It is essential to equip midwives and nurses working in the perinatal period with comprehensive knowledge and awareness regarding child abuse prevention. However, most midwives and nurses in Japan do not have the opportunity to learn about abuse prevention during their basic education. We aimed to develop an e-learning program to assist obstetric midwives and nurses in acquiring the knowledge needed to provide support and handle cases with a high risk of abuse, as well as to assess the program’s usefulness. This study employed a single-group pre–post design; e-learning served as the intervention. Seventy-one obstetric midwives and nurses were recruited. The program’s usefulness was the difference between the participants’ pretest and post-test knowledge and efficacy scores. The score data were analyzed using the t-test. A paired t-test revealed that the post-test scores of knowledge and efficacy were significantly higher than those of the pretest, with a large effect size (d = 1.71). Platforms where basic knowledge on how to respond to high-risk abuse cases are lacking in nursing education; thus, this e-learning program is recommended for nurses working in the perinatal field throughout Japan. This educational opportunity for perinatal midwives and nurses will increase awareness and contribute to abuse prevention. Child abuse is a global social issue, and within the realm of perinatal nursing, supporting caregivers to prevent subsequent abuse is a critical responsibility. The effectiveness of programs for tertiary prevention intervention for abuse has not been established, as demonstrated by previous studies ,2. HenceAt the same time, there is little education or guidance related to abuse prevention targeted for perinatal nurses , and JapThis lack of educational opportunities ,13 may hThe provision of educational opportunities for nurses on abuse prevention is expected to increase nurses’ awareness of abuse . To contWe aimed to develop an e-learning program designed to equip obstetric nurses and midwives with the essential knowledge required to effectively support and manage high-risk abuse cases. Additionally, we sought to assess the effectiveness and usefulness of this program through comprehensive evaluation. We hypothesized that obstetrics nurses and midwives would improve their post-test scores of knowledge, and the sense of efficacy and satisfaction would be improved by participating in the e-learning program we have developed.This study involved a single-group pre–post design with e-learning serving as the intervention. It was conducted in the obstetric wards of medical facilities near Tokyo, Japan. We conducted the study from December 2016 to July 2017. Of the 136 participants who consented to participate, 71 completed the study . Data from these 71 participants were included in the analysis .The target population comprised midwives and nurses who had worked in obstetric care aged 20–65 years old. The participants were gathered through snowball sampling during the study period. Posters that invited participation in the study were displayed in the obstetric wards of medical facilities near Tokyo. The posters included a QR code to provide details of the study, which the participants accessed. Prior to their involvement in the study, the participants were provided with detailed information about the research and were given the opportunity to provide informed consent, ensuring adherence to ethical considerations. After consenting, they were asked to complete a pretest.The e-learning program was developed for midwifery education by the authors (KB and YK), such as the training required to acquire the Clinical Ladder of Competencies for Midwifery Practice in Japan (CLoCMiP ). The e-The e-learning program comprised four chapters with several sections composed of short videos (5–10 min) and a quiz with multiple-choice questions with a single correct answer. If the selected answer was correct, the user could proceed to the next section. The e-learning program took approximately 90 min to complete. The participants who completed the e-learning program were asked to complete a post-test and a satisfaction questionnaire. They were sent a reward (a Quo card worth 1000 yen) via post as an incentive.Knowledge and awareness (sense of efficacy) must be increased to support and handle high-risk abuse cases ,20,31. ATo check the level of understanding of the e-learning program, we administered a 15-item knowledge test before and after the e-learning program . The test content consisted of knowledge needed to prevent or support abuse cases, such as “definition of abuse”, “definition of specific pregnant women”, and “risk factors for abuse”.Upon the completion of the e-learning program, the participants’ sense of efficacy was evaluated through the following two questions: “If you were to encounter a case of (suspected) abuse, would you be able to respond with confidence?” and “If you were to encounter a case of (suspected) abuse, would you be able to respond positively?” All items were rated on a five-point scale (higher scores indicated higher levels of a sense of efficacy).The quality of the e-learning program was evaluated using an anonymous questionnaire to determine the level of satisfaction in terms of “design”, “system functions”, “overall satisfaction”, “return to clinical practice”, “recommendation to colleagues”, and “content of educational materials”. All items were rated on a five-point scale (higher scores indicated higher levels of satisfaction).t-test was conducted to compare the differences in the knowledge test scores (0–15 points) and the sense of efficacy (0–5 points) between the pre-test and post-test. In addition, a McNemar’s test was conducted to measure the change in the percentage of correct answers for each item between the pre-test and post-test. We calculated effect sizes [A ct sizes  from theThis research project was approved by the Ethical Committee of St. Luke’s International University (16-A075) in November 2016. The participants were provided with detailed written information about the study and offered written consent before the completion of the pretest. They were told that they could withdraw at any time without prejudice. To ensure their privacy, they were asked to complete the questionnaires online. We provided an online support system for the participants to contact the administrator (KB) to help them operate the e-learning program. To avoid potential harm , the resThe participant characteristics are presented in p < 0.001). The effect size was large for the post-test (d = 1.71) [p < 0.001). The item with the lowest percentage of correct answers in both the pre-test and post-test was “Matters to be considered by the Regional Council for Measures for Children in Need of Protection.”Before and after the e-learning program, a pre-test and post-test were conducted to evaluate the participants’ knowledge using the total score  . The sco = 1.71) . McNemarp < 0.001), as illustrated in p < 0.001), as indicated in Before engaging in the e-learning program, the participants were asked the question, “If you were to encounter a case of (suspected) abuse at this time, would you be able to respond with confidence?” Out of the respondents, approximately 10%  answered with a rating of 4 or 5. However, following the completion of the e-learning program, the number of confident responders increased significantly to approximately 50% . This observed increase in confidence scores was found to be statistically significant  with a large effect size (d = 1.71). In previous studies [The scores on the knowledge test regarding abuse increased significantly after the implementation of e-learning . Of these, approximately half were unable to access the educational program after completing the pretest. The researchers sent reminder e-mails to the registered e-mail addresses of each participant two weeks before the end of the study period, informing them about where to access the e-learning program; they also responded to participants’ system-related problems individually by e-mail. However, despite these measures, there were still dropouts. As most of the participants who did not complete the educational program did not use e-learning, it is possible that there was a need for a face-to-face version of the program. Furthermore, as a previous study  demonstrFourth, this study was conducted before the COVID-19 pandemic and did not consider the long-term impacts on society and health caused by COVID-19 . There iDespite these limitations, this is the first study to develop an e-learning program that efficiently provides the necessary multifaceted knowledge regarding the primary prevention of abuse cases and to confirm the effectiveness of the “knowledge,” “efficacy,” and “satisfaction” improvements obtained in this study. Future research should modify the content of the e-learning program and test the effectiveness of the program with professionals not limited to the nursing profession or the medical frame of reference. To truly prevent abuse, the dissemination of abuse e-learning programs that have been validated for effectiveness is necessary.We demonstrated the usefulness of the developed e-learning program for acquiring knowledge and improving the sense of efficacy necessary to support high-risk cases of abuse. To our knowledge, this is the first study in Japan to develop and demonstrate the effectiveness of the e-learning program for obstetric nurses and midwives to acquire the knowledge to prevent abuse. In subsequent studies, the contents need to be revised based on issues identified in this study, and their effectiveness should be tested using a comparative study design. However, this e-learning tool could be used from the perspective that abuse prevention is an urgent need in the perinatal nursing field. The practical use of one of the training programs in CLoCMiP , the nat


The conditions on the mating matrix associated with a stable equilibrium are specified for an autosomal locus with five alleles. This points the way to the maintenance of Hardy-Weinberg proportions with non-random mating. The myth of random mating is exposed. Crow  explainsCrow (1999), in discussing the origins of the Hardy-Weinberg law, reproduces the argument of Hardy (1908), including Hardy’s question: ‘in what circumstances will this distribution  an AA is p2 . In counij} is subject to the same constraints as those set out above when mating is at random.As noted earlier, when resorting to the notion of random mating to justify the use of the Hardy-Weinberg principle, the appeal is to the apparent simplicity of the concept. But, of course, the mating regime expressed in the elements {cLi , followeIn the final section of his paper, Mayo Stark  was awarIn detail, the genotypic proportions are:The mating frequencies areThe model has the property Edwards  wP, 2Q and R of the three possible genotypes would be related so that Q2 = PR’.Weinberg Emery’s Elements of Medical Genetics has a typical demonstration of the Hardy-Weinberg principle  are displayed on the margins. The mating proportions are simply the products of the marginal frequencies. The demonstration continues to derive offspring frequencies, which are the same as those of the parent, by applying Mendel’s law. “Non-random mating” is listed as a “potentially disturbing factor”.rinciple . FIG. 7.Hardy indicated how Hardy-Weinberg proportions could be reached and sustained in an idealized setting. One could say that it is an unattainable ideal. He did not pursue the question as to whether there is any way, other than by ‘random mating’, that stationarity can be achieved.Up to this point there is no appeal to chance which enters the picture when the biologist seeks to apply the principle to a population. Matings occur perhaps by chance and gametes are transmitted at least partly by chance. The probability calculus and statistical theory are useful in deciding whether the Hardy-Weinberg model can be used for analytical and predictive purposes.Weinberg found the model useful for studying the human propensity to produce twins. An account of his life and work is given by Sperlich and Früh .


MW 7.8 Kahramanmaraş earthquake on the East Anatolian Fault Zone. Seismicity is composed of isolated spatio-temporal clusters within 65 km of future epicentre, displaying non-Poissonian inter-event time statistics, magnitude correlations and low Gutenberg-Richter b-values. Local comparable seismic transients have not been observed, at least since 2014. Close to epicentre and during the weeks prior to its rupture, only scarce seismic activity was observed. The trends of seismic preparatory attributes for this earthquake follow those previously documented in both laboratory stick-slip tests and numerical models of heterogeneous earthquake rupture affecting multiple fault segments. More comprehensive earthquake monitoring together with long-term seismic records may facilitate recognizing earthquake preparation processes from other regional deformation transients.Short term prediction of earthquake magnitude, time, and location is currently not possible. In some cases, however, documented observations have been retrospectively considered as precursory. Here we present seismicity transients starting approx. 8 months before the 2023  MW 7.8 Kahramanmaraş earthquake on the East Anatolian Fault. They are consistent with experiments and models of heterogeneous rupture affecting multiple fault segments.Unique seismic transients since 2014 were detected during 8 months before the 2023  Individual earthquakes cannot be predicted in a deterministic way despite the urgent social-economic need to warn people and protect critical infrastructure. In some cases, however, the processes leading to the nucleation of an earthquake may have an extended duration, i.e. months-to-years, that can be monitored, and potentially recognised.1. Some interplate earthquakes have been observed to be preceded by increased seismic and aseismic slip in the region leading up to the mainshock2. This has been particularly well documented in several subduction zone megathrust earthquakes5. An alternative view is that foreshocks occur as part of a cascade of failures, such that the large earthquake that occurs after them is governed by the proximity of a fault to failure in a large event6.Earthquake foreshocks are the most relevant detectable earthquake precursors, but their identification as such is typically only possible once the mainshock has occurred. Their predictive power may be tied to whether the foreshock collective behaviour can be uniquely attributed to loading by aseismic slip and/or fluid flow, meaning that the foreshocks act as passive tracers of the preparatory process7. In some large earthquakes on plate-bounding transform faults, such as the 1992 MW 7.3 Landers, the 1999 MW 7.1 Hector Mine and the 2019 MW 7.1 Ridgecrest events, spatio-temporal localisation of the seismicity towards the main fault traces  has been observed over time scales of 2-3 years before the mainshock8, promoting the interaction between seismicity and the coalescence of fault branches and fractures framing the principal slip zone activated in future large earthquakes. The ultimate phase just before rupture may include the occurrence of slow-slip transients and/or foreshocks at multiple spatial and temporal scales9. Tracking these processes and identifying slow-slip events or small earthquakes as indicators of an upcoming large earthquake, however, remains a challenge. This is the case as the long recurrence times of large earthquakes of typically a century or more only provide a limited number of examples since the onset of instrumental seismology. An additional challenge is that analysing long-term deformation records, seismic and/or aseismic deformation transients can also occur without resulting in a major earthquake10.On the decadal time scale, during the inter-seismic period, increasing levels of background seismic activity may represent enhanced damage generation over a broader area hosting a notable future earthquake11 substantially improved the earthquake detection threshold, which enabled the search for seismicity transients in greater detail. We additionally access continuous recordings from more than 40 stations in the area operated by AFAD  and KOERI  agencies, to recover a high-resolution view of the seismicity during the preceding weeks. The observed seismicity transients suggest an extended earthquake preparation process starting in June 2022 and lasting for approximately 8 months prior to the occurrence of the MW 7.8 Kahramanmaraş earthquake, including accelerating seismic activity, non-Poissonian inter-event time statistics and magnitude distribution in time, as well as low Gutenberg-Richter b-values. Close to the mainshock epicentre and during the weeks prior to the mainshock, only scarce seismic activity is observed. These observations suggest a different initiation mechanism compared to the cascade of close (<200 m) foreshocks observed before other large strike-slip earthquakes including the MW 7.6 1999 Izmit event.We here document seismic signatures on the Pazarcık segment of the East Anatolian Fault Zone (EAFZ) that preceded the rupture of a major earthquake over months before the mainshock. A densification of seismic monitoring in the epicentral area in 2014MW 7.8 earthquake struck the Pazarcık segment of the EAFZ bounding the Arabian and Anatolian tectonic plates12 . Although the earthquake ruptured both the Pazarcık and Amanos segments of the EAFZ, the nucleation point was located off the main fault branch on a splay fault to the east. The rupture then propagated dynamically onto the main fault trace  in the NE. Representing the second largest fault zone in Türkiye after the NAFZ, the seismic activity on the EAFZ has been monitored by the national agencies AFAD and KOERI with increasing efforts to assess the seismic hazard and risk of the region. Geodetic and geological studies indicate that the slip rates along the main fault trace of the EAFZ and its secondary branches decrease from ∼10 mm/yr near the Karlıova triple junction in the NE down to ∼4 mm/yr near Kahramanmaraş junction17. The centuries-long historical earthquake records of Anatolia indicate that large earthquakes have previously occurred on the EAFZ. On the Pazarcık segment where the 2023 MW 7.8 Kahramanmaraş earthquake occurred, historical reports document an earthquake of similar magnitude in the year 111419. The last large (M 7.0) earthquake occurred in 1795 on this segment20. Toward the NE, the last large earthquake on the EAFZ was the 2020 MW 6.8 Sivrice earthquake, which ruptured about 45 km of the Pütürge segment21  and N = 5041 events above the local completeness magnitude MC = 1.5, estimated using the goodness-of-fit method26.To understand how the seismicity around the R not exceeding 65 km from the epicentre of the MW 7.8 earthquake . These clusters were identified from seismicity located at epicentral distances ake Fig. . Detaileake Fig. , (II) quake Fig. , (III) eake Fig. , C7 was R < 10 km) hosted spatially dispersed seismicity  = 261) with b = 0.9 ± 0.1 and stationary seismicity rates in the 9 years preceding the mainshock. Quarry blast clusters Q5, Q6 and Q8 located within the region (R < 50 km) also displayed quasi-stationary rates throughout the analysed time period . Of particular importance are the on-fault seismicity clusters C1 and C2 that started nearly simultaneously in July 2022 on the main EAFZ and the splay fault hosting the future MW 7.8 epicentre, respectively. They contained distinct event sequences with pronounced temporal clustering and two MW > 4 earthquakes each . In the last months preceding the mainshock, the region surrounding the future earthquake up to R < 50 km was characterised by a transient b-value decrease related to the activation of C1 and C2 clusters, overprinting the b-value decrease observed in the broader region (R < 90 km) since mid-2021  remained stationary throughout the whole analysed time period. Finally, in January 2020, the MW 6.8 Sivrice/Elazig earthquake occurred on the NE portion of the EAFZ. No permanent changes in the seismicity rates from the study region are observed after this earthquake within the broader region R < 130 km . However, the features of these clusters are significantly different from that observed for clusters C1 and C2 that directly precede the mainshock. The latter two clusters display very low b-values down to b = 0.61 ± 0.06 and b = 0.7 ± 0.03, respectively, indicating the presence of a highly stressed region27 or damage concentration28 to the north of the future nucleation zone in the last months preceding the earthquake. In addition, cluster C1 displays a statistically significant deviation from a random (Poissonian) magnitude distribution in time (i.e. magnitude correlations) indicating some level of interaction between subsequent events -based workflow31 to generate a catalogue of earthquake detections and locations. The initial catalogue locations were refined using the absolute (NLLoc32) and, for selected regions, relative (HypoDD33) location techniques (see Methods section). This led to a single event NLLoc catalogue of 1055 located events that occurred before the mainshock in the study area. Excluding the events located within the Q5, Q6 and Q8 areas previously identified as quarry blasts left 1029 events representing earthquakes. The catalogue has a local magnitude of completeness of MC = 0.48 in the 50 km radius around the mainshock and records a total of 252 events above MC since January 1st 2023. For comparison, the AFAD catalogue for the same region displays a MC = 1.45, and a total of 22 events above MC within 50 km radius from the mainshock during the same time period.To identify potential immediate foreshocks around the R < 50 km of the epicentre of the MW 7.8 earthquake, the C2 area activating the northern end of the secondary segment hosted 151 events since Jan 1st, becoming most active on Jan 5th and 26th . Interestingly, co-seismic slip during the mainshock was the largest around this segment34, signifying a large stress accumulation on this segment during the interseismic period. In contrast, the Pütürge segment of the EAFZ displayed abundant seismicity during this time period, including a MW 4.5 earthquake and its corresponding aftershock sequence from January 15th . Moreover, with the enhanced seismicity catalogue, we did not find evidence of a cascade process due to immediate foreshocks (with MW > 0.48) located at distances less than 500 m from the epicentre as observed before the 1999 MW 7.4 Izmit earthquake40 or the 1999 MW 7.1 Hector Mine41. This difference in behaviour supports the diversity of the initiation process of large earthquakes. The 1999 Izmit earthquake occurred on a structurally mature fault with a cumulative offset of up to 90 km, likely resulting in progressive smoothing of the fault plane. The south-western portion of the EAFZ where the 2023 earthquake initiated is a comparatively less mature tectonic structure, accounting for only up to 27–30 km cumulative offset and numerous secondary fault systems43.In the sequence studied here the seismicity did not show a progressive localisation towards the future hypocentre, and none of the identified seismicity clusters corresponded to its nucleation zone  activity (MW −10 to −7) rates prior to system-wide stick-slip failure often show an exponential increase, especially for smooth faults36. However, rough laboratory faults that likely are more representative of complex faults in nature46 display persistent and/or transient local seismicity clusters (reflecting asperities evolution) at high levels of stress. As in our field observations, laboratory AE clusters often result in complex accelerating and decelerating seismic activity (not necessarily leading to a major event), varying b-values reflecting transient and local stress changes and damage localisation47. In these experiments the evolution of clusters progresses, collectively preparing a wider fault area for large failure events48. This suggests, the nucleation of a large earthquake somewhere along rough heterogeneous faults is a statistical event, conditioned by an intrinsically complex failure process of individual asperities of various sizes and strengths48.The presence of localised seismic activity clusters bears similarities to observations of seismicity ahead of large stick-slip events on rough laboratory faults that emphasise the importance of fault heterogeneity/complexity in the preparation process49. The initiation phase, on the other hand, takes place on a secondary fault that has received little attention. Our study shows that a full understanding of the initiation phenomenon, necessary for any future development of warnings, would require a greater densification of local and regional seismological and geodetic networks to reduce or even close the observational gap between the laboratory (where such processes can be observed) and the field. This seismic sequence, in addition to the Kaikoura, Denali and Ridgecrest sequences, shows that this densification should not be done only in the immediate vicinity of major faults, but on a regional scale that includes secondary faults. Several dense, regional and multi-parametric networks have been developed in the last few decades  was present in the probabilistic seismic hazard models published before the earthquakeOur results add to the accumulating evidence that at least some large earthquakes display a monitorable preparation phase that bears some similarity to laboratory and theoretical models of the failure process. However, the variability of apparent earthquake nucleation processes observed for different events, the difficulty of distinguishing preparatory processes from other deformation transients that do not lead to major earthquakes, the participation of secondary faults, and an unknown false alarm rate, all suggest that with our current state of knowledge, intermediate-term earthquake warning—if possible—still lies in seismology’s future.53 between January 1st, 2014 and the occurrence of the MW 7.8 mainshock. The selection of the start time for the catalogue was chosen because earlier times were affected by strong changes in the regional network11 and hence, by different earthquake detection thresholds. The catalogue was constrained spatially to seismic events located within 130 km epicentral distance from the MW 7.8 mainshock epicentre provided in the same catalogue  in Fig. N = 9483 events.In the analysis we used a seismic catalogue provided by AFAD Disaster and Emergency Management Authority in Turkey5455:To calculate cumulative seismic moment release  using DBSCAN algorithm56 assuming key parameter epsilon=2.5 km and minimum number of events in the cluster N = 40. We then investigate differences in seismicity rates, seismic energy release, b-value, magnitude correlations and interevent time statistics for each cluster.Nine spatio-temporal clusters of seismicity were selected in the area surrounding the mainshock . The b-value calculations for each selected cluster of seismicity followed the b-positive method57 via the maximum likelihood estimator. The b-positive methodology suppresses the potential bias from short-term catalogue incompleteness. The uncertainties (95% c.i.) in b-value were estimated using bootstrap resampling57. Visual inspection of probability density functions (PDFs) of the magnitude and origin times  the conservative magnitude of completeness , magnitude of completeness MC was calculated using the goodness-of-fit method26. The MC was selected in such a way that 95% of earthquakes forming the selected catalogue follow the Gutenberg–Richter power law. The b-value itself was calculated using the b-positive method57. For the initially selected catalogue of N = 9483 earthquakes, we obtained b = 0.9 ± 0.1 with N = 5041 events above MC = 1.5.For the selected portion of the seismicity catalogue , we used a moving event window of 120 events with a step of 15–20 events and attributed each calculated b-value to the origin time of the last event in each window. Estimation of b-value in each window followed as well the b-positive method57. Before calculation, we removed seismicity associated with clusters Q5, Q6 and Q8 containing quarry blasts. Two more clusters detected in a broader region (up to R < 130 km) related to quarry blasts, as evidenced from KOERI catalogue, were removed as well.To investigate the temporal evolution of the MC and tested for magnitude correlations between consecutive events forming the cluster. Magnitude correlations between events would indicate that the events are not randomly drawn from the G-R distribution as expected from a Poissonian process. The input to the statistics is the time-ordered sequence of magnitudes MC:For each cluster C1–C9 and Q5, Q6 and Q8, we extracted events above 58, the PDF of empirical magnitude difference data, Following ref. . The picks were spatially and temporally clustered using DBSCAN56. This results in a catalogue of 1097 possible seismic events with a total of 5868 P- and 4960 S-picks. We calculated new event locations by employing the probabilistic location software NLLoc61 while using the regional, 1-D velocity model from [25]. The search area encompassed a 340 km × 400 km × 82 km volume with its lower left corner positioned at 36.0 N and 35.4 E. Based on the event origin times obtained from NLLoc we visually investigated all events with an origin time difference of less than 5 s for possible duplicate events. Such duplicates can be created by GaMMA by splitting P- and S-picks belonging to the same event into separate events. All identified duplicates were merged into a single event and relocated. This resulted in a catalogue of 1055 events with absolute locations and median errors in the x-, y- and z-directions of 4.8 km, 5.5 km and 6.5 km, respectively  to be used in the relocation procedure, we required a normalised cross-correlation coefficient of 0.6 or larger. To obtain cross-correlation differential times, we filtered waveforms between 2 and 10 Hz, and used 1 s and 2 s long-time windows centred at the P- and S-onset times, respectively. We combined these data with the differential travel times obtained from the automatic picks and ran hypoDD in singular value decomposition (SVD) mode to obtain the relocated event hypocentres. To link events for the relative relocation, we require at least 8 catalogue and 8 cross-correlation differential times for an event combination together with a maximum inter-event separation of 20 km from the single event localisations and a maximum station distance to the cluster centroid of 100 km. From a total of 89 initially selected events, 86 remain after relative relocation (Supplementary Fig. x-, y- and z-directions are 18 m, 35 m and 57 m, respectively.We performed a relative relocation of the events occurring in the vicinity of cluster C2 during the beginning of 2023 using cross-correlation and catalogue differential times at all available common stations using the software hypoDDSupplementary InformationPeer Review FileDescription of Additional Supplementary FilesSupplementary Dataset 1


Lymphovascular invasion (LVI) is a well-known poor prognostic factor for early breast cancer. However, the effect of LVI on breast cancer subtype and node status remains unknown. In this study, we aimed to evaluate the clinical significance of LVI on the recurrence and long-term survival of patients with early breast cancer by comparing groups according to the subtype and node status.We retrospectively reviewed the medical records of 4554 patients with breast cancer who underwent breast cancer surgery between January 2010 and December 2017. The primary endpoints were disease-free survival (DFS) and overall survival (OS). Univariate and multivariate analyses were performed to identify prognostic factors related to the DFS and OS according to the nodal status and breast cancer subtype.During a follow-up period of 94 months, the median OS and DFS were 92 and 90 months, respectively. The LVI expression rate was 8.4%. LVI had a negative impact on the DFS and OS, regardless of the lymph node status. LVI was associated with higher recurrence and lower survival in the luminal A, human epidermal growth factor receptor 2-positive, and triple-negative breast cancer subtypes. The Cox proportional hazards model showed that LVI was a significant prognostic factor for both DFS and OS. No correlation has been observed between LVI and the Oncotype Dx results in terms of prognostic value in early breast cancer.LVI is an independent poor prognostic factor in patients with early breast cancer, regardless of the node status and molecular subtype. Therefore, the LVI status should be considered when making treatment decisions for patients with early stage breast cancer; however, further prospective studies are warranted. The totLymphovascular invasion (LVI) is associated with the recurrence of solid tumors, including early breast cancer . HoweverHowever, few studies have investigated the correlation between LVI and recurrence and survival according to the molecular subtypes. Therefore, this study aimed to evaluate the prognostic significance of LVI on the recurrence and long-term survival according to the molecular subtype in patients with early breast cancer who underwent breast surgery.22.1in situ or occult breast cancer, or did not undergo axillary surgery were excluded from the study. Finally, 4,554 patients were included in the analysis , and the requirement for informed consent was waived owing to the retrospective study design.2.2th American Joint Committee on Cancer (AJCC) TNM staging system  to identify LVI and reported in routine pathology reports. Lymphatic invasion was defined as the presence of tumor emboli within the endothelial line space, whereas vessel invasion was defined as the presence of fibrin clots or erythrocytes and a lack of smooth muscle or elastic fibers in the endothelial line space. Because immunohistochemical staining is not routinely performed, distinguishing between lymphatic and vessel invasion using light microscopy was challenging. Thus, in our study, LVI was defined as the presence of tumor cells within the endothelial line spaces around the tumor Figure 2in situ hybridization assay was performed. Positive silver in situ hybridization assay results were categorized as HER2 positive, and vice versa. ≥ 20% Ki‐67 index values were classified as highly proliferative tumors.Breast cancer molecular subtypes were defined based on the immunohistochemical staining results as follows: a) hormone receptor (HRs)-positive (ER/PR) and HER2 negative tumors, b) HRs positive and HER2 positive tumors, c) HRs negative and HER2 positive tumors, and d) tumors negative for both HRs and HER2, defined as triple-negative breast cancer (TNBC). According to the guidelines of the American Society of Clinical Oncology (ASCO) 2010, the positive status of ER or PR is defined as the presence of at least 1% stained cancer nuclei of ER or PR. HER2 positivity was defined as a score of 3 on immunohistochemical analysis , 14. HER2.3Recurrence was defined as recurrence in the ipsilateral breast or counterlateral breast, regional or non-regional lymph node areas, or distant organs. Disease-free survival (DFS) was defined as the time from diagnosis to disease recurrence or death, whichever occurred first. Overall survival (OS) was defined as the time from diagnosis to death from any cause.p < 0.05. All the statistical analyses were performed using SPSS software .Categorical factors were analyzed using the chi-square test. The Kaplan–Meier method was used to draw DFS and OS curves, and group differences were calculated using the log-rank test. A multivariate Cox proportional hazards model was used to identify significant independent factors associated with DFS and OS. Statistical significance was defined as 33.1LVI was observed in 381 patients (8.4%). Comparisons of the clinicopathological characteristics of the patients with and without LVI are shown in p=0.011). The LVI-positive group underwent more total mastectomies and axillary lymph node dissections than the LVI-negative group.In addition, the LVI-positive group had a higher percentage of patients with high Ki-67 levels than the LVI-negative group. Regarding the molecular subtypes, the LVI-positive group had a lower percentage of luminal type but a higher proportion of HER2 positive and TNBC subtypes. The percentage of patients who received adjuvant chemotherapy and radiotherapy was higher in the LVI-positive group than that in the LVI-negative group . Although a limited number of patients underwent the 21-gene RS assay and had a favorable luminal subtype, we further analyzed the DFS to explore the impact of the presence of LVI on the survival outcomes according to the Oncotype Dx risk classification. Patients with positive LVI showed a trend towards worse DFS; however, the difference was not statistically significant regardless of the 21-gene RS risk classification  to explore the association between the multigene assay and the anatomical presence of LVI in patients with HR-positive and HER2-negative tumors. Patients were classified into three groups based on the RS according to the TAILORx trial ; 163 56Figure 64This study demonstrated the clinical significance of LVI in early breast cancer in a large population with a long 10-year follow-up period. The detection rate of LVI was 8.4% in our study, which is consistent with previous studies , 17, butOur study demonstrated that LVI is an independent poor prognostic factor for survival in patients with early breast cancer. Whether LVI should be considered an independent prognostic factor is debatable. While some studies have suggested that LVI is an independent prognostic variable not affected by the lymph node status or pathological features , other sAccording to the findings of this study, while radiation therapy status was not statistically different between LVI negative and positive groups, radiation therapy was also an independent prognostic factor for overall survival. Since postmastectomy radiation therapy is administered for patients with risk factors such as large tumor size, close or positive resection margin, high histologic grade, and hormone receptor negative tumors, such factors might have affected the overall prognosis . The St.Our study demonstrated the prognostic power of LVI; however, discordant findings were observed between LVI and node metastasis. Our data showed that 8.7% of the patients were LVI-positive, while 20.4% were node-positive. In the subgroups, node negative disease (N0) was 82.7% in the LVI-negative group and 54.3% in the LVI-positive group. Although the presence of LVI increased as the N stage increased , LVI was not a prerequisite condition for axillary node metastasis. Previous studies have also stated that lymph node metastasis can occur even in the absence of LVI in breast cancer . Thus, lFurthermore, no association was observed between LVI and Oncotype Dx, indicating its prognostic value in early breast cancer. This finding is in agreement with a study by Al-Zawi et al., which stated that LVI did not have a statistically significant impact on the Oncotype Dx RS . Recent Our study had several limitations, mostly owing to its retrospective study design. Second, the rate of LVI expression was slightly lower than that reported in other studies. This is because a smaller tumor size could have affected the results of LVI detection. Third, Oncotype Dx result was only available for small portion of study population. Therefore, we cannot perform powerful analysis about LVI and oncotype Dx result. Finally, the possibility of selection bias cannot be excluded. Despite these limitations, our study had a long follow-up period of up to 140 months and more than 4,000 patients were included in the analysis.In conclusion, LVI in patients with early breast cancer is an independent risk factor for poor prognosis. Patients with positive LVI showed a higher recurrence rate and poorer survival in all breast cancer subtypes. Therefore, the LVI status should be considered when making treatment decisions for patients with early breast cancer; however, further prospective studies are warranted.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving humans were approved by Institutional Review Board of Severance Hospital, Seoul, Republic of Korea . The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin owing to the retrospective study design.SL: Writing – original draft, Writing – review & editing. JG: Validation, Writing – review & editing. BA: Data curation, Writing – review & editing. JA: Data curation, Writing – review & editing. JK: Data curation, Writing – review & editing. HP: Data curation, Writing – review & editing. SK: Writing – review & editing. B-WP: Writing – review & editing. SP: Data curation, Formal analysis, Supervision, Validation, Writing – review & editing.


Granville and Vance counties have some of the highest opioid-related death rates in North Carolina, and have significant unmet needs with regard to opioid treatment. Medication for opioid use disorder (MOUD) is the most effective evidence-based approach to address opioid use disorder. Despite demonstrated efficacy and substantial need, access to MOUD is still insufficient in many parts of the United States. In order to connect patients with needed MOUD services, the district health department, Granville Vance Public Health (GVPH), established an office-based opioid treatment (OBOT) program.In this formative pilot study, we sought to describe patients’ goals and outcomes in a program delivered at a rural local health department using an integrated care approach.We used a mixed methods concurrent nested research design. The primary method of investigation was one-on-one qualitative interviews with active OBOT patients (n=7) focused on patients’ goals and perceived impacts of the program. Trained interviewers followed a semistructured interview guide developed iteratively by the study team. The secondary method was a descriptive quantitative analysis  of treatment retention and patient-reported outcomes (anxiety and depression).Participants in the OBOT program were 39.6 years of age on average, and 25.3% (20/79) were uninsured. The average retention in the program was 18.4 months. The proportion of individuals in the program with moderate to severe depression  decreased between program initiation  and at the most recent assessment . In qualitative interviews, participants credited the OBOT program for reducing or stopping the use of opioids and other substances . Many participants noted how the program helped them manage withdrawal symptoms and cravings, which helped them feel more in control of their use. Participants also attributed improvements in quality of life to the OBOT program, such as improved relationships with loved ones, improved mental and physical health, and improved financial stability.Initial data show promising patient outcomes for active GVPH OBOT participants, including reduction in opioid use and improvements in quality of life. As a pilot study, a limitation of this study is a lack of a comparison group. However, this formative project demonstrates promising patient-centered outcome improvements for GVPH OBOT participants. Medication for opioid use disorder (MOUD) is the most effective evidence-based approach to address opioid use disorder (OUD) . MOUD enDespite demonstrated efficacy and substantial need, access to MOUD is still insufficient in many parts of the United States , especiaTo connect patients with needed MOUD services, the district health department serving both Vance and Granville counties, Granville Vance Public Health (GVPH), established an office-based opioid treatment (OBOT) program in Vance County to increase local access to treatment services beginning in 2018. GVPH’s offering is unique in that OBOT services are provided through a local health department integrated into the primary care clinic rather than an OBOT-focused agency, a traditional behavioral health agency, or an opioid treatment program for higher-level care. The GVPH OBOT program follows a harm reduction model , which eThe GVPH OBOT program developers made an intentional decision to incorporate OBOT in primary care to alleviate stigma for patients and facilitate participation, a unique model. The GVPH OBOT program offers MOUD , patient support for medication costs, one-on-one counseling (availability dependent on funding), weekly or twice-monthly group visits that include individual health monitoring check-ins and facilitated group discussions, infectious disease testing, and primary care services. GVPH’s OBOT program also offers wraparound service links to needed community resources, such as job support, nutrition security, childcare services, transportation, and clothing and appliance donations. Using a mixed methods approach, we describe patients’ goals and report on initial outcomes in the program from patients’ perspectives.We used a mixed methods concurrent nested approach, with the primary method being qualitative. Participants in the OBOT program were active (actively enrolled in the OBOT program) or inactive .For the qualitative portion of the study, we conducted in-depth one-on-one semistructured interviews with currently enrolled patients of the GVPH OBOT program  followed a semistructured interview guide developed iteratively by the study team. All interviews were recorded and transcribed for analyses.Patient interviews covered several topics , includiQualitative content analysis was used to analyze participant narratives . A codebThe quantitative portion of our study focused on descriptive analysis of patient characteristics, including demographics, treatment retention, and anxiety and depression outcomes. Patient characteristics were described with frequencies and proportions for categorical variables and mean with SDs or medians with IQR for continuous measures. Quantitative data were collected by GVPH for all patients who entered the program from January 2018 through July 2020 as a standard of care. The university team retrospectively analyzed data that was captured during this time period. Depression was evaluated using the Patient Health Questionnaire (PHQ-9)  and anxiThis study was approved by the Duke Health Institutional Review Board (Pro00104650). Verbal consent was obtained before conducting all qualitative interviews. For verbal consent, study personnel provided potential participants with a description of the purpose of the project, details about the length of the interview and content discussed during the interview, possible benefits and risks associated with participating in the study, how the information will be kept confidential, the payment received, right to decline participation or withdraw from the study, and who to contact if individuals had questions. Data for the quantitative study were retrospectively collected under institutional review board (IRB) waiver of signed consent. Privacy and confidentiality were ensured in the qualitative study by storing data on secure drives that were only accessible to IRB-approved research team members. Qualitative data were deidentified for analysis and no identifying information is provided in publications. Privacy and confidentiality were ensured in the quantitative study because retrospectively collected data from GVPH were deidentified before sharing it with analysts. Qualitative participants were offered a US $30 gift card for participation. No incentives were offered to the quantitative analysis participants because the quantitative study was retrospective.The qualitative study included 7 actively enrolled patients . Patients highlighted the quality of life outcomes they felt were particularly important by discussing initial goals for joining the program, successes they attributed to the program, and what they were excited about for their future. Patients often describe the program helping them “get back on track,” with discussions relating to 5 themes, which are as follows: (1) reducing or abstaining from opioids or other substances; (2) improving financial stability; (3) engaging in the workforce or training or education programs; (4) working on healthy relationships; and (5) improving mental and physical health.The first theme was reducing or stopping the use of opioids or other substances; this theme was expressed by all participants and was particularly present as an initial motivation for joining the program, with many participants expressing that their main goal was to start MOUD to help manage withdrawal symptoms associated with delayed or reduced opioid use. Outside of opioids, participants also mentioned having a goal to reduce or stop their use of marijuana, cocaine, or benzodiazepines. One patient described the change they wished to see in their life related to opioid use:Honestly, at first, there was no goal other than to not wake up in the morning and the first thing that popped into my head is I have to [use drugs]. My main goal was to be able to function during the day.Participant 4Participants also discussed this theme when asked about successes they attributed to being on MOUD through the program. Many noted how MOUD helped them manage withdrawal symptoms and cravings, which helped them feel more in control of their use and make decisions to stop using. Some participants also discussed the program’s positive impact on their use of other drugs like cocaine and marijuana.It is a big thing to have something to help with the edginess of opioids, the [MOUD] really helps. It’s been definitely a lifesaver for me…And because my life has changed since I’ve been in the program, [next month] will be a year [without using opioids]…The program has definitely worked out for me.Participant 2Participants who discussed improving financial stability focused on obtaining a new job, owning a home, getting out of debt, or saving money and improving their finances more generally. This theme was brought up when discussing goals, successes of participants attributed to the program, and what they were excited about for the future. Many explained that not having to spend money on opioids to manage withdrawal symptoms allowed them to save more money or use their money instead on longer term goals. One participant also explained that for a period of time, the program had grant funding to cover costs associated with medication, which contributed further to their ability to save money. One participant described how not having to pay for opioids to prevent withdrawal symptoms has allowed her to save money for the longer-term goal of getting corrective dental work:I’ve got more money in my savings than I’ve ever had in my life, and that’s thanks to getting off drugs…Fixing my teeth, that’s my main goal right now because that totally changes the way you live your life. I damaged my teeth really bad when I was on drugs, and that stuff’s really expensive to get fixed…I’m looking forward to that, and because I’m able to save some money, now that’s possible.Participant 3Many participants highlighted engaging in the workforce or in a training or educational program as an initial goal. Many were able to achieve this because of the stability MOUD provided and the support they obtained from the program. Several described starting jobs or training programs, and others expressed feeling excited about the opportunity to pursue further education or training that they would not have been able to maintain while they were managing withdrawal symptoms. One participant expressed their excitement to continue their education to fulfill a 10-year goal:I’m looking into going back to school in the near future…which has been a goal of mine for about 10 years now…I thought about maybe going and getting some kind of certificate or something, for now, just to get my foot in the door start making money. Somewhere better than what I’m making [now]. And then going and figuring out what exactly I want to do.Participant 1Several participants identified improving relationships with friends or family as an initial goal and resulting success of the program. Some explained that with MOUD, they did not have to spend time seeking out opioids to manage symptoms of withdrawal, so they could instead spend that time with their loved ones:… I want to get through this [and have] a normal routine… [Being with] family and friends and not having to get out and search for opiates and stuff like that. It just took so much time and effort to do that and I didn’t have time for the other things.Participant 6A few participants also explained how being on MOUD allowed them to make decisions to move on from relationships they felt were not helpful for their recovery and focus instead on forming positive relationships through support groups or engaging with their community through activities like team sports or church.Although some participants started the program with the goal of improving their physical or mental health, many described resulting physical or mental health improvements they attributed to their participation in the program. Participants explained how being enrolled in the OBOT program helped them establish better sleep habits; abstain from or reduce substance use; engage in healthy weight loss; quit smoking tobacco; address anxiety and depression; and feel “stable,” “peaceful,” or “more present” in their life.One participant described improvements in their mental health and feeling a sense of control they did not feel before joining the program:My mental health is great. I haven’t had any episodes or depression in 3 years. Sometimes I’ll have mood swings, but it’s very minor and it’s not anything like it used to be like. Sometimes I would be up for days and just go off on a shopping spree or drug spree and I had no control over my impulses and things like that. Now, I have that control and it’s just a miracle really.Participant 7From January 2018 to July 2020, the GVPH OBOT program saw 79 patients, including 1478 visits (average of 18 visits per patient). The average age of participants was 40 years with a range of 24-68 years. A little more than half  were female. The majority of participants were White  and 75% (59/79) had either public or private insurance, as shown in From January 2018 to July 2020, there were 35 active (enrolled in the program) and 44 inactive (patients who had left the program as of July 2020) patients. Overall, 73% (58/79) of patients had completed 3 months of the OBOT program . Among aAmong active participants, improvements in median patient-reported depression and anxiety scores were observed as patients progressed through the program . DepressThis study provides preliminary evidence showing promising retention outcomes and improved patient outcomes associated with enrollment in the GVPH OBOT program. In terms of retention, approximately 75% (58/79) of individuals who started the OBOT program were still enrolled in the program after 3 months, and more than 50% (45/79) of all patients who started the OBOT program were still enrolled at 6 months, exceeding definitions of successful retention . The quaThe primary strength of this study is the holistic lens through which patient outcomes are described, with quantitative and qualitative methods. Patient characteristics were largely similar among the quantitative and qualitative samples, except for insurance type. The similarities among both samples signal that the qualitative sample was generally representative of the patients who were enrolled in the OBOT program.As a formative study, limitations of this study include the lack of a comparison group and limited data for tracking outcomes quantitatively. Another key limitation was the inability to conclude which aspects of the GVPH-OBOT program or GVPH more generally led to the outcomes described. MOUD is the most effective treatment for OUD, and a significant proportion of the improvements shared by participants were likely due strictly to MOUD. It is less clear what other program offerings directly influenced outcomes. Other studies provide evidence that GVPH-OBOT offerings, such as covering medication costs and counseling, improve outcomes. For example, one study found that covering medication costs, a GVPH-OBOT offering improves retention . One-on-GVPH follows an Academic Health Department Model , which eAs funds become available to local municipalities from the National Opioid Settlement, opportunities exist to conduct comparative effectiveness research and natural experiments on new and existing interventions for OUD. This is a unique opportunity for researchers, clinicians, and patients to capture patient-centered outcomes and promote evidence-based interventions to improve the lives of individuals with OUD, as well as the consequent health of our communities.Preliminary data suggest that GVPH’s OBOT services provided through a local health department are associated with a reduction in patients’ opioid dependence and an improvement in quality of life. Though GVPH serves a smaller population than urban NC counties, each life affected, including family members and community members of individuals with OUD, is critically important. GVPH’s OBOT program provides a vital access point to treat OUD for individuals in Granville and Vance counties. Initial results demonstrate promising improvements in the quality of life for individuals in the GVPH OBOT program, and additional program evaluation will need to be conducted to better understand which outcome improvements can be attributed to which features of the GVPH OBOT program. Other district health departments in the United States can look toward GVPH’s OBOT program for guidance on how to develop, refine, and evaluate their MOUD programs.


Well-being and social functioning improved among the majority of participants. These results demonstrate the utility of the all-virtual, digital therapeutic program and its ability to help individuals with MUD to reduce or cease methamphetamine use. The program was efficiently implemented and was well received by participants and clinical personnel, indicating its ability to deliver comprehensive, effective care and to retain the difficult-to-engage population of persons with MUD. Of the 27 completers, 16 responded to a 1-month follow-up survey and reported no meth use in the month since completing the program.This study assessed the feasibility and utility of a digital, all-virtual program designed for treatment of methamphetamine use disorder (MUD). Forty-nine adults with moderate- to severe-level MUD (per DSM-5 criteria) commenced the 8-week intervention. All aspects of the program were delivered via smartphone-based app. Intervention components included counseling , app-based therapeutic tasks, remote biological drug testing, medical oversight by psychiatrists/nurse practitioners, and contingency management procedures . Of the 49 participants who commenced treatment, 27 participants (55%) completed the program. Repeated-measures mixed-model analyses show that participants were more likely to test negative for meth use from week 1 to week 8 (OR = 1.57, 95% CI ;  Methamphetamine (meth) is increasingly implicated in drug overdose mortality and morbidity across the United States , and metEffective treatment for individuals with stimulant use disorder remains an elusive target, and no medication has been approved by the FDA for the treatment of patients with methamphetamine use disorder (MUD). Clinicians rely on behavioral therapies that have only limited effectiveness among the diverse populations of stimulant users, especially for those with MUD. Cognitive behavioral therapy , contingRetention in care is a particular challenge for MUD treatment programs. A meta-analysis of outcomes across modalities and SUDs from 1965 through 2016 found that an average of 30% of patients did not complete treatment, but meth users dropped out sooner and completed at lower rates than patients with other SUDs . Recent Improvements are necessary in the design and delivery of behavioral therapies that have proven effective for MUD . Toward Several digital healthcare platforms have shown promise in delivering therapeutic components and in helping patients stay involved in treatment , 25, incThis article reports results of a field study that implemented the Affect digital therapeutic program to assess its feasibility and utility for treatment of MUD.2.2.1.This single-group demonstration study assessed the feasibility and clinical utility of a digital therapeutic program  delivered by HIPAA-compliant smartphone-based app. The app-based program (see details in “Procedures” Intervention below) includes behavioral components—CM, CBT, CRA, group/individual counseling—that are employed in usual care for MUD. Reduction in meth use and cessation of meth use were measured by self-report and remote, video-supervised saliva drug tests twice weekly during the 8-week program. The study protocol was approved by the WCG Institutional Review Board. From the beginning of screening to the end of the intervention period, the study took 6 months.Retention–measured as program completion—was the primary outcome for establishing the utility and feasibility of the Affect program. –Participationinvolvement in protocol-specified program activities was measured by participant encounter attendance and interaction with the app during the 8-week intervention . Effectiveness–preliminary demonstration of effectiveness in terms of reduction or cessation of meth use was measured as intra-participant change in meth use, including duration of days abstinent from meth.Primary outcomes were: 2.2.Participants were recruited through multi-media advertising and by word of mouth. Study participant flow is presented in 2.3.Upon completion of screening and consents, participants were enrolled, were provided the Affect app and orientation (guidance on use of the app and brief refresher on program parameters covered in informed consent), and assigned to a licensed counselor and to a medical provider. Participants were asked to use the app to attend twice-weekly group therapy, once-weekly individual therapy, and one visit (remote) with the medical provider to evaluate overall health and ensure the study did not impose risk to the individual. Additionally, all participants were mailed saliva drug test kits [Medical Disposables ] to be sAll appointments were managed and accessed via the Affect app and conducted over secure video conference. Individual sessions were 30 min and group counseling sessions were 1 h, all occurring synchronous (live), accessed via the app, and conducted by a licensed addiction counselor. Topics followed a general curriculum derived from the Matrix Model . At the 2.4.The 8-week Affect program of care for MUD was developed by board-certified addiction psychiatrists and clinicians with extensive expertise in treating patients with MUD and other SUDs. The Affect app delivers all program components, including CM to engage and retain patients while eliciting behavioral change through incentives provided for stimulant-negative results of drug tests and for participation in program activities . Participants received app-based prompts for a daily series of behavioral therapeutic tasks and patients engaged with the app and did the incentivized tasks at times convenient to them.Each day, the Affect app notified the participant of 3–5 new tasks to be completed. These tasks are part of a broader curriculum of content designed to support the participant’s recovery and enable Affect to gather critical participant data necessary to inform care. For example, data collection tasks include basic surveys to gather data regarding daily cravings, substance use, and emotional state. Education tasks include verbal and video content related to the stages of recovery, including topics such as withdrawal management. Motivational tasks include brief verbal or video content coupled with reflection questions, such as reflections on triggers. Skill-building tasks include challenges to promote new, healthy behaviors, such as regular sleep, exercise, and community support group participation.Program tasks were designed to support behavior change regarding drug avoidance, relapse prevention, prosocial activities, and other lifestyle behaviors that inhibit drug use and enhance life without drugs. Tasks were monitored via the app for satisfactory completion. The timely completion of a task was rewarded at $0.50 each. Behavioral therapy tasks were monitored by the app and by the Care Team for satisfactory completion and verified via direct review of responses in the app . The maximum possible compensation for tasks was $140. Saliva tests were incentivized at a scaled rate (increasing with consecutive tests negative for meth from $10–$30) with $340 maximum possible compensation. Of a total possible compensation of $480 during the intervention period, the average “earned” was <$250.The app provided a framework to help structure participants’ time in treatment and recovery, offering a user-friendly calendar of upcoming appointments for therapeutic sessions such as group counseling sessions or appointments with psychiatrists and other healthcare providers. Participants engaged in weekly telemedicine sessions with clinical personnel for individual and group therapy.2.5.2.5.1.Meth use was measured by self-report (at intake into the study and twice weekly during the intervention) and by remotely conducted, twice-weekly drug tests during the intervention period using 5-panel saliva-based drug tests [Medical Disposables ].2.5.2.Retention was a binary measure of completion at the end of the 8-week intervention. Participants who withdrew and those who were terminated for unexplained non-response to Affect personnel (or inaction per app-directed activities) for more than seven consecutive days were deemed non-completers.2.5.3.The Visual Analog Scale (VAS) was used to measure craving for meth . Patient2.5.4.Baseline covariates were collected at study intake. These covariates were used to control the outcomes used in the analyses. The covariates included sociodemographic factors , and substance use severity factors (baseline meth use and meth craving). The sociodemographic and substance use severity factors were collected as part of a battery of baseline measures administered to participants after study enrollment; all participants self-reported current meth use at intake.2.6.Statistical analyses were conducted using SAS 9.4 and STATA 16 software. For all statistical analyses, statistical significance alpha was set at 0.05 using two-tailed hypothesis-testing analyses.2.6.1.T-tests were used to test for differences in participant characteristics for the continuous variables, which were age and craving score. Chi-square tests were used to test for differences in the categorical variables of gender  and employment (employed vs. not employed), race/ethnicity, sexual orientation, being a parent (yes vs. no), and in a relationship (yes vs. no). Results showed no statistically significant differences in characteristics among participants who finished the 8-week program (N = 27), those who did not complete the program (N = 22), or those who did not “attend” the required intake appointment meeting and were dropped from the study . Normality assumptions for these continuous variables were examined and tested using the Shapiro–Wilk test for normality. Since the distribution of these outcomes was normally distributed, t-test comparisons were made between completers and non-completers.2.6.3.Meth use was examined in two ways using results from the saliva tests and from self-report. Logistic mixed models analyses were conducted to examine the repeated assessments of meth use using self-reported meth use at study intake (baseline) and twice weekly during the intervention, and by twice-weekly saliva tests from week 1 to week 8. The meth drug test and the self-reports were measured dichotomously . Next, logistic repeated-measures mixed models were used to examine meth use outcomes  at week 1 to week 8 in comparison to meth use at baseline, controlling for age, gender, race/ethnicity, and employment status, in a relationship, being a parent, and sexual orientation. Finally, in order to assess the quality of the statistical models, the Akaike Information Criterion (AIC), Bayesian Information Criterion, and log-likelihoods were examined. The lower the value of the AIC and BIC, the better the model fits the data. We obtained the AIC and BIC for the null model  and compared this to the final model.2.6.4.Craving for meth was measured weekly from week 1 to week 8. Linear mixed models were used to assess the repeated measures across 8 weeks controlling for baseline, age, gender, race/ethnicity and employment status, in a relationship, being a parent, and sexual orientation. The craving scores were normally distributed based on the distribution plot and the Shapiro–Wilk test for normality. The quality of the statistical models was also assessed using the Akaike Information Criterion (AIC), Bayesian Information Criterion, and log-likelihood.3.3.1.p = 0.09). Almost half of participants were females: 51.9% for completers, 45.5% for non-completers, and 36.7% for the individuals who were dropped due to non-attendance at intake. As shown in p = 0.78), race/ethnicity (p = 0.86), employment status (p = 0.85), being in a relationship (p = 0.27), being a parent (p = 0.67), or sexual orientation (p = 0.75).Participants who completed the program had a mean age of 44.4 (SD = 9.8) compared with non-completers ; the dropped individuals who did not engage in the required intake session had a mean age of 41.6 (SD = 12.2). No significant differences were found in terms of age among these three groups (3.2.n = 27) and non-completers (n = 22). The average number of days in the 8-week (56-day) program was 55.1 days (SD = 1.61) for completers compared with 21.9 days for non-completers . Significant and more favorable differences were also found between completers vs. non-completers in terms of: (1) the average number of negative drug screens with mean = 5.19, SD = 5.9 for completers vs. a mean = 0.33, SD = 0.79 for non-completers, , (2) the average number of meetings attended by completers  vs. non-completers , , and (3) the longest duration of no meth use (consecutive days) for completers  vs. non-completers , =3.51, p = 0.001 (see p = 0.08), gender (p = 0.72), race/ethnicity (p = 0.54), employment status (p = 0.76), in relationship (p = 0.19), being a parent (p = 0.70), or sexual orientation (p = 0.51).As a preliminary analysis, we examined differences in outcomes between program completers (.001 see . As show3.3.p = 0.049) relative to the baseline reference , week 1 to week 8. The meth use test results  were examined using logistic repeated-measures mixed-model analyses, where we controlled for age, gender, race/ethnicity and employment, in a relationship, being a parent, and sexual orientation. Results indicate that participants were more likely to test negative for meth use at week 1 to week 8 , week 1 to week 8. Self-reported meth use  was analyzed using logistic repeated-measures mixed models, where we controlled for age, gender, race/ethnicity and employment, in relationship, being a parent and sexual orientation.p = 0.024) relative to the baseline reference (at intake)  see . No sign3.5.t = 1.732, 95% CI ; p = 0.26) compared to the baseline craving score. No significant results were found for age, gender, and employment status, in a relationship, being a parent and sexual orientation. See Preliminary analyses were performed to examine self-reported craving ratings among participants at baseline, week 1 to week 8. At baseline, participants reported an average craving score of 3.69, SD = 1.89. Using linear mixed models repeated measures analyses, results show that the change in craving scores was not significantly different between week 1 to week 8  for more than seven consecutive days in any period of the 8-week study period equated to “non-completer” status for the purpose of determining retention. The Lappan study ],an study  reportedan study ] show than study , 36–38].4.2.participation was a construct composed of the number of “attended” therapeutic tasks/activities per the Affect app relative to not-attended events such as: scheduled/planned virtual interactions for program activities , completed remote drug tests, and kept appointments with referred service providers . Participants who consistently engaged in program activities were more likely to complete the program and reduce meth use according to self-report and drug tests; the 27 completers attended an average of 35 meetings compared to less than 7 attended by non-completers. Overall, more than 41% of all activities and tasks were attended, 8% were not attended due to cause or cancelation, and more than 49% were not attended.In addition to retention , 4.3.The effectiveness measure is a composite of self-reported meth use (daily Yes/No) and meth-negative saliva test results obtained twice weekly over the course of the program. A participant who provided at least four consecutive meth-negative saliva tests during the final 4 weeks of the 8-week program met criteria for positive reduction in meth use at a significant level, indicating within-participant effectiveness. Reductions in saliva test meth use across the analysis sample were statistically significant. These findings were consistent with self-reported meth abstinence with a Kappa test of concordance statistic of 0.78.4.4.not associated with relapse to use of meth nor with dropout. Notably, participants with higher craving appear to stay in the program longer. The apparent paradox that high craving did not associate with relapse to meth is intriguing but statistically unsubstantiated.Analyses could not detect significant differences in craving trajectories, but subgroups appeared to have erratic patterns in which early-phase high craving scores were 4.5.At exit interviews, 12 participants expressed interest in continuing in the Affect program and were offered the opportunity to remain for another 8 weeks but without the CM component. All 12 were retained without CM in the post-study program, which suggests the program’s viability and acceptability to people with MUD. The commercialization of the Affect program for MUD is being explored in a NIDA-funded Small Business Innovation Research project.4.5.1.General well-being was measured by end-of-treatment administration of the Treatment Effectiveness Assessment  using a Preliminary Results of Follow-ups. Of the 27 completers, 16 responded to 1-month follow-up surveys; ~56% of respondents self-reported no meth use in the month since program completion.5.The results of the study indicate that in this sample of individuals with MUD, the Affect digital therapeutic program for MUD was feasible to administer, was acceptable to participants, was effective in retaining participants in the program, and helped the majority of program participants to significantly reduce meth use. To thoroughly demonstrate effectiveness of the Affect program for MUD, a larger scale test would compare the Affect program against a research-tested MUD care program . ResultThe original contributions presented in the study are included in the article/The Study involving human participants was reviewed and approved by Western Institutional Review Board (WCG). The patients/participants provided their written informed consent to participate in this study.KM contributed to planning, conceptualizing, and writing the manuscript. JD helped in conceptualizing and reviewing the manuscript. AA performed the data analysis and helped to write the manuscript. MZ provided comments and reviewed the manuscript. AM assisted in conceptualizing and reviewing the manuscript. BP contributed to conceptualizing and writing the manuscript. All authors contributed to the article and approved the submitted version.This study was funded by Affect Therapeutics, Inc.KM and JD were employed by Affect Therapeutics, Inc.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.