Ophidiophobia (snake phobia) is one of the most common specific phobias. It has been proposed that specific phobia may have an evolutionary origin, and that attentional bias to specific items may promote the onset of phobia. Noninvasive imaging studies of patients with specific phobia reported that the medial prefrontal cortex (mPFC), especially the rostral part of the anterior cingulate cortex (rACC), and amygdala are activated during the presentation of phobogenic stimuli. We propose that the mPFC-amygdala circuit may be involved in the pathogenesis of phobia. The mPFC receives inputs from the phylogenically old subcortical visual pathway including the superior colliculus, pulvinar, and amygdala, while mPFC neurons are highly sensitive to snakes that are the first modern predator of primates, and discriminate snakes with striking postures from those with non-striking postures. Furthermore, the mPFC has been implicated in the attentional allocation and promotes amygdala-dependent aversive conditioning. These findings suggest that the rACC focuses attention on snakes, and promotes aversive conditioning to snakes, which may lead to anxiety and ophidiophobia. Specific phobia is a type of anxiety disorder with a lifetime prevalence ranging from 3% to 15% across various countries , we hypothesized that the ACC, which receives projections from the pulvinar  weighing 7.1–8.6 kg, which was the same monkeys used in the previous experiment , in which neuronal activity during 500-ms after (post) stimulus onset was compared with that during 100-ms before (pre) stimulus onset. The mPFC neurons were defined as snake-responsive neurons if a given mPFC neuron showed significant responses to at least one of the six snake images. The 235 mPFC neurons were tested with all six snake images in the DNMS task, and 95 neurons responded to one or more snake images (snake-responsive neurons). The numbers of mPFC neurons and snake-responsive neurons in the individual monkeys are indicated in χ2-test; p = 0.284). F = 6.215, p < 0.0001; post hoc tests indicated that response magnitudes to the three snake images with striking postures were larger than those to the three snake images with non-striking postures .Only neuronal responses to sample stimuli were analyzed , while the mPFC neurons were categorized as non-striking-selective neurons if the response magnitudes to the three snake images with non-striking postures were larger than those to the three snake images with striking postures . The remaining mPFC neurons were defined as nonselective neurons. Of the 95 snake-responsive mPFC neurons, 64 neurons responded stronger to snakes with striking postures (striking-selective), 20 neurons responded stronger to snakes with non-striking postures (non-striking-selective), and 11 neurons showed no difference in response magnitudes between these two categories of the snake images , the combined data from the two monkeys were further analyzed. The ratio of the striking-selective neurons was significantly greater than that of the non-striking-selective neurons . Furthermore, averaged response magnitudes of all snake-responsive neurons to the snakes with striking postures and those to the snakes with non-striking postures were compared by paired t-tests (p < 0.05). The results indicated that the averaged response magnitudes to the snakes with striking postures were significantly larger than those to the snakes with non-striking postures (paired t-test: t(94) = 5.459, p < 0.0001; Snake-responsive neurons were further categorized based on comparison of response magnitudes to the snake images with striking postures with those to non-striking postures. For this categorization, two peri-event histograms, one for the snakes with striking postures and the other for the snakes with non-striking postures, were constructed. The mPFC neurons were categorized as striking-selective neurons if the response magnitudes to the three snake images with striking postures were larger than those to the three snake images with non-striking postures . The results indicated that averaged response latencies to the snakes with striking postures were significantly shorter than those to the snakes with non-striking postures (paired t-test: t(86) = 3.804, p = 0.0003; Response latencies to the snake images were also analyzed. For each neuron, the same two data sets used to analyze response magnitudes for snakes with striking and non-striking postures (see above) were also used to analyze response latencies. Response latency of the mPFC neuron was measured as the period between the stimulus onset and the time point at which the neuronal firing rate exceeded the mean ± 2 SD of the baseline firing rate. The mean response latencies of all striking-selective neurons were compared to non-striking-selective neurons by paired To investigate temporal changes in population coding of snake postures in the mPFC, the initial 200-ms after stimulus onset was divided into four 50-ms epochs: epoch 1 (0–50 ms), epoch 2 (50–100 ms), epoch 3 (100–150 ms) and epoch 4 (150–200 ms). The mean response magnitude in each epoch was similarly calculated, as follows: (mean firing rate in each epoch) minus (mean firing rate during the 100-ms pre-period). These four data sets were separately analyzed by multidimensional scaling (MDS). MDS can convert the relationships (Euclidean distances as dissimilarity in this study) between all possible pairs of stimuli to a geometric representation of the stimuli in a space  = 32.97, p < 0.0001), and that the distances in the mPFC MDS in epoch 3 were also significantly and positively correlated with the corresponding data in the pulvinar MDS space in epoch 2  = 39.74, p < 0.0001). These findings suggest that the mPFC receives information from the pulvinar to discriminate snake postures.A previous study reported that response magnitudes and latencies in the mPFC were positively correlated with the corresponding data in the pulvinar , and that functional connectivity between the rACC and amygdala increased . The mPFC is reported to be involved in attentional allocation to various salient visual stimuli  (Dinh et al., Second, the mPFC neurons were recorded from the two monkeys. Since the proportions of snake-responsive and striking-selective neurons among the mPFC neurons were similar between the two monkeys , the datThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by the Ethical Committee for Animal Experiments in University of Toyama.HNishij conceived the study and designed the experiment. HD and QL performed the experiment. QL and HNishij analyzed the data and wrote the article. HNishij, HNishim, JM, TS, RM, CT, and TO revised the article. All authors contributed to the article and approved the submitted version.The 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. The handling editor declared a past co-authorship with one of the authors RM.


RGB optical imaging is a marker-free, contactless, and non-invasive technique that is able to monitor hemodynamic brain response following neuronal activation using task-based and resting-state procedures. Magnetic resonance imaging (fMRI) and functional near infra-red spectroscopy (fNIRS) resting-state procedures cannot be used intraoperatively but RGB imaging provides an ideal solution to identify resting-state networks during a neurosurgical operation. We applied resting-state methodologies to intraoperative RGB imaging and evaluated their ability to identify resting-state networks. We adapted two resting-state methodologies from fMRI for the identification of resting-state networks using intraoperative RGB imaging. Measurements were performed in 3 patients who underwent resection of lesions adjacent to motor sites. The resting-state networks were compared to the identifications provided by RGB task-based imaging and electrical brain stimulation. Intraoperative RGB resting-state networks corresponded to RGB task-based imaging ( Non-invasive functional brain mapping is an imaging technique that allows the locating of functional areas of the patient’s brain. This technique is used during brain tumor resection surgery to indicate to the neurosurgeon the cortical tissues which should not be removed without cognitive impairment. Functional magnetic resonance imaging (fMRI)  is the pn cortex ,10,11,12As opposed to functional task-based analyses, resting-state functional connectivity aims to identify the low frequency cortical hemodynamic fluctuations (<0.1 Hz) that reflect the patient neuronal activity at rest and that are linked to resting-state networks . These fIn these works, we demonstrate that intraoperative optical resting-state can be implemented intraoperatively using two standard fMRI resting state techniques . The coThe study was conducted at the neurological center of the Pierre Wertheimer hospital in Bron, France. Three patients presenting a tumor close to the motor cortex area were included in the study. All experiments were approved by the local ethics committee of Lyon University Hospital (France) and the participating patients signed written consent. The videos were acquired with the wide field optical device described in  after thThe neurosurgeon performed EBS after RGB imaging using a bipolar electrode (Nimbus Medtronic neurostimulator). A biphasic current was used . The current was first set to 1 mA, and increased to 6 mA. When a functional area was identified by EBS, the neurosurgeon placed a colored pastille on the patient cortex and a RGB image was acquired to store the position of the functional area in the RGB image.Once the video was acquired, the quantitative model described in  was applThe first image of the video sequence was segmented into three classes: gray matter, surface blood vessel, and buried blood vessel. The objective is to use in the modified Beer–Lambert law, and this for each pixel of the camera, the appropriate mean path length of photons travelled in tissue. For this purpose Monte Carlo simulations were performed using MCX software . For eac0.08 Hz ,20,21). bert law ,8. To co(v3.2.0)  and FFTW[v3.3.7) ). Then, H) was obtained by convolving the hemodynamic impulse response function [H by 1 and The task-based analysis consisted in analyzing the correlation between measured and theoretical cortical hemodynamic changes. The theoretical hemodynamic time curve . Input data were normalized as follow:p respectively. The normalization transforms the temporal vector K sources:S is a matrix of dimension A is the mixing matrix of dimension K sources:W is an unmixing matrix of dimension A can be estimated by calculating the pseudo-inverse of the matrix W.The ICA identifies original signals from a mixture of signals by assuming that the original signals are independent of each other. In our analysis, the original signal was K independent sources. The number of independent components depends on the size of analyzed data. Between 10 and 20 independent components were used to analyze data acquired by a high-density diffuse optical tomography device [A  , the nory device . Since oT was applied to the images:I, The task-based maps were compared to the resting-state maps to evaluate the identification performance of cortical functional zones. For this purpose, the NumPy Python library (v1.19.4)  was usedX in Equation (Y in Equation (X in Equation (Y in Equation (The DICE coefficient  was compEquation ) and resEquation ). We alsEquation ) and ICAEquation ):(5)DICEEquation ).X in Equation  would be obtained with task-based fMRI. To evaluate this case, the overlap coefficient  was compEquation ) and resEquation ).(6)OveEquation ).Finally, we tested if the functional brain areas identified by EBS corresponded to the identifications provided by the task-based and resting-state maps by testing if EBS results were included in the binary task-based and resting-state maps.The task-based and resting-state maps computed for the three patients are represented in For patient 1 and 2, the task-based maps corresponded to the resting-state seed maps  to identify the connected portion of tissue. However, the neurosurgeon must have an idea of the position of the functional area. In case the tumor has strongly displaced the functional areas, this method can be put in default. This issue could be addressed by using preoperative fMRI maps to automatically place the resting-state seeds. Thresholding operations (see Equation ) can be In this study, we present the methodology for the identification of resting-state networks using RGB imaging during neurosurgery. The detection of functional brain areas using the resting-state seed and ICA analyses presented a strong similarity with those identified with a task-based analysis. These areas corresponded to the identification provided by EBS when patients are awake and under general anesthesia. This work demonstrates that RGB imaging combined with quantitative modeling of brain hemodynamic biomarkers can robustly assess functional brain areas during patient rest and before brain tumor resection surgery. This reinforces the relevance of using conventional RGB imaging for intraoperative functional brain imaging.


The idiotype network is experimentally modified to provide protective immunity against various microbial pathogens. Both internal and non-internal image-idiotype antibodies can trigger specific immune responses to antigens. The current outbreak of Severe Acute Respiratory Syndrome 2 (SARS-2) has provided a great opportunity to take advantage of idiotype / anti-idiotype antibodies as a protective regimen when no approved vaccine is available on earth. The current review identifies successful applications of idiotype/ anti-idiotype antibodies in various viral diseases and highlights their importance in COVID-19 pandemics. In the absence of vaccines and targeted therapies, polyclonal idiotype/ anti-idiotype antibodies against the viral structure may be a potential approach to the prevention and treatment of COVID-19 patients. SARS-CoV‐2, a member of the Coronaviridae family of the order Nidovirales are enveloped, positive‐sense, single‐stranded, and highly diverse RNA virus . It has via binding through the Angiotensin-converting enzyme 2 (ACE2). Subsequently, the coronavirus genome (ss RNA) attaches to the host’s ribosomes leading to the translation of 2 co-terminal and large polyproteins further processed by proteolytic enzymes [Corona viruses are spherical as shown by Cryo-electron microscopy . Corona  enzymes , 27. Pro enzymes , 29.Viral invasion leads to the development of either innate or adaptive immunity. Innate immunity is associated with the recognition of pathogen-associated molecular patterns (PAMPs) causing cytolysis, through the natural killer cells and the interferons causing the death of virus along with its resident cell. Adaptive immunity, on the other hand, plays a vital role in clearing the virus either through the cell-mediated immunity by cytotoxic T cells including CD8 + and the CD4 + subset, that kill the virus-infected cells or through the production of the B cells with antibody as a major arm .The humoral immune system gives rise to natural antibodies secreted by plasma cells upon an initial viral infection . B lymphL and VH) that result in a unique surface for antigen binding and these two V domains culminate the generation of the idiotype (Id) [Antigen-specific approaches in immunotherapy have gained much attention with experimental animals showing promising results upon antigen-based treatments leading to improvement in disease status . The immype (Id) . The terype (Id) . Idiotopype (Id) . The binype (Id)  as well ype (Id) .Idiotype are picked up by antigen-presenting cells (APCs) such as macrophages, dendritic cells, and B lymphocytes, and are then presented to T cells on MHC class II molecules. B lymphocytes continuously present Id-peptides on MHC class II molecules , 44. TheVaccine development is a lengthy and costly process, and it takes years to develop a successful licensed vaccine . MultiplBesides vaccines, various therapeutic interventions have been tested to cure COVID 19 patients including Hydroxychloroquine, Azithromycin, and Remdesivir. Hydroxychloroquine has been found to interfere with the glycosylation of ACE2 resulting in the prevention of virus binding , 61. AziIn human history, COVID-19 is the second major respiratory challenge after influenza. Influenza virus threatens global health despite efforts to develop an effective vaccine . Being aEven the development of the Covid 19 vaccine is still in its infancy, with the need to develop a universal vaccine against several antigenically different viruses, including those currently in circulation and those may come to light in the future. The development of idiotype vaccines may reduce the risk of unwanted side effects that are usually produced from the most common antigenic vaccines . IdiotypAntibodies may be of the IgM, IgG, and IGA types that are directed to the spike (S) protein of SARS-CoV2. Idiotype is a sequence switch of antibodies that attaches to the receptor binding domain (RBD) of the viral S protein. The initial antibody belongs to the IgM isotype which later changes to the IgG isotype. Class switching can also occur with the IgA isotype, which is produced by large-scale plasma cells in the laminar propria of mucosal surfaces. IgA antibodies play an important role in the immune defense of the virus, the entry point of the virus to the mucosal surface of the respiratory tract, related to the formation of an important immunoglobulin. IgA can neutralize SARS-CoV 2 before it reaches the epithelial cells and attaches to them. IgA may play a role in a mucosal vaccine to promote the development of idiotypic vaccines . PreviouIn severe SARS-CoV 2 infections, binding to different cytokines or variable domains of other antibodies (anti-idiotype antibodies) is thought to reduce the inflammatory response. Furthermore, the presence of IgG dimers may interfere with the activation of FcγR on innate immune cells . It has The biggest challenge today is the COVID-19 pandemic. At present, more than 2.69 million people have been killed worldwide and about 122 million positive cases have been reported. Vaccine and effective treatment strategies are growing rapidly, but time is needed to make effective progress. Significant life-saving support was offered in the treatment of plasma in patients with COVID 19. Considering past and present research, it has been pointed out that neutralizing antibodies in the form of hyperimmune serum has always been valuable in saving lives. Timely implementation of controlled studies on immunoglobulins for the development of idiotype / anti-idiotype vaccines is needed.


Posttraumatic stress disorder (PTSD) and substance use disorder (SUD) have high comorbidity. Although prior research indicated that PTSD can effectively be treated with Prolonged Exposure (PE) in these patients, reported effects are small and treatment dropout rates high. Eye Movement Desensitization and Reprocessing (EMDR) and Imagery Rescripting (ImRs) are other promising treatment options for PTSD, that have not yet been examined in this patient group. Furthermore, it is unclear whether PTSD treatment is most effective when offered simultaneous to or after SUD treatment.In this article, the Treatment Of PTSD and Addiction (TOPA) study is described: a Dutch randomized controlled trial (RCT) that studies the effectiveness of PTSD treatment as an add-on to regular SUD treatment in patients with SUD and co-occurring PTSD. Effects of PE, EMDR, ImRs, and a 3-month SUD treatment only condition will be compared, as well as simultaneous SUD/PTSD treatment to sequential SUD/PTSD treatment. The primary outcome measure is PTSD symptoms. Secondary outcomes are: treatment completion, psychological distress, substance use, interpersonal problems, emotion dysregulation, and trauma-related emotions guilt, shame, and anger.This study is the first to compare effects of PE, EMDR, and ImRs in one study and to compare simultaneous SUD/PTSD treatment to sequential SUD/PTSD treatment as well. This RCT will provide more knowledge about the effectiveness of different treatment strategies for PTSD in patients with co-occurring SUD and will ultimately improve treatment outcomes for patients with this common co-morbidity worldwide.NL7885. Registered 22 July 2019.Netherlands Trial Register (NTR), Identifier:  Posttraumatic stress disorder (PTSD) and substance use disorder (SUD) often co-occur, with an estimated prevalence of SUD amongst individuals with PTSD of 46% in an epidemiologic study in the United States . StudiesProlonged Exposure (PE) and Eye Movement Desensitization and Reprocessing (EMDR) are both first line treatments for PTSD that have been studied extensively and shown to be effective treatments for reducing PTSD symptoms , also inHitherto it is unknown how treatment completion can be increased in this difficult to treat group of patients. In a recent RCT a 90-min trauma-focused motivational enhancement session was added prior to PE therapy in order to increase treatment completion and effectiveness of PE in patients with PTSD/SUD. Unfortunately, adding this session did not lead to better PE retention than PE alone .In patients with co-occurring PTSD/SUD, the effectiveness of EMDR has been studied in only one randomized pilot study . AlthougDiagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) [ImRs is a therapy that is becoming increasingly popular for treating PTSD and other disorders. A meta-analysis of 19 studies showed that ImRs is effective in reducing aversive imagery and related psychological complaints, with large effects obtained in a small number of sessions . In chro (DSM-5)  has expa (DSM-5) , and wit (DSM-5) . A revie (DSM-5) . Individ (DSM-5) . This su (DSM-5) . Given tIn summary, although prior studies indicated PE is an effective PTSD treatment for patients with co-occurring PTSD and SUD, effects were small and treatment drop-out rates were high. EMDR and ImRs are other promising treatment options for PTSD, that have not yet been examined in this difficult to treat patient group. Furthermore, head-to-head comparisons of these active PTSD treatments are scarce, and completely lacking in SUD/PTSD patients.In most published studies in which a trauma-focused treatment was added to SUD treatment, it is unclear whether treatments for PTSD and SUD were delivered simultaneously (starting at the same time) or sequentially (starting PTSD treatment after finishing SUD treatment) , 29 A DuBesides studies that have examined PTSD treatments that were added to SUD treatments, there are several studies that have examined the effectiveness of integrated treatments that integrate SUD and PTSD components within one treatment. Most consistent evidence is found for COPE (concurrent treatment of substance use disorders and PTSD using prolonged exposure), that includes motivational enhancement and CBT for SUD, psychoeducation relating to both disorders, and PE for PTSD , 35. AnoThis paper describes the study design of the Treatment Of PTSD and Addiction (TOPA) study, a Dutch RCT in patients with co-occurring PTSD and SUD who will receive PTSD treatment as an add-on to regular SUD treatment.To compare effectiveness of PE, EMDR, and ImRs as add-on to regular SUD treatment with SUD treatment only in patients with co-occurring PTSD/SUD.To compare effectiveness of simultaneous SUD/PTSD treatment with sequential SUD/PTSD treatment in patients with co-occurring PTSD/SUD.To explore differential effectiveness between active PTSD treatments  in patients with co-occurring PTSD/SUD.The primary objectives of this study are:We expect that at 3-month follow-up, all trauma focused therapies will have led to a stronger reduction of the primary outcome PTSD symptoms than the SUD treatment only condition (objective 1). In addition, we expect that, compared to the SUD treatment only condition, all trauma focused therapies will have led to a stronger reduction of the following secondary outcomes: psychological distress, substance use, interpersonal problems, emotion dysregulation, guilt, shame and anger. We expect a greater reduction of PTSD symptoms in the simultaneous treatment condition compared to the sequential treatment condition at 6 and 9-month follow-up (objective 2). We have no specific hypothesis about the direction of the differences in effectiveness between the three active PTSD treatments (objective 3).Due to the COVID-19 outbreak in March 2020, temporary changes in both treatment as well as assessments had to be made, as the regular face-to-face contacts were temporarily not allowed at the treatment facility center where this study is conducted. In this article the original design of the study is described in the method section. At the end of the method section, all adjustments that were made due to COVID-19 outbreak are described.This study is a single blind 6-arm randomized controlled trial, consisting of 3 arms for simultaneous SUD/PTSD treatment with the PTSD treatments consisting of PE, EMDR, and ImRs, and 3 arms for sequential SUD/PTSD treatment with the PTSD treatments also consisting of PE, EMDR, and ImRs. Within the first 3 months after baseline, the three sequential treatment arms together form the SUD treatment only condition, as is depicted in the trial flow Fig. . First, Participants are recruited at the Jellinek Center in Amsterdam and Utrecht. Study participants are patients who apply for SUD treatment at the addiction treatment center, for whom treatment of co-occurring PTSD is also indicated. All patients treated in the two participating locations are adults (18 years of age or older), and both males and females can participate in the study. The criteria for inclusion in the study are a) age 18 years or older; b) SUD(s) according to the DSM-5 , with a primary diagnosis involving one of the following substances: alcohol, cannabis, cocaine (snorting), amphetamine, benzodiazepine, opioid; c) PTSD according to the DSM-5 criteria; d) sufficient understanding of the Dutch language to be able to fill out Dutch questionnaires and follow therapy in Dutch. The exclusion criteria are: a) acute psychotic disorder; b) mental retardation or cognitive impairment (estimated IQ < 70); c) current physical or sexual abuse or death threats; d) current acute suicidal behavior (high suicide risk and suicide attempt in the last 3 months); e) life threatening self-injury; f) homelessness; g) involvement in a compensation case or legal procedures concerning admission or stay in the Netherlands, h) involvement in legal procedures regarding the index trauma, i) engagement in any other current PTSD treatment.n = 41 in sequential treatment and n = 121 in simultaneous treatment, power is 99% to detect a small-to-medium effect size (f = 0.15) in a comparison of pre-post change between simultaneous and sequential treatment, with alpha = 0.05, and within-person correlation coefficient = 0.60. To detect a small effect (f = 0.10) power is 81%. We expect 20% of the participants to drop out of the study, therefore in total 204 participants will be included in the study.First, we calculated the required sample size for the comparison between the three types of active PTSD treatments. Second, we calculated whether that sample size will provide sufficient power to compare the two timings of PTSD treatment. Three pairwise comparisons will be conducted between the active treatment arms . To detect a small-to-medium effect size (f = 0.15) in a pairwise comparison of pre-post change between two active treatment arms, with Bonferroni-corrected alpha = 0.0167, power = 0.85 and within-person correlation coefficient = 0.60, 54 participants are needed per arm. To make three pairwise comparisons 3 * 54 = 162 participants are needed. The allocation ratio between sequential and simultaneous PTSD treatment is 1:3. With All participants receive regular SUD treatment plus either one of the following PTSD interventions: PE, EMDR or ImRs. SUD treatment starts directly after randomization for all participants. For patients allocated to the simultaneous treatment condition, PTSD treatment starts within 2 weeks after the start of the SUD treatment. For those in the sequential treatment condition, PTSD treatment starts 3 months after the start of the SUD treatment.All PTSD treatments are provided by trained therapists and consist of twelve 90-min face-to-face sessions, conducted twice a week. Every treatment is executed by two different PTSD therapists, who alternately provide a session, inspired by the therapist rotation model. Among other things, this approach has shown to decrease avoidance behavior in sessions. Therefore, it is promising to improve trauma-focused treatment . In all PE involves confrontation with distressing stimuli related to the trauma until anxiety is reduced. It is a manualized intervention including both imaginal and in vivo exposure components , 39. ImaEMDR is a manualized intervention, intended to reduce the liveliness of the traumatic memories and to change dysfunctional beliefs about self or others in terms of the traumatic event . In the ImRs is a technique that changes the meaning of emotional memories and images (like intrusions and nightmares). With ImRs the individual is instructed to imagine the trauma memory as vividly as possible, as if it is happening in the here and now, and to imagine that the sequence of events is changed in a direction that the person desires . The proPTSD treatment completion is defined as a participant completing all 12 sessions of PTSD treatment within the allocated timeframe or being an early responder. For the simultaneous treatment condition, the timeframe for PTSD treatment is between baseline and 3-month follow-up. For the sequential treatment condition, the timeframe for the PTSD treatment is between 3-month and 6-month follow-up. Non-completers or drop-outs are participants who do not complete their PTSD treatment within the allocated timeframe. Participants who do not show for one of more treatment session are contacted by their therapists and motivated to commit to the treatment. Treatment is halted when a participant decides to stop or when the end of the timeframe is reached.Early response is defined as agreement between the participant and therapists about being free of PTSD symptoms, a total score below 13  on the PTSD checklist for DSM-5 (PCL-5) for 2 consecutive sessions and after consultation with at least one researcher and with colleagues in weekly peer-supervision. In case a participant in the sequential condition is free of PTSD symptoms at the first follow-up measure (T1), the participant will still start with the PTSD treatment until these criteria of early response are reached.Therapists in this study are experienced and licensed master’s level psychologists. All therapists are trained in all three methods to avoid therapist effects. Before participation in the trial, therapists attended a two-day training in PE provided by Agnes van Minnen, a 5 day training in EMDR provided by Erik ten Broeke and a two-day training in ImRs provided by Arnoud Arntz. After finishing the trainings, all therapists had to pass a treatment integrity assessment with pilot patients by handing in a video for each type of therapy to demonstrate their competence. During the study, all therapists receive weekly one-hour peer-supervision sessions and tree yearly two-hour supervision sessions: one with each of the abovementioned trainers. There are several highly experienced therapists in each peer-supervision group. When questions arise that cannot be solved in peer-supervision, the trainers are consulted.All treatments sessions are recorded on audio. A random selection of sessions will be rated for treatment fidelity by trained junior researchers, using fidelity rating scales that were constructed in consultation with the professionals who provided the therapist training, before the start of the trial. For each treatment type, we will determine adherence to the protocol and test whether the rated sessions contained more elements of the allocated treatment type compared to elements of the other treatment types, to test treatment differentiation. This will be done with a simple t-test or non-parametric test, depending on the distribution of the data.Alongside PE, EMDR or ImRs, all study participants receive regular SUD treatment. Inpatient as well as outpatient participants can take part in the study. Standard care for SUD treatment includes both cognitive behavioral therapy (CBT)  as well All patients attending an intake at the Jellinek Center are screened for PTSD with the J-PTSD screening questionnaire . After tAfter the baseline assessment (T0), patients are randomly assigned to PE, EMDR, ImRs or SUD treatment only (each 25% chance). All patients receive SUD treatment shortly after the baseline assessment. Patients allocated to PE, EMDR or ImRs receive PTSD and SUD treatment simultaneously (75% of the sample), whereas patients in the 3-month SUD treatment only condition receive PTSD treatment after completing 3 months SUD treatment (25% of the sample). Patients in the SUD treatment only condition are randomly allocated to either PE (33% chance), EMDR (33% chance) or ImRs (33% chance) and start with the PTSD treatment after the 3 months follow-up assessment (T1).After randomization, only disclosure of the timing will be given to the participants. Disclosure of treatment type will be done by the therapist at the start of the first session of the PTSD treatment.Randomization is carried out by an independent researcher from Arkin who uses a computer-generated block randomization schedule. First patients are allocated to: simultaneous PE, simultaneous EMDR, simultaneous ImRs of sequential treatment with allocation probabilities per condition of 1/4. Block sizes are 4 and 8. Second, participants randomized to sequential treatment are allocated to: sequential PE, sequential EMDR or sequential ImRs, with allocation probabilities per condition of 1/3, after completion of the 3-months follow-up (T1) assessment. Block sizes are 3 and 6. Randomization is stratified by type of care  and location (Amsterdam or Utrecht). To prevent selection bias, all researchers are blind to order of block size and will not have access to the randomization schedule.Assessments take place at baseline (T0), after 3 months T1), 6 months (T2) and 9 months (T3). The T0 takes place within 1–2 weeks before the start of SUD treatment. Therefore, participants randomized to simultaneous SUD/PTSD treatment will receive PTSD treatment between baseline (T0) and 3-month follow-up (T1), whereas participants randomized to sequential SUD/PTSD treatment will receive PTSD treatment between 3-month (T1) and 6-month (T2) follow up. See also the flow chart in Fig. , 6 monthFurthermore, participants and their therapists also administer self-report questionnaires during therapy sessions. Study drop-out is minimized by having the follow-up assessments organized by the junior researcher, independently of the treatment facility, inviting participants for assessments regardless of treatment completion. Reminder calls are made before each assessment.At the eligibility screening interview, SUDs are determined with the SUD criteria of the Dutch version of the Structured Clinical Interview for DSM-5 Disorders-Clinician version (SCID-5-CV) which is called the SCID-5-S . FurtherThe main study parameter is severity of PTSD symptoms and is measured at every assessment with the Dutch translation of the Clinician Administered PTSD Scale for DSM 5 (CAPS-5). The CAPS is the gold standard in PTSD assessment. It is a 30-item structured interview, corresponding to the DSM-5 diagnosis for PTSD, to assess PTSD symptoms over the past month. The sum of items 1 through 20 provides the total severity score . The DutTreatment completion: Completion of PTSD treatment (yes/no) and completion of SUD treatment (yes/no) is administered by the involved therapists.Brief Symptom Inventory (BSI): The BSI is a 53-item questionnaire that measures psychological distress and is developed from the longer Symptom Checklist (SCL-90-R) with very good internal consistency and test-retest reliability. All questions are scored on a Likert scale ranging from 0 to 4 and reflects the degree of distress in the last week. Total scores range from 0 to 212. It covers nine primary symptom dimensions. On all scales, higher scores indicate higher levels of complaints [mplaints .Alcohol Use Disorder Identification Test (AUDIT): The AUDIT is a World Health Organization (WHO) initiated screening instrument for problematic alcohol use in the past year. It consists of 10 statements about the amount of drinking and problems due to drinking. Items are scores on a Likert scale ranging from 0 to 4, therefore total scores range from 0 to 40, with higher scores indicating higher levels of excessive drinking. The self-reported AUDIT is used in this study [is study .Drug Use Disorders Identification Test (DUDIT): The DUDIT is a sensitive and specific instrument to screen for drug-related problems. It consists of 11 items and is developed as a parallel instrument to the AUDIT. Total scores range from 0 to 44, with higher scores indicate more drug use and problems related to drug use [drug use .The AUDIT and the DUDIT are originally based on alcohol and drug use during the last year. In this study, at T1, T2 and T3 patients are asked about their alcohol or drug use in the previous 3 months instead of the previous year.MATE-Q-NL, module 1: The Meten van Addicties voor Triage en Evaluatie , is a Dutch questionnaire that measures lifetime substance use and substance use over the past 30 days [ 30 days . Only usInventory of Interpersonal Problems (IIP-32): The IIP-32 is a short version of the Inventory of Interpersonal Problems (IIP) and consists of two sections respectively asking participants what they find hard to do (for example ‘join in groups’) and things they do too much (for example ‘get irritated’) [itated’) . The IIPitated’) .Difficulties in Emotion Regulation Scale (DERS): The DERS measures emotion dysregulation across various dimensions on a 36-item self-report scale, with all questions scored on a Likert scale from 1 to 5. Higher scores indicate higher levels of emotion regulation problems. Internal consistency of the DERS is high and test-retest reliability is good [ is good .Trauma Related Guilt Inventory (TRGI): The TRGI is a 32-item questionnaire with a 5-point Likert scale, measuring feelings of guilt related to trauma exposure. Higher scores indicate higher levels of guilt The TRGI has high internal consistency and adequate temporal stability [tability . In thistability . BeliefsTrauma Related Shame Inventory (TRSI): The TRSI consists of 24 items, which can be scored on a 4-point Likert scale. Higher scores indicate higher levels of shame. In this study the same index will be used as in the study of Boterhoven [terhoven . As wellterhoven .Self Expression and Control Scale (SECS): The Zelf Expressie en Controle Vragenlijst (ZECV) is the Dutch translation of the Self Expression and Control Scale (SECS). This 40-item scale assesses internalised and externalised anger and anger control, scored on a Likert scale ranging from 1 to 4. Higher scores indicate higher levels of anger. Psychometric properties are good [are good .Extension of the Life Event Checklist for DMS-5 (LEC-5): The original LEC is a self-report questionnaire measuring exposure to possibly traumatic events. It was developed together with the CAPS-5 [e CAPS-5 .The LEC-5 is based on the DSM-5 and assesses exposure to 17 potentially traumatic events. According to the DSM-5, an event is considered traumatic if there is actual or threatened death, serious injury or sexual violence . In the PTSD Checklist for DSM-5 (PCL-5): The PCL-5 is a 20-item self-report measure of PTSD symptoms according to the DSM-5 with a Likert scale ranging from 0 to 4. The total score is an index of PTSD symptom severity and has strong internal consistency and test-retest reliability [iability . This quSession checklist: A session checklist is used to gather retrospective information on the use of 12 categories of substances, on gambling, and the use of psychiatric medication in the days prior to the session. This information is registered at the start of each treatment session. This information will be used to keep up with modifications in substance and medication use during therapy.An economic evaluation is conducted alongside the randomized trial and is performed according to the intention-to-treat principle. We will evaluate the relationship between costs and health outcomes of treatments. We will perform both a cost-effectiveness analysis with PTSD symptoms as effect measure and a cost-utility analysis using QALYs.EuroQol (EQ-5D-5L): The EQ-5D-5L is a self-report instrument comprising five dimensions , that is administered at T0 and all follow-up measures to calculate health utilities [tilities . Health tilities .Trimbos/iMTA Questionnaire for costs associated with Psychiatric illness (TiC-P): The TiC-P is used to measure healthcare uptake and productivity losses (absenteeism and presenteeism) between baseline and last follow-up measure (T3). Healthcare costs per participant will be determined by multiplying healthcare uptake by unit costs as described in the Dutch costing guideline [uideline .International Trauma Questionnaire : The Internationale Trauma Vragenlijst (ITV) is the Dutch translation of the International Trauma Questionnaire (ITQ). It is a self-report questionnaire that measures PTSD and complex PTSD (CPTSD) and is based on the International Classification of Disease (ICD-11), in which (in contrary to the DSM-5) the diagnosis complex PTSD is also included. Part 1 of the questionnaire consists of 9 questions involving PTSD and part 2 consists of 9 questions regarding CPTSD, scored on a Likert scale ranging from 0 to 4 with higher scores indicating higher levels of complaints [mplaints . In thisChildhood trauma Questionnaire – short form (CTQ-sf): The CTQ-sf is a 28-item self-report questionnaire with questions on a Likert scale ranging from 1 to 5, that measures child abuse and neglect and can be used to identify individuals with a history of maltreatment. It has good validity and reliability and is the most widely used instrument to assess childhood trauma [d trauma , 71.Daily Emotional Support (DES) subscale from Social Support Questionnaire of Transactions (SSQT): The DES subscale of the SSQT consists of 5-items and is included in the current study to measure emotional support [ support .Neurocognitive assessment: Impulsivity and cognitive interference are measured by a computerized emotional STROOP task including substance-related, PTSD-related, and neutral words (Inquisit) and delay discounting is measured using a computerized version (MATLAB) [(MATLAB) . Neuroco(MATLAB) –76. We tBaseline characteristics: Demographic characteristics, treatment history, and patient preference of type and timing of PTSD treatment are administered.Treatment characteristics: The number of sessions of PTSD-treatment attended and the number of sessions of SUD-treatment attended are administered.Therapist characteristics: Therapist working experience and therapist preference of type and timing of PTSD treatment are administered.All analyses will be conducted on an intention-to-treat basis. To compare types and timing of PTSD treatment,  Linear Mixed Models ((G)LMMs) will be used to model the primary and secondary outcome measures, with the underlying distribution  binomial) depending on the type of outcome variable and its distribution. Next to these analyses based on classical statistics, a  Bayesian approach will be used to model the outcome parameters so that the relative evidence for the null-hypothesis  and the alternative hypothesis can be estimated. Prior distributions have been specified.The primary outcome measure will be the continuous variable PTSD symptom severity, as measured with the CAPS-5 at all follow-up assessments. Additionally, based on the same CAPS-5 assessments we will evaluate the dichotomous variables loss of PTSD diagnosis (no longer meeting criteria for PTSD) and full remission of PTSD (CAPS-5 score < 20), as these dichotomous variables are easy to interpret and are needed to calculate the number needed to treat. Most secondary outcome measures are continuous variables, with the exception of treatment completion of PTSD treatment and completion of SUD treatment, which are dichotomous variables.The 3 treatment conditions will be compared with SUD treatment only condition  at 3-month follow-up (T1 measure) with a linear regression model. Baseline CAPS-5 score will be included as covariate.The effect of timing of PTSD treatment on the primary outcome will be evaluated  with (G)LMMs. Baseline CAPS-5 score will be included as covariate and timing of treatment as fixed effect. Overall effects will be evaluated, as well as between-group differences at separate follow-up time points (6-months and 9-months after baseline), by adding time and an interaction between group and time to the model. The intercept will be treated as a random effect.The 3 treatment conditions will be compared head-to-head  with (G)LMMs. Baseline CAPS-5 score will be included as covariate and treatment type as a fixed effect. Overall effects will be evaluated, as well as between-group differences at separate follow-up time points, by adding time and an interaction between group and time to the model. The intercept will be treated as a random effect.Secondary outcome parameters will be analysed with (G)LMMs, with the underlying distribution depending on the type of outcome variable and its distribution, in accordance with the above described analyses.We expect to have insufficient statistical power to detect statistically significant interaction effects between timing and type of PTSD-treatment. However, descriptive statistics of PTSD symptom severity (CAPS-5 scores) and treatment completion rates of all randomized groups will be presented , to explore whether there is anecdotal evidence for the existence such interaction-effects, which would be relevant for future research.An economic evaluation will be conducted alongside the randomized trial and will be performed according to the intention-to-treat principle. Using a societal perspective, we will evaluate the relationship between costs, as measured with the TiC-P – and health outcomes of treatments at 9 months follow-up. A (secondary) health care perspective analysis will also be done. We will perform both a cost-effectiveness analysis with PTSD symptoms as effect measure and a cost-utility analysis using QALYs, based on the EQ-5D-5L.Due to the COVID-19 outbreak in March 2020, the Jellinek treatment centers were entirely closed for new treatments for 6 weeks. During this time, inclusion of new participants was temporarily halted. The informed consent procedure and eligibility interview was conducted through video calling, however the baseline assessment was temporarily halted for participants who met the inclusion criteria. All assessments for patients that were already included were conducted by phone in line with lockdown restrictions. All included participants were informed about the changes in the procedure by a participant information letter about the modifications of the procedure. During these assessments an extra questionnaire on COVID-19 effects was temporarily included. This questionnaire consisted of 20 questions involving the effects of the Covid-19 outbreak on personal daily life and  health. This questionnaire was designed by The Netherlands Study of Depression and Anxiety (NESDA) cohort study.Patients in all treatment arms who had already started with treatment received the remainder of both their SUD and PTSD treatment through video calling during lockdown. No adjustments were made to the treatment protocols. For patients whose SUD treatment was postponed because of the COVID-19 measures, the PTSD treatment was also postponed until the COVID-19 measures were lifted and the SUD treatment as usual started.Six weeks after the start of the first Covid lockdown new patients were included again, however they received their treatment as well as the assessments through video calling from the start. Baseline assessments also restarted, although measurements were done either by video calling or face-to-face.When a range of lockdown measures lifted over the summer in 2020 and face-to-face sessions were possible again at the treatment center, all PTSD treatments were continued with face-to-face sessions. Since then, new participants all receive their entire treatment face-to-face at the location. However, when a therapist or patient is not allowed to come to the treatment facility center due to COVID-related symptoms, the session is delivered through video calling. For all sessions and assessments it is registered whether the session or assessment has been done by video calling or through a face-to-face session.Completion of this RCT will provide more knowledge about the relative effectiveness of three treatment strategies for PTSD and their optimal timing in a population of patients with co-occurring SUD and PTSD. We will directly compare the effects of a PTSD treatment that is well-established for SUD nonetheless leads to high drop-out percentages (PE) and one treatment which is well-established for PTSD without SUD co-morbidity (EMDR) and one promising treatment for PTSD (ImRs). Furthermore, alcohol and drug use, treatment completion, psychological complaints, interpersonal problems, emotion regulation, trauma related emotions and cost-effectiveness of the three interventions will be examined. In addition, we will examine whether simultaneous or sequential treatment of SUD and PTSD is most effective.Strengths of this study are that we expect to include a cultural and socioeconomic diverse sample, since the participating centers are located in large cities and both intramural and extramural patients are included. A representative sample will be acquired by applying a minimum of exclusion criteria. The relatively long follow-up measurements of 9 months will provide insights in the long-term effects of the therapies. All therapists will be trained in all methods to prevent bias.An important limitation of this study is the risks of high dropout rates at follow up measurements. Previous studies in this patient group have reported high assessment dropout rates . We expePatients with both PTSD and SUD have a high burden of disease. Currently, there is evidence that a simultaneous PE treatment is effective to treat PTSD in patients with co-occurring SUD, although effects are small, treatment dropout rates are high, and there is reluctance among therapists to offer PTSD and SUD treatment at the same time. Treatment guidelines for co-occurring PTSD and SUD can be improved based on the findings of this study, which may improve treatment outcomes of patients with this common comorbidity.


Tumor-to-tumor metastasis is the rare phenomenon in which one tumor exhibits metastatic deposits from another. To the best of our knowledge, there has been no prior reported case of tumor-to-tumor metastasis of a diffuse large B cell lymphoma (DLBCL) to a primary gastric adenocarcinoma.A 70-year-old man presented with chest discomfort. An echocardiogram showed the presence of a right ventricular tumor. A positron emission tomogram showed multiple foci of abnormal activity in right cervical lymph nodes, cardiac wall, and stomach. A right cervical lymph node biopsy specimen revealed histological features of DLBCL. An esophagogastroduodenoscopy showed a large circumferential ulceration on the gastric body. Subsequent biopsy revealed adenocarcinoma cells surrounded by infiltrating lymphoma cells. On immunohistochemical staining, lymphoma cells were positive for CXCR4 and adenocarcinoma cells were positive for CXCL12/SDF-1. The patient was treated with six cycles of R-CHOP chemotherapy regimen, resulting in a complete remission.This patient’s case implies that the interaction between a chemokine and its receptor may be the underlying mechanism for the observed tumor-to-tumor metastasis. Specifically, our case would suggest an involvement of the CXCL12 (SDF-1)/CXCR4 axis in the observed metastasis of DLBCL to primary gastric adenocarcinoma. Tumor-to-tumor metastasis is the rare phenomenon in which one tumor is involved by metastatic deposits from another . The rec18F-Fluorodeoxyglucose (FDG) positron emission tomogram showed multiple foci of abnormal FDG accumulation in right cervical and mediastinal lymph nodes, cardiac wall, and stomach with elevated maximum standardized uptake values of more than 27  was not detected in the biopsy specimens. On the other hand, biopsy specimens from three other sites , the patient was referred to our hospital. An echocardiogram showed the presence of a large immobile mass attached to his right ventricle extending to the outflow tract  had independent tumors. Collision of both tumors was reported in 14 cases (26.4%). There were 4 cases with contiguous and 5 cases with intermingling tumors.The occurrence of both primary gastric lymphoma and gastric adenocarcinoma in the same patient is a rare entity. 56 cases of synchronous occurrence of both primary gastric lymphoma and gastric adenocarcinoma have been summarized by Hamaloglu et al. . In theiH. pylori-negative DLBCL and adenocarcinoma in the stomach. Further, it should be noted that the gastric lymphoma in our case may not be primary but metastatic tumor from the cardiac legion since it was the largest /CXCR4 axis in the process of tumor-to-tumor metastasis /CXCR4 axis in tumor-to-tumor metastasis of DLBCL to primary gastric adenocarcinoma.


Workplace-based mindfulness programs have good evidence for improving employee stress and mental health outcomes, but less is known about their effects on productivity and citizenship behaviors. Most of the available evidence is derived from studies of mindfulness programs that use class-based approaches. Mindfulness apps can increase access to training, but whether self-directed app use is sufficient to realize benefits equivalent to class-based mindfulness programs is unknown.We assessed the effectiveness of a mindfulness app, both with and without supporting classes, for reducing employees’ perceived stress. Changes in mindfulness, mental health, quality of life, perceptions of job demand, control and support, productivity indicators, organizational citizenship, and mindful behaviors at work were also investigated.Tasmanian State Service employees were invited by the Tasmanian Training Consortium to a 3-arm randomized controlled trial investigating the effects of a mindfulness app on stress. The app used in the Smiling Mind Workplace Program formed the basis of the intervention. The app includes lessons, activities, and guided meditations, and is supported by 4 instructional emails delivered over 8 weeks. Engagement with the app for 10-20 minutes, 5 days a week, was recommended. Reported data were collected at baseline (time point 0), 3 months from baseline (time point 1 [T1]), and at 6-month follow-up (time point 2). At time point 0, participants could nominate a work-based observer to answer surveys about participants’ behaviors. Eligible participants (n=211) were randomly assigned to self-guided app use plus four 1-hour classes , self-guided app use , or waitlist control . Linear mixed effects models were used to assess changes in the active groups compared with the WLC at T1 and for a head-to-head comparison of the app+classes and app-only groups at follow-up.P=.02; Cohen d=–0.21) and higher mindfulness . These effects were retained in the app+classes group at 6 months. No significant changes were observed for the app-only group or for other outcomes. There were no significant changes in observer measures at T1, but by time point 2, the app+classes participants were more noticeably mindful and altruistic at work than app-only participants.App use time was considerably lower than recommended . Compared with the WLC at T1, no significant change in perceived stress was observed in either active group. However, the app+classes group reported lower psychological distress (β=−1.77, SE 0.75; Including classes in the training protocol appears to have motivated engagement and led to benefits, whereas self-guided app use did not realize any significant results. Effect sizes were smaller and less consistent than meta-estimates for class-based mindfulness training.Australian New Zealand Clinical Trials Register ACTRN12617001386325; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372942&isReview There is growing evidence in support of workplace-based mindfulness programs for increasing employee mindfulness, reducing stress, and improving mental health and well-being ,2. In thUnmanaged stress is known to lead to psychological distress, depression, and anxiety ,7, whichThe occupational health psychology and workplace management literature points to the importance of considering factors that affect employee stress at both the organizational and individual levels . A combiMindfulness meditation involves the sustained practice of intentionally applying nonjudgmental attention to the current experience. There is some evidence that this practice improves attentional capacities , prosociSmartphone apps are an increasingly popular and accessible mode of delivery for mindfulness training and practice . App funAccording to a review of 23 mindfulness apps against the Mobile App Rating Scale , the topThis study examines the efficacy of an app-based, low-dose workplace-based mindfulness program in a large, geographically and occupationally diverse Australian public service workforce. The trial followed an earlier pilot RCT of a 5-week Mindfulness at Work Program within the same workforce . The MinThe primary aim of this study is to assess the efficacy of the Smiling Mind Workplace Program app, offered both with and without supporting classes, in reducing employee stress (aim 1). We hypothesize that employees using the Smiling Mind Workplace Program app in conjunction with a series of four 1-hour classes (app+classes group) or using the Smiling Mind Workplace Program app self-guided without supporting classes (app-only group) would each report a consistent moderate-sized reduction in perceived stress when compared with a waitlist control (WLC) group.The secondary aims are to explore the effects of this low-dose mindfulness intervention on psychological distress, mindfulness, health-related quality of life, perceived job demands, control, and resources (aim 2); explore changes in health-related LPT (aim 3); and explore observer-reported changes in participants’ organizational citizenship and mindful behaviors (aim 4). The effect retention was also investigated (aim 5).A 3-arm, open-label, parallel-group RCT was conducted between February 2018 and April 2019. The study was approved by the University of Tasmania health and medical human research ethics committee (H0016587) and registered with the Australian and New Zealand Clinical Trials Register in February 2018 (12617001386325). Baseline data were collected using web-based surveys administered in February 2018 (time point 0 [T0]). Postintervention surveys were conducted 3 months from baseline in May 2018 (time point 1 [T1]), with a 6-month follow-up in July 2018 (time point 2 [T2]). App use data were obtained at T1 and T2. The active intervention groups completed their training between T0 and T1. The control group was invited to access the intervention between T1 and T2. A further data collection wave was conducted 14 months from baseline (time point 3); however, analyses were not conducted because of high (85%) attrition (data not reported).The study sample was drawn from the Tasmanian State Service (TSS). The TSS employs approximately 18,000 people from 18 service agencies and centers across the island state of Tasmania, Australia. TSS employees work in a wide variety of roles . An invitation was widely disseminated via email and staff newsletters to express interest in joining a study of app-based mindfulness training for employee stress protection  and 2 qyes was selected, the first name and email address of the nominee were entered, and the observer was invited to complete brief surveys about their observations of their paired participant’s behaviors at each of the study time points.In the baseline surveys (T0), respondents were asked if they wished to nominate a work-based observer to join the study to answer some questions about the participants’ behaviors at work. If An independent statistician (PO) randomized eligible participants into the 3 groups, stratified by whether they had an observer. Group allocations were sent to the TTC, who notified the participants of their training schedule and coordinated the seminars. It was not feasible to blind the TTC staff, study participants, or teacher to treatment . All datReleased to the market in 2014, the Smiling Mind Workplace Program aims to enable working adults to develop mindfulness skills and embed mindfulness practices into daily life. The established low-dose mindfulness program involves a series of 5 learning modules delivered in 4 interactive 1-hour face-to-face workshops. These are led by a Smiling Mind facilitator over 8 weeks and supported by the use of the Smiling Mind Workplace Program app. This app comprises 41 elements, including videos and audio lessons, guided meditations, and practical activities such as moving with awareness between meetings, breathing techniques, and listening exercises to help cultivate workplace mindfulness. Use of the app-based activities and meditations is supported by fortnightly emails relating to the content covered in the workshops and app-based lessons. The recommended minimum engagement with the Smiling Mind Workplace Program app is 10 to 20 minutes’ mindfulness practice each weekday. Smiling Mind Workplace Program history and content are provided in To maximize accessibility, Smiling Mind Workplace Program workshops were delivered in a seminar format in university venues located in the north, northwest, and south of the state. Classes ran twice, in the morning and afternoon, on the advertised dates. Participants were able to attend in person or via videoconferencing, and catch-up recordings were made available. All classes were led by the same mindfulness teacher with certification from the University of Massachusetts Center for Mindfulness and >10 years of teaching experience. No supplementary messaging, incentives, or other forms of contact from the study team were used to encourage intervention engagement.The app+classes group participants were invited to download and use the Smiling Mind Workplace Program app and attend four 1-hour classes scheduled fortnightly during work time. These participants were sent fortnightly generic emails from the Smiling Mind team to support the use of the app-based materials.The app-only group participants were invited to download and use the Smiling Mind Workplace Program app and received fortnightly emails but were not invited to attend the classes.The WLC group participants received no information during T0 to T1. After data collection for T1 was complete, the WLC group was invited to a single 2-hour seminar and to download and use the Smiling Mind Workplace Program app self-guided, in conjunction with the fortnightly emails.All groups retained access to the Smiling Mind Workplace Program app for 12 months.Demographic variables  were collected from participants at T0, as were past or planned exposure to other mindfulness or stress management training and self-ratings of readiness for change (percent).The 10-item Perceived Stress Scale  was useThe PHQ-9  was usedThe Kessler 10-item measure  was usedThe 15-item Mindful Attention and Awareness Scale  was usedThe 35-item, 8-dimension Assessment of Quality of Life (AQoL) measure , which aPerceptions of job demand, control, and support were used to assess work-related psychosocial risk at all time points. Demand and control were assessed using 7 items drawn from the Household, Income, and Labour Dynamics in Australia survey . Scores Effects on productivity were based on estimates of health-related LPT . ParticiThe total number of days lost through absenteeism and presenteeism is thus reported as health-related LPT.The degree to which changes in participants’ mindful behaviors  were noticeable to work colleagues was assessed at all time points using a 9-item observed mindfulness measure . This iA 16-item Organizational Citizenship Behaviors observer report instrument  was usedIntervention adherence was assessed using self-reported seminar attendance and app use data from the Smiling Mind Workplace Program server. Whether the participants downloaded and engaged with the app (yes or no) was recorded. Engagement was calculated as the proportion of time spent in the Smiling Mind Workplace Program app activities out of a potential maximum of 343 minutes for the entire program. Participants’ perceptions of the acceptability of the intervention were assessed using qualitative data from 2 open questions in the T1 survey. Observers provided free-text responses at the end of each survey about their experience in the study and to share any additional information about their paired participants.d=−0.54; mean difference −4.21, SE 0.14) [The required sample size was calculated using a pooled PSS estimate from a meta-analysis of 13 RCTs of workplace-based mindfulness programs (Cohen SE 0.14) . The recd standardized mean difference effect estimates were computed using the Lakens [Intention-to-treat analyses were conducted using an original assigned group approach . Signifie Lakens  guideline Lakens  guideline Lakens .The flow of participants and observers is illustrated in Of the 211 participants and 136 observers, 15 (7.1%) participants and 6 (4.4%) observers advised withdrawal during the study period. The participants’ reasons for withdrawal were time pressures , changing job , difficulty accessing the app-based materials , extended leave , and no reason . Observers’ reasons included no longer being in contact with their paired participant  or their participant had withdrawn . Of the 211 participants, complete survey data were provided by 167 (79.1%) participants at T1 and 129 (61.1%) participants at T2.Participant characteristics were similar across the intervention groups , except Postintervention RCT effect estimates are presented in r=−0.33) but not in the app-only group. Investigation of T0:T1 change in PSS scores by meditation time and program engagement suggests an inverse linear dose–response pattern in the app+classes group. This pattern was not evident in the app-only group  attendees in the first class, 36 (51%) in the second, 33 (53%) in the third, and 32 (46%) in the fourth class. ly group .d=−0.21) and mindfulness (Cohen d=0.19). At T1, the Kessler-10 data showed that 15% (8/54) of respondents in the app+classes group transitioned into a lower category for risk of clinical mental health problems, whereas 2% (1/54) of participants shifted to a higher-risk category. No significant effects were found for either psychological distress or mindfulness in the app-only group, and an equal number reported beneficial  and detrimental changes in risk status . Of the 70 participants in the WLC, 14% (9/64) shifted to higher risk and 9% (6/64) to lower-risk categories during the initial intervention period.The results  show thaNo discernible trends in the quality of life data were evident for either the app+classes group or the app-only group when compared with the WLC group. Similarly, psychosocial risk factors did not change significantly in either active group at T1.The raw productivity and workplace incident results are presented in Table S1 of P=.01; T1: ICC=0.32, P=.03; T2: ICC=0.39, P=.03). At T1, observers reported a small but nonsignificant trend toward higher observed mindful behaviors in both active groups compared with the WLC. At the 6-month follow-up (T2), head-to-head comparison between the active groups showed that the app+classes participants displayed more noticeably mindful behaviors than the app-only participants .Observer-reported outcomes are illustrated in The distribution of data in the organizational citizenship compliance subscale showed that responses were bounded at the top from baseline; thus, these data were excluded from the analyses. Although the results for altruism were not significant, plots  illustraResults comparing the app+classes and app-only groups at the 6-month follow-up (T2) are reported in The frequency of themes derived from the qualitative data is reported in The data that support the findings of this study are available on request from the corresponding author (LB).This RCT assessed the effects of participating in a low-dose, app-based workplace-based mindfulness program delivered both with and without supporting classes in a sample of public sector employees. The study hypothesis that using the Smiling Mind Workplace Program app, either self-guided or with supporting classes, would result in moderate-sized reductions in perceived stress was not supported. Although the app+classes group engaged more with the training, neither group achieved the recommended dose. Despite the low engagement, when compared with the inactive control group, the app+classes group reported significant increases in mindfulness and decreases in psychological distress. These benefits were retained at 6-month follow-up, at which point the app+classes group also reported significantly lower perceived job demands than the app-only group. No significant effects were observed for either intervention group for health-related quality of life or productivity. Although the Smiling Mind Workplace Program app was well-received by most participants in the active groups, those whose training protocol was entirely self-guided engaged less with training and reported no statistically significant changes in any of the study outcomes.The null result for perceived stress was unexpected, given consistent positive findings from other workplace-based mindfulness programs  and the The significant changes in mindfulness and distress were encouraging but lower than meta-analytic estimates from workplace-based mindfulness programs delivered via face-to-face classes or web-based learning platforms -63. ThesHigher engagement with the Smiling Mind Workplace Program app by app+classes participants appears to have been motivated by seminar attendance, a sentiment volunteered in free-text data by 24% (17/70) of app+classes participants. For example, one of the participants stated:I was fortunate to be selected to attend sessions which I believe was VERY important. This helped tremendously with getting the motivation to work through the app sessions. Other colleagues from my work who were not selected to attend sessions have very low motivation and barely did any of the app sessions.The self-guided app-only group not only missed the class-based educational and discursive opportunities but also engaged less than the app+classes participants with the in-app educational videos, lessons, and practice resources. This poorer engagement may explain the pattern in PSS changes depicted in The absence of significant improvement in mindfulness or distress in the app-only group indicates that self-guided use of the Smiling Mind Workplace Program app was insufficient to realize consistent changes within the main intervention period (T0 to T1). This finding is in keeping with previous work that has shown that face-to-face classes in the training protocol are associated with stronger improvements in mindfulness . The conCompared with the WLC group, no change was observed immediately after the intervention for either intervention group for participants’ perceptions of psychosocial risk factors, job demand, control, and support. However, at 6 months, the app+classes group reported a reduction in job demands that approached significance and a trend toward higher job control compared with the app-only group. Job demands and control are key factors associated with work-related stress in the theoretical job-demands-resources model, where it is the perception that demands outweigh available resources that leads to job strain. Job strain is understood to be responsible for a range of workplace health and performance problems . MindfulAn explanation for the sequential development of benefits following mindfulness training is provided in the Garland  MindfulnThe null result for quality of life was unexpected, given that significant improvements were recorded on the briefer 4-dimension AQoL following the pilot face-to-face workplace-based mindfulness program in the same population . MoreoveTrends in productivity data indicate that all 3 groups had decreased the number of health-related presenteeism and absenteeism days at the 6-month follow-up. Changes in productivity may also be sequential to changes in stress and mindfulness; however, our results did not show a causal link between mindfulness training and increased productivity. We propose that health-related LPT is an informative measure for assessing productivity effects in future workplace-based mindfulness program research, as higher mindfulness has been shown to alleviate psychological distress, depression, and anxiety, and these conditions are strongly associated with absenteeism and presenteeism ,68.The use of observer data to supplement self-reported changes in mindfulness and related behaviors addresses a limitation noted in approximately half of the published mindfulness studies . AlthougThere were timing and contextual considerations within our study. Baseline data collection coincided with the end of the summer break, a period during which many public sector employees are returning from annual leave. In contrast, the postintervention surveys coincided with political elections and major flooding in and around the state’s capital city, where many public sector employees are located. Thus, employee stress levels may have been lower than usual in the preintervention surveys and elevated after the intervention through these contextual factors.The necessary lack of blinding and use of a waitlist rather than an active control means that nonspecific factors such as social desirability, expectancy, or experimenter effects cannot be ruled out as potential effect moderators. For example, our qualitative data appear to suggest that participants in the app-only group may have felt their lower dose training protocol to have a lower status than the app+classes protocol. Careful design of the WLC conditions in future research is recommended to help address this bias risk. Although an additional survey was conducted 14 months from baseline (time point 3), there was a very high degree of attrition, with only 15.2% (32/211) of the starting sample providing data. Follow-up analyses were therefore limited to the 6-month data. Raw data for productivity and workplace incidents are provided in Strengths of this study include participant characteristics reflecting those of the broader TSS workforce, meaning the reported findings can be generalized to similar public sector workplaces with some confidence. Collecting objective app use data enabled us to overcome a reliance on self-report adherence to the training protocol; however, we did not record engagement with the Smiling Mind generic emails and were therefore not able to include exposure to this guiding material in our dose-exposed calculations. The use of observer reports was another strength of this study, although the ceiling effects in the organizational citizenship and observed mindfulness data prevented complete analyses. The use of multisource data increases confidence in self-reported study findings, and this study has shown that the collection and use of observer-reported data are both feasible and informative. We suggest that more studies collect observer reports to help build an evidence base around the effects of mindfulness training on workplace social and performance outcomes. More work is needed to understand the effects of mindfulness training on workplace productivity and health-related LPT.Despite the absence of effects for the primary study outcome, that is, perceived stress, the results for mindfulness, distress, and job demands support the Smiling Mind Workplace Program app as a workplace stress reduction intervention when supported by classes. Importantly, no evidence of adverse effects was observed from this low-dose mindfulness intervention. However, previous workplace mindfulness training research ,2 indica


Observations from rifted margins reveal that significant structural and crustal variability develops through the process of continental extension and breakup. While a clear link exists between distinct margin structural domains and specific phases of rifting, the origin of strong segmentation along the length of margins remains relatively ambiguous and may reflect multiple competing factors. Given that rifting frequently initiates on heterogenous basements with a complex tectonic history, the role of structural inheritance and shear zone reactivation is frequently examined. However, the link between large-scale variations in lithospheric structure and rheology and 3-D rifted margin geometries remains relatively unconstrained. Here, we use 3-D thermo-mechanical simulations of continental rifting, constrained by observations from the Labrador Sea, to unravel the effects of inherited variable lithospheric properties on margin segmentation. The modelling results demonstrate that variations in the initial crustal and lithospheric thickness, composition, and rheology produce sharp gradients in rifted margin width, the timing of breakup and its magmatic budget, leading to strong margin segmentation. The evolution of rifts and rifted margins is controlled by the rheology of the lithosphere. Thus, pre-existing lateral rheological variations can dominate the rifting process and lead to margin segmentation, with along-strike changes in crustal structure and nature and timing of continental breakup. A synthesis of key features at Atlantic rifted margins2 suggests that most rifted margins undergo a similar sequence of deformation phases, which reflect progressive thinning of the continental lithosphere that produces a transition from distributed to highly localized deformation. While this sequence produces genetically similar ‘domains’ from the un-rifted continent to the seafloor , significant segmentation can occur either at plate-scale , between different rifted margins (e.g. between the Labrador Sea and the Baffin Bay through the Davis Strait4), or within a single basin (e.g. Labrador Sea5). Thus, changes in rifting style, strain distribution, crustal architecture, timing, and nature of continental breakup can develop across distinct rifted margins and along the length of individual rift systems.The formation of rifted continental margins occurs through multiple phases of extension with distinct structural, sedimentary, and magmatic characteristics6, inheritance is commonly invoked to explain the segmentation of both rifts and rifted margins8. Numerical modelling supports this inferred link between pre-rift structure and rifted margin architecture, with a wide range of 2-D investigations demonstrating the first-order effects of the initial thermal and rheological structure on continental rifting14. 2-D modelling also suggests that extension velocity14, multiphase rifting16, and complex deformation network localization19 exert a first-order control on rifted margin structure. Furthermore, 3-D numerical simulations can now achieve similar spatial resolutions to 2-D studies and were used to illustrate the margin-parallel effects of structural inheritance22, fault network coalescence23 and out-of-plane25 or oblique27 boundary conditions. Nonetheless, to date no studies have explicitly examined the effects of a heterogeneous pre-rift lithosphere, with domains of varying rheology , on the 3-D evolution of continental rifting and rifted margin segmentation. This in part reflects that many rifted margins initiate on complex pre-rift lithosphere6, which may be difficult to accurately reconstruct without sufficient data to connect onshore and offshore domains28. In the case of the Labrador Sea, geological, and geophysical data indicate an offshore along-strike segmentation that is clearly defined by onshore variations of crustal and lithospheric thickness, composition, and thermal structure30.As most rift basins form along (or near) former orogens31. The Early to Late Cretaceous rifting initiated on an Archean to Proterozoic cratonic lithosphere with different tectonic terrains amalgamated during the late Mesoproterozoic Grenvillian orogenic collision (ca. 1.08–0.97 Ga)5. Recent studies revealed important changes in rift geometry, crustal architecture, timing, and nature of breakup along the Labrador margin33. These changes occur across major Precambrian structures, which run perpendicular to the main NW rift trend and define three margin segments , parallel to the pre-rift tectonic domains42. The E-W trend is related to the Mesozoic rifting as heat flow steadily decreases from the distal margin to its hinterland. Whereas, the N-S trend is ascribed to pre-rift variation in both basal heat  and crustal radiogenic heat production42. This suggests that the effect of the Labrador rifting on the thermal structure was restricted to the rifted domain and negligible in the margin hinterland.Geophysical data collected from the hinterland of the Labrador Sea  reveal the existence of variable heterogeneity in the un-rifted lithosphere of the distinct margin segments5 and thermo-mechanical modelling to examine the effects of variations in pre-rift lithosphere rheology on rift evolution and margin architecture. The numerical design and assessment are directly informed by the geological and geophysical constraints on pre-rift and syn-rift evolution, which are outlined above  lower crust  to compute melting. We extract the temperature and pressure fields at each time step of the models to calculate melt fraction based on the parametrization for batch melting of anhydrous and hydrous peridotite47  in the north and magma-poor  in the south. The magma supply in the northern segment of the Labrador Sea is contemporaneous with the nearby Davis Strait Palaeocene flood basalts. The latter have been linked to adiabatic decompression melting due simply to the tectonics of rifting in the Davis Strait−1) remains colder than the anhydrous peridotite solidus47, and fails to produce any melt  is able to generate small volumes of melt but very late during the rifting process , the thermal regime in slow rifting  content suffice to explain the increase in magmatism along the Labrador margin. Although the northward decrease in margin width indicates a decrease in the amount of extension, it does not necessarily correlate with a decrease in extension rate , geothermal gradient, and the competition between frictional and viscous strain  dictate the nature and timing of tectonic processes controlling lithospheric thinning. However, the 3-D models with variable lithosphere rheology between the southern, central, and northern segments provide new insights into how lateral rheological variation can promote segmentation along rifted margins.Our geodynamic models emphasise the role of pre-rift rheological heterogeneities in defining rift evolution and crustal architecture along rifted margins. The results of the 2-D experiments are consistent with previous numerical studies on the role of rheology in lithospheric The segmentation is not only expressed by a reactivation of pre-existing structures (e.g. sutures and shear zones), as shown in previous studies, but can also be driven by a change in the processes controlling rifting within each segment, as indicated by our 3-D models. It manifests laterally in the distribution of rift structures, the variability in crustal architecture, and the change in the timing and magmatic budget of continental breakup. In addition, this magmatic budget variability is more likely to be driven by changes in the extension rate during rifting and/or changes in the geochemistry  of the mantle underneath the rifted plate.3. The Scotian margin, for instance, shows major changes in the crustal architecture and the magmatic budget during breakup, with a magma-poor segment in the north and a magma-rich segment in the south48. Whereas the Norwegian margin, on the other hand, appears to be affected by a strong structural segmentation from the earliest phases of extension preserved in the proximal domain50 to segmentation along the necking and hyperextension-exhumation domains51. Unlike the Labrador Sea, which opened perpendicular to Precambrian terrains, these margins initiated on, and parallel to, Palaeozoic Appalachian and Caledonian terrains, respectively, with a substantially more complex structural inheritance.We note that most Atlantic margins exhibit some degree of segmentation and along-strike variability49. Nonetheless, because the basement terrains do not continue into the un-rifted onshore domain, their pre-rift lithospheric properties  remain enigmatic. While the assimilation of such pre-rift structural inheritance into numerical simulations presents significantly more challenges than the simulations presented here, they also provide new opportunities to rigorously examine the relationship between inherited shear zone rheology and extensional reactivation. In examining such complex structural inheritance scenarios, future modelling efforts may include the effects of grain size evolution and strain healing to help provide further constraints on lithospheric and rifted margin processes.Indeed, recent detailed mapping along the proximal Norwegian margin demonstrates strong structural inheritance at a range of scalesThe Labrador Sea provides an ideal natural laboratory to constrain the pre-rift variations of the basement lithospheric properties and examine their impact on rifting processes, segmentation, and nature of continental breakup. Our findings show that variations in heat flow, lithospheric and crustal thickness and composition exert a first-order control on the evolution of rifted margins, which in most cases initiate on a lithosphere with strong inherited lateral heterogeneities. We also demonstrate that observations from margin hinterland could be used as a proxy to gain insights into the initial  state of the lithosphere.44. The ASPECT version and parameter files required to reproduce our experiments can be found in the following GitHub branch: https://github.com/naliboff/aspect/tree/labrador_sea_gouiza_naliboff_2020.We model the thermal-mechanical evolution of continental extension in a heterogenous initial lithosphere using the open-source and CIG-supported finite element code ASPECT version 2.0.1-preVelocity and pressure are solved for assuming incompressible viscous flow, where the Stokes equations are defined as:u is velocity, μ is viscosity, p is pressure ρ is density, and g is gravity.Above, Cp is the heat capacity, T is temperature, t is time, H is the rate of internal heating. Respectively, the terms on the right-hand side correspond to internal head production, shear heating, and adiabatic heating.Temperature evolves through a combination of advection, heat conduction, shear heating, and adiabatic heating:ρ0), thermal expansivity (α), reference temperature (T0), and temperature:Density varies linearly as a function of the reference density  of dislocation and diffusion creep (Eq. ):6\documA is the viscous prefactor, n is the stress exponent, Q is the activation energy, P is pressure, V is the activation volume, T is temperature, and R is the gas constant, d is grain size, and p is the grain size exponent.Above, C), angle of internal friction (ϕ), and pressure (P):Brittle (plastic) behaviour follows a Drucker-Prager yield criterion formulation, where the yield stress in 3-D is a function of the cohesion  and weaken the cohesion and friction linearly by a factor of 4 between plastic strain values of 0.5 and 1.552.The procedure for calculating the viscosity at every point follows the viscosity rescaling method, which first compares the predicted effective stresses from viscous flow and plastic failure. If the viscous stress exceeds the plastic yield stress, the viscosity is reduced so the effective stress exactly matches the plastic yield stress53 minimizes diffusion of distinct layers and improves the accuracy of interface advection through time.Throughout the model domain we use quadratic elements (Q2) elements to solve the advection-diffusion equation for temperature, while the Stokes equation is solved on elements that are quadratic for velocity and continuous linear for pressure (Q2Q1). The element size is 10 km beneath 300 km depth, 5 km from 100 to 200 km depth, and 2.5 km above 100 km depth. In total, the 3-D numerical simulations contain ~463 million degrees of freedom. Compositional fields are used to track and advect distinct lithologic domains (e.g. rock types) and other time-dependent quantities (strain). The use of discontinuous Galerkin element with a limiter for compositional fields−4. In most models we use a conservative maximum time step of 20,000 years to limit numerical instabilities during advection and improve the non-linear convergence behaviour. This value is adjusted proportionally as the boundary velocity values increase or decrease. We use this outlined numerical approach to construct a series of 2-D and 3-D continental rifting simulations that reveal the relationship between initial lithospheric structure and rifted margin structure. In order to provide a robust sensitivity analysis of key modelling variables, we first carefully consider the geologic constraints on the pre-rift lithospheric structure.Nonlinearity introduced by the constitutive model is resolved using standard Picard iterations for the velocity and pressure to a tolerance of 10The simulations in this study use a wide range of initial conditions  and material properties to characterize different scenarios for pre-rift lithospheric structure. The details of these simulation features and the methods used to define them are outlined in Supplementary note The forward modelling software used in this study (ASPECT) is community driven, actively developed, and used for a wide range of mantle convection and lithospheric dynamics investigations. In the duration since the models in this study were designed and run, development on portions of the code relating to lithospheric rheology, adiabatic heating, material tracking, free surface stabilization, and non-linear solver schemes has occurred. While these changes do not affect the first- or second-order conclusions reached in this study, future investigations should take advantage of new or updated functionality. Readers wishing to build on the results presented here are encouraged to contact the authors for advice and guidance on how to modify the provided parameter files to take advantage of these changes.Supplementary InformationDescription of Supplementary MoviesSupplementary Movie 1Supplementary Movie 2Supplementary Movie 3Supplementary Movie 4Supplementary Movie 5Supplementary Movie 6Supplementary Movie 7Supplementary Movie 8Supplementary Movie 9Supplementary Movie 10Supplementary Movie 11Supplementary Movie 12Supplementary Movie 13Supplementary Movie 14Supplementary Movie 15Supplementary Movie 16Supplementary Movie 17Supplementary Movie 18Peer Review File


Rapid vaccination may be of benefit in long-term care facilities (LTCF) that are affected by an ongoing COVID-19 outbreak. However, there are concerns regarding the safety and effectiveness of such an approach, particularly regarding the vaccination of pre-symptomatic patients. Here, we report the effectiveness of vaccination in a German LTCF hit by an outbreak that was detected 5 days after the first vaccine doses were administered. In detail, 66.7% of the unvaccinated patients experienced an unfavorable course; this proportion was much lower (33.3%) among the vaccinated patients. Even though this study is limited by a small number of patients, the observation and the comparison with related published data shows that vaccination (i) is safe and (ii) may still be of benefit when given shortly before an infection or even in pre-symptomatic LTCF-patients. COVID-19 (coronavirus disease 2019) outbreaks in long-term care facilities (LTCF) can last for weeks, are difficult to contain, and are associated with high mortality. A recently published UK-wide cohort study involving 907 cases of SARS-CoV-2 (severe acute respiratory syndrome coronavirus type 2) infection from 69 LTCF outbreaks reported a mortality of 48% . They haThe reasons why LTCFs are particularly vulnerable to SARS-CoV-2 outbreaks are poorly understood. Most of the previous studies of risk factors for SARS-CoV-2 infections in LTCFs have been limited by scope and poor quality of administrative, demographic, and infection control data . HoweverThe average incubation time of 5–7 days and the observation that such outbreaks can go on for weeks points toward a potential role for rapid vaccine prophylaxis in LTCF outbreaks. A Scottish prospective cohort study, analyzing a total of 1,331,993 people with a mean age of 65.0 years (SD 16.2) vaccinated between 8 December 2020, and 22 February 2021, found that the first dose of the BNT162b2 mRNA vaccine was associated with a vaccine effect of 91% (95% CI 85–94) for reduced COVID-19 hospital admission at 28–34 days post-vaccination  of the unvaccinated patients experienced an unfavorable course. This proportion was much lower  among the vaccinated patients. Hence, despite the short period between the first vaccination and detection of infection, two thirds of the vaccinated patients in our sample experience only mild symptoms and were treated as outpatients. However, this difference failed statistical significance  due to the small sample size.The two groups of vaccinated and unvaccinated individuals did not differ in the proportion of confirmed COVID-19 infections . Hence, the mortality in vaccinated individuals with COVID-19 was 76.6%  lower compared to unvaccinated COVID-19 cases in the LTCF patients described by Burton et al. [The largest report on COVID-19 mortality in non-vaccinated patients of LTCF is the above-mentioned UK study by Burton et al. [Our findings suggest that, although the first administration of a vaccine against SARS-CoV-2 shortly before or during incubation of a COVID-19 infection is not sufficient to prevent symptomatic disease, particularly in immunosenescent elderly individuals, the course of a COVID-19 disease may be positively affected by a vaccination. There was also no evidence of aggravation of an incubating infection by vaccination. As many outbreaks in LTCFs can last for several weeks, targeted vaccination in these facilities, even after the first cases are known, seems to be a safe and helpful measure to reduce the high mortality associated with these outbreaks. In the interpretation of the findings, limitations must be taken into account. First, the data stem from an observational study. Hence, the group of vaccinated and non-vaccinated individuals may differ systematically regarding potentially confounding covariates. This limits causal interpretation of the reported group differences. This is also true for the between-study comparisons of the mortality rates of the vaccinated individuals in our study with the unvaccinated care home residents reported by Burton et al. Potential differences in relevant covariates between the samples of both studies including possible differences in patient characteristics, health care structure and virus variants. Second, the results of our study rely on data from a single LTCF, which limits generalizability. Alternative study designs, such as randomized controlled trials, or comprehensive covariate adjustment methods  in prospective studies with larger samples  are required to support the findings in this study. However, investigating the described constellation in a proper study is difficult. Therefore, to date, respective data are scarce. The very limited number of patients and the heterogeneity do not permit an effectiveness vaccine evaluation.This outbreak report is limited by a small number of patients, which did not reveal a statistically significant difference between vaccinated and non-vaccinated patients. However, this observation and the comparison with related published data shows that vaccination (i) is safe and (ii) may still be of benefit when given shortly before an infection or even in pre-symptomatic LTCF-patients. Therefore, the findings of our study suggest that rapid vaccination in LTCF can attenuate an acute COVID-19 outbreak. The outbreak of COVID-19 within LTCFs is unavoidable without thorough screening of employees and visitors of LTCFs. Therefore, regular testing of those persons should help to reduce the number of outbreaks of COVID-19. Furthermore, standardized hygiene concepts implemented in LTCFs could help to prevent further spread of COVID-19. However, these measures should not be considered as complete and are subject to regular and further investigations.