EFFects of Exposure and Cognitive behavioral Therapy for chronic BACK pain ("EFFECT-BACK"): study protocol for a randomized controlled trial.

INTRODUCTION: Chronic back pain is a widespread medical condition associated with high socioeconomic costs and increasing prevalence. Despite the advanced implementation of multidisciplinary approaches, providing a satisfactory treatment offer for those affected is often not possible. Exposure therapy (EXP) promises to be an effective and economical form of treatment and in a previous pilot study showed to be superior to cognitive behavioral therapy (CBT) in reducing perceived limitations of movement. The current study aims to further compare the efficacy of both treatment methods and identify those patient groups that particularly benefit from EXP. METHODS: The general objective of this randomized multicenter clinical trial (targeted N = 380) is to improve and expand the range of treatments available to patients with chronic back pain. As the primary objective of the study, two different psychological treatments (EXP and CBT) will be compared. The primary outcome measure is a clinically significant improvement in pain-related impairment, measured by the QPBDS, from baseline to 6-month follow-up. Secondary outcome measures are absolute changes and clinically significant improvements in variables coping, psychological flexibility, depressiveness, catastrophizing, exercise avoidance and fear of exercise, and intensity of pain. Participants are recruited in five psychological and medical centers in Germany and receive ten sessions of manualized therapy by trained licensed CBT therapists or clinical psychologists, who are currently in their post-gradual CBT training. Potential predictors of each treatment's efficacy will be explored with a focus on avoidance and coping behavior. CONCLUSION: This study will be the first RCT to compare CBT and EXP in chronic back pain in a large sample, including patients from different care structures due to psychological and medical recruitment centers. By identifying and exploring potential predictors of symptom improvement in each treatment group, this study will contribute to enable a more individualized assignment to treatment modalities and thus improves the care situation for chronic back pain and helps to create a customized treatment program for subgroups of pain patients. If our findings confirm EXP to be an efficacious and efficient treatment concept, it should gain more attention and be further disseminated. TRIAL REGISTRATION: ClinicalTrials.gov NCT05294081. Registered on 02 March 2022.

Leveraging Single-Case Experimental Designs to Promote Personalized Psychological Treatment: Step-by-Step Implementation Protocol with Stakeholder Involvement of an Outpatient Clinic for Personalized Psychotherapy.

Our objective is to implement a single-case experimental design (SCED) infrastructure in combination with experience-sampling methods (ESM) into the standard diagnostic procedure of a German outpatient research and training clinic. Building on the idea of routine outcome monitoring, the SCED infrastructure introduces intensive longitudinal data collection, individual effectiveness measures, and the opportunity for systematic manipulation to push personalization efforts further. It aims to empower psychotherapists and patients to evaluate their own treatment (idiographic perspective) and to enable researchers to analyze open questions of personalized psychotherapy (nomothetic perspective). Organized around the principles of agile research, we plan to develop, implement, and evaluate the SCED infrastructure in six successive studies with continuous stakeholder involvement: In the project development phase, the business model for the SCED infrastructure is developed that describes its vision in consideration of the context (Study 1). Also, the infrastructure's prototype is specified, encompassing the SCED procedure, ESM protocol, and ESM survey (Study 2 and 3). During the optimization phase, feasibility and acceptability are tested and the infrastructure is adapted accordingly (Study 4). The evaluation phase includes a pilot implementation study to assess implementation outcomes (Study 5), followed by actual implementation using a within-institution A-B design (Study 6). The sustainability phase involves continuous monitoring and improvement. We discuss to what extent the generated data could be used to address current questions of personalized psychotherapy research. Anticipated barriers and limitations during the implementation processes are outlined.

A systematic review of peer support interventions for student mental health and well-being in higher education.

BACKGROUND: Higher education institutions (HEIs) are seeking effective ways to address the rising demand for student mental health services. Peer support is widely considered a viable option to increase service capacity; however, there are no agreed definitions of peer support, making it difficult to establish its impact on student mental health and well-being. AIMS: This systematic review aims to better understand and evaluate peer support in HEIs. METHOD: Five databases, OpenGrey and Grey Matters were searched in May 2021. Included studies were quantitative, longitudinal (with and without a control) or cross-sectional with a control. The vote-counting method was used for synthesis. The risk of bias was assessed with the National Institutes of Health Quality Assessment Tool. RESULTS: Three types of peer support were represented in 28 papers: peer-led support groups, peer mentoring and peer learning. Peer learning and peer mentoring had more positive, significant results reported for the outcomes of anxiety and stress. Peer-led support groups were the only type targeting students with mental health difficulties. CONCLUSIONS: The heterogeneity of measures and outcomes prevents firm conclusions on the effectiveness of peer support for mental health and well-being. Most studies were rated 'poor' or 'fair' in their risk of bias. There is not a solid evidence base for the effectiveness of peer support. Nonetheless, HEIs can use the terminology developed in this review for shared discussions that guide more robust research and evaluation of peer support as an intervention.

Ecological and environmental factors affecting the risk of tick-borne encephalitis in Europe, 2017 to 2021.

BackgroundTick-borne encephalitis (TBE) is a disease which can lead to severe neurological symptoms, caused by the TBE virus (TBEV). The natural transmission cycle occurs in foci and involves ticks as vectors and several key hosts that act as reservoirs and amplifiers of the infection spread. Recently, the incidence of TBE in Europe has been rising in both endemic and new regions.AimIn this study we want to provide comprehensive understanding of the main ecological and environmental factors that affect TBE spread across Europe.MethodsWe searched available literature on covariates linked with the circulation of TBEV in Europe. We then assessed the best predictors for TBE incidence in 11 European countries by means of statistical regression, using data on human infections provided by the European Surveillance System (TESSy), averaged between 2017 and 2021.ResultsWe retrieved data from 62 full-text articles and identified 31 different covariates associated with TBE occurrence. Finally, we selected eight variables from the best model, including factors linked to vegetation cover, climate, and the presence of tick hosts.DiscussionThe existing literature is heterogeneous, both in study design and covariate types. Here, we summarised and statistically validated the covariates affecting the variability of TBEV across Europe. The analysis of the factors enhancing disease emergence is a fundamental step towards the identification of potential hotspots of viral circulation. Hence, our results can support modelling efforts to estimate the risk of TBEV infections and help decision-makers implement surveillance and prevention campaigns.

The Puzzle of Evaluating Moral Cognition in Artificial Agents.

In developing artificial intelligence (AI), researchers often benchmark against human performance as a measure of progress. Is this kind of comparison possible for moral cognition? Given that human moral judgment often hinges on intangible properties like "intention" which may have no natural analog in artificial agents, it may prove difficult to design a "like-for-like" comparison between the moral behavior of artificial and human agents. What would a measure of moral behavior for both humans and AI look like? We unravel the complexity of this question by discussing examples within reinforcement learning and generative AI, and we examine how the puzzle of evaluating artificial agents' moral cognition remains open for further investigation within cognitive science.

Doctors Speak: A Qualitative Study of Physicians' Prescribing of Antidepressants in Functional Bowel Disorders.

Tricyclic antidepressants (TCAs) are frequently prescribed for chronic functional pain disorders. Although the mechanism of action targets pain perception, treating patients with TCAs for disorders conceptualized as "functional" can promote stigmatization in these patients because it hints at psychological dimensions of the disorder. The goal of this study was to understand how physicians prescribe TCAs in the face of this challenge. We interviewed eleven gastroenterologists in tertiary care clinics specializing in functional gastrointestinal disorders, such as irritable bowel syndrome. We found that the physicians interviewed (1) were aware of the stigma attached to taking antidepressants for a medical condition, (2) emphasized biological, as opposed to psychological, mechanisms of action, (3) while focusing on biological mechanisms, they nevertheless prescribed TCAs in a way that is highly attentive to the psychology of expectations, making specific efforts to adjust patients' expectations to be realistic and to reframe information that would be discouraging and (4) asked patients to persist in taking TCAs despite common and, at times, uncomfortable side effects. In this context of shared decision making, physicians described nuanced understanding and behaviours necessary for treating the complexity of functional disorders and emphasized the importance of a strong patient-provider relationship.

No open-label placebo effect in insomnia? Lessons learned from an experimental trial.

BACKGROUND: Open-label placebo (OLP) treatment seems to be effective in several medical conditions but has not yet been investigated in insomnia. Furthermore, it needs to be evaluated whether providing a plausible treatment rationale is essential to obtain OLP effects. METHODS: In two consecutive nights, the sleep of patients with primary insomnia (n = 45) was assessed via subjective and objective measures. Before the second night, they received a single OLP pill that was randomly provided either with a treatment rationale (OLP+) or without (OLP-). When (M)ANOVAs did not reveal differential effects between the two OLP groups, the OLP+ group was compared post-hoc to a formerly assessed no pill control sample (NPC; n = 23). RESULTS: Neither the MANOVAs nor the ANOVAs revealed significant interaction effects of treatment group and assessment night. The OLP+ condition was superior neither to OLP- nor to NPC in improving the patients' sleep. DISCUSSION: Our findings do neither confirm the general efficacy of OLP in primary insomnia nor differential effects depending on the treatment rationale. Possible explanations lie in the dosing scheme (i.e., single OLP application), the provision of the OLP rationale by video and the experimental instead of therapeutic character of our investigation. Trials with larger samples and longer-term OLP treatment in insomnia are needed. Providing the rationale face-to-face and in a clinical setting might be additionally beneficial.

Psychological Predictors of Response to Open-Label Versus Double-Blind Placebo in a Randomized Controlled Trial in Irritable Bowel Syndrome.

OBJECTIVE: There is growing evidence that open-label placebo (OLP) may be an efficacious treatment of chronic and functional conditions. However, patient-level predictors of response to OLP have not been clearly identified. The aim of this study is to evaluate the psychological predictors of response to OLP and to compare this to double-blind placebo (DBP) and no-pill control (NPC). METHODS: This study is a secondary analysis of data collected in a 6-week randomized controlled trial evaluating placebo effects in irritable bowel syndrome (IBS). The primary outcome was change in IBS severity. Hierarchical linear regression identified predictors of placebo response in general and compared them between those randomized to OLP, DBP, and NPC. Predictor variables included personality traits, generalized anxiety, depression, visceral sensitivity (a measure of symptom-specific anxiety), and pain catastrophizing. RESULTS: A total of 210 participants (mean age = 42.3 years, 73.3% female) were included. Regression models revealed that visceral sensitivity was a predictor of response to OLP and NPC but not DBP. Interestingly, the effects were opposite, with high visceral sensitivity predicting less improvement in NPC and more improvement in OLP. Pain catastrophizing was a negative predictor of response to OLP (i.e., high pain catastrophizing was associated with less improvement in OLP). Neither visceral sensitivity nor pain catastrophizing played a significant role for response to DBP. CONCLUSIONS: IBS participants who score low on the Pain Catastrophizing Scale but high on the Visceral Sensitivity Index seem to benefit particularly from OLP. Our study suggests that different psychological mechanisms may be involved in DBP and OLP interventions.

Patients' experiences treated with open-label placebo versus double-blind placebo: a mixed methods qualitative study.

BACKGROUND: There is increasing evidence suggesting that open-label placebo (OLP) is an effective treatment for several medical conditions defined by self-report. However, little is known about patients' experiences with OLP, and no studies have directly compared patients' experiences in double-blind placebo (DBP) conditions. METHODS: This study was nested in a large randomized-controlled trial comparing the effects of OLP and DBP treatments in individuals with irritable bowel syndrome (IBS). We randomly selected 33 participants for interviews concerning their experiences in the parent trial. The data were qualitatively analyzed using an iterative immersion/crystallization approach. We then compared the qualitative interview data to the quantitative IBS severity data assessed during the parent trial, using a mixed methods approach. RESULTS: Two prominent interview themes were identified: (1) the participants' feelings about their treatment allocation and (2) their reflections about the treatment. Both OLP and DBP participants mentioned hope and curiosity as major feelings driving them to engage with their treatment. However, while DBP participants tended to be more enthusiastic about their allocation, OLP participants were more ambivalent. Furthermore, OLP participants reflected more on their treatment, often involving noticeable cognitive and emotional processes of self-reflection. They offered a variety of explanations for their symptom improvement and were significantly less likely to attribute it to the treatment itself than DBP participants (Χ2 [3] = 8.28; p = .041). Similarly, the participants' retrospective narratives of symptom improvement were significantly correlated with their corresponding quantitative IBS severity scores only in DBP (p's ≤ .006) but not in OLP (p's ≥ .637). CONCLUSION: OLP and DBP participants share feelings of hope, uncertainty and curiosity but differ in the extent of conscious reflection. The counter-intuitive OLP prompts more self-examination, ambivalent feelings and active engagement compared to DBP. At the same time, OLP participants are more reluctant to attribute symptom improvement to their treatment. Our findings substantially add to the emerging picture of factors that distinguish OLP and DBP and their potential mechanisms.

Frequency of Adverse Events in the Placebo Arms of COVID-19 Vaccine Trials: A Systematic Review and Meta-analysis.

Importance: Adverse events (AEs) after placebo treatment are common in randomized clinical drug trials. Systematic evidence regarding these nocebo responses in vaccine trials is important for COVID-19 vaccination worldwide especially because concern about AEs is reported to be a reason for vaccination hesitancy. Objective: To compare the frequencies of AEs reported in the placebo groups of COVID-19 vaccine trials with those reported in the vaccine groups. Data Sources: For this systematic review and meta-analysis, the Medline (PubMed) and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched systematically using medical subheading terms and free-text keywords for trials of COVID-19 vaccines published up to July 14, 2021. Study Selection: Randomized clinical trials of COVID-19 vaccines that investigated adults aged 16 years or older were selected if they assessed solicited AEs within 7 days of injection, included an inert placebo arm, and provided AE reports for both the vaccine and placebo groups separately. Full texts were reviewed for eligibility by 2 independent reviewers. Data Extraction and Synthesis: Data extraction and quality assessment were performed independently by 2 reviewers, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline and using the Cochrane risk-of-bias tool. Meta-analyses were based on random-effects models. Main Outcomes and Measures: The primary outcomes were the proportions of placebo recipients reporting overall, systemic, and local (injection-site) AEs as well as logarithmic odds ratios (ORs) to evaluate group differences. Outcomes were tested for significance using z tests with 95% CIs. Results: Twelve articles with AE reports for 45 380 participants (22 578 placebo recipients and 22 802 vaccine recipients) were analyzed. After the first dose, 35.2% (95% CI, 26.7%-43.7%) of placebo recipients experienced systemic AEs, with headache (19.3%; 95% CI, 13.6%-25.1%) and fatigue (16.7%; 95% CI, 9.8%-23.6%) being most common. After the second dose, 31.8% (95% CI, 28.7%-35.0%) of placebo recipients reported systemic AEs. The ratio between placebo and vaccine arms showed that nocebo responses accounted for 76.0% of systemic AEs after the first COVID-19 vaccine dose and for 51.8% after the second dose. Significantly more vaccine recipients reported AEs, but the group difference for systemic AEs was small after the first dose (OR, -0.47; 95% CI, -0.54 to -0.40; P < .001; standardized mean difference, -0.26; 95% CI, -0.30 to -0.22) and large after the second dose (OR, -1.36; 95% CI, -1.86 to -0.86; P < .001; standardized mean difference, -0.75; 95% CI, -1.03 to -0.47). Conclusions and Relevance: In this systematic review and meta-analysis, significantly more AEs were reported in vaccine groups compared with placebo groups, but the rates of reported AEs in the placebo arms were still substantial. Public vaccination programs should consider these high rates of AEs in placebo arms.

Norway spruce deploys tissue-specific responses during acclimation to cold.

Climate change in the conifer-dominated boreal forest is expected to lead to warmer but more dynamic winter air temperatures, reducing the depth and duration of snow cover and lowering winter soil temperatures. To gain insight into the mechanisms that have enabled conifers to dominate extreme cold environments, we performed genome-wide RNA-Seq analysis from needles and roots of non-dormant two-year Norway spruce (Picea abies (L.) H. Karst), and contrasted these response to herbaceous model Arabidopsis We show that the main transcriptional response of Norway spruce needles exposed to cold was delayed relative to Arabidopsis, and this delay was associated with slower development of freezing tolerance. Despite this difference in timing, Norway spruce principally utilizes early response transcription factors (TFs) belonging to the same gene families as Arabidopsis, indicating broad evolutionary conservation of cold response networks. In keeping with their different metabolic and developmental states, needles and root of Norway spruce showed contrasting results. Regulatory network analysis identified both conserved TFs with known roles in cold acclimation (e.g. homologs of ICE1, AKS3, and of the NAC and AP2/ERF superfamilies), but also a root-specific bHLH101 homolog, providing functional insights into cold stress response strategies in Norway spruce.

The effect of patient-centered communication on medication intake: an experimental study.

It is not only crucial to provide patients with information, but also to communicate this information in a way to enable patient participation in health decisions. Experimental studies investigating the association between the communication style of health professionals and patients' health decisions are rare, which limits causal conclusions. This study investigated the effect of a doctor's patient-centered communication style on the likelihood to take a medication.Healthy women (N = 120) were randomly allocated to one of three groups. They either received a medical consultation characterized by a patient-centered communication style (PC group) or by a doctor-centered communication style (DC group) or they received no consultation at all (control group). All participants were told that the study would investigate the effects of a 'concentration-enhancing medication'. Voluntary intake of the medication (a placebo pill) served as behavioral outcome. Participants' self-rated intention to take the medication was measured at three assessment points. Data were analyzed using a Chi-square-test and a mixed analysis of covariance.In each group, 40 participants were analyzed. Following the consultation, groups did not differ regarding the behavioral outcome, but participants' intention to take the medication was higher in the PC group compared with the control group.Our results indicate that patient-centered communication has a beneficial influence on participants' intention to take medication. Future studies should investigate the role of communication in individuals with health conditions that require a specified treatment plan and taking medication over the long-term.

Placebo nasal spray protects female participants from experimentally induced sadness and concomitant changes in autonomic arousal.

BACKGROUND: To investigate the powerful placebo effects in antidepressant drug trials and their mechanisms, recent pioneering experimental studies showed that expectation manipulation combined with an active placebo attenuated induced sadness. In the present study, we aimed at extending these findings by assessing the psychophysiological response in addition to mere self-report. METHODS: One hundred and thirteen healthy female students were randomly assigned to a drug expectation group (active placebo, positive treatment expectation), placebo expectation group (active placebo, no treatment expectation), or a no-treatment group (no placebo, no treatment expectation). After placebo intake, sadness was induced by self-deprecating statements using the Velten method combined with sad music, including a rumination phase. Sadness was measured using the Positive and Negative Affect Schedule Expanded Form (PANAS-X). Heart rate and skin conductance were assessed continuously. RESULTS: After mood induction and after rumination, self-reported sadness was significantly lower, and skin conductance level was significantly higher, in the drug expectation group than in the no-treatment group. The mood induction was further accompanied by a heart rate deceleration within all groups. LIMITATIONS: Generalizability is limited by sample selectivity and focusing on sadness as a symptom of depression, exclusively. CONCLUSION: Expectation-induced placebo effects significantly influenced sadness-correlated changes in autonomic arousal, and not only subjectively reported sadness, indicating that placebo effects in the context of affect are not merely due to subjective response bias. The systematic modification of treatment expectation could be utilized in clinical practice to optimize current therapeutic approaches to improve mood regulation.

Candidate regulators and target genes of drought stress in needles and roots of Norway spruce.

Drought stress impacts seedling establishment, survival and whole-plant productivity. Molecular responses to drought stress have been most extensively studied in herbaceous species, mostly considering only aboveground tissues. Coniferous tree species dominate boreal forests, which are predicted to be exposed to more frequent and acute drought as a result of ongoing climate change. The associated impact at all stages of the forest tree life cycle is expected to have large-scale ecological and economic impacts. However, the molecular response to drought has not been comprehensively profiled for coniferous species. We assayed the physiological and transcriptional response of Picea abies (L.) H. Karst seedling needles and roots after exposure to mild and severe drought. Shoots and needles showed an extensive reversible plasticity for physiological measures indicative of drought-response mechanisms, including changes in stomatal conductance (gs), shoot water potential and abscisic acid (ABA). In both tissues, the most commonly observed expression profiles in response to drought were highly correlated with the ABA levels. Still, root and needle transcriptional responses contrasted, with extensive root-specific down-regulation of growth. Comparison between previously characterized Arabidopsis thaliana L. drought-response genes and P. abies revealed both conservation and divergence of transcriptional response to drought. In P. abies, transcription factors belonging to the ABA responsive element(ABRE) binding/ABRE binding factors ABA-dependent pathway had a more limited role. These results highlight the importance of profiling both above- and belowground tissues, and provide a comprehensive framework to advance the understanding of the drought response of P. abies. The results demonstrate that a short-term, severe drought induces severe physiological responses coupled to extensive transcriptome modulation and highlight the susceptibility of Norway spruce seedlings to such drought events.

Open-Label Placebo Treatment: Outcome Expectations and General Acceptance in the Lay Population.

BACKGROUND: Most physicians sometimes apply therapies without specific active ingredients. Although patients seem to judge such placebo treatments as acceptable under certain circumstances, deception is still an ethical problem. Open-label placebos (OLPs) might be a promising approach to solve this dilemma. This study compared general acceptance and outcome expectations of OLPs and deceptive placebos (DPs). METHODS: In an experimental online study, 814 participants read a case vignette of a person with insomnia receiving a pill. The participants were then randomly allocated into two groups, where the second part of the vignette described the pill as either a deceptive placebo (DP group) or as an open-label placebo (OLP group). The Credibility/Expectancy Questionnaire (CEQ) assessed outcome expectations after the first (pre-assessment) and the second (post-assessment) parts of the vignette. Treatment acceptance was measured at post-assessment. Data from 798 participants were analyzed by a mixed multivariate analysis of variance (MANOVA), t-tests, and post-hoc mediation analyses. RESULTS: The MANOVA revealed a significant group main effect and a significant time × group interaction effect. At post-assessment, outcome expectations were higher in the DP group than in the OLP group. Acceptance of the placebo treatment was also higher in the DP group than in the OLP group. Mediation analyses confirmed that higher acceptance in the DP group was mediated by higher expectations. CONCLUSIONS: When laypersons read about placebo treatment, their outcome expectations toward DPs were higher than toward OLPs. Surprisingly, the application of DPs was rated as more acceptable than OLPs. This result might be explained by indirect effects of treatment expectations.

Expectation-induced placebo effect on acute sadness in women with major depression: An experimental investigation.

BACKGROUND: Meta-analyses demonstrate that placebo effects play an important role in antidepressant treatment. Expectations seem to constitute a highly relevant placebo mechanism in this context. This study investigated whether an expectation manipulation combined with the intake of an active placebo could reduce acute sadness in depressed participants following a sadness-inducing mood manipulation. METHODS: Women who suffered from a major depressive episode (N = 94) were randomly allocated to the drug expectation group (expectation to receive a fast-operating antidepressant), the placebo expectation group (expectation to receive a placebo) or the no treatment group (no expectation, no placebo). The drug expectation and the placebo expectation group received a placebo. All participants watched a sadness-inducing film. Sadness was assessed at baseline, after randomization and after placebo intake and mood induction. Data were analyzed by a 3 × 3 analysis of variance. RESULTS: There were significant between-group differences in sadness change from the baseline after mood induction. While sadness increased in the no treatment group, it did not change in the placebo expectation group. In the drug expectation group, sadness even decreased. LIMITATIONS: Only a single medication intake was simulated. Effects on acute sadness do not allow inferences about depression symptoms. CONCLUSION: This experimental study found a placebo effect on sadness in clinically depressed participants. The effects were even larger than expected. Future research must investigate placebo effects on depression symptoms as well as long-term placebo intake.

Holistic resource-rational analysis.

We argue that Lieder and Griffiths' method for analyzing rational process models cannot capture an important constraint on resource allocation, which is competition between different processes for shared resources (Klein 2018, Biology and Philosophy33:36). We suggest that holistic interactions between processes on at least three different timescales - episodic, developmental, and evolutionary - must be taken into account by a complete resource-bounded explanation.

Valuation mechanisms in moral cognition.

May cites a body of evidence suggesting that participants take consequences, personal harm, and other factors into consideration when making moral judgments. This evidence is used to support the conclusion that moral cognition relies on rule-based inference. This commentary defends an alternative interpretation of this evidence, namely, that it can be explained in terms of domain general valuation mechanisms.

Discovery of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates: novel and highly selective aggrecanase inhibitors.

Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A series of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, and orally bioavailable aggrecanase inhibitors. These compounds have unique P1' groups comprising novel piperidine- or piperazine-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1' groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1' portion of 1,2,3,4-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.