restrictions.We conducted a mixed methods web-based survey during a period in which many countries were under social restrictions due to COVID-19  . This suParticipant recruitment was conducted on the web via four subreddits dedicated to Pokémon GO or Harry Potter: Wizards Unite . A recruitment post was pinned to the top of each of subreddit from May 15-29, 2020, directing individuals to the participant information page via Qualtrics . ParticiThe survey included a total of 40 questions, both quantitative and qualitative. Demographic information was collected from the participants, including age, gender, and country of residence. Responses from quantitative questions relating to video game use, exercise, and mental well-being are reported here, as well as responses from two qualitative questions regarding motivation to play and the impact of games on mental health .Participants were asked whether they identified as a “hardcore gamer,” a “casual gamer,” or a “midcore gamer” to identify their usual play patterns and levels of engagement . HardcorRespondents were asked to report their typical exercise frequency prior to the COVID-19 pandemic (number of hours per day and days per week) and during COVID-19 lockdown (number of hours per day and days per week).The World Health Organization–5 Well-Being Index (WHO-5)  is a 5-iThis paper focuses on responses to two qualitative questions: (1) “What motivates you to play Pokémon GO or Harry Potter: Wizards Unite during the COVID-19 shutdown?” and (2) “How has playing video games affected your mental health during the shutdown?”P<.01 for all analyses.Quantitative survey data were analyzed using SPSS 25.0 (IBM Corporation). Reported total hours of participation in gaming and exercise per week were calculated by multiplying the number of hours by the number of days they were performed. Differences between male and female participants and between self-identified player types were examined using chi-square analysis or multinomial logistic regression for categorical dependent variables or analysis of variance (ANOVA) for continuous dependent variables. Repeated-measures ANOVA was also used to assess mean differences in hours of participation in gaming and exercise per week by gender and player type over time . Finally, binary logistic regression was used to determine factors associated with impaired mental well-being. Here, game play and exercise change scores (pre–COVID-19 minus during COVID-19 lockdown) were incorporated in the analysis. Due to the large sample size, the significance level was set at Qualitative responses were analyzed via thematic analysis using NVivo  . ThematiIn total, 2165 participants responded to the survey. The sample was reduced to 2004 after excluding participants with more than 30% missing survey data. In the sample, most participants were male  and aged between 25 and 34 years . Participants were drawn from 66 different countries, although almost half were from the United States . The characteristics of the survey respondents are presented in 21901=160.23, P<.001), and significantly younger than casual gamers .When asked to self-identify as a hardcore, casual, or midcore gamer, most respondents considered themselves casual gamers , followed by midcore gamers , and hardcore gamers . Hardcore gamers were significantly more likely to be male  than female  , and men  exercised significantly more than women . During the COVID-19 lockdown, participants decreased their exercise to an average of 6.50 hours per week (SD 7.81). Repeated measures ANOVA showed that this reduction in exercise from before to during the lockdown was significant . A significant player type–by-time interaction was also identified, with hardcore gamers exhibiting a greater reduction in exercise during the COVID-19 lockdown than casual gamers . There was no significant gender-by-time interaction. We also identified a significant positive correlation between total hours of gaming and exercise per week both during COVID-19 lockdown  and prior to lockdown .Prior to the COVID-19 pandemic, participants reported exercising for an average of 7.50 hours per week (SD 11.12). At this time, hardcore players  exercised significantly more than casual gamers , being younger (P<.001), and reduced exercise (P=.008) as significant predictors of poor mental health during the COVID-19 lockdown. At a significance level of P<.01, self-identified player type (P=.22) and difference in video game play (P=.04) were not significant predictors of poor mental health  at the time the survey was conducted. A multivariate binary logistic regression analysis was conducted with age, gender, self-identified gaming type, difference in video game play, and difference in exercise entered as predictors. The model identified being female , and men  played significantly more than women . During the COVID-19 lockdown, participants increased their video game playing time to an average of 20.82 hours per week (SD 17.49). Repeated measures ANOVA indicated that the difference in video game playing time between the pre-lockdown and lockdown periods was significant . Notably, a significant player type–by-time interaction was found; casual gamers increased their video game playing time during COVID-19 lockdown  to almost match that of hardcore gamers . Similarly, a significant gender-by-time interaction was identified; women increased their video game playing time during COVID-19 lockdown  to equal that of men . Further, virtually all participants  reported that they were continuing to play either Pokémon GO or Harry Potter: Wizards Unite during lockdown.Three in four participants  reported that during the COVID-19 lockdown, they played video games “a little more” to “a lot more.” Of these 1675 participants, 20% (n=335) reported “no change,” and only 4.7% (n=79) reported playing “a little less” to “a lot less.” Prior to the COVID-19 pandemic, participants played video games for an average of 16.38 hours per week (SD 19.12). At this time, hardcore gamers  played significantly more than casual gamers  indicated that they played Pokémon GO or Harry Potter: Wizards Unite during the pandemic because these games were “fun” and “entertaining.” Some participants noted that these games provided them with “something to do” during the lockdown, as there were few alternatives they could enjoy while “stuck at home” and, in some cases, under financial constraints due to being unemployed or underemployed. Other participants mentioned that COVID-19–related restrictions gave them more time to play, with one 25-year-old male participant stating that it gave him “an opportunity to come back to the game after a few years,” that he “missed playing it,” and that it gave him “something to do in [his] downtime.”Almost one-third of the participants  stated that achievements and challenges were key motivating factors for playing Pokémon GO or Harry Potter: Wizards Unite. Participants stated that the “daily challenges” and “daily tasks” gave them a “sense of accomplishment.” Many Pokémon GO players said that they were driven to accomplish the primary objective of the game, “catch Pokémon,” as well as other objectives such as hunting for “shinies” (color-variant Pokémon) and receiving in-game rewards. Several participants specifically identified having tasks and challenges to complete in Pokémon GO and Harry Potter: Wizards Unite as providing them with beneficial temporal structure and achievable goals, given the disruptions to work or school posed by COVID-19–related restrictions. For example, one female participant aged 35 years noted that it provided “a challenge/task to complete when most of the deadlines have been removed from my life.” Another female participant aged 24 years said, “I’ve been playing Wizards Unite during the lockdown as a way to fill time and have an activity that provides a sense of progress and achievement.”Many respondents  highlighted that they liked or even “loved” the new changes made to Pokémon GO and Harry Potter: Wizards Unite. The games became “more accessible to play from home,” and the “increased rewards and events have kept [people] engaged.” One 30-year-old male participant praised Niantic for their efforts: “Niantic has done well to implement features that make playing from home easier.” Notably, changes such as the “Knight Bus” in Harry Potter: Wizards Unite  and the opening of the “GO Battle League” in Pokémon GO  reduced or eliminated the need to walk outdoors. One female Harry Potter: Wizards Unite player (age 53 years) elaborated:The Knight Bus completely changed game play for me…Online instructions and the ability to ‘travel’ to a Fortress has made the game 100% more interesting.Pokémon GO players also appreciated the addition of “spotlight hours, improvements to the incense and such” , but it was “GO Battle League” that was cited as “game-changing,” with one male player (age 30 years) mentioning that the removal of walking requirements to participate had “renewed [his] interest in the game” by providing “a measurable way to make [and measure] progress.”One-fifth of respondents  noted that they used Pokémon GO or Harry Potter: Wizards Unite while exercising. Many stated that these games motivated them to exercise more, with one 24-year-old male participant mentioning that “it is the only thing that motivates me to go on walks outside” and another 33-year-old female participant saying that these games were “the only reason to step outside” and she was “actually exercising more during lockdown.” For others, it gave them “something to do during exercise” , or during other activities such as “walking the dog” or spending time with family members. Some elaborated on their exercise routines during the COVID-19 restrictions, with a typical example below:Pokémon GO is the one thing that keeps me going outdoors and moving each day. It gives me a purpose to keep walking to different parts of the city but also lets me do so while staying away from clusters of other people.Female participant, age 28 yearsAnalysis of responses to the second qualitative question indicated that more than three in four participants  believed that playing video games during COVID-19 lockdown had been beneficial to their mental health; 20.7% of the participants (295/1427) gave a neutral response, and only 2.1% (30/1427) reported a negative impact. For participants who reported a positive mental health impact, several key themes described the role of video during the COVID-19 lockdown .Approximately half of the participants who reported a positive mental health impact  identified that video games had been helpful in “providing a much-needed escape” and “a great distraction” from the current situation. A number of participants emphasized that games were particularly helpful in how they took their “mind off the constant depressing news coverage of COVID-19.” One 34-year-old female participant elaborated: “I can focus on the game instead of obsessively checking the news and stressing out.” Another male participant (age 27 years) said: “[They] kept me away from watching the news all day. It was quite nice to not be surrounded by COVID news all the time.”Almost half of the participants  stated that video games gave them “something to do,” helped them to “stay busy,” and kept them “entertained” during COVID-19 lockdown. Games gave them “something fun to focus on” and “helped to relieve boredom” while “being at home 24/7.” Many described how games gave them “something to look forward to,” with one 30-year-old male participant even stating that beyond keeping him “motivated and busy,” games helped him to “get out of bed and do something.”In addition to providing an escape and serving as a way to pass the time or be entertained, many participants  identified that video games had helped them “cope” and maintain “a calm and positive outlook.” Playing video games allowed them to “relieve some stress” and “relax,” and it “lifted [their] mood.” One 30-year-old female participant wrote that video games were “possibly the only thing keeping me sane right now.” Some respondents also wrote about using video games to alleviate specific mental health conditions:It’s kept me in a safe place mentally. While college was in session I had depression and anxiety and it’s still lingering as of now. It takes my mind off of the outside world.Male participant, age 19 yearsI suffered from anxiety and depression prior to the shutdown, too, and used games for the same escape then.Female participant, age 42 yearsOne in five respondents  emphasized the importance of video games in strengthening social connections. Many indicated that they played video games with others in their household , thus “providing bonding opportunities.” Multiplayer games provided an opportunity to stay in touch with friends and “still share in something together.” One 30-year-old participant stated: “It has helped because it’s the only social interaction I get.” Some participants highlighted the importance of the local “community” these games create, noting that playing let them feel “less isolated”:In Pokémon GO, the local app group makes me feel part of a community, even if we cannot all meet face to face right now.”Female participant, age 31 yearsMy HWPU [Harry Potter: Wizards Unite]/ingress community connections have been vital in having someone to talk to, and learning about other people's experiences.Female participant, aged 54 yearsThe COVID-19 pandemic has significantly disrupted normal activities worldwide. In this study, we sought to examine the impact of COVID-19 on people’s physical and mental well-being and on video game use. We also sought to explore the potential role of video games (and AR games in particular) in supporting the mental well-being of players during COVID-19 lockdown. We summarize our key findings in accordance with our three objectives.Due to the COVID-19–related stay-at-home restrictions, exercise levels dropped significantly from an average of 7.5 hours to 6.5 hours per week during the pandemic. Despite this drop, on average, players continued to exercise well above the level of 150 minutes (2.5 hours) of moderately intense activity recommended per week by the WHO to achieve health benefits . PreviouFurther, consistent with emerging research , our stuConsistent with reports from popular media, this study found a significant increase in the use of video games during COVID-19 lockdown, mostly driven by casual gamers—women in particular—increasing their video game play. Despite the inconveniences to normal gameplay caused by COVID-19 restrictions, nearly all respondents continued to play Pokémon GO and Harry Potter: Wizards Unite. In fact, the qualitative results indicated that the in-game changes Niantic made to Pokémon GO and Harry Potter: Wizards Unite were a key motivating factor in players’ continued use of the game during the pandemic, with many reporting that they “loved” the changes or had returned to the game because of them. This is also consistent with recent research on social media reactions across three popular Pokémon GO subreddits, which showed overwhelming appreciation toward the in-game changes to Pokémon GO .Despite previous concerns about increased video game use during COVID-19 lockdown , more thOur study was limited in ways that must be taken into consideration when interpreting the results. First, although the study drew participants from 66 countries, the survey was conducted in the English language only, thus excluding participation by non-English speakers. Examining cultural effects on AR game use and gamers’ well-being could be an interesting area for future research. Second, our survey was cross-sectional; therefore, we are unable to imply causality between game play and physical activity based on the current study alone. However, we have examined the data in ways that provide clear direction for future longitudinal research. Third, our study may be subject to sample bias, with recruitment occurring via four subreddit forums dedicated to Pokémon GO or Harry Potter: Wizards Unite; thus, the results may not be generalizable to the entire population. Fourth, this study also relied on self-reported data, which creates potential for recall bias. For our mental health assessment, we relied on the WHO-5 as a noninvasive assessment of subjective well-being. Although this measure cannot be used to clinically diagnose mental illness, previous research supports the use of the WHO-5 to effectively screen for depression. However, further research would benefit from the inclusion of more specific mental health issues, such as the Depression Anxiety Stress Scales  and the Prior to the COVID-19 pandemic, the potential of video games to improve people’s physical and mental well-being  had alreA recent report from Canada  stated tParticipants in this study indicated that they were using games in general to stabilize their mood and prevent further emotional stress. Overwhelmingly, the participants indicated that video games were beneficial to their mental health. Holistically, AR games such as Pokémon GO and Harry Potter: Wizards Unite provide virtual socialization with other people, motivate players to sustain exercise, and offer a daily routine during the lockdown, therefore establishing mental coping strategies to benefit well-being during COVID-19 lockdown. As stated recently in a commentary on gaming in the time of COVID-19, Kriz  suggesteLocation-based AR games such as Pokémon GO and Harry Potter: Wizards Unite already held the potential to be deployed as digital interventions with a beneficial impact on physical and mental health before the COVID-19 pandemic. We provide insight into the effects of continued playing of Pokémon GO or Harry Potter: Wizards Unite on a global sample of AR players. Participants reported increased game play, which coincided with their maintaining exercise levels well above international recommended levels, and using these games as a means of mental coping. Increased game play was significantly associated with increased exercise and was not associated with worse mental health during COVID-19 lockdown.Mentally, our participants reported they continued to play the games out of a desire for entertainment, to have some structure in their daily lives, to have a feeling of accomplishment, and as a means to continue exercising. On a larger scale, the participants played video games to cope with the negative psychological impact of COVID-19 lockdown. They used games to distract themselves, escape briefly from reality, have something to do during their days, manage their emotions and mental health, and stay socially connected with other people. User goals such as these indicate that Pokémon GO and Harry Potter: Wizards Unite were already being used as veritable digital behavioral interventions by the participants to self-regulate emotional distress, especially during the periods of intensive social isolation associated with the COVID-19 pandemic.By understanding the phenomenon of how game players worldwide are using the interactive and immersive medium of video games to manage their own mental health, we are glimpsing the massive potential video games have to become behavioral “medicines” for populations under stress. Location-based AR games have greater potential due to their propensity to encourage exercise and social connections. It would be beneficial for the health care system and digital health professionals to leverage this interactive software effectively during the mental health crisis emerging during COVID-19 lockdown, providing virtual relief and maintaining holistic well-being.


A previously healthy 42-year-old male developed a fever and cough shortly after returning to Canada from overseas. Initially, he had mild upper respiratory tract infection symptoms and a cough. He was aware of the coronavirus disease-2019 (COVID-19) and the advisory to self-isolate and did so; however, he developed increasing respiratory distress over several days and called 911. On arrival at the emergency department (ED), his heart rate was 130 beats/min, respiratory rate 32 per/min, and oxygenation saturation 82% on room air. As per emergency medical services (EMS) protocol, they placed him on nasal prongs under a surgical mask at 5 L/min and his oxygen saturation improved to 86%. A previously healthy 42-year-old male developed a fever and cough shortly after returning to Canada from overseas. Initially, he had mild upper respiratory tract infection symptoms and a cough. He was aware of the coronavirus disease-2019 (COVID-19) and the advisory to self-isolate and did so; however, he developed increasing respiratory distress over several days and called 911. On arrival at the emergency department (ED), his heart rate was 130 beats/min, respiratory rate 32 per/min, and oxygenation saturation 82% on room air. As per emergency medical services (EMS) protocol, they placed him on nasal prongs under a surgical mask at 5 L/min and his oxygen saturation improved to 86%.1.What COVID-19 patients should be considered for intubation?Answer: While a majority of patients will have minor illnesses and never present to the ED, the progression of disease for those who may ultimately require intensive care unit level of care is relatively slow (9–10 days).,2.What's different about intubating patients who may have COVID-19?Answer: Simply put, it's the same for the most part with a few important differences. We're performing a rapid sequence intubation (RSI) with the goal of a high first-pass success (FPS) rate with your “team” that you are familiar with. The accompanying algorithm is very similar in approach to what most emergency medicine physicians do currently  These sick patients likely carry a greater viral load and 2) conventionally performed airway procedures will produce airborne particles (aerosol generating procedures [AGPs]).urrently . It's di3.How do I protect myself and my team?Answer: There is considerable discussion and concern amongst healthcare providers around the availability and access of appropriate personal protective equipment (PPE) for high-risk AGPs such as intubation. Lessons from previous experiences (severe acute respiratory syndrome [SARS]) reveal that a significant proportion of infections is related to breaches in the donning and doffing process.4.How should we approach support to preoxygenation?Answer: Preoxygenation in COVID-19 patients will deviate from familiar ED practice. Disclaimer: There is no concrete evidence to support specific no-risk preoxygenation techniques in this population. However, the overlying principle is to use the lowest flow necessary to achieve an acceptable saturation. Pushing flows to achieve higher oxygen saturation increases risk without benefit. What exactly does that mean? Aiming for an oxygen saturation of 90–92% may be reasonable, if achievable. It may initially mean having low flow (< 6 L/min) nasal prongs and then escalating to 15 L/min using a non-rebreather face mask), which is usually well tolerated. For most emergency physicians, preoxygenation will transition to using a bag-valve-mask (BVM) that can be purposely modified for COVID-19 patients (https://vimeo.com/406929923). The key difference from our standard equipment use is that from here on, anything applied to the face or trachea (mask or tube) needs a viral filter (very rapidly.l filter . Applyin5.What is the best approach to intubation in COVID-19 patients?Answer: Perform RSI and use a video laryngoscope (VL) as part of an old-fashioned “double setup.” (Be prepared to perform a cricothyrotomy.) Pretty simple here, awake intubations are essentially contraindicated. Period. Ideally using a video laryngoscope that keeps your face safely away from the patient's face. However, RSI alone is not an approach. Practice with and use checklists/visual aids which are accessible and ideally posted in the room , and go in on a “profoundly” paralyzed patient. Driver et al. achieved an FPS rate of 98% with routine use of a bougie in combination with a Macintosh blade VL device.room see . No airwaimeairway.ca for procedure videos for laryngoscopy tips).An out-of-package bougie is straight with a coude tip and is meant for Macintosh blade devices. Recognize for some Macintosh VL devices that a slight bend on the distal portion of the bougie may be necessary. The nuances of VL use are beyond the scope of this article; however, use of a hyper-angulated VL can be a primary approach for those trained and confident with the nuances of tube delivery and/or be considered if an “optimized” Macintosh VL approach fails . Don't look for the oxygen saturations to rise, but do ask for help if a second provider is available in PPE. You won't see an end-tidal CO2 trace unless you gently provide pressure support. Anytime you squeeze the bag, there is some risk to aerosolization; however, your patient has been rendered apneic. The risk of controlled ventilation (6–10 breaths over 1 minute) must be balanced against worsening hypoxemia that results in cardiac arrest (bad). A third option is your rescue supraglottic device . If you are able to maintain saturations, you have to consider whether a second attempt at VL will be of value by you or your help. Alternatively, move to your exit strategy (see ,tegy see . If you KEY POINTS•Airway management of COVID-19 patients requires a paradigm shift from a focus primarily on patient-oriented outcomes to one that focuses on provider safety.•RSI using a familiar VL device is the default method to secure the airway.•Slow down to ensure patient and provider safety.•Train in donning and doffing PPE, best practice airway skills wearing PPE, and as a team executing your plans.


High diversions particularly, like Sober ureterostomy, can lead to damage to the ureter vasculature and raise the inherent problem of potentially difficult subsequent reconstruction. They should consequently be reserved for carefully selected cases , 2.In Sober or “en Y” ureterostomy the ureter is transected, the proximal end is then anchored to the muscle, sheath, and the skin, while the distal end is connected with the lowest part of the renal pelvis to maintain the patency of the natural urinary tract and possibly preserve bladder function . FrequenEndoscopic revision of the right ureter and renal pelvis through the stoma was performed. A sticky, plastic substance, with a chewing gum like consistency as described by the urologist, was found in the right renal pelvis. Its complete removal was impossible due to its size and plasticity. The extracted material presented as drop like translucent sticky structures with a smooth surface. Those macroscopic characteristics were reminiscent of the adhesive covered part of the pouch, which prompted further investigations in collaboration with the Department of Advanced Materials and Technologies, Faculty of Materials Engineering, Silesian University of Technology, Gliwice, Poland. Fragments of the suspected foreign body were analyzed with a Hitachi 3400 N scanning electron microscope (SEM) and a Thermo Noran System Six energy dispersive spectrometry (EDS) device, to evaluate its microstructure and chemical composition.The size of the specimen and EDS method limitations allowed only for qualitative analysis of its chemical composition, which consisted of carbon, chlorine, calcium, silicon, and sulfur. The organic and probably polymeric nature of the specimen could also be assumed, which is consistent with the nature of the adhesives used in pouching devices as described above. Moreover, beside ultrastructural similarities Fig. , the EDSThose findings strongly corroborated the hypothesis that the artifact was likely the effect of back flushing of adhesives from the skin/pouch interface to the urinary tract, and its collection in the renal pelvis and, to a lesser degree, the urinary bladder. This complication was, to our best knowledge, very rarely described and several factors probably contributed to its genesis .Firstly, the ureterostomy was performed in the first year of the boy’s life, and was kept for about 8 years, when the foreign body was detected for the first time. As mentioned before, temporary cutaneous ureterostomies are rarely performed nowadays, considering that their major drawback is that subsequent urinary reconstruction can be more difficult than primary reconstructive surgery . The uroSecondly, reassessment of the daily ostomy care revealed that during the appliance changing, too small an opening was cut off in the skin barrier by the child’s caregivers. That could lead to a reduction of the distance between the edges of the adhesive and sealing paste covered skin barrier, and the stoma lumen. While an inadequately large pouch opening exposes the skin to the irritating contact with urine, a too small one may promote adhesives washing out by the urine and their deposition in the pouch.Finally, the pouch, which was daily drained and sealed before sleep, was too small in regard to the amount of urine produced during the night. Its overfilling probably facilitated the backflow of urine containing molecules of the sealing paste and adhesives to the renal pelvis, and subsequently led to the formation of the foreign body. In that respect, it is recommended to drain the pouch when it is one-third, or half filled. Alternatively, night drainage device systems are available; they are connected to the bottom pouch valve and drain urine excess, allowing undisturbed sleep while preventing pouch overfilling. It is also worth noting that many ureterostomy pouches are fitted with antireflux mechanisms, which obviously minimize the risk of the discussed complication.Backward urine flow from the urostomy pouch to the renal pelvis can be a source of extrinsic particles which can accumulate in the urinary tract.The shadowing and twinkling artifact observed in ultrasound, usually considered as specific to kidney stones, may also be observed in some atypical circumstances, such as those described in this case , 9.


To evaluate the feasibility and acceptability of a mobile-based brief intervention (BI), generate preliminary estimates of the impact of the BI and fine-tune the procedures for a definitive randomised controlled trial.Parallel three-arm single-blind individually randomised controlled pilot trial. Eligible and consenting participants were randomised to receive mobile-based BI, face-to-face BI and information leaflet.Educational institutions, workplaces and primary care centres.Adult hazardous drinkers.Seventy-four participants were randomised into the three trial arms; forty-eight (64·9 %) completed outcome evaluation. There were no significant differences between the three arms on change in any of the drinking outcomes. There were however in two-way comparisons. Face-to-face BI and mobile BI were superior to active control for percent days heavy drinking at follow-up, and mobile BI was superior to active control for mean grams ethanol consumed per week at follow-up.The encouraging findings about feasibility and preliminary impact warrant a definitive trial of our intervention and if found to be effective, our intervention could be a potentially scalable first-line response to hazardous drinking in low-resource settings. India is experiencing a steady increase in alcohol consumption, and increasing levels of alcohol-related problems,3. Despite the higher prevalence of hazardous drinking (pattern of drinking that confers reasonably high risk of harm), compared to those already experiencing harm due to AUD, for example, dependent drinkers (20 % v. 4 %), Indian health policy focuses predominantly on the latter; resulting in the former not having access to adequate help,4.Alcohol use disorders (AUD) are major contributors to morbidity, mortality and disability across the world, the key barrier has been in the translation of the research evidence into implementation in routine practice. Some of the challenges influencing the implementation of BI in routine practice in low- and middle-income countries (LMIC) include the shortage and inequitable distribution of health professionals, high clinical workload and competing clinical priorities–11.Brief interventions (BI) are short personalised, supportive and non-judgemental interventions delivered to help the individual to understand that their drinking is putting them at risk and to encourage them to reduce or give up their drinking. Although there is extensive evidence demonstrating the effectiveness of BI in reducing hazardous drinking. Although there is growing evidence that digital health interventions may lower alcohol consumption, all the studies have been conducted in high-income countries and the interventions are web-based and require computer literacy; characteristics that limit the potential scalability of these interventions in LMIC.One evidence-based solution to make interventions accessible in low-resource settings is through the use of technology, thus addressing the key barrier related to shortage of human resources, but the potential of such interventions for hazardous drinking has not been explored in LMIC,16.On the other hand, the relatively less sophisticated short message services (SMS) and interactive voice response (IVR) can be used to reach large numbers quickly and at low cost, to overcome language and literacy barriers, and to access people in remote areas. SMS-based interventions have been tested on multiple therapeutic targets such as appointment attendance, motivation, self-efficacy, relapse prevention and social support in those with drug or alcohol dependence. This first version of the package was tested through a case series, by refining the intervention content and delivery mechanisms through an iterative process, to develop the final intervention (submitted for peer review). The pilot randomised controlled trial described in this paper is aimed to empirically evaluate the feasibility and acceptability of the mobile-based BI, generate preliminary estimates of the impact of the BI and fine-tune the procedures for a definitive randomised controlled trial.The aim of the Alcohol use disorders-Mobile based Brief Intervention Treatment (AMBIT) study was to develop and evaluate a mobile-based BI for people with hazardous drinking in India. The preliminary formative research efforts in this study informed the development of the first version of the treatment package–20. Recent evidence has also indicated increasing levels of alcohol consumption amongst young women in India. The study was implemented in the following settings: educational institutions , workplaces (thirteen police stations and four bus depots) and primary care .The study was conducted in Goa, a small state on the west coast of India. In Goan men, the prevalence of high-risk drinking in a community was 14·8 %, and that of hazardous drinking ranged from 15 % in samples drawn from primary care to 21·3 % in samples of industrial workersParallel three-arm single-blind individually randomised controlled trial. The trial protocol was registered on ClinicalTrials.gov (registration identifier NCT04078360).. Recruitment commenced on 20 September 2019 and because of the COVID-19 pandemic we had to discontinue recruitment on 16 March 2020, before we achieved the target sample size.A sample of 120 participants was planned to be recruited in the intervention and control groups, approximately evenly spread out across all study settings and interventions. The sample size was not based on formal power calculations as the study is not designed to test a hypothesis. The sample size estimations have been made based on our previous experiences of pilot randomised controlled trial and deemed sufficient to achieve the goals of understanding the acceptability, feasibility and preliminary impact of the intervention, and (d) had personal ownership of a mobile phone and familiarity with the use of SMS/IVR. The exclusion criteria were (a) females (in workplaces and PHC). There is insufficient evidence to indicate that hazardous drinking in women in India is as widespread across the lifespan as it is with men, so women older than the typical college-going age (25 years) were not included in the study and consequently were not screened at the workplace and primary care site, (b) harmful and dependent drinkers (AUDIT score >15), (c) individuals owning a shared/family phone and (d) those who expressed an inability to use SMS and IVR.The inclusion criteria were (a) adult (aged 18–65 years) males and females in educational institutions, or (b) adult males in workplaces and primary health centres (PHC), who were (c) hazardous drinkers defined as a score of 8–15 on the Alcohol Use Disorder Identification Test (AUDIT). The AUDIT is a 10-item screening questionnaire developed by the WHO for the detection of AUDParticipants across all three settings were recruited through screening by trained researchers, who identified hazardous drinkers through appropriate screening procedures. Eligible participants were recruited if they provided voluntary informed consent to participate.To reduce stigmatisation associated with drinking, at educational institutions and workplaces, a ‘Health and Wellness Camp’ (tested during the formative research phase for acceptability and feasibility) was organised. In the screening room/booth set-up in the Camp, researchers screened for two other health-related issues  in addition to AUD screening. At the PHC, where questions about drinking behaviours are not unusual, we did not expect similar stigmatisation and hence we directly conducted universal screening for hazardous drinking to identify eligible participants.In addition, recruitment was also undertaken through referrals from the following sources: (a) self: potential participants who got to know about our study at all three settings through the various forms of advertising  approached a researcher for screening at their respective and preferred location and (b) gatekeepers : the researchers sought assistance from these gatekeepers to build awareness about the study and these gatekeepers referred potential participants to the researchers and informed people at the site about the health and wellness programme and asked them to make contact with the study team. Self-referring participants and those sign-posted by the gatekeepers were then screened using the procedures described.,25. It has been translated into Konkani (Goan vernacular), using a systematic translation-back translation method with two teams of translators, followed by an item-by-item analysis and selection by consensus. Other screening tools that were used as part of the ‘Health and Wellness Camp’ activities included the International Physical Activity Questionnaire (IPAQ) and Perceived Stress Scale (PSS), both of which have been validated in LMIC. The PSS is one of the most widely used psychological instrument for measuring the perception of stress and has been empirically validated with populations of mainly college students or workers. The IPAQ is a widely used questionnaire developed to collect health-related physical activity data and is suitable for use among young and middle-aged adults. Participants screening positive for hazardous drinking as well as PSS or IPAQ were recruited into the study. Those who screened negative for hazardous drinking but positive on PSS and IPAQ were provided relevant information and advice about stress management and healthy physical activities. Those screening positive for harmful drinking or alcohol dependence on the AUDIT were provided relevant information and advice related to AUD, and information about relevant local services to access help.All potentially eligible participants were screened using the AUDIT to identify hazardous drinking. The AUDIT has been validated in India, used in cross-national studies and used extensively in the study setting. The TLFB has high test–retest reliability and concurrent validity has been established in various types of AUD. It has been used in previous research in the study settings. (c) In addition, for the participants receiving the mobile-based intervention, we collected information required for the delivery of the intervention such as preferred days/time to receive the SMS/IVR, and preference for SMS and/or IVR.(a) Sociodemographic information such as age, gender, employment status, educational status and marital status; (b) Time-Line Follow Back (TLFB): the TLFB is a calendar method of collecting data about quantity and frequency of drinking and various memory aids are used to enhance recall Stratified randomisation was used. Consenting eligible participants were randomised within the following three strata: educational institutions, workplaces and healthcare centres. Within each stratum, they were randomised to receive SMS/IVR-based BI, face-to-face BI or active control. An independent data manager generated a randomisation list and participants were randomised using Sequentially Numbered Opaque Sealed Envelopes to maximise allocation concealment. The research workers administering the outcome tools and the lead investigators were blind to arm allocation.https://viamo.io/) platform, messages/IVR calls were sent automatically to them as per schedule. Each week messages were focused on specific content areas derived from the formative research of the study. Some of the components of the intervention include self-awareness messages, self-reflection messages, motivational messages, messages on safe drinking, alcohol reduction, drinking management, risk management, craving management and drinking alternatives, health education messages, personalised feedback and information, and goal setting. Dropout from the intervention was defined as participants choosing to stop receiving the intervention messages by informing the project team. The messages were in English or the vernacular language based on the choice of the participants. The messages were predominantly ‘push’ messages (not requiring a response from the recipient) with a few ‘pull’ messages (requiring a response from recipient). Further details of the intervention are available in a separate peer-reviewed publication.Mobile based-BI – the intervention included SMS or IVR calls twice or thrice a week delivered for a duration of 8 weeks. Once the participant’s mobile number was uploaded on our technology partner’s  intervention and was delivered by a trained researcher. The BI was delivered over a single session lasting 5 to 10 min. This included sharing their AUDIT score and its interpretation with the participant, personalised feedback, providing information about safe drinking limits, potential risks to health and social wellbeing if drinking continued at the present level, collaborative exploration of potential benefits of reducing drinking, and strategies to reduce drinking.Active control – this was a BI leaflet consisting of information on alcohol consumption, and tips to manage and reduce drinking.The primary outcome was change in percent days abstinent (PDA). Secondary outcomes include change in quantity of drinking (grams ethanol/week), change in patterns of drinking (percent days heavy drinking (PDHD)) and change in intensity of drinking (grams ethanol per drinking day). All these outcomes were calculated from the TLFB administered at 3 months post-randomisation and covered the 2 weeks preceding the outcome evaluation.v. IVR, proportion of participants that listened to the complete IVR and proportion of participants with high engagement (response to more than 50 % of messages requiring a response). The feasibility and acceptability were also examined through a nested qualitative study, the findings of which will be presented in a separate publication.Feasibility and acceptability were assessed by examining data on the number and proportion of dropouts from treatment (participants choosing to stop receiving the intervention messages), reasons for refusal to participate, reasons for dropout, proportion of participants choosing SMS The following process data were also collected during the course of the study: number of participants screened for AUD in each setting; number and proportion of participants screened positive for hazardous drinking; number and proportion of those with hazardous drinking who were eligible for the pilot trial; number and proportion of participants consenting for the treatment; and number and proportion of participants completing outcome assessmentv. those in the control arm were all analysed as proportions or means as appropriate and compared using chi-square test (for proportions), t-test (for means of two groups) and ANOVA (for means of three groups) as appropriate. For an overall statistically significant one-way ANOVA result, the Tukey’s post hoc test was used to confirm the differences between two groups. The trial process indicators are presented consistent with CONSORT guidelines including a trial flow chart. The primary analysis was intention-to-treat at the 3-month end point regardless of treatment adherence and adjusted for baseline AUDIT and recruitment site. Linear regression was conducted for comparing the difference between arms on change in the various drinking outcomes, and effect sizes are reported as adjusted mean differences with 95 % CI. Post hoc analysis included linear regression to compare the difference between arms on the various drinking outcomes at follow-up.Baseline characteristics of individuals who consented and did not consent, participants who did and did not complete outcome assessments, baseline characteristics of participants in the intervention arms sd 6·2) (range 0–32). Of the 114 hazardous drinkers, 103 (90·4 %) were eligible for participation and 11 were excluded because 8 did not know how to respond to the text messages sent to a mobile phone and/or had previously not responded to the text messages on a mobile phone and/or did not know how to use IVR calls, and 3 females were not recruited from educational institutions, as we had met the numbers for recruitment. Lower education, being employed and recruitment in PHC were significantly associated with refusal of consent to participate , P = 0·008) and mean grams ethanol consumed per week (62·6 (112·3) v. 21·9 (45·2), P = 0·02) (Appendix A).In the overall sample, comparing baseline and follow-up, there was a significant decrease in mean PDHD (10·1 (18·7) v. 0·8 (3·4), P = 0·02). In the mobile BI arm, there was within-arm increase in mean PDA (86·5 (16·5) v. 98·1 (3·2), P = 0·009) and reduction in mean grams ethanol consumed per week (38·3 (51·3) v. 3·7 (8·0), P = 0·01) (Appendix B).There were significant within-arm changes in both the BI arms, with no within-arm changes in the active control arm for any of the outcomes. In the face-to-face BI arm, there was within-arm reduction in mean PDHD (9·1 (12·9) There were no significant differences between the arms on change in any of the drinking outcomes Tables  and 5.v. 0·8 (3·4), P = 0·006), and in mobile BI arm compared to the active control arm (7·1 (9·6) v. 0·4 (1·6), P = 0·003). The mean grams ethanol consumed per week at follow-up was significantly lower in the mobile BI arm compared to the active control arm (55·6 (70·9) v. 3·7 (8·0), P = 0·005) (Appendix C).Mean PDHD at follow-up was significantly lower in the face-to-face BI arm compared to the active control arm (7·1 (9·6) P = 0·01) and mobile BI ; P = 0·01) were superior to active control for PDHD at follow-up, and mobile BI was superior to active control ; P = 0·02) for mean grams ethanol consumed per week at follow-up (Appendix D).Face-to-face BI ; Our pilot trial has demonstrated that it is feasible to identify and recruit people with hazardous drinking in clinical, educational and workplace settings in Goa, that it is feasible to deliver a basic mobile-based intervention to such individuals, that this is potentially acceptable to the target group, and there are preliminary indications that a SMS-based BI might be superior to usual care even if it is enhanced, and at least as impactful as a face-to-face BI., but there is limited evidence for both effectiveness and systematic implementation of BI in LMIC,33. Although the effectiveness evidence makes BI a highly competitive option for public health interventions to reduce alcohol-related harm, implementation at scale has been challenging for several reasons. These include lack of trained healthcare staff, high clinical workload of existing staff, reluctance of patients experiencing alcohol problems to disclose such problems with healthcare providers, concerns about patient confidentiality and privacy, stigma related to AUD, all leading to limited accessibility, acceptability and adherence to treatment,34–37.The effectiveness of BI for hazardous drinking has been extensively researched and established India has an unique opportunity to significantly increase the penetration and coverage of BI to counter the increasing prevalence of hazardous drinking in the country.For the change in drinking outcomes in our trial, although the changes are in the right direction, there are no significant differences between the arms. On the other hand, for the outcomes at follow-up, both BI demonstrated effects with the mobile BI showing even stronger effects than did the face-to-face BI. Our findings suggest the potential applicability of mobile-based BI for the management of hazardous drinking in low-resource settings. More importantly a mobile-based BI is uniquely positioned to overcome some of the key challenges to scaling up evidence-based BI, especially in low-resource settings. By eliminating the need of a human resource to deliver the intervention, we automatically exclude supply side barriers such as lack of trained professionals and reluctance to engage because of limited clinical time. This also overcomes demand side barriers related to stigma and related concerns about confidentiality. Finally, such a technology-enabled intervention has the added advantage of standardising the content of the intervention delivered by eliminating the variability in quality that can occur when delivered by humans. For such a programme to be scaled up, the only infrastructural requirement is telecom and with 1·2 billion mobile phone subscriptions (and growing) and a tele-density of 87 %As expected for a pilot trial not powered to test effectiveness, there were few statistically significant interventions effects. However, for the outcomes related to overall amount of alcohol consumed and heavy drinking days, the face-to-face and mobile-based interventions had more favourable outcomes compared to the control arm. Besides the lack of power to examine effectiveness, our study had other limitations. The drinking outcomes were based on self-report data, which could lead to differential social desirability responses between trial arms. Although our testing of multiple hypotheses increases the chances of false-positives, it is not unusual to do so in pilot trials to identify and test appropriate outcome measures for a definitive trial.sd = 7·9) in the mobile BI arm and −13·7 (sd = 19·5) in the face-to-face BI arm, Type I error = 0·05, and 90 % power, we will need to recruit 326 participants, allowing for 35 % loss to follow-up. Finally, the findings of the pilot trial indicate that we will need to make vigorous attempts to ensure that the dropout from outcome evaluation is as low as possible.Our findings do indicate that for a trial of BI targeting hazardous drinking, outcomes focused on quantity or intensity of drinking might be better suited than those that measure frequency of drinking. So, the following power calculations for a definitive trial are based on the mean change in grams ethanol per drinking day observed in this pilot trial. Assuming a mean change of −20·4 (The evidence base for effectiveness of BI is predominantly derived from high-income countries and implementation of BI at scale is fraught with challenges. Thus, our intervention is unique, as it is designed to be delivered using basic mobile phone technology making it potentially scalable even in low-resource settings. Considering our feasibility findings, a definitive trial of our intervention is warranted. If effective, our intervention could be positioned as a first-line response to hazardous drinking in India and other similar LMIC.