Activation of human STING by a molecular glue-like compound.

Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING. Our cryo-EM structures show that NVS-STG2 induces the high-order oligomerization of human STING by binding to a pocket between the transmembrane domains of the neighboring STING dimers, effectively acting as a molecular glue. Our functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models.

Mitigating inequity: ethically prioritizing patients for CAR T-cell therapy.

Manufacturing capacity and institutional infrastructure to deliver chimeric antigen receptor T-cell therapies (CAR-T) are pressured to keep pace with the growing number of approved products and expanding eligible patient population for this potentially life-saving therapy. Consequently, many cell therapy programs must make difficult decisions about which patient should get the next available treatment slot. This situation requires an ethical framework to ensure fair and equitable decision-making. In this perspective, we discuss the application of Accountability for Reasonableness (A4R), a priority-setting framework grounded in procedural justice, to the problem of limited CAR-T slots at our institution. We formed a multidisciplinary working group spanning several hematological malignancies. Through multiple rounds of partner engagement, we used A4R guiding principles to identify 4 main criteria to prioritize patients for CAR-T: medical benefit, safety/risk of complications, psychosocial factors, and medical urgency. Associated measures/tools and an implementation process were developed. We discuss further how ethical principles of fairness and equity demand a consistent approach within health systems that does not disadvantage medically underserved or underrepresented populations and supports overcoming barriers to care. In our commitment to transparency and collaboration, we make our tools available to others, ideally to be used to engage in their own A4R process, adapting the tools to their unique environments. Our hope is that our preliminary work will support the advancement of further study in this area globally, aiming for justice in resource allocation for all potential CAR-T candidates, wherever they may seek care.

A 15% Trichloroacetic Acid + 3% Glycolic Acid Chemical Peel Series Improves Appearance of Hand Lentigines: An Evaluator-Blinded, Split-Hand Prospective Trial.

BACKGROUND: Improving the appearance of lentigines on the hands is a key component to hand rejuvenation. Soft tissue fillers revolumize hands, but do not address pigmentary changes. OBJECTIVE: This study investigated the effiacy of a 15% trichloroacetic acid (TCA) + 3% glycolic acid (GA) combination peel in improvement of appearance of hand lentigines. METHODS: A prospective evaluator-blinded, split-hand study was performed using a 15% TCA + 3% GA peel to treat patients with hand lentigines. Subjects received a total of 3 treatments at 4-week intervals on 1 hand, with the other hand serving as an untreated control. Final photographs were taken 12 weeks after the last treatment. Two blinded board-certified dermatologists graded improvement in hand lentigines using a 5-point scale. RESULTS: Eighteen of 20 patients completed the study (90%). The mean age was 64.4 years (SE 1.6, range 51-71). The mean pain scores were 3.8 (SE 0.4) on a 10-point scale (1 = no pain, 10 = extremely painful). Blinded evaluators correctly identified the after-treatment photographs in 16 patients (88%). Physician and patient-graded mean improvement of lentigines was significant for treated versus control hands ( p < .01). No adverse events were noted. CONCLUSION: A series of three 15% TCA + 3% GA peels are effective and safe in the treatment of hand lentigines.

Personal Actions to Create a Culture of Inclusion: Navigating Difficult Conversations With Medical Colleagues.

Microaggressions between members of a team occur often in medicine, even despite good intentions. Such situations call for difficult conversations that restore inclusivity, diversity, and a healthy work culture. These conversations are often hard because of the unique background, experiences, and biases of each person. In medicine, skillful navigation of these interactions is paramount as it influences patient care and the workplace culture. Although much has been published about difficult interactions between providers and patients, significantly less information is available to help navigate provider-to-provider interactions, despite their critical role in improving multidisciplinary patient care teams and organizational environments. This article is intended to serve as a guide for medical professionals who are interested in taking personal responsibility for promoting a safe and inclusive culture by engaging in and modeling difficult conversations with colleagues. The article outlines important considerations to assist with intentional preparation and modulation of responses for all parties involved: conversation initiators, observers of the incident, and conversation receivers. Although these interactions are challenging, together as medical professionals we can approach each other with humility and compassion to achieve our ultimate goal of promoting humanity, not only for our patients but for ourselves and one another.

Daily Rapid Antigen Exit Testing to Tailor University COVID-19 Isolation Policy.

We evaluated daily rapid antigen test (RAT) data from 323 COVID-19-positive university students in Connecticut, USA, during an Omicron-dominant period. Day 5 positivity was 47% for twice-weekly screeners and 26%-28% for less-frequent screeners, approximately halving each subsequent day. Testing negative >10 days before diagnosis (event time ratio (ETR) 0.85 [95% CI 0.75-0.96]) and prior infection >90 days (ETR 0.50 [95% CI 0.33-0.76]) were significantly associated with shorter RAT positivity duration. Symptoms before or at diagnosis (ETR 1.13 [95% CI 1.02-1.25]) and receipt of 3 vaccine doses (ETR 1.20 [95% CI 1.04-1.39]) were significantly associated with prolonged positivity. Exit RATs enabled 53%-74% of students to leave isolation early when they began isolation at the time of the first positive test, but 15%-22% remained positive beyond the recommended isolation period. Factors associated with RAT positivity duration should be further explored to determine relationships with infection duration.

Once weekly selinexor, carfilzomib and dexamethasone in carfilzomib non-refractory multiple myeloma patients.

BACKGROUND: Proteasome inhibitors (PIs), including carfilzomib, potentiate the activity of selinexor, a novel, first-in-class, oral selective inhibitor of nuclear export (SINE) compound, in preclinical models of multiple myeloma (MM). METHODS: The safety, efficacy, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of selinexor (80 or 100 mg) + carfilzomib (56 or 70 mg/m2) + dexamethasone (40 mg) (XKd) once weekly (QW) was evaluated in patients with relapsed refractory MM (RRMM) not refractory to carfilzomib. RESULTS: Thirty-two patients, median prior therapies 4 (range, 1-8), were enrolled. MM was triple-class refractory in 38% of patients and 53% of patients had high-risk cytogenetics del(17p), t(4;14), t(14;16) and/or gain 1q. Common treatment-related adverse events (all/Grade 3) were thrombocytopenia 72%/47% (G3 and G4), nausea 72%/6%, anaemia 53%/19% and fatigue 53%/9%, all expected and manageable with supportive care and dose modifications. MTD and RP2D were identified as selinexor 80 mg, carfilzomib 56 mg/m2, and dexamethasone 40 mg, all QW. The overall response rate was 78% including 14 (44%) ≥ very good partial responses. Median progression-free survival was 15 months. CONCLUSIONS: Weekly XKd is highly effective and well-tolerated. These data support further investigation of XKd in patients with MM.

Kinetics of response to first- and second-line therapies in multiple myeloma: Assessment by both M-spikes and light chains.

OBJECTIVES: The prognostic value of kinetics of response to multiple myeloma (MM) therapy is controversial. We aimed to expand the knowledge on this topic by reviewing the kinetics of response to both first- and second-line MM therapy, utilizing a homogeneously treated cohort and analyzing separately both M-spike and light chain (LC) responses for each patient. METHODS: We reviewed all patients who received first-line cyclophosphamide, bortezomib and dexamethasone induction followed by autologous transplant with melphalan and lenalidomide maintenance in our center between 2007 and 2019. RESULTS: Analyzing 360 patients, we observed no correlation between response kinetics to first- versus second-line therapy at the individual patient level. Time to best response to first-line therapy was not a predictor of outcome; however, longer time to best response was highly predictive of a favorable outcome in the second-line setting, independent of other factors. Patients with IgA-MM cleared their M-spike faster than IgG-MM, probably reflecting different half-lives of these isotypes rather than disease biology, as the clearance of LC in both subtypes was similar. CONCLUSIONS: Analyzing both M-spike and LC responses in a homogenously treated cohort, we identified important insights regarding the prognostic value of kinetic patterns. Prospective analysis may shed more light on unsolved questions.

Clinical significance of clonal hematopoiesis in the setting of autologous stem cell transplantation for lymphoma.

Autologous stem cell transplantation (ASCT) remains a key therapeutic strategy for treating patients with relapsed or refractory non-Hodgkin and Hodgkin lymphoma. Clonal hematopoiesis (CH) has been proposed as a major contributor not only to the development of therapy-related myeloid neoplasms but also to inferior overall survival (OS) in patients who had undergone ASCT. Herein, we aimed to investigate the prognostic implications of CH after ASCT in a cohort of 420 lymphoma patients using ultra-deep, highly sensitive error-correction sequencing. CH was identified in the stem cell product samples of 181 patients (43.1%) and was most common in those with T-cell lymphoma (72.2%). The presence of CH was associated with a longer time to neutrophil and platelet recovery. Moreover, patients with evidence of CH had inferior 5-year OS from the time of first relapse (39.4% vs. 45.8%, p = .043) and from the time of ASCT (51.8% vs. 59.3%, p = .018). The adverse prognostic impact of CH was not due to therapy-related myeloid neoplasms, the incidence of which was low in our cohort (10-year cumulative incidence of 3.3% vs. 3.0% in those with and without CH, p = .445). In terms of specific-gene mutations, adverse OS was mostly associated with PPM1D mutations (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.13-2.67, p = .011). In summary, we found that CH is associated with an increased risk of non-lymphoma-related death after ASCT, which suggests that lymphoma survivors with CH may need intensified surveillance strategies to prevent and treat late complications.

Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.

The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS­ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 µM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS­ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.

Effect of patient characteristics on posttraumatic stress disorder treatment retention among veterans: A systematic review.

To identify baseline patient characteristics (i.e., demographic and psychological factors, military background) associated with better posttraumatic stress disorder (PTSD) treatment retention among veterans, we conducted a systematic review. After an electronic database search for studies of PTSD treatment in veterans, two reviewers independently screened the literature for eligibility, abstracted study-level information, and assessed risk of bias. As most studies used multivariate models to assess multiple potential predictors of retention simultaneously, the results were described narratively. The GRADE approach, adapted for prognostic literature, was used to assess the overall quality of evidence (QoE). In total, 19 studies reported in 25 publications met the inclusion criteria (n = 6 good quality, n = 9 fair quality, n = 4 poor quality). Definitions of treatment completion and dropout varied, and some studies lumped different therapy approaches together. Older age and higher treatment expectations were associated with better retention (moderate QoE). In 5 of 6 studies, baseline PTSD severity was not associated with retention, and the remaining study reported an association between better retention and more severe PTSD symptoms; the presence of more co-occurring psychiatric disorders was associated with better retention (moderate QoE). QoE was low or insufficient to support conclusions for any other characteristics due to inconsistent results, imprecision, potential publication bias, possible study population overlap, study limitations, or lack of studies. More research is needed regarding the associations between modifiable factors (e.g., motivation, barriers, expectations) and retention, and consistent definitions of treatment completion and minimally adequate treatment should be adopted throughout the field.

Magnetic Resonance Imaging Radiomics-Based Machine Learning Prediction of Clinically Significant Prostate Cancer in Equivocal PI-RADS 3 Lesions.

BACKGROUND: While Prostate Imaging Reporting and Data System (PI-RADS) 4 and 5 lesions typically warrant prostate biopsy and PI-RADS 1 and 2 lesions may be safely observed, PI-RADS 3 lesions are equivocal. PURPOSE: To construct and cross-validate a machine learning model based on radiomics features from T2 -weighted imaging (T2 WI) of PI-RADS 3 lesions to identify clinically significant prostate cancer (csPCa), that is, pathological Grade Group ≥ 2. STUDY TYPE: Single-center retrospective study. POPULATION: A total of 240 patients were included (training cohort, n = 188, age range 43-82 years; test cohort, n = 52, age range 41-79 years). Eligibility criteria were 1) magnetic resonance imaging (MRI)-targeted biopsy between 2015 and 2020; 2) PI-RADS 3 index lesion identified on multiparametric MRI; (3) biopsy performed within 1 year of MRI. The percentages of csPCa lesions were 10.6% and 15.4% in the training and test cohorts, respectively. FIELD STRENGTH/SEQUENCE: A 3 T; T2 WI turbo-spin echo, diffusion-weighted spin-echo echo planar imaging, dynamic contrast-enhanced MRI with time-resolved T1-weighted imaging. ASSESSMENT: Multislice volumes-of-interest (VOIs) were drawn in the PI-RADS 3 index lesions on T2 WI. A total of 107 radiomics features (first-order histogram and second-order texture) were extracted from the segmented lesions. STATISTICAL TESTS: A random forest classifier using the radiomics features as input was trained and validated for prediction of csPCa. The performance of the machine learning classifier, prostate specific antigen (PSA) density, and prostate volume for csPCa prediction was evaluated using receiver operating characteristic (ROC) analysis. RESULTS: The trained random forest classifier constructed from the T2 WI radiomics features good and statistically significant area-under-the-curves (AUCs) of 0.76 (P = 0.022) for prediction of csPCa in the test set. Prostate volume and PSA density showed moderate and nonsignificant performance (AUC 0.62, P = 0.275 and 0.61, P = 0.348, respectively) for csPCa prediction in the test set. CONCLUSION: The machine learning classifier based on T2 WI radiomic features demonstrated good performance for prediction of csPCa in PI-RADS 3 lesions. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: 2.

Weekly carfilzomib plus cyclophosphamide and dexamethasone in the treatment of relapsed/refractory multiple myeloma: Final results from the MCRN-003/MYX.1 single arm phase II trial.

The MCRN-003/CCTGMYX.1 is a single arm phase II trial of weekly carfilzomib, cyclophosphamide and dexamethasone (wKCd), exploring a convenient immunomodulator (IMiD)-free regimen in relapsed myeloma. Weekly carfilzomib (20/70 mg/m2 ), dexamethasone 40 mg and cyclophosphamide 300 mg/m2 was delivered over 28-day cycles. The primary endpoint was overall response after four cycles. Secondary endpoints included toxicity, response depth, PFS and OS. Exploratory endpoints included the impact of cytogenetics, prior therapy exposure and serum free light chain (sFLC) escape; 76 patients were accrued. The ORR was 85% (68% ≥very good partial response [VGPR] and 29% ≥complete response [CR]). The median OS and PFS were 27 and 17 months respectively. High-risk cytogenetics conferred a worse ORR (75% vs. 97%, p = .013) and median OS (18 months vs. NR, p = .002) with a trend toward a worse median PFS (14 vs. 22 months, p = .06). Prior proteasome inhibitor (PI) or lenalidomide did not influence OS or PFS. The sFLC was noted in 15% of patients with a median PFS of 17 months when included as a progression event. The most common ≥ grade 3 non-hematologic adverse events were infectious (40%), vascular (17%) and cardiac (15%). The wKCD is a safe and effective regimen in relapse, especially for patients ineligible for lenalidomide-based therapies.

Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma.

Selinexor is an oral inhibitor of the nuclear export protein exportin 1. Preclinical studies demonstrated synergistic antimyeloma activity between selinexor and proteasome inhibitors (PI) through suppression of NF-κB signaling and nuclear retention of tumor suppressor proteins. We tested selinexor in combination with low-dose bortezomib and dexamethasone (SVd) for the treatment of relapsed or refractory multiple myeloma (MM). The primary objectives of this study were to determine the safety profile, overall response rate (ORR), and a recommended phase 2 dose (RP2D) of SVd. We enrolled 42 patients to receive selinexor (60, 80, or 100 mg orally) plus bortezomib (1.3 mg/m2 subcutaneously) and dexamethasone (20 mg orally) once or twice weekly in 21- or 35-day cycles. Patients had a median of 3 (range 1-11) prior lines of therapy, and 50% were refractory to a PI. Treatment-related grade 3 or 4 adverse events reported in ≥10% of patients were thrombocytopenia (45%), neutropenia (24%), fatigue (14%), and anemia (12%). Incidence (4 patients, 10%) and grade (≤2) of peripheral neuropathy were low. The ORR for the entire population was 63%: 84% ORR for PI nonrefractory and 43% for PI-refractory patients. The median progression-free survival for all patients was 9.0 months; 17.8 months for PI nonrefractory, and 6.1 months for PI refractory. SVd treatment produced high response rates in patients with relapsed or refractory MM, including borezomib-refractory MM, with no unexpected side effects. The RP2D is selinexor (100 mg once weekly), bortezomib (1.3 mg/m2 once weekly for 4 weeks), and dexamethasone (40 mg once weekly) per 35-day cycle. This trial was registered at www.clinicaltrials.gov as #NCT02343042.

Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia.

Novel therapies are needed for patients with relapsed or refractory multiple myeloma (MM). We conducted a multicenter, phase 1 study in advanced hematological malignancies to assess the safety, efficacy, and recommended phase 2 dose (RP2D) of oral selinexor, a selective inhibitor of the nuclear export protein XPO1. In the dose-escalation phase, 25 patients with heavily pretreated MM (22) or Waldenstrom macroglobulinemia (3) were administered selinexor (3-60 mg/m2) in 8 or 10 doses per 28-day cycle. In the dose-expansion phase, 59 patients with MM received selinexor at 45 or 60 mg/m2 with 20 mg dexamethasone, twice weekly in 28-day cycles, or selinexor (40 or 60 mg flat dose) without corticosteroids in 21-day cycles. The most common nonhematologic adverse events (AEs) were nausea (75%), fatigue (70%), anorexia (64%), vomiting (43%), weight loss (32%), and diarrhea (32%), which were primarily grade 1 or 2. The most common grade 3 or 4 AEs were hematologic, particularly thrombocytopenia (45%). Single-agent selinexor showed modest efficacy with an objective response rate (ORR) of 4% and clinical benefit rate of 21%. In contrast, the addition of dexamethasone increased the ORR with all responses of ≥partial response occurring in the 45 mg/m2 selinexor plus 20 mg dexamethasone twice weekly cohort (ORR = 50%). Furthermore, 46% of all patients showed a reduction in MM markers from baseline. Based on these findings, we conclude that selinexor in combination with dexamethasone is active in heavily pretreated MM and propose a RP2D of 45 mg/m2 (80 mg) plus 20 mg dexamethasone given twice weekly. This trial was registered at clinicaltrials.gov as #NCT01607892.

Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma.

This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ≥60 months' follow-up). Patients were randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an ≈30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as #NCT00689936 and EudraCT as 2007-004823-39.

Nature and Predictors of Response Changes in Modified-Delphi Panels.

OBJECTIVES: To describe the extent and nature of changes in participants' responses after exposure to group feedback and discussion in modified-Delphi panels and to identify factors affecting those changes. METHODS: We analyzed data from 2 online modified-Delphi panels, each consisting of 2 rating rounds and an online discussion round. We included responses from 55 participants who answered 38 questions in both rating rounds. Because not all participants answered each question twice, our sample consisted of 1846 cases (response changes). We used mixed-effect logistic and multinomial logistic regression to identify factors predicting response changes and their direction relative to group median-our consensus measure. RESULTS: Participants changed, on average, 49% of their responses. A response was changed in 47% of the 1846 cases: 28% of responses were changed toward consensus and 19% away from it. Although some measures of subjective participation experiences had a marginally significant impact on the propensity and direction of response changes, several objective measures of discussion engagement were statistically significant predictors of both the presence and direction of response changes. CONCLUSION: Our results illustrate the nature of response changes and highlight the importance of exposing participants to alternative perspectives and encouraging them to explain their perspectives.

Transaldolase inhibition impairs mitochondrial respiration and induces a starvation-like longevity response in Caenorhabditis elegans.

Mitochondrial dysfunction can increase oxidative stress and extend lifespan in Caenorhabditis elegans. Homeostatic mechanisms exist to cope with disruptions to mitochondrial function that promote cellular health and organismal longevity. Previously, we determined that decreased expression of the cytosolic pentose phosphate pathway (PPP) enzyme transaldolase activates the mitochondrial unfolded protein response (UPRmt) and extends lifespan. Here we report that transaldolase (tald-1) deficiency impairs mitochondrial function in vivo, as evidenced by altered mitochondrial morphology, decreased respiration, and increased cellular H2O2 levels. Lifespan extension from knockdown of tald-1 is associated with an oxidative stress response involving p38 and c-Jun N-terminal kinase (JNK) MAPKs and a starvation-like response regulated by the transcription factor EB (TFEB) homolog HLH-30. The latter response promotes autophagy and increases expression of the flavin-containing monooxygenase 2 (fmo-2). We conclude that cytosolic redox established through the PPP is a key regulator of mitochondrial function and defines a new mechanism for mitochondrial regulation of longevity.

The Rehabilitation Treatment Specification System: Implications for Improvements in Research Design, Reporting, Replication, and Synthesis.

Despite significant advances in measuring the outcomes of rehabilitation interventions, little progress has been made in specifying the therapeutic ingredients and processes that cause measured changes in patient functioning. The general approach to better clarifying the process of treatment has been to develop reporting checklists and guidelines that increase the amount of detail reported. However, without a framework instructing researchers in how to describe their treatment protocols in a manner useful to or even interpretable by others, requests for more detail will fail to improve our understanding of the therapeutic process. In this article, we describe how the Rehabilitation Treatment Specification System (RTSS) provides a theoretical framework that can improve research intervention reporting and enable testing and refinement of a protocol's underlying treatment theories. The RTSS framework provides guidance for researchers to explicitly state their hypothesized active ingredients and targets of treatment as well as for how the individual ingredients in their doses directly affect the treatment targets. We explain how theory-based treatment specification has advantages over checklist approaches for intervention design, reporting, replication, and synthesis of evidence in rehabilitation research. A complex rehabilitation intervention is used as a concrete example of the differences between an RTSS-based specification and the Template for Intervention Description and Replication checklist. The RTSS's potential to advance the rehabilitation field can be empirically tested through efforts to use the framework with existing and newly developed treatment protocols.

The Importance of Voluntary Behavior in Rehabilitation Treatment and Outcomes.

Most rehabilitation treatments are volitional in nature, meaning that they require the patient's active engagement and effort. Volitional treatments are particularly challenging to define in a standardized fashion, because the clinician is not in complete control of the patient's role in enacting these treatments. Current recommendations for describing treatments in research reports fail to distinguish between 2 fundamentally different aspects of treatment design: the selection of treatment ingredients to produce the desired functional change and the selection of ingredients that will ensure the patient's volitional performance. The Rehabilitation Treatment Specification System (RTSS) is a conceptual scheme for standardizing the way that rehabilitation treatments are defined by all disciplines across all areas of rehabilitation. The RTSS highlights the importance of volitional behavior in many treatment areas and provides specific guidance for how volitional treatments should be specified. In doing so, it suggests important crosscutting research questions about the nature of volitional behavior, factors that make it more or less likely to occur, and ingredients that are most effective in ensuring that patients perform desired treatment activities.

A Theory-Driven System for the Specification of Rehabilitation Treatments.

The field of rehabilitation remains captive to the black-box problem: our inability to characterize treatments in a systematic fashion across diagnoses, settings, and disciplines, so as to identify and disseminate the active ingredients of those treatments. In this article, we describe the Rehabilitation Treatment Specification System (RTSS), by which any treatment employed in rehabilitation may be characterized, and ultimately classified according to shared properties, via the 3 elements of treatment theory: targets, ingredients, and (hypothesized) mechanisms of action. We discuss important concepts in the RTSS such as the distinction between treatments and treatment components, which consist of 1 target and its associated ingredients; and the distinction between targets, which are the direct effects of treatment, and aims, which are downstream or distal effects. The RTSS includes 3 groups of mutually exclusive treatment components: Organ Functions, Skills and Habits, and Representations. The last of these comprises not only thoughts and feelings, but also internal representations underlying volitional action; the RTSS addresses the concept of volition (effort) as a critical element for many rehabilitation treatments. We have developed an algorithm for treatment specification which is illustrated and described in brief. The RTSS stands to benefit the field in numerous ways by supplying a coherent, theory-based framework encompassing all rehabilitation treatments. Using a common framework, researchers will be able to test systematically the effects of specific ingredients on specific targets; and their work will be more readily replicated and translated into clinical practice.