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Circulating tumor cells (CTCs) and tumor-derived extracellular vesicles (tEVs) are two crucial methodologies of liquid biopsy. Given their distinct size differences and release dynamics, CTCs and tEVs potentially offer synergistic capabilities in the non-invasive detection of differentiated thyroid cancer (DTC), a typically indolent tumor. We present the Combined DTC CTC/tEV Assay, integrating dual liquid biopsy processes: i) DTC CTC enrichment by Click Chips, followed by analysis of seven DTC-specific genes, and ii) DTC tEV enrichment by Click Beads, succeeded by mRNA cargo quantification in DTC tEVs. This method utilizes click chemistry, leveraging a pair of biorthogonal and highly reactive functional motifs (tetrazine, Tz, and trans-cyclooctene, TCO), to overcome the challenges encountered in the conventional immunoaffinity-based enrichment of CTCs and tEVs. The Combined DTC CTC/tEV Assay synergistically combines the diagnostic precision of CTCs with the sensitivity of tEVs, demonstrating superior diagnostic accuracy in DTC detection and boasting an AUROC of 0.99. This outperforms the individual diagnostic performance of using either DTC CTC or DTC tEV alone. This integration enables full utilization of a patient's blood sample, and marks a significant evolution in the development of nanomaterial-based liquid biopsy technologies to address challenging unmet clinical needs in cancer care.

In 2020, Canada's largest cluster of Bartonella quintana endocarditis, an infection caused by a louseborne bacterium, was detected among persons experiencing homelessness in Winnipeg, Manitoba, Canada (1). Over a 6-month [...]

We analyzed body lice collected from persons experiencing homelessness in Winnipeg, Manitoba, Canada, during 2020–2021 to confirm vector species and ecotype and to identify louseborne pathogens. Of 556 lice analyzed from 7 persons, 17 louse pools (218 lice) from 1 person were positive for the louseborne bacterium Bartonella quintana.

We extended our previous observations with other tumor models to study seven ovarian tumor cell lines-OVCAR3, OVCAR4, OVCAR8, SKOV3, Kuramochi, OAW28, and CaOV3. We found that NK cells targeted and killed poorly differentiated OVCAR8 and CAOV3; these two tumor lines express lower MHC-class I and higher CD44 surface receptors. OVCAR3 and OVCAR4 were more resistant to NK cell-mediated cytotoxicity, and SKOV3, Kuramochi and OAW28 had intermediate sensitivity to NK cell-mediated cytotoxicity, likely representing well-differentiated and moderately differentiated ovarian tumor cell lines, respectively. Similar trends were observed for secretion of IFN-γ by the NK cells when co-cultured with different ovarian tumor cell lines. Treatment with both IFN-γ and TNF-α upregulated MHC-class I in all ovarian tumor cell lines and resulted in tumor resistance to NK cell-mediated cytotoxicity and decreased secretion of IFN-γ in co-cultures of NK cells with tumors cells with the exception of OVCAR8 and CAOV3 which did not upregulate MHC-class I and remained sensitive to NK cell-mediated cytotoxicity and increased secretion of IFN-γ when co-cultured with NK cells. Similarly, treatment with NK cell supernatants induced resistance to NK cell-mediated cytotoxicity in OVCAR4 but not in OVCAR8, and the resistance to killing was correlated with the increased surface expression of MHC-class I in OVCAR4 but not in OVCAR8. In addition, OVCAR4 was found to be carboplatin sensitive before and after treatment with IFN-γ and NK cell supernatants, whereas OVCAR8 remained carboplatin resistant with and without treatment with IFN-γ and NK cell supernatants. Overall, sensitivity to NK cell-mediated killing correlated with the levels of tumor differentiation and aggressiveness, and more importantly, poorly differentiated ovarian tumors were unable to upregulate MHC-class I under the activating conditions for MHC-class I, a feature that was not seen in other tumor models and may likely be specific to ovarian tumors. Such tumors may also pose a significant challenge in elimination by the T cells; however, NK cells are capable of targeting such tumors and can be exploited to eliminate these tumors in immunotherapeutic strategies.

Hepatitis E virus (HEV) is a nonenveloped, single-stranded, positive-sense RNA virus within the family Hepeviridae, subfamily Orthohepevirinae, which is divided into 4 genera: Paslahepevirus, Rocahepevirus, Chirohepevirus, and Avihepevirus (1). Human [...]

Patients diagnosed with epithelial ovarian cancers (EOCs) often suffer from disease relapse associated with the emergence of resistance to standard platinum‑based chemotherapy. Treatment of patients with chemo‑resistant disease remains a clinical challenge. One mechanism of chemoresistance includes overexpression of pro‑survival proteins called inhibitors of apoptosis (IAP) which enable cancer cells to evade apoptosis. Due to their anti‑apoptotic activity, association with poor prognosis, and correlation with therapy resistance in multiple malignancies, IAP proteins have become an attractive target for development of anticancer therapeutics. Second mitochondrial activator of caspase (SMAC) mimetics are the most widely used IAP antagonists currently being tested in clinical trials as a monotherapy and in combination with different chemotherapeutic drugs to target different types of cancer. In the present study, the antitumor efficacy of combination therapy with birinapant, a bivalent SMAC mimetic compound, and carboplatin to target platinum‑resistant EOC cells was investigated. A 3D organoid bioassay was utilized to test the efficacy of the combination therapy in a panel of 7 EOC cell lines and 10 platinum‑resistant primary patient tumor samples. Findings from the in vitro studies demonstrated that the birinapant and carboplatin combination was effective in targeting a subset of ovarian cancer cell lines and platinum‑resistant primary patient tumor samples. This combination therapy was also effective in vitro and in vivo in targeting a platinum‑resistant patient‑derived xenograft (PDX) model established from one of the patient tumors tested. Overall, our study demonstrated that birinapant and carboplatin combination could target a subset of platinum‑resistant ovarian cancers and also highlights the potential of the 3D organoid bioassay as a preclinical tool to assess the response to chemotherapy or targeted therapies in ovarian cancer.

We tested liver samples from 372 Norway rats (Rattus norvegicus) from southern Ontario, Canada, during 2018–2021 to investigate presence of hepatitis E virus infection. Overall, 21 (5.6%) rats tested positive for the virus. Sequence analysis demonstrated all infections to be rat hepatitis E virus (Rocahepevirus ratti genotype C1).

Human granulocytic anaplasmosis (HGA) is a tickborne infection caused by the intracellular bacterium Anaplasma phagocytophilum (1), an emerging pathogen in North America (2-5). HGA can manifest as a subclinical infection; [...]

Annual temperatures in the circumpolar Arctic are rising at 2-3 times the global average, reducing ecologic barriers for arthropod reproduction and fueling shifts in insect diversity and distribution (2,2). The [...]

Abstract Super‐resolution optical imaging tools are crucial in microbiology to understand the complex structures and behavior of microorganisms such as bacteria, fungi, and viruses. However, the capabilities of these tools, particularly when it comes to imaging pathogens and infected tissues, remain limited. MicroMagnify (µMagnify) is developed, a nanoscale multiplexed imaging method for pathogens and infected tissues that are derived from an expansion microscopy technique with a universal biomolecular anchor. The combination of heat denaturation and enzyme cocktails essential is found for robust cell wall digestion and expansion of microbial cells and infected tissues without distortion. µMagnify efficiently retains biomolecules suitable for high‐plex fluorescence imaging with nanoscale precision. It demonstrates up to eightfold expansion with µMagnify on a broad range of pathogen‐containing specimens, including bacterial and fungal biofilms, infected culture cells, fungus‐infected mouse tone, and formalin‐fixed paraffin‐embedded human cornea infected by various pathogens. Additionally, an associated virtual reality tool is developed to facilitate the visualization and navigation of complex 3D images generated by this method in an immersive environment allowing collaborative exploration among researchers worldwide. µMagnify is a valuable imaging platform for studying how microbes interact with their host systems and enables the development of new diagnosis strategies against infectious diseases.

Northern Canada is warming at 3 times the global rate. Thus, changing diversity and distribution of vectors and pathogens is an increasing health concern. California serogroup (CSG) viruses are mosquitoborne arboviruses; wildlife reservoirs in northern ecosystems have not been identified. We detected CSG virus antibodies in 63% (95% CI 58%–67%) of caribou (n = 517), 4% (95% CI 2%–7%) of Arctic foxes (n = 297), 12% (95% CI 6%–21%) of red foxes (n = 77), and 28% (95% CI 24%–33%) of polar bears (n = 377). Sex, age, and summer temperatures were positively associated with polar bear exposure; location, year, and ecotype were associated with caribou exposure. Exposure was highest in boreal caribou and increased from baseline in polar bears after warmer summers. CSG virus exposure of wildlife is linked to climate change in northern Canada and sustained surveillance could be used to measure human health risks.

Whole blood is the optimal specimen for anaplasmosis diagnosis but might not be available in all cases. We PCR tested serum samples collected in Canada for Anaplasma serology and found 84.8%–95.8% sensitivity and 2.8 average cycle threshold elevation. Serum can be acceptable for detecting Anaplasma spp. when whole blood is unavailable.

Introduction: The expanding geographical range of blacklegged ticks (BLTs), Ixodes scapularis, and its ability to transmit Borrelia burgdorferi, Anaplasma phagocytophilum, Babesia microti, and Borrelia miyamotoi poses an emerging public health risk. Our study determined the geographic distribution and the minimum infection rate (MIR) of B. burgdorferi‐, A. phagocytophilum‐, Ba. microti‐, and B. miyamotoi‐infected BLTs in Manitoba submitted to the Public Health Agency of Canada's passive tick surveillance programme from 1995 to 2017. Methods: Regression models were used to test the association of the MIR by year for each pathogen. Ticks were tested using PCR for B. burgdorferi since 1995, A. phagocytophilum since 2006, and Ba. microti and B. miyamotoi since 2013. The global positioning system coordinates of infected and uninfected ticks submitted during the surveillance period were plotted on a map of Manitoba using ArcGIS Pro version 3.1.2 to detect changes in the geographic distribution of ticks over time. Results: The overall MIR for B. burgdorferi was 139.7 (95% confidence interval [CI]: 129.0–150.5) per 1000 BLTs; however, it varied over time. After remaining stable from 1995 to 2005, the MIR increased by 12.1 per 1000 BLTs per year from 2005 to 2017 (95% CI: 7.0%–17.2%, p‐value <0.01). The geographic distribution of B. burgdorferi‐infected BLTs was centred around Winnipeg, Manitoba, and spread outward from this locality. The MIRs of A. phagocytophilum, Ba. microti, and B. miyamotoi were 44.8 per 1000 BLTs (95% CI: 38.1–51.6), 10.8 (95% CI: 6.6–15.0), and 5.2 (95% CI: 2.3–8.1) per 1000 BLTs, respectively, and showed no significant change over time. Conclusion: Passive surveillance revealed the presence of A. phagocytophilum‐, Ba. microti‐, and B. miyamotoi‐infected BLTs in southern Manitoba and revealed an increased risk of exposure to B. burgdorferi‐infected BLTs due to the increasing geographic range and MIR. [ABSTRACT FROM AUTHOR]

Pulmonary lymphomas are rare. With the current less invasive approaches used to obtain material for diagnosis, the diagnosis of pulmonary lymphoma is now frequently established in a small biopsy rather than in a resection. Therefore, the diagnosis has become more challenging and requires correlation with the clinico-radiologic presentation and with ancillary studies (immunohistochemistry, flow cytometry, cytogenetics, and/or molecular analysis). Due to the rarity of pulmonary lymphomas, clinical suspicion of a lymphomatous process is low at initial presentation, and material may be only submitted for histopathology. For this reason, herein, we provide recommendations to arrive at the correct diagnosis of the most common lung B-cell lymphomas (marginal zone lymphoma of mucosa-associated lymphoid tissue, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, lymphomatoid granulomatosis) in the setting of small biopsies, utilizing only immunohistochemistry. The differential diagnosis varies according to the lymphoma subtype and includes reactive conditions, solid tumors, and other hematolymphoid malignancies. Although morphology and immunohistochemistry may be sufficient to establish a diagnosis, in some cases, the best recommendation is to obtain additional tissue via a VATS biopsy/wedge resection with material submitted for flow cytometry, cytogenetics, and/or molecular studies to be able to properly classify a pulmonary lymphoid process.

Children with complete DiGeorge anomaly (cDGA) have congenital athymia, resulting in severe T cell immunodeficiency and susceptibility to a broad range of infections. We report the clinical course, immunologic phenotypes, treatment, and outcomes of three cases of disseminated nontuberculous mycobacterial infections (NTM) in patients with cDGA who underwent cultured thymus tissue implantation (CTTI). Two patients were diagnosed with Mycobacterium avium complex (MAC) and one patient with Mycobacterium kansasii. All three patients required protracted therapy with multiple antimycobacterial agents. One patient, who was treated with steroids due to concern for immune reconstitution inflammatory syndrome (IRIS), died due to MAC infection. Two patients have completed therapy and are alive and well. T cell counts and cultured thymus tissue biopsies demonstrated good thymic function and thymopoiesis despite NTM infection. Based on our experience with these three patients, we recommend that providers strongly consider macrolide prophylaxis upon diagnosis of cDGA. We obtain mycobacterial blood cultures when cDGA patients have fevers without a localizing source. In cDGA patients with disseminated NTM, treatment should consist of at least two antimycobacterial medications and be provided in close consultation with an infectious diseases subspecialist. Therapy should be continued until T cell reconstitution is achieved.

Abstract BackgroundThe high-intensity focused electromagnetic field (HIFEM) procedure is an effective method for noninvasive toning and shaping of buttocks. ObjectivesTo investigate and compare the efficacy of simultaneous application of HIFEM procedure with radiofrequency (RF) heating vs HIFEM standalone procedure on the buttocks. MethodsSixty-seven subjects (21-67 years, BMI 16-34 kg/m2 ResultsData of 32 subjects from group A and 31 subjects from group B were reviewed at 1-month follow-up. On average, subjects from group A showed a 31.3% higher increase in muscle thickness, as shown in the MRI evaluation. The gluteal muscle thickness continued to grow and peaked at a 3-month follow-up, wherein 27 patients were evaluated in each group (n ConclusionsOur results suggest that simultaneous use of HIFEM + RF is safe and significantly more effective for gluteal contouring than the HIFEM procedure alone. Level of Evidence: 2

Abstract Objective Derive and confirm factor structure of the Montgomery‐Åsberg Depression Rating Scale (MADRS) in patients with treatment‐resistant depression (TRD) and evaluate how the factors evident at baseline change over 4 weeks of esketamine treatment. Methods Two similarly‐designed, short‐term TRANSFORM trials randomized adults to esketamine or matching placebo nasal spray, each with a newly‐initiated oral antidepressant, for 4 weeks (TRANSFORM‐1: N = 342 patients; TRANSFORM‐2: N = 223 patients). The factor structure of MADRS item scores at baseline was determined by exploratory factor analysis in TRANSFORM‐2 and corroborated by confirmatory factor analysis in TRANSFORM‐1. Change in MADRS factor scores from baseline (day 1) to the end of the 28‐day double‐blind treatment phase of TRANSFORM‐2 was analyzed using a mixed‐effects model for repeated measures (MMRM). Results Three factors were identified based on analysis of MADRS items: Factor 1 labeled affective and anhedonic symptoms (apparent sadness, reported sadness, lassitude, inability to feel), Factor 2 labeled anxiety and vegetative symptoms (inner tension, reduced sleep, reduced appetite, concentration difficulties), and Factor 3 labeled hopelessness (pessimistic thoughts, suicidal thoughts). The three‐factor structure observed in TRANSFORM‐2 was verified in TRANSFORM‐1. Treatment benefit at 24 h with esketamine versus placebo was observed on all 3 factors and continued throughout the 4‐week double‐blind treatment period. Conclusions A three‐factor structure for MADRS appears to generalize to TRD. All three factors improved over 4 weeks of treatment with esketamine nasal spray.

In July 2021, a PCR-confirmed case of locally acquired Babesia microti infection was reported in Atlantic Canada. Clinical features were consistent with babesiosis and resolved after treatment. In a region where Lyme disease and anaplasmosis are endemic, the occurrence of babesiosis emphasizes the need to enhance surveillance of tickborne infections.

Babesiosis is an emerging infectious disease caused by a zoonotic hemoprotozoan parasite of the genus Babesia, which consists of [approximately equal to]100 species (1-4). Human disease in North America is [...]

Abstract Background The universal nature of the human–companion animal relationship and their shared ticks and tick-borne pathogens offers an opportunity for improving public and veterinary health surveillance. With this in mind, we describe the spatiotemporal trends for blacklegged tick (Ixodes scapularis) submissions from humans and companion animals in Ontario, along with pathogen prevalence. Methods We tested tick samples submitted through passive surveillance (2011–2017) from humans and companion animals for Borrelia burgdorferi, Borrelia miyamotoi, Anaplasma phagocytophilum and Babesia microti. We describe pathogen prevalence in ticks from humans and from companion animals and constructed univariable Poisson and negative binomial regression models to explore the spatiotemporal relationship between the rates of tick submissions by host type. Results During the study, there were 17,230 blacklegged tick samples submitted from humans and 4375 from companion animals. Tick submission rates from companion animals were higher than expected in several public health units (PHUs) lacking established tick populations, potentially indicating newly emerging populations. Pathogen prevalence in ticks was higher in PHUs where established blacklegged tick populations exist. Borrelia burgdorferi prevalence was higher in ticks collected from humans (maximum likelihood estimate, MLE = 17.5%; 95% confidence interval, CI 16.97–18.09%) than from companion animals (9.9%, 95% CI 9.15–10.78%). There was no difference in pathogen prevalence in ticks by host type for the remaining pathogens, which were found in less than 1% of tested ticks. The most common co-infection B. burgdorferi + B. miyamotoi occurred in 0.11% of blacklegged ticks from humans and animals combined. Borrelia burgdorferi prevalence was higher in unengorged (21.9%, 95% CI 21.12–22.65%) than engorged ticks (10.0%, 95% CI 9.45–10.56%). There were no consistent and significant spatiotemporal relationships detected via regression models between the annual rates of submission of each host type. Conclusions While B. burgdorferi has been present in blacklegged ticks in Ontario for several decades, other tick-borne pathogens are also present at low prevalence. Blacklegged tick and pathogen surveillance data can be used to monitor risk in human and companion animal populations, and efforts are under consideration to unite surveillance efforts for the different target populations. Graphic Abstract

The landscape of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostic testing is rapidly evolving. While serology testing has limited diagnostic capacity for acute infection, its role in providing population-based information on positivity rates and informing evidence-based decision making for public health recommendations is increasing. With the global availability of vaccines, there is increasing pressure on clinical laboratories to provide antibody screening and result interpretation for vaccinated and non-vaccinated individuals. Here we present the most up-to-date data on SARS-CoV-2 antibody timelines, including the longevity of antibodies, and the production and detection of neutralizing antibodies. Additionally, we provide practical guidance for clinical microbiology laboratories to both verify commercial serology assays and choose appropriate testing algorithms for their local populations.

The article focuses on the APUS Analog Research Group (AARG) and its research and outreach initiatives within space analog environments. Topics include the evaluation of digital stress measurement tools in analog astronaut missions, the impact of science communication efforts during analog missions, and the development and testing of supply cache systems for extended human exploration on Mars.

Aims: Rat‐associated zoonotic pathogen transmission at the human–wildlife interface is a public health concern in urban environments where Norway rats (Rattus norvegicus) thrive on abundant anthropogenic resources and live in close contact with humans and other animal species. To identify potential factors influencing zoonotic pathogen occurrence in rats, we investigated associations between environmental and sociodemographic factors and Leptospira interrogans and Bartonella spp. infections in rats from Windsor, Ontario, Canada, while controlling for the potential confounding effects of animal characteristics (i.e., sexual maturity and body condition). Methods and Results: Between November 2018 and June 2021, 252 rats were submitted by collaborating pest control professionals. Kidney and spleen samples were collected for L. interrogans and Bartonella spp. PCR and sequencing, respectively. Of the rats tested by PCR, 12.7% (32/252) were positive for L. interrogans and 16.3% (37/227) were positive for Bartonella species. Associations between infection status and environmental and sociodemographic variables of interest were assessed via mixed multivariable logistic regression models with a random intercept for social group and fixed effects to control for sexual maturity and body condition in each model. The odds of L. interrogans infection were significantly higher in rats from areas with high building density (odds ratio [OR]: 3.76; 95% CI: 1.31–10.79; p = 0.014), high human population density (OR: 3.31; 95% CI: 1.20–9.11; p = 0.021), high proportion of buildings built in 1960 or before (OR: 11.21; 95% CI: 2.06–60.89; p = 0.005), and a moderate number of reports of uncollected garbage compared to a low number of reports (OR: 4.88; 95% CI: 1.01–23.63; p = 0.049). A negative association was observed between median household income and Bartonella spp. infection in rats (OR: 0.26; 95% CI: 0.08–0.89; p = 0.031). Conclusions: Due to the complexity of the ecology of rat‐associated zoonoses, consideration of environmental and sociodemographic factors is of critical importance to better understand the nuances of host–pathogen systems and inform how urban rat surveillance and intervention efforts should be distributed within cities. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether there are changes in nerve conduction studies (NCS) of the median nerve after distal radius fracture (DRF) and to determine how operative fixation through a volar approach with a locking plate contributes to nerve conduction changes. We hypothesized that a considerable percentage of patients would have electrodiagnostic evidence of median neuropathy at the wrist after fracture, but fixation with a volar locked plate would not worsen the electrodiagnostic findings. Methods: This was a prospective cohort study of 14 neurologically asymptomatic patients who underwent surgical treatment of an isolated DRF using a volar plate. All patients underwent surgery within 2 weeks of injury. On the day of surgery and at the 6-week follow-up, patients were clinically examined, Quick–Disabilities of the Arm, Shoulder, and Hand questionnaire was completed, and patients underwent NCS using a handheld device with the unaffected limb, which was used as a comparison. Preoperative and postoperative nerve function were compared with the unaffected limb as a baseline. Results: Patients without symptoms after DRF had a 28% incidence of prolonged latencies compared with reference values for the device used. Distal sensory latencies of the median nerve were 3.64 ± 0.32 ms in the unaffected arm, 3.76 ± 0.70 ms before surgery, and 3.81 ± 0.52 ms after surgery. Distal motor latencies of the median nerve were 3.91 ± 0.59, 3.60 ± 0.68, and 3.88 ± 0.36 ms in respective arms and time points. Quick–Disabilities of the Arm, Shoulder, and Hand scores improved from 77 before surgery to 46 at 6 weeks. Conclusions: Asymptomatic patients may satisfy nerve conduction criteria for median neuropathy at the wrist after DRF; however, open reduction and treatment with a volar locked plate has no significant effect on NCS findings. Type of study/level of evidence: Prognostic II.

Abstract Background The current analysis utilized data collected via an online patient community platform, PatientsLikeMe (PLM) to compare patient-reported experiences in patients with major depressive disorder (MDD) with suicidal ideation (MDSI) to those with MDD but without suicidal ideation. Methods PLM members who joined PLM between May-2007 and February-2018 and reported a diagnosis of MDD were included. The MDSI cohort included patients with MDD who reported at least one suicide-related symptom at a severity greater than “none”. Demographics, comorbidities, symptoms, and side-effects were compared between MDSI and MDD cohorts. Factors correlated with suicidal ideation (SI) were determined by a random forest procedure. Results Patients in the MDSI cohort (n = 266) were younger (median age, 36 vs 44 years) with an earlier disease onset (before 30 years, 83% vs 71%), and a longer diagnosis latency (median, 4 vs 2 years) vs patients in the MDD cohort (n = 11,963). Majority of patients were women in both cohorts (73% vs 83%). Median number of psychiatric comorbidities was higher in the MDSI cohort (4 vs 3). Unprompted symptoms (e.g., loneliness, feeling of hopelessness, social anxiety, impulsivity, and self-hating thoughts) were more frequent in the MDSI cohort. Hopelessness, loneliness, anhedonia, social anxiety, and younger age were highly correlated with suicidal ideation. Conclusions This analysis utilized patient-reported data to better understand symptoms, experiences, and characteristics of patients with MDSI compared to patients with MDD. The results identified various risk factors correlated with suicidal ideation that may help guide clinical judgement for patients with MDD who may not voluntarily report suicidal ideation.

Abstract Background Treatment resistant depression (TRD) is common among patients with depression, and is associated with clinical and functional disability. However, the risk and risk factors for being granted disability pension (DP) among patients with TRD have not been investigated. Methods All antidepressant initiators in Sweden with a diagnosis of depression in specialized care were identified in nationwide registers 2006–2013 and followed regarding treatment trials. TRD was defined as the start of a third sequential trial. Patients with TRD who were not on DP (N = 3204) were matched by age, sex, history of depression, calendar year, and time for treatment start with 3204 comparators with depression and ongoing antidepressant treatment. A proportional Cox Regression was performed with DP as outcome, adjusted for various sociodemographic and clinical covariates. Results Compared to the comparison cohort, TRD was associated with a doubled risk for all-cause DP (aHR 2.07; 95%CI 1.83–2.35), DP due to depression (2.28; 1.82–2.85) and to any mental disorder (2.24; 1.95–2.57) but not due to somatic diagnoses (1.25; 0.84–1.86). Among significant risk factors for DP in TRD were female sex, being > 29 years of age, unemployment and a diagnosis of comorbid personality disorder (ICD-10 codes F60.0–9). Conclusion TRD is associated with an elevated risk for DP compared to other patients with depression, with large potential costs for the affected patients and for society. Clinical and therapeutic implications for patients with TRD who are granted DP should be further investigated. Limitation: No clinical data, e.g. type of depression or reason for treatment switch, was available for this study.