As of March 2022, the patient enrollment has been completed and 230 patients have been discussed in both Heart Teams. The current trial will indicate the usefulness of QFR, which enables a wireless multivessel physiological interrogation, in the discussions of Heart Teams to determine the optimal revascularization strategy for MVD.In patients with multivessel disease (MVD), functional information on lesions improves the prognostic capability of the SYNTAX score. Quantitative flow ratio (QFR®) is an angiography‐derived fractional flow reserve (FFR) that does not require a pressure wire or pharmacological hyperemia. We aimed to investigate the feasibility of QFR‐based patient information in Heart Teams' discussions to determine the optimal revascularization strategy for patients with MVD. We hypothesized that there is an acceptable agreement between treatment recommendations based on the QFR approach and recommendation based on the FFR approach. The DECISION QFR study is a prospective, multicenter, randomized controlled trial that will include patients with MVD who require revascularization. Two Heart Teams comprising cardiologists and cardiac surgeons will be randomized to select a revascularization strategy (percutaneous coronary intervention or coronary artery bypass graft) according to patient information either based on QFR or on FFR. All 260 patients will be assessed by both teams with reference to the anatomical and functional SYNTAX score/SYNTAX score II 2020 derived from the allocated physiological index (QFR or FFR). The primary endpoint of the trial is the level of agreement between the treatment recommendations of both teams, assessed using Cohen's  This discussion should consider the anatomical complexity of the coronary tree assessed using the SYNTAX score (SS).The SYNTAX score II (SSII) is a refined version of the SS and generates an estimate of 4‐year mortality. While SS considers only anatomical information, SSII also considers patient characteristics, such as age, sex, and comorbidities. Recently, SSII was redesigned (SYNTAX score II 2020) based on the extended follow‐up database in the SYNTAX trial, generating an estimate of the 10‐year mortality and 5‐year major adverse cardiac event (MACE) rate, which has been externally validated.The original SS is calculated based on an angiographic diameter stenosis (DS) of 50%, with visual estimation. However, angiography‐guided PCI is associated with worse clinical outcomes compared with PCI guided by functional assessment using fractional flow reserve (FFR).The functional SYNTAX score (FSS) was developed as another approach to improve the prognostic capability of SS. In FSS, only lesions whose functional significance is confirmed using FFR are scored1.2QFR) is an FSS calculated based on functional assessment using QFR.QFR demonstrated good reclassification from anatomical SS for predicting 2‐year patient‐oriented cardiovascular events  in a post‐hoc study of the SYNTAX II trial.QFR could be calculated in only 35.8% of patients because of the lack of two paired projections that met the requirements for QFR calculation.To date, various types of angiography‐derived FFR, such as Quantitative flow ratio , FFRangio® (Cathworks), and vFFR® , have emerged and are commercially available with relatively simple mathematical formulas. These indices can be calculated based on three‐dimensional angiography in a short time without the need for a pressure wire or pharmacological hyperemia.1.3CT changed the Heart Team's treatment decision in 7% of patients and modified vessel selection for revascularization in 12% of patients.Compared with anatomical information alone, the addition of coronary functional information leads to better treatment decisions by the Heart Team. The SYNTAX III trial investigated the agreement of treatment decisions between a Heart Team using the angiography approach and that of a team using the coronary computed tomography angiography (CCTA) approach.QFR and the FSSQFR‐based SSII (SSIIQFR) in Heart Team discussions for the treatment of patients with MVD. The primary hypothesis of this study is that there is an acceptable agreement between the treatment recommendation based on the QFR approach and the recommendation based on the FFR approach.However, to the best of our knowledge, the feasibility of using QFR as the basis for treatment decision‐making in Heart Team discussions for patients with MVD has not been investigated. Thus, this prospective study aimed to evaluate the feasibility of using QFR‐based patient information based on the FSS22.1QFR and SSIIQFR in virtual Heart Team discussions compared with FFR‐based patient information using FSS and SSII derived from wire‐based FFR (FSSFFR and SSIIFFR). We will evaluate the level of agreement between two treatment recommendations generated by two virtual Heart Teams that are randomized to either the “QFR approach” or the “FFR approach.” All patients will be assessed by both Heart Teams in a cross‐over design.The DEtermination of the appropriate proCedure of revascularization In the multidisciplinary Heart Team discusSION based on Quantitative Flow Ratio (DECISION QFR) trial is a prospective, multicenter, single‐blinded randomized controlled trial that includes patients with MVD who require revascularization (PCI or CABG) Figure . The triQFR/SSIIQFR. In contrast, in the FFR approach, the Heart Team makes recommendations based on the FSSFFR/SSIIFFR .2.22) or receiving hemodialysis; (4) atrial fibrillation at the time of angiography; (5) severe valvular diseases; and (6) heart failure requiring oxygen supply  chronic coronary syndrome requiring revascularization (PCI or CABG); and (2) multiple lesions with DS of ≥50%  located in ≥2 vessels including the proximal left anterior descending . The exclusion criteria are as follows: (1) left main coronary artery lesion or ostial lesion of right coronary artery (RCA) disease that is not recommended for the QFR analysis; (2) history of CABG; (3) advanced chronic kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m chronic 2.3Invasive coronary angiography (ICA) is performed as follows: (1) nitrate is administrated into the coronary arteries before ICA; 2) lesions need to be clearly visualized without vessel shortening or overlapping in at least two projections; (3) prespecified projection angles for QFR analysis  are assessed using FFR unless they have ≥90% DS. Pharmacologic hyperemia is induced using intravenous or intracoronary administration of adenosine triphosphate or intracoronary injection of papaverine or nicorandil. We will use a ≥5‐Fr guiding catheter and measure FFR at the distal part of the target lesions while ensuring not to reach a pressure sensor in the part of vessel with a diameter of <2.0 mm. For the co‐localization with QFR analysis, the positions of a pressure wire sensor are recorded on angiographic still images. The absence of major pressure signal drift (3 mmHg) is confirmed using a pullback maneuver after the FFR measurements. The procedure time during the FFR measurement  will then be recorded.2.5The lesions for which FFR is measured are eligible for the QFR analysis. Offline QFR analysis will be performed by an experienced analysts at an independent core laboratory  using the QAngio XA 3D software version 2.0 . One of the advantages of FSS based on QFR is that on‐site physiological assessment is not necessarily required because treatment decisions  are generally made after a patient leaves the catheter laboratory. Thus, we will apply the offline QFR analysis in the current trial. The analysts will be blinded to the FFR results. Details regarding the QFR calculation have been reported elsewhere.2.6https://syntaxscore2020.com). The SYNTAX II score 2020, the latest generation of the SSII, is applied for the SSII in the current trial. It generates two estimates of 5‐year MACE and 10‐year mortality rates for PCI and CABG treatments, respectively.FFR and FSSQFR) by summing the individual points of physiologically significant lesions (FFR and QFR ≤ 0.8) and excluding physiologically nonsignificant lesions.FFR and SSIIQFR).The SS, SSII, and FSS are calculated at the core laboratory using an app‐based calculator (2.7QFR/SSIIQFR or FSSFFR/SSIIFFR) and the baseline patient information including cine angiography and anatomical SS and SSII. Each team decides a treatment recommendation from the following options:(1)CABG only: The patient is recommended to receive CABG because the benefits of CABG are highlighted according to the risk assessment using  SS and SSII.(2)Equipoise: The patient is recommended to receive either CABG or PCI because the benefits of each treatment are equipoised according to the risk assessment using  SS and SSII.(3)PCI only: The patient is recommended to receive PCI because the benefits of PCI are highlighted according to the risk assessment using  SS and SSII.We created two Heart Teams (Heart Team A and Heart Team B) involving three cardiologists  and two cardiac surgeons from St. Luke's International Hospital. Each team will conduct virtual discussions and decides on the optimal treatment recommendation regarding the revascularization strategy (PCI or CABG). The strategy is decided according to the allocated functional information (FSSFFR/SSIIFFR for QFR approach and FSSQFR/SSIIQFR for FFR approach), and the second decision is made based on identical information (unblinded decision).The allocation information (QFR or FFR approach) is blinded before the first decision (primary endpoint). After the first decision, each team is provided with the allocation and opposite functional information  the level of agreement between target vessels for the revascularization (PCI and/or CABG) in the QFR approach and the target vessels in the FFR approach; (3) the level of agreement between decisions based on QFR information (blinded decision) and decisions after knowing the FFR information (unblinded decision) in the QFR approach; (4) the level of agreement between FSSQFR and FSSFFR assessed using interclass correlation coefficient (ICC); (5) procedure time of QFR analyses compared with that of FFR measurements; and (6) incidence rate of complications during FFR measurements.The primary endpoint of the current trial is the level of agreement between the treatment recommendation based on the QFR approach and the recommendation based on the FFR approach. The level of agreement is assessed using Cohen's 2.9κ based on the decision components of “CABG only” and “equipoise/PCI only” as described above. A κ value of 0.61–0.80 between the two ratings is interpreted as a “substantial agreement,” and a κ value of 0.41–0.60 is considered a “moderate agreement.”κ > 0.60), while the trial will be considered positive if the lower boundary of the 95% confidence interval (CI) is >0.40. We expect that the kappa value will be lower than that in the κ value reached in the SYNTAX III trial  because the agreement of the treatment recommendations between the two teams will be deteriorated by using the SYNTAX score II 2020. The calculator of the original SYNTAX score II, which was applied in the SYNTAX III trial, offers treatment recommendations  based on the specific thresholds of treatment effect of CABG over PCI in terms of 4‐year mortality.κ for the treatment recommendation agreement was 0.63 [95% CI: 0.25–1.00], when 85.7% (18/21) agreement of the recommendation is observed. We will also evaluate the level of recommendation agreement between the two Heart Teams after unblinding to identify a between‐team decision variance.The level of agreement between the treatment recommendations will be assessed using Cohen's κ of 0.60. According to the calculation with “irr” package in R version 3.6.2 (R Foundation), a sample size of 235 will be sufficient to achieve 80% power and reach a positive trial with a two‐sided α of 0.05. Assuming an attrition rate of 10%, to account for nonanalyzable cases, a total of 260 patients will be included in the current trial.We assume that both approaches will result in “CABG only” recommendation in 20% of the enrolled patients, with a In the current study, we will exclude those patients without a full‐set QFR measurement from the primary analysis because values cannot be assigned to vessels without measuring the QFR. As a countermeasure for an inflated nonanalyzable rate, we recommend that operators should perform angiography with prospective consideration of QFR analysis or to use a prespecified angiographic protocol Table .3Invasive functional assessment using a wire‐based functional index  is recommended for deciding on revascularization in patients with chronic coronary syndrome.FFR or FSSQFR as well as the patients' baseline characteristics. We consider that QFR/FFR in the Heart Teams' discussions plays a significant role not only for the FSS but also for the per‐vessel functional information. FSS is a reasonable tool that can be used to summarize the anatomical complexity of patients while considering functional significance. However, as a consequence of summarization, the score itself does not present lesion information, such as the locations of functionally significant lesions, whereas the score is weighted based on the location of the lesion. For example, even with identical FSS points, one patient may have a functionally significant lesion(s) in the LAD while another may not have significant lesions in the LAD. This information is crucial for the decision‐making regarding the optimal revascularization strategy in the Heart Teams' discussion. We consider that the misclassification of QFR especially in the LAD potentially impacts the Heart Teams' decision even if the FSSFFR and FSSQFR are comparable. Furthermore, in the current trial, the Heart Teams will discuss optimal treatment strategy by considering the vessel‐by‐vessel feasibility of each revascularization mode based on the functional information and lesion characteristics . Per‐vessel functional information will also play an important role in the Heart Teams' decisions.We set the primary endpoint of the current trial as an agreement between two Heart Teams' treatment decisions, which will be generated based on the functional and anatomical information representing FSSIn the current trial, the Heart Teams will use QFR/FFR as a surrogate marker of myocardial ischemia, in which severity is generally graded continuously, while the functional SYNTAX score will be calculated based on each physiological index as a dichotomized parameter (≤0.8 or >0.8) according to the historical definition. CT® (Heart Flow) is another FFR simulation and a potential tool for FSS calculation that does not require the use of a pressure wire.CT enables a noninvasive anatomical and functional assessment of a coronary tree without requiring ICA. Thus, from the viewpoint of invasiveness, FFRCT is more favorable compared with QFR. Furthermore, this technology implemented a sophisticated computed fluid dynamics model based on Navier−Stokes equations that separately considers the inlet and outlet flows among coronary artery branches while QFR calculation is based on Hagen‐Poiseuille and Borda‐Carnot equations; this simplifies the model by considering that the coronary artery is a single straight tubular model while using the volumetric flow estimated from contrast frame count.CT (0.82 [95% CI: 0.76−0.87]).CT, QFR may have an advantage of better diagnostic accuracy as it generates an FSS with better prognostic value. Nevertheless, it should be appreciated that the simple model used in QFR calculation potentially yields reduced accuracy in complex lesions which are often observed in patients with MVD. In the substudy of the SYNTAX II trial enrolling patients with three‐vessel disease, deteriorated diagnostic performance was reported for bifurcation lesions and small vessels.CT to anatomical information (obtained via CCTA) on the Heart Team decision‐making as described above. Nevertheless, the trial neither mandated FFR measurements nor investigated the usefulness of FFRCT‐based patient risk assessment in comparison with that of a conventional functional assessment using FFR. The current trial will compare the feasibility of QFR‐based patient risk assessment as an alternative to FFR‐based patient risk assessment in the decision‐making of Heart Teams.FFRRecently, several studies revisited the role of physiology‐guided revascularization in patients with MVD. In the post‐hoc analysis of the ISCHEMIA trial, which was presented at the annual scientific session of American College of Cardiology in 2021, anatomical complete revascularization was found to be superior to conservative management in terms of long‐term composite cardiovascular endpoints (11.8% vs. 15.4% adjusted difference −3.6% [−6.9 to −0.7%]) whereas functional complete revascularization was not found to be superior to conservative management (12.9% vs. 15.4% adjusted difference −2.5% [−5.7% to 0.3%]). Although these findings were not supported with adequate sample size and just represented associations and not causality, it was suggested that anatomically complete revascularization may be more important than functionally complete revascularization. Furthermore, the FUTURE trial did not prove the advantages of FFR‐guided treatment strategy in terms of 1‐year ischemic cardiovascular events or death compared with angiography‐guided revascularization strategy.4QFR and SSIIQFR in Heart Team discussions for the risk assessment of patients with MVD. QFR is a potentially useful tool for multivessel functional assessment owing to its advantage of being minimally invasive.The DECISION QFR trial will be the first prospective study to investigate the feasibility of QFR using FSSProf. Reiber is the CSO of Medis Medical Imaging Systems and has a part‐time appointment at Leiden University Medical Center as a professor of medical imaging. All other authors have no conflict of interest to disclose. The authors declare no conflicts of interest.Supplementary information.Click here for additional data file.


Early obstruction of a self‐expandable metal stent placed for distal malignant biliary obstruction is more likely to occur in the presence of duodenal invasion. An anti‐reflux self‐expandable metal stent (ARMS) has been developed for the purpose of preventing duodenal fluid reflux into the bile duct. In this study, we evaluated the usefulness and safety of a duckbill‐type ARMS (D‐ARMS) in the situation of duodenal invasion.We retrospectively analyzed 10 consecutive patients who received D‐ARMS for distal malignant biliary obstruction with duodenal invasion. We evaluated non‐occlusion cholangitis, recurrent biliary obstruction (RBO), and adverse events after D‐ARMS placement.There were no cases of non‐occlusion cholangitis. RBO was observed in 2 patients (20%), and time to RBO was 236 days and 117 days, respectively. The causes of RBO were overgrowth and sludge formation. The median time to RBO was 382 days . Only one adverse event was observed (cholecystitis).D‐ARMS shows potential as an optimal ARMS. The various types of biliary drainage for distal malignant biliary obstruction include transpapillary drainage by endoscopic retrograde cholangiopancreatography (ERCP) procedure, percutaneous drainage, and endoscopic ultrasonography (EUS)‐guided drainage. Transpapillary drainage by ERCP is a common procedure if the endoscope can reach the papilla, and is performed at many facilities. The usefulness of biliary drainage with a self‐expanding metal stent (SEMS) is widely recognized, but sludge formation and food impaction are cited as causes of stent obstruction.We conducted a retrospective study of consecutive patients who received a D‐ARMS for distal malignant biliary obstruction with duodenal invasion at the Dokkyo Medical University Saitama Medical Center, Japan. The study was approved by the review board at Dokkyo Medical University Saitama Medical Center  and was conducted in accordance with the tenets of the Helsinki Declaration. Evaluation of D‐ARMS was based on the TOKYO criteria 2014.Ten consecutive patients with distal malignant biliary obstruction and duodenal invasion were treated with D‐ARMS between December 2019 and March 2021. Distal malignant biliary obstruction was diagnosed based on the clinical, laboratory, radiological, and pathological findings. Distal malignant biliary obstruction was defined as a site of stenosis at least 2 cm away from the liver hilum. Malignancy was diagnosed pathologically by EUS‐guided fine needle aspiration or ERCP. The duodenal invasion was diagnosed when duodenal erosions, ulcers, or strictures thought to have been caused by malignancy were observed endoscopically or when invasion into the duodenal muscular layer was confirmed by EUS, regardless of whether these findings were confirmed pathologically. Patients with resectable tumors or surgically altered anatomy were excluded. Patients who underwent biliary drainage, as well as initial drainage, were included.The D‐ARMS is a laser‐cut covered SEMS with a 12.5 mm duckbill‐shaped anti‐reflux valve attached to the duodenal end . Endoscopic sphincterotomy was performed in all patients. D‐ARMS length was determined by the cholangiographic findings and was 60 mm in all patients. Patients who had previously undergone biliary drainage received D‐ARMS placement immediately after removing the previous stent. In the case of concurrent cholangitis, balloon sweeping was performed when biliary sludge or food residue was suspected. The stent was placed across the papilla so that the end of the stent on the papillary side protruded 5–10 mm into the duodenum ; and were categorized as early (within 30 days) or late (31 days or later). The time point of adverse events was defined as the point when symptoms associated with these conditions were observed.Statistical analyses were performed using JMP version 14 software . TRBO was estimated using the Kaplan–Meier method.n = 7, 70%), bile duct cancer , and ampullary cancer . D‐ARMS was the first stent placement in one patient (10%), a plastic stent had been placed previously in five patients (50%), a covered SEMS had been placed previously in three patients (30%), and a percutaneous transhepatic biliary drainage tube had been placed previously in one patient (10%). One patient was placed with D‐ARMS as the initial drainage because he had obvious duodenal invasion and multiple liver metastases, and was diagnosed as unresectable at the time of ERCP. Of the three patients with a covered SEMS, two patients had a D‐ARMS placed after SEMS removal, and one patient had a stent‐in‐stent placement that added a D‐ARMS inside a SEMS. Chemotherapy was performed in seven patients (70%) after D‐ARMS placement. The mucosal invasion was confirmed endoscopically in nine patients (90%) and invasion into the duodenal muscular layer was confirmed by EUS in one patient (10%). Tumor invasion to the duodenum was categorized according to the Mutignani classification as type I (n = 7), type II (n = 2), and type III (n = 1).The patient characteristics are summarized in Table Table After D‐ARMS placement, duodenal stent insertion was performed in one patient and gastrojejunal bypass surgery was performed in 1 patient, but neither patient had complications of RBO.As an adverse event other than RBO, one case of cholecystitis developed early (at 15 days) after D‐ARMS placement due to an impacted gallstone in the cystic duct. Fluoroscopy confirmed that D‐ARMS did not cover the cystic duct. Although the patient improved following percutaneous drainage, there was repeated relapse. EUS‐guided gallbladder drainage was performed and the patient's condition improved.ARMS was developed for the purpose of prolonging TRBO and preventing duodenal fluid reflux, and various types of ARMS have been reported.In the present study, we examined the usefulness and safety of D‐ARMS in the situation of duodenal invasion where duodenal fluid easily flowed back into the bile duct. We found no cases of non‐occlusion cholangitis within the observation period. Although it has been reported that migration is greater with ARMS than conventional SEMS, perhaps due to the high outflow pressure at the check valve,Recent reports from Japan have described the usefulness of this stent.For reintervention after RBO, it is desirable to place a new stent after removing the initial stent. It is easy to place a laser‐cut type‐covered SEMS at the target location, but removal is often difficult due to the characteristics of the stent. D‐AMRS removal was attempted in two of the present patients with RBO but was difficult, so we performed additional placement of SEMS in the form of a stent‐in‐stent. However, Kin et al. reported that D‐ARMS could be removed in six of nine cases that developed RBO,Early obstruction of a SEMS is more likely to occur in the presence of duodenal invasion,There are several limitations to this study, including its small sample size, single‐arm retrospective study design, and short observation period. In addition, the intervention was performed for duodenal tumor invasion in only two patients. As we included patients in whom the mucosal layer was visually invaded by endoscopy as well as those in whom only the duodenal muscular layer was invaded by EUS, the gastric outlet obstruction symptoms might not have developed within the observation period. In the pathological evaluation of surgical specimens, duodenal invasion is defined as invasion of the muscular layer even if the mucosal layer of the duodenum is not invaded. In the past, the duodenal invasion was defined as the endoscopic observation of invasion into the mucosal layer. Now that the use of EUS is widespread, we think that the definition of duodenal invasion should include invasion into the muscle layer on EUS. If the invasion is observed in the muscular layer, duodenal peristalsis is reduced, and it is thought that reflux of duodenal fluid into the bile duct is likely to occur. The large number of patients who died relatively early after stent placement affected the follow‐up data. Further verification in randomized controlled trials is required in the future.The authors declare that they have no conflict of interest.This research received no external funding.The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Dokkyo Medical University Saitama Medical Center .


The first total synthesis of a tetracyclic marine pyridinium alkaloid hinged on recent advances in chemoselectivity management: While many classical methods failed to afford the perceptively simple pyridine‐containing core of the target, nickel/iridium photoredox dual catalysis allowed the critical C−C bond to be formed in good yield. Likewise, ring closing alkyne metathesis (RCAM) worked well in the presence of the unhindered pyridine despite the innately Lewis acidic Mo(+6) center of the alkylidyne catalyst. Finally, an iridium catalyzed hydrosilylation was uniquely effective in reducing a tertiary amide without compromising an adjacent pyridine and the lateral double bonds; this transformation is largely without precedent. The second strained macrocycle enveloping the core was closed by intramolecular N‐alkylation with formation of the pyridinium unit; the reaction proceeded site‐ and chemoselectively in the presence of an a priori more basic tertiary amine. The conquest of a polycyclic marine pyridinium alkaloid was only made possible by the remarkable chemoselectivity profile of contemporary transition metal catalysts that operate in the presence of basic sites. Ni/Ir photoredox catalysis, Mo‐alkylidynes for alkyne metathesis, and an Ir‐catalyzed lactam‐selective hydrosilylation stand out in this regard. A with formation of iminium ion B in the first place  3‐alkylpyridine precursors. Of them, the “Baldwin‐Whitehead postulate” became particularly famous, which centers upon a transannular Diels–Alder cycloaddition of an intermediate of type e Scheme .[1] SiF or G as key intermediates, which are thought to evolve via (transannular) 1,4‐conjugate additions either into the tetracyclic or pentacyclic estate as shown in Scheme G→D, is accompanied by the generation of a pyridinium ring, which may get (partly or fully) reduced once the core is formed. Several biomimetic studies provide strong evidence that all of the proposed key steps are feasible and facile.The circumstantial evidence for the alternative biosynthesis pathway proposed by Marazano and co‐workers is arguably stronger. These authors advocated for the intervention of 5‐amino‐2,4‐pentadienal derivatives such as 1)3) inhibit the growth of Mycobacterium tuberculosis H37Ra under both aerobic and hypoxic conditions. I23 has to adopt for macrocyclization to proceed is preserved in the half‐chair structure of the piperidinone ring of product 24 in the solid state . No such ambiguity was noticed when the enolate derived from 23 was alkylated with 28; the trans‐disubstitution of the resulting product 26 is clearly manifested in the coupling constant for the protons at the branching points . Treatment of this functionalized diyne with the “canopy catalyst” 2925 was identical in all regards with the compound formed by alkylation of 24. However, its separation from the silanolate residues derived from the catalyst during work‐up proved somewhat more difficult than in the case of 24, resulting in an isolated yield of only 61 %.For this reason, it was clear that RCAM had to precede reduction of the piperidinone, whereas the best timing for the attachment of the handle needed for the projected second macrocyclization was less apparent. Because it could go before or after the RCAM reaction, both orders of events were explored. Specifically, deprotonation of 25, which was selectively hydrogenated over excess nickel boride to furnish the corresponding Z‐alkene 30,[4 or LiBHEt3 do not meet this requirement.2H6 out (Scheme 3)2] (Vaska's complex) as catalyst with tetramethyldisiloxane (TMDS)30 to be transformed into the corresponding enamine 31 as the expected primary product;3CN/HOAc in MeOH proved effective, furnishing product 32 in 63 % yield over both steps as the only detectable product. This step proceeded stereoselectively, in that protonation occurred exclusively from the less hindered side to give the cis‐configured piperidine.32 and, ultimately, by conversion of this product into epi‐tetradehydrohalicyclamine B (7).With the two routes converging at product lkene 30,59, 6032 in hand, the stage was set for the final macrocyclization via pyridine‐N‐alkylation. To this end, the TBDPS‐ether was cleaved and the resulting primary alcohol converted into iodide 33 under standard conditions.7 in 49 % yield; this outcome is notable if one considers the strain and rigidity of the incipient 13‐membered ringa priori more nucleophilic tertiary amine in vicinity to the pyridine: it is the even higher strain and less favorable kinetics of closure of the 11‐membered ring, which would be formed on N‐alkylation of the piperidine, that prevent this potentially competing site from interfering. Despite the ionic nature of and the presence of a tertiary amine in the resulting product 7, this compound could be isolated as the corresponding iodide salt by conventional flash chromatography on silica, without need to resort to reverse phase HPLC.With 7 matched the literature very well.epi‐tetradehydrohalicyclamine B comprising the cis‐configured piperidine unit. This spectral fingerprint (see the Supporting Information) attests to the stiffness of the 13‐membered ring that places these protons in the anisotropy cone of the pyridine and the C10–C11 alkene;30 via enamine 31 exclusively provides the cis‐configured piperidine 32. The price to pay for this selective course is the need to find an alternative route to the isomeric natural product tetradehydrohalicyclamine B (6), which will be subject to further investigations in this laboratory.Regardless of the uncertainty concerning the escorting anion in the natural product derived for the marine sponge,The first conquest of a tetracyclic pyridinium alkaloid of prominent biosynthetic pedigree bears witness to significant recent advances in chemoselectivity management beyond the scope of classical organic synthesis. If one considers that pyridine derivatives inhibit countless acidic reagents and metal catalysts, it is truly remarkable that nickel/iridium photoredox dual catalysis triumphs over canonical cross coupling as well as 1,4‐addition reactions when it comes to the elaboration of such building blocks. Equally noteworthy is the fact that the latest generation of alkyne metathesis catalysts is not obstructed by their presence either; this observation is particularly striking since the operative molybdenum alkylidyne unit comprises the early transition metal in the highest possible oxidation state. Finally, the current total synthesis hinged upon the stunning selectivity profile of a catalyst system comprised of Vaska's complex/TMDS that allows for direct catalytic reduction of a lactam without touching a flanking pyridine. Taken together, these virtues of contemporary catalysis open access to valuable material that cannot easily be obtained from the producing marine organism; relevant bio‐data will be reported in due course.The authors declare no conflict of interest.1As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.Supporting InformationClick here for additional data file.


To investigate whether early changes in fear of movement (kinesiophobia), self‐efficacy and catastrophizing were mediators of the relationship between allocation to the pre‐habilitation intervention and later changes in health outcomes.The original pre‐habilitation trial  recruited 118 participants awaiting lumbar fusion surgery, half of whom received a prehabilitation intervention designed based on the modified fear‐avoidance model and half of whom received usual care. Mediation analysis was performed to test each mediator separately. Analysis was performed on each outcome of interest separately . Mediation analysis was carried out using PROCESS. Beta coefficients and bootstrapped 95% CIs were used to interpret the results.None of the potential mediators was found to mediate the relationship between allocation to the intervention and 3‐month scores on any of the health outcomes tested.Screening patients for higher levels of catastrophizing and fear avoidance and lower levels of self‐efficacy could help ensure only the patients who are most likely to benefit from the intervention are included.Prehabilitation interventions for spinal fusion surgery have been found to improve health outcomes for patients. Theory‐based interventions that target key mechanisms are more effective at improving outcomes than non‐theory‐based interventions. While no mediating effects were found for this particular intervention, the analysis suggests that the underlying theoretical model and treatment targets are appropriate and could drive improvement if more strongly targeted. Further testing of potential mediating variables specific to the model underlying our trial was warranted.A systematic review of seven mediation analysis studies found evidence for catastrophizing and self‐efficacy as mediators of pain and disability outcomes across a range of interventions for MSK pain  in kinesiophobia, pain catastrophizing and/or self‐efficacy would mediate the effects of the PREPARE pre‐habilitation programme on health outcomes at 3‐month post‐surgery.2The AGReMA guideline   effects can help us learn more about how an intervention might achieve its effects, and indeed whether the intervention worked in the way it was hypothesized to. Mediation analysis can also be used when an intervention is found to be ineffective, to examine why this was the case (e.g. whether the hypothesized mediators did not change as expected)    for both the Potential confounding factors were identified as sex, depression score at baseline and steps per day at baseline. These were identified through discussions with clinical members of the research team as well as the use of a directed acyclic graph (DAG)  and an ‘outcome’ model with treatment allocation and each potential mediator as the independent variable and each outcome as the dependent variable (b path). All available data were used, including imputed data for the ODI, as per the original trial analysis , but the timing of the assessments limited the more nuanced ordering of the potential mediators  can give us an idea of whether the intervention was able to affect the proposed mediating variables, whereas ‘conceptual’ theory (the b path in the model) can give us an idea of how well the variables of interest fit the underlying intervention theory. Interpreting the estimates in each path can therefore help us understand more about the mediating effect itself    : 0.96 [95% CI −0.10 to 0.24] for self‐efficacy; −0.90 [95% CI −1.41 to −0.39] for fear avoidance; −0.68 [95% CI −1.11 to −0.26 for catastrophizing]).Estimates on the hs Table , estimat4The present study used mediation analysis to test whether the effect of intervention allocation on health outcomes at 3‐month post‐surgery was mediated by fear of movement, exercise self‐efficacy or pain catastrophizing scores at 3‐week post‐surgery. We found none of these variables to be mediators of the effects of the pre‐habilitation intervention on health outcomes at 3‐month post‐surgery.a path appear to corroborate Lotzke et al's theory that the ‘dose’ of the intervention might not be strong enough for the intervention to be more effective than conventional care  targets appropriate variables, supporting the treatment fidelity of our active intervention.Our previous results were found to be non‐significant on the primary outcome variable (disability), but significant on secondary variables . Understanding the level of treatment fidelity is crucial for interpreting an intervention's effectiveness. With non‐significant results and an unknown level of treatment fidelity, one cannot tell whether the problem was an ineffective treatment or a lack of treatment fidelity . Unmeasured confounding is a key issue in mediation analysis, even when randomization is present. Three key potential confounders were identified by the study team and controlled for in the analysis, but other unmeasured confounders, such as BMI, previous surgeries and medication use could also have had an impact on the results seen in the trial. Missing data were also an issue, with around 15% of data missing in each arm. Moreover, it is important to keep in mind that none of these results IS powered for mediation analyses, and a larger sample may have resulted in significant effects.4.2This study provides further insight into the PREPARE pre‐habilitation intervention by formally testing the hypotheses for how the underlying theoretical rationale using mediation analysis. While no mediating effects were identified, the results suggest that the underlying theoretical model is associated with functional improvement. Screening patients for higher levels of catastrophizing and fear avoidance, and lower levels of self‐efficacy, could help ensure only the patients who are most likely to benefit from the intervention are included.ML, RS, HL and MH had the original idea for the trial and collected the data used in this analysis. GM conducted the mediation analysis and drafted the manuscript. All authors discussed the results and commented on drafts of the manuscript. All authors approved the final draft for submission.No funding was secured for the present study. The original PREPARE RCT was funded with grants from AFA Research Funding No. 120216; Eurospine Research Grants No. TFR 8‐2014; the Swedish Research Council (VR) No. 2015‐02511; the Health and Medical Care Executive Board of the Västra Götaland Region (VGR) and Doctor Felix Neubergh grants.None declared.


The objective of the study was to investigate the administration and use of routine outcome monitoring session by session in the context of improving guided‐self‐help interventions when delivered remotely at Step 2 care in the English Improving Access to Psychological Therapies (IAPT) services.Qualitative research using recordings of telephone‐treatment sessions.Participants (11 patients and 11 practitioners) were recruited from four nationally funded IAPT services and one‐third sector organisation commissioned to deliver Step 2 IAPT services, in England. Data collection took place prior to the COVID‐19 pandemic. Transcripts of telephone–treatment sessions were analysed using thematic analysis.Four themes were identified: (1) lack of consistency in the administration of outcome measures (e.g. inconsistent wording); (2) outcome measures administered as a stand‐alone inflexible task ; (3) outcome measures as impersonal numbers ; and (4) missed opportunities to use outcome measures therapeutically .Shifting the perception of outcome measures as impersonal numbers to being process clinical tools ensures a personalised delivery of psychological interventions and has the potential to enhance engagement from practitioners and patients what may reduce drop‐out rates and improve clinical outcomes.The administration of outcome measures needs to ensure validity and reliability. Therapeutic yield from session‐by‐session outcome measures could be enhanced by focusing on three main areas: (1) adopting a collaborative conversational approach, (2) maximising the use of total and items scores and (3) integrating outcome measures with in‐session treatment decisions.  There is room to improve low‐intensity psychological interventions delivered by telephone by optimising the use of session‐by‐session outcome measures. Moving towards a collaboratively conversational approach of session‐by‐session measurement establishes outcome measurement as a clinical process tool embedded in treatment leading to a personalised delivery of psychological interventions.We hypothesise that therapeutic use of session‐by‐session measures would enable services and practitioners to better utilise standard procedures to inform psychological interventions.We anticipate shifting the perception of outcome measures as impersonal numbers to being process clinical tools as having the potential to enhance engagement from practitioners and patients that may potentially reduce early attrition rates and influence clinical outcomes.We would recommend placing more emphasis/dedicated time to the ability to use outcome measures from a collaborative conversational approach; making sure this is within the low‐intensity competencies, assessed during training and monitored in clinical supervision.The UK policy and guidelines recommend the use of routine outcome monitoring to ensure psychological therapies are delivered effectively and efficiently to the best standard of care  over a maximum of eight sessions. Step 2 care is delivered by psychological well‐being practitioners (PWPs) trained over one year to a standardised curriculum accredited by the British Psychological Society.IAPT heralded a change in direction for mental health services and providers with an emphasis placed on the routine collection of sessional outcome data. Sessional outcome data informed the status of treatment in relation to discharge (improved) at Step 2 or stepping up to more intense interventions at Step 3 and marked a move away from services relying either on clinical judgement or paired pre/post‐treatment data when it was available. In contrast, IAPT has recorded 98% outcome data completeness for pre/post‐treatment scores from all clinical contacts IAPT, .The move from low rates of pre–post measurement to high rates of session‐by‐session measurement has changed the assessment of patient progress in psychological treatments. The IAPT manual highlights how the use of session‐by‐session outcome measures aims to benefit services, practitioners and patients IAPT, . HoweverAt a service level, outcome measures can be used to monitor and support service performance, address variability across practitioners and enhance the overall quality and cost‐effectiveness of service delivery IAPT, . HoweverAt a practitioner level, session‐by‐session outcome measures can provide information to identify targets for interventions and for session work, help to inform the appropriateness of treatment, evaluate treatment effectiveness, support a discussion of clinical cases in supervision and facilitate conversations on difficult topics IAPT, . ResearcAt a patient level, session‐by‐session outcome measures have the potential for people to see their progress and improvements over time, contribute to the understanding of their problem, enhance engagement and support the development of the therapeutic relationship IAPT, . PatientDespite the benefits of session‐by‐session use of outcome measures, challenges faced in clinical practice remain unresolved. Evidence on the value of providing feedback and facilitating a patient–practitioner dialogue about outcome measure monitoring is emerging and could prove fruitful in maximising their use during ongoing treatment  with common mental health problems  receiving Step 2 care in IAPT services delivered by telephone.Data collection took place between September 2018 and July 2019 (i.e. prior to the COVID‐19 pandemic). Data were collected from 18 PWPs and 106 patients, comprising 123 recordings. All participants provided consent to take part and to be recorded. From the 123 recordings, 66 were assessments and 57 were treatment sessions (37 Session 1 and 20 Session 2). This study focused on treatment sessions to explore the implementation and therapeutic use of outcome measures, meaning a subsample of the full data set was used. For findings related to assessments, please see Irvine et al.  and Drewn = 52). To allow exploration of the use of outcome measures across practitioners and between sessions within the same dyad (patient–practitioner), a subsample of 16 transcripts was selected. The subsample was selected to include one transcript for each of the 11 practitioners that provided recordings of treatment sessions, and five transcripts that corresponded to the same patient–practitioner dyad. For practitioners providing multiple recordings, transcripts were randomly selected.The complete treatment data set included 57 transcripts corresponding to 11 practitioners and 40 patients. Six of the 11 practitioners provided multiple recordings  and 30 min for Session 2 (Range 27–37 min). The recordings were transcribed verbatim by an independent transcription company (approved by the University of Manchester), and transcripts were checked for accuracy by two researchers. Following transcription, any identifiable information was removed from the transcripts in accordance with ethics guidelines. Data were securely stored in online servers at the Universities of Manchester and York.SD = 13.0, range 26–72). The average length of experience delivering psychological interventions was 3 years .Nine of the 11 practitioners were women and the mean age was 35 years . Six were diagnosed with anxiety, one with depression and four with both (anxiety and depression); four patients reported co‐morbid physical health conditions, and four were employed.From the 11 patients included in the subsample, ten were women and the average age was 38 years  checklist . In addition, MB, KL and DM have experience in training practitioners; and NL is a strategic mental health lead with experience of managing IAPT services. All authors have a shared perception about the value of outcome measures in treatment effectiveness and service delivery.administration of outcome measures and were labelled ‘Lack of consistency in the administration of the outcome measures’ and ‘Outcome measures administered as a stand‐alone inflexible task’. The other two themes focused on information about the lack of therapeutic use of outcome measures within and between treatment sessions and were labelled ‘Outcome measures as impersonal numbers’ and ‘Missed opportunities to use outcome measures therapeutically’. Table The analysis yielded four themes; the first two related to the Differences across and within practitioners were evident with inconsistent use of the formal and standardised wording of the items presented in the questionnaires, differences in the rationale for its use, lack of clarity when presenting the rating options and conflicting information provided during the session. The theme comprised three sub‐themes . Item 8 on the PHQ‐9 reads ‘Moving or speaking so slowly that other people could have noticed? Or the opposite ‐being so fidgety or restless that you have been moving around a lot more than usual’ and this was rephrased as ‘Any changes to your movements? Have you noticed you moving or speaking more slowly or the opposite, that you've been more fidgety or restless?’ (Patient ID 100‐ Practitioner ID 03‐ Session 2).‘all the time’, ‘definitely’, ‘half the time’, making their answers ambiguous where the options were ‘Nearly every day (3)’, ‘More than half the days (2)’, ‘Several days (1)’, ‘Not at all (0)’. In a minority of cases, some practitioners attempted to gather clarification:Similarly, data showed a lack of consistency in the presentation of the rating options. Rating options were presented using either the categorical  or the numerical options (e.g. 0); both options were rarely presented. On multiple occasions, patients provided an answer outside of the rating options, and there was usually no attempt to clarify this. For instance, patients replied using words such as ent from those stated in the questionnaires  and rating options were usually only introduced at the beginning of the questionnaire.There were occasions where rating options presented by the practitioner were differThere were data showing the PWP providing further explanation of an item when there was a misunderstanding by the patient, but after the clarification, there was no review of scores. The following extract illustrates a dialogue between patient‐practitioner related to item 3 of the IAPT Phobia Scale: ‘How much do you avoid certain situations because of a fear of particular objects or activities ’:Similarly, there were times when ratings provided during the administration of the measures were not consistent with the qualitative narrative given by the patient later on in the treatment session, and these inconsistencies were not explored and ratings remained unchanged.Data analysis revealed a lack of consistency in the rationale for the use of outcome measures session by session when presented to the patients. Data from Session 1 often indicated that outcome measures were presented to patients as something that needs to be done at every treatment session without providing a rationale.In a few recordings, practitioners provided a rationale, which included collecting information about symptoms, monitoring progress, checking treatment is on track and facilitating a conversation about changes over time; an extract illustrating this is included below:Consistencies were identified in the implementation of outcome measures, highlighting this was done as a stand‐alone, expedited, mechanical exercise not integrated within the treatment session; patients were invited to expand on their experiences immediately after completing the measures. This theme comprised three sub‐themes , and when they were completed in the session, its completion was usually rushed. This expedited approach in the administration of measures was evident in many of the patient–practitioner interactions. An extract illustrating this is included below:Patients sometimes provided a narrative description of their experiences or circumstances to an item question and this information was omitted, forgotten or disregarded by practitioners. Hence, although outcome measures were eliciting additional information, on multiple occasions the focus was on identifying a numerical or categorical response and closing down a patient's story.The administration of the measures was often mechanical and lacking flexibility. The extract below illustrates how the patient provided details in relation to a sleeping question elicited in the PHQ‐9, but the practitioner avoided this information and moved on to the next item.However, while patients' extended accounts were generally avoided, responses to suicide risk were picked up subsequently, although not immediately:After the administration of the outcome measures, PWPs often provided a new opening to the session inviting patients to talk about their personal experiences and feelings since the last session. This demonstrated the value placed on a patient's story but was disconnected from the administration of the measures:When patients completed the outcome measures in advance, PWPs usually did not use the scores, and when they were completed within the session, the use of this information was limited to summation, categorisation and/or comparison of total scores. In addition, this theme captured a difference between using closed and open questions after providing feedback to patients on their total scores. This theme comprised two sub‐themes  and/or comparing total scores between sessions. Usually, the practitioner provided this information to patients  and patients were generally passively receiving it; afterwards, the session moved quickly to address a different topic:Patients often provided information about an overall feeling of improvement or deterioration, but this was not crosschecked or linked to total scores.There were only four examples in the data where practitioners were proactive in looking for explanations behind the total scores, which were indicating a reduction, an increase, or no changes on symptoms. When doing this, practitioners attempted to crosscheck patients' experiences by using a closed question after providing feedback on total scores: ‘Does that seem accurate?’ (Patient ID 106‐Practitioner ID 26‐Session 1), ‘Does that feel right?’ (Patient ID 022‐Practitioner ID 07‐Session 1), ‘Does that kind of fit with how things have been?’ (Patient ID 100‐Practitioner ID 03‐Session 1), ‘Is that reflective of how you are feeling at the moment?’ (Patient ID 094‐Practitioner ID 04‐Session 1).In contrast to the use of closed questions, there was only one example in the data set where the practitioner used an open question in Session 2 inviting the patient to think about what he/she has been doing differently between sessions to understand the reduction in total scores: ‘But what do you think has kind of happened over the last week to kind of have such a big change on your scores?’ (Patient ID 013‐Practitioner ID 06‐Session 2).The patient initially said he/she did not know why the scores were reduced but then talked about making changes to their sleep routine, eating healthier, relaxing a bit more, consciously making an effort to feel better and talking about their problems. After this conversation, the patient highlighted that reflecting together on the questionnaires was helpful:There was a lack of integration and therapeutic use between the administration of outcome measures and decision‐making during treatment sessions. Several examples became apparent through data analysis as missed opportunities to use scores in a therapeutic way. These missed opportunities included the lack of use of (i) item scores and (ii) information gathered from the administration of the IAPT Phobia Scale and the WSAS. This theme comprised two sub‐themes  down (b) depressed or (c) hopeless. Similarly, in the GAD‐7, there are three items asking about different facets within an item , for example Item 1: Feeling (a) nervous, (b) anxious or (c) on edge. Questions exploring how the patient is rating items including multiple aspects would help to understand responses and inform treatment decisions.Focusing on item scores could be particularly relevant to inform the session when total scores show a deterioration or no changes across sessions, a careful look into item scores could help to identify changes that might get lost when attention is on the total score. Figure The lack of therapeutic use of outcome measures extends to the Phobia Scale and the WSAS, which were administered in the majority of the sessions (i.e. 11 sessions). However, these data were not utilised during the session and further details were not gathered to personalise scores.. Figure The PHQ‐9 and/or the GAD‐7 may not capture the key issue of importance, and therefore tracking changes on these additional measures could be helpful to monitor patient progress and prevent an improvement in depression and/or anxiety measures mislead treatment outcomes. If an improvement in the PHQ‐9 and/or GAD‐7 is not accompanied by better functioning in life (e.g. WSAS), this should be addressed before the end of treatment to improve the likelihood of long‐term recoveryThis study explored the administration and therapeutic use of session‐by‐session routine outcome measure within and between treatment sessions in psychological interventions delivered by telephone at Step 2 care in IAPT services. Findings indicated a lack of consistency in the administration of the outcome measures within and across practitioners, posing a question about the validity, reliability and meaningfulness of the data collected during telephone‐treatment sessions. Therefore, implementation procedures should be in place to ensure high‐quality data (e.g. use exact wording when referring to items). During COVID‐19, many services asked patients to complete measures online prior to the session; these implementation procedures are still valid when practitioners refer back to items.Findings highlight the lack of clinical use of outcome measures within and between treatment sessions. This could be explained by previous studies into the attitudes of mental health practitioners on outcome measures which highlighted practitioners did not see the value of using outcome measures as they felt they were capable of assessing and monitoring their own work , and its potential impact on dropout rates and on clinical outcomes. Furthermore, research investigating administration and clinical use of outcome measures by telephone at Step 3 could enlighten similarities/differences compared to Step 2 care.A collaborative conversational approach towards the administration of session‐by‐session measurement and the clinical use of item and total scores to inform the treatment work, offer a valuable strategy for tailoring and personalising patient progress that is aligned with the values of patient‐centred care (Department of Health, Cintia L. Faija: Conceptualization; Formal analysis; methodology; Writing – original draft; Writing – review & editing. Penny Bee: Funding acquisition; Writing – review & editing. Karina Lovell: Funding acquisition; Writing – review & editing. Nicky Lidbetter: Funding acquisition; Writing – review & editing. Judith Gellatly: Conceptualization; Project administration; Supervision; Writing – review & editing. Kerry Ardern: Conceptualization; Writing – review & editing. Kelly Rushton: Conceptualization; Writing – review & editing. Helen Brooks: Conceptualization; Funding acquisition; Writing – review & editing. Dean McMillan: Funding acquisition; Writing – review & editing. Christopher J. Armitage: Funding acquisition; Writing – review & editing. Rebecca Woodhouse: Writing – review & editing. Michael Barkham: Conceptualization; Funding acquisition; methodology; Supervision; Writing – original draft; Writing – review & editing.The authors declare they have no competing interests.


Integr Environ Assess Manag 2022;18:863–867. © 2022 Merck, Sanofi, Johnson & Johnson Services, Inc, F.Hoffmann‐La Roche Ltd, Teva Pharmaceuticals, GlaxoSmithKline, Novartis Pharma AG, and Pfizer lnc. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).The pharmaceutical manufacturing industry, via the AMR Industry Alliance, has developed and implemented steps to help minimize the potential impact of pharmaceutical manufacturing on the spread of antimicrobial resistance (AMR). One of these steps was to publish predicted no‐effect concentrations (PNECs) to serve as targets for antibiotic manufacturing wastewater effluent risk assessments aimed to help protect environmental receptors and to mitigate against the spread of antibiotic resistance. Concentrations below which adverse effects in the environment are not expected to occur (PNECs) were first published in 2018 and are updated annually. The current list now stands at 125 antibiotics; however, it is recognized that this list does not encompass all manufactured antibiotics. Therefore, a statistical evaluation of currently available data was conducted and a default PNEC of 0.05 µg/L for antibiotics in the absence of other data was derived.  PNECs were previously published for 125 antibiotics; however, it is recognized that this list does not encompass all manufactured antibiotics.A default PNEC value is necessary in order to provide a target for antibiotics with limited data. The Wellcome Trust Review on Antimicrobial Resistance recommends setting minimum standards for the manufacturing of antibiotics based on the current state of the science O'Neill, . The useThe original signatories to the AMR Industry Roadmap, which are now part of the AMR Industry Alliance, made commitments to build and to share common practices addressing manufacturing‐related concerns by specifically focusing on reducing the environmental impact from the production of antibiotics. While the major source of human pharmaceuticals entering into the environment (PIE) is via patient excretion following use of medicine that is taken to prevent, cure, or alleviate a medical condition , a comparatively smaller contribution to PIE stems from wastewater emissions from industry during the manufacturing of the pharmaceutical ingredients .The environmental predicted no‐effect concentration (PNEC‐ENV) and minimum inhibitory predicted no‐effect concentration (PNEC‐MIC) values were taken from PNEC discharge targets published by the AMR Industry Alliance . The folFor purposes of the methodology, antibiotics were defined as those active pharmaceutical ingredients (APIs) classified by the WHO Collaborating Centre for Drug Statistics Methodology as per their Anatomical Therapeutic Chemical (ATC) codes. Environmental toxicity data generated for antibiotics in support of regulatory drug approvals in the European Union (EMA European Medicines Agency), as well as other company voluntary programs, were compiled. Data from peer‐reviewed literature were also collected when the studies were deemed to be reliable . Studies performed in compliance with the OECD Principles of Good Laboratory Practice were used preferentially.The PNEC‐ENV values were derived from toxicity endpoint data with an assessment factor applied, consistent with European Guidance ECHA, . Since cThe lowest chronic no observed effect concentration (NOEC) or 10% effect concentration (EC10) of all species tested for each API was divided by a factor of 10, representing extrapolation to ecosystem effects, to derive a PNEC‐ENV value. In cases where multiple EC10 or NOEC values were available for the same species for the same API, and they were within 1 order of magnitude, the geometric mean of the two values was used to determine the PNEC‐ENV. The geometric mean is used when comparable data on the same end‐point and species are available ECHA, . For allMinimum inhibitory concentration (MIC) data from the EUCAST database were compiled by Bengtsson‐Palme and Larsson . The MICth percentile of all PNEC‐ENV and PNEC‐MIC values were calculated using TIBCO® Spotfire® 10.10.2. Further, 5th percentiles were also calculated for individual antibiotic drug classes . The 5th percentile was selected in order to identify the PNEC, which would be protective with 95% confidence. The approach of statistical extrapolation is consistent with regulatory guidance, is applicable when more than 15 NOECs are available, and has the advantage of using the whole sensitivity distribution in an ecosystem to derive a PNEC  , survival of antibiotic‐resistant genes, and whether or not these genes can be transferred to other bacteria via horizontal gene transfer, ultimately resulting in human health risks (Murray et al., Assessing site‐specific risk from manufacturing wastewater effluent has become common practice in the evaluation of pharmaceuticals in the environment. One challenge in conducting the risk assessment is the availability of PNEC values. The AMR Industry Alliance has combined resources to set PNEC targets for antibiotics and to make the PNECs publicly available. However, the list is not comprehensive, and assessors are left with the challenge of what to use in the absence of PNEC data. Based on the above statistical evaluation, antibiotic manufacturers may opt to employ a default value of 0.05 µg/L if the compound belongs to one of the classes studied Table  and whenContinued engagement in scientific discussion with all stakeholders with the aims of expanding the knowledge‐base, developing and improving ways to assess risks, and optimizing strategies to deal with AMR, without compromising patient access to necessary medicines, is fundamental to continuing to develop ways to mitigate against AMR.The authors are all full‐time employees of international pharmaceutical companies, working as environmental toxicologists, risk assessors, microbiologists, and engineers.This article contains online‐only Supporting Information.The supporting information contains all environmental toxicity data developed or compiled by the authors for each antibiotic in the dataset. The table also includes PNEC‐MIC and PNEC‐ENV values and an explanation of how the PNEC‐ENV was derived.Click here for additional data file.


With a stretched healthcare system and elective surgery backlog, measures to improve efficiency and decrease costs associated with surgical procedures need to be prioritized. This study compares the benefits of multi‐disciplinary involvement in an enhanced recovery after surgery (ERAS) protocol‐led overnight model following total hip replacement (THR) and total knee replacement (TKR).Patients in each of two private hospitals undergoing THR or TKR were prospectively enrolled. One hospital (Overnight) was fully committed to the ERAS protocol implementation on all levels and formed the treatment group while in the other hospital (control), patients only had the anaesthetic and operative procedure as part of the ERAS protocol but did not follow the perioperative measures of the protocol. Outcomes on hospital length of stay (LOS), inpatient rehabilitation, functional outcomes, satisfaction, adverse events and readmission rates were investigated.P < 0.0001). The Overnight group had lower rates of inpatient rehabilitation utilization , similar improvements in functional hip and knee scores and no increased rate of adverse events or readmission. All patients in both groups were satisfied with their treatment.Median LOS in the Overnight group was significantly smaller than in the control group (1 vs. 3 days, Overnight THR and TKR can safely be performed in the majority of patients, with a multi‐disciplinary approach protocol and involvement of all perioperative stakeholders. There are significant public and private elective surgery backlogs as a result of the pandemic measures needed for COVID‐19. Overnight short stay joint replacement is safe and feasible with similar patient functional outcomes as well as satisfaction when an ERAS protocol is implemented with the involvement of all stakeholders. Overnight short‐stay joint replacement surgery will save costs and hospital resources, therefore allowing more patients to undergo surgery within a defined budget. Prior to the COVID‐19 pandemic, backlogs and increasing demand on the already stretched healthcare system was pushing it to the brink of economic unsustainability.Considering the current situation of cost and waitlists for joint replacement surgery in the Australian setting, especially in the post COVID landscape, it is imperative to harness the benefit of such models for both the patient as well as the system. By getting suitable patients home on the same day or following an overnight stay in hospital, the healthcare system would benefit with increased case capacity (from decreased bed blocks) and significantly decreased costs per case. Patients would benefit from being able to recover in a familiar setting with all the support from allied health services that they would have had as an inpatient as well as support from family and friends, return to remote work sooner and the aforementioned cost savings. Further, evidence in the literature shows no benefit and increased costs from inpatient rehabilitation following all total hip (THR) and total knee (TKR) joint replacement surgeries.This study aims to compare the benefits of multi‐disciplinary involvement in an ERAS protocol following THR and TKR. We report on the safety of this approach and its effect on overnight joint replacement surgery in an Australian setting through outcomes on hospital length of stay (LOS), inpatient rehabilitation utilization rates, patient functional outcomes, patient satisfaction, adverse events and hospital readmission rates.Consecutive patients in each of two private hospitals undergoing THR or TKR under the lead investigator were prospectively enrolled for inclusion in this study. Exclusion criteria were patients with a background history of substance abuse, malignant hyperthermia or allergy to anaesthetic agents, patients with impaired cognitive function and revision surgery procedures.The two private hospitals where patients underwent surgery had different goals and practices regarding perioperative patient care which formed the basis of the different groups. One of the two hospitals was fully committed to the ERAS/overnight protocol implementation on all levels and formed the treatment group (Overnight). This group involved a uniform goal towards an overnight stay with perioperative and ward nurses, allied health staff and hospital administration all aiming to achieve this outcome. In the other hospital, patients only had the anaesthetic and operative procedure as part of the Overnight protocol (surgeon/anaesthetist controlled elements). The remainder of the patient care team – nursing, allied health and hospital administration staff, did not specifically aim to achieve an overnight or short stay outcome for the patient's hospitalization. The perioperative measures detailed in the ERAS/Overnight protocol Appendix  were notAll TKRs were cemented and performed with a standard medial parapatellar approach, with the same posterior stabilized or medial pivot implants used in all patients. All THRs were performed using the SuperPATH approach with uncemented implants and a ceramic on polyethylene bearing.The overnight protocol and differences between the overnight and control groups are provided in Appendix The primary outcome measure was LOS postoperatively, defined as the number of nights in the hospital after the surgery. The secondary outcome measures included early patient functional score improvements (preoperative to 6 week post‐operative Oxford Hip and Knee scores), patient satisfaction with their treatment (yes/no), adverse events  and readmission into the hospital after discharge for any cause within 90 days of surgery.t‐tests. Categorical variables with skewed distributions such as LOS are reported as median and interquartile range (IQR) with median tests used to compare them. Frequency and percentages were reported for categorical variables and chi‐squared tests were done for their comparison. To make an accurate comparison of hospital LOS, we undertook a survival analysis approach where LOS in nights was used as the time variable and all subjects were considered to have an event at the end of LOS. Kaplan‐Meyer survival curves were generated to compare the LOS by hospitals for different sub‐groups. Statistical comparison of the curves was carried out by using log‐rank test.Normally distributed demographic data with continuous variables are reported as means and standard deviations with independent sample Ethics Approval was obtained from Hunter New England Ethics Committee (Ref: 2020/ETH01441).A total of 101 patients undergoing 56 THR and 55 TKR were included in the study across the two groups. The control group had 28 THR and 23 TKR patients. A summary of the demographic comparisons between the two groups are provided in Table P < 0.0001) . When comparing TKR, median LOS was also 1 day in the Overnight group and 3 days in the control group (P < 0.0001). Sub‐analysis comparing similar ASA grades showed similarly decreased median LOS in the Overnight group for ASA 2 patients  and ASA 3 patients .Overall median LOS in the Overnight group was 1 day and significantly lower than the median LOS in the control group of 3 days (P < 0.0001) . 60.9% of control group patients and 9.1% of Overnight group patients who underwent TKRs were discharged to rehabilitation facilities (P < 0.0001). Sub‐analysis comparing similar ASA grades showed decreased discharge to rehabilitation facilities in the Overnight group for ASA 2 patients  and no significant difference in ASA three patients .41.2% of all joint replacement patients were discharged to rehabilitation facilities in the control group, compared with 4% in the Overnight group (P = 0.195). There was a difference in median VAS pain score between the two groups on day of discharge from hospital . Sub‐analysis of THR and TKR showed significant differences in only the THR median VAS pain score on day of discharge from hospital .There were no significant differences in median VAS pain score between the two groups on D0 . Oxford Knee scores improved significantly from a mean of 15.27 preoperatively to a mean of 42.05 6 weeks postoperatively in the Overnight group, and from 13.48 to 40.22 in the control group. The mean improvement in Oxford Knee scores between the groups was 0.03 lower in the control group (P = 0.987). All patients in both groups were satisfied with their treatment.Oxford Hip scores improved significantly from a mean of 8.68 preoperatively to a mean of 44.32 by 6 weeks postoperatively in the Overnight group, and from 13.79 to 45.54 in the control group. The mean improvement in Oxford Hip scores between the groups was 3.89 lower in the control group (P = 0.495). One patient in the Overnight group was readmitted with a complication‐requiring reoperation for wound dehiscence, after a fall 3 weeks postoperatively, compared with no patients in the control group (P = 0.495). There were no other complications or readmissions within 90 days in either group.Four percent of patients had a blood transfusion in the control group compared with 0 in the Overnight group . The anaesthetic and operative Overnight measures were identical between the two groups, with the major difference to this higher median LOS being perioperative hospital uptake of Overnight measures. Similarly, the majority of patients who went to inpatient rehabilitation in the control group hospital had already been cleared for discharge home by physiotherapy, again reflecting hospital messages and subsequent patient expectations contributing to increased hospital LOS and use of inpatient rehabilitation facilities. The findings in this study on subgroup analysis of ASA 2 and ASA 3 patients also show that for the majority of patients, Overnight arthroplasty is feasible even with the presence of underlying comorbidities.Cost savings associated with a successful Overnight model are substantial. The cost of a joint replacement as an Overnight patient without inpatient rehabilitation is estimated to be around AUD 13 000  in this study, with this also including 6 weeks of rehab at home physiotherapy services. For the same procedure, the cost of a 5 day inpatient hospital stay ($21 000–$22 000)This study shows that overnight joint replacement surgery does not come at any increased risk to patient safety. This is also consistent with other studies on the subject.These findings on the effectiveness of a multi‐disciplinary Overnight protocol in safely decreasing hospital LOS following THR and TKR to overnight, should be interpreted while considering the study limitations. The different patient populations undergoing surgery at the two hospitals had different ASA grade distributions with more ASA 2 patients in the Overnight group and more ASA 3 patients in the control group. We acknowledge that the Overnight protocol and overnight stay joint replacement surgery is not for all patients. Certain individual patients may require additional support following their surgery, more nights in hospital and access to inpatient rehabilitation. This should be offered on an as needs basis considering individual patient factors, rather than the blanket inpatient rehabilitation pathways for all patients. However, the subgroup analysis showed significant differences between the two hospitals even when comparing only ASA 2 patients, and a trend towards similar findings in ASA 3 patients although this did not reach statistical significance. Furthermore, the majority of patients from the control group who went to inpatient rehabilitation had already been cleared for discharge home by physiotherapy prior to their transfer to the rehabilitation service. This may reflect potential payment incentives guiding patient care. Secondly, a formal cost analysis was not within the scope of this study. However, we feel the extrapolation of hospital LOS reduction and decreased use of inpatient rehabilitation facilities presents sufficient evidence on the cost saving benefit of our multi‐disciplinary Overnight protocol.Overnight THR and TKR can safely be performed in the majority of patients, with a multi‐disciplinary approach Overnight protocol and involvement of all perioperative stakeholders.None declared.Jason Chinnappa: Conceptualization; formal analysis; investigation; methodology; supervision; validation; writing – original draft; writing – review and editing. Sam Aktas: Data curation; project administration; writing – original draft. Abdul Majid Dabboussi Majid Dabboussi: Data curation; investigation; project administration; writing – original draft. Md Bayzidur Rahman: Data curation; formal analysis; methodology; writing – review and editing. Sol Qurashi: Conceptualization; methodology; project administration; resources; writing – original draft; writing – review and editing.Appendix S1 ERAS Protocol.Click here for additional data file.


An adult patient was diagnosed with multisystem Langerhans cell histiocytosis with lung and bone lesions. Her lung lesions improved after smoking cessation. Radiotherapy was performed for the bone lesions. Follow‐up assessment at 2 years after diagnosis showed no recurrence. Our case shows that remission is possible even without systemic treatment. Even in adult cases of multisystemic Langerhans cell histiocytosis, remission may be achieved without systemic therapy if the symptoms of lung involvement are relieved by smoking cessation. Blood tests at the time of initial examination are shown in Table s Figure . Respiras Figure , leading3Langerhans cell histiocytosis is a disease characterized by aggregation of CD1a+/CD207+ cells and inflammatory cell infiltration. Although the etiology is unknown, the tumor is considered to result from activation of the mitogen‐activated protein kinase pathway and defined as an inflammatory bone marrow tumor in the Histiocyte Society's 2016 revised classification.4We experienced a case of MS‐LCH in an adult with lung and bone involvement in whom the symptoms of pulmonary lesions were rapidly relieved by smoking cessation and other lesions were treated locally. Patients with such a condition may experience relief of symptoms, even without undergoing systemic therapy.Chie Yamamoto served as the author of the report. Taishi Harada, Ryo Sawada, Takumi Sugimoto, and Hiroki Hayata provided significant revisions to the report.No funding was received for this work.The authors declare no conflicts of interest associated with this manuscript.This study was conducted according to the principles of the Declaration of Helsinki.Patient consent was obtained for the publication of this report and accompanying images.


We investigate whether autistic people's vulnerability is taken into account at each stage of the criminal justice system (CJS). Defense lawyers from 12 nations were included in the study although the sample was predominantly from the UK. Lawyers completed an online survey regarding one case in which they had defended an autistic client between January 2015 and January 2020; and on one case in which they had defended a nonautistic client charged with a similar offense, to provide a comparison group. Ninety‐three lawyers (85% in the UK) reported on one autistic case, and 53 also reported on one nonautistic case. 75% of autistic clients were not given reasonable adjustments during the process. Only 43% were offered an appropriate adult during police investigations, even though they had an existing diagnosis of autism. 59% of prosecution barristers and 46% of judges said or did something during the trial that made the lawyers concerned that they did not have an adequate understanding of autism. Lawyers were 7.58 times more likely to be concerned about their autistic client's effective participation in court and were 3.83 times more likely to be concerned that their autistic clients would engage in self‐harm, compared with their nonautistic clients. There is a failure to identify and address autistic peoples' disability within the CJS. There is a need for mandatory autism training for police officers and the judiciary, with a focus on identifying autism and understanding the needs of autistic people so that reasonable adjustments are offered in all cases.This study sought to investigate if the needs of autistic people are being overlooked by the police and other professionals within the CJS. Results show that autistic people are not always given the support they need during police questioning or in court. The experience of being involved with the police may also have a more negative impact on autistic peoples' mental health than that of nonautistic people. The report concludes that reform is needed to ensure a fair trial for all  must be offered an appropriate adult (AA) during police questioning  effectively, the level of autism awareness within the CJS, as indicated by lawyers' satisfaction with the way autistic defendants were treated, and whether the defendant's autism was considered by the judge to be a mitigating factor. Finally, we identify any high‐risk mental health concerns such as self‐harm and suicidality among autistic defendants. The assessment of mental health concerns will be ascertained through the survey of lawyers rather than by assessing autistic defendants directly. We compare autistic and nonautistic cases to examine four key questions across each stage of the justice process :Participants were defense solicitors and barristers who had defended an autistic client in the 5 years prior to taking part in the study (since January 2015). Legal professionals were recruited via UK, European and American professional bodies  and adverts placed on social media . A further effort to recruit legal professionals from other countries was made by placing adverts on Reddit, which has a substantial American user base.A case–control design compared autistic with nonautistic clients of the same lawyer who were charged with a similar category of offense of which a verdict had been reached within the 5 years prior to data collection . Autistic clients received an autism diagnosis from a medical professional .Written informed consent was obtained in an online tick box format from all participants. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. All procedures involving human participants were approved by the Psychology Research Ethics Committee, University of Cambridge (PRE.2019.044).Data were collected using an online survey. Survey questions were developed in collaboration with members of the autistic community with lived experience of the UK CJS to ensure that the content of the survey was relevant. Four autistic adults took part in a focus group and provided written feedback during the design phase and final draft of the survey. Lawyers and barristers were also consulted during the design phase to ensure the content was relevant to legal professionals. Four of the consultants practice in the UK and one practices in both the USA and UK. Survey items were then subdivided into seven sections to improve readability based on feedback from legal professionals: (i) the client , (ii) the alleged crime (offense category and previous convictions), (iii) the trial (concerns regarding effective participation in court), (iv) the verdict and sentencing, (v) reasonable adjustments, (vi) the legal professional's role in the case, and (vii) concerns regarding the client's mental health during their involvement with the CJS. Data on mental health concerns are not derived by assessing individuals directly but from the accounts provided by lawyers based upon assessments of their client carried out during the justice process. Following consultation with lawyers, it was agreed that the term ‘reasonable adjustments/amendments’ is a familiar legal term to lawyers in the UK and USA, therefore we did not define this term in the survey. Lawyers in other countries may have interpreted the definition of reasonable adjustments differently. All items included a ‘do not know’ response option.Each section consisted of multiple‐choice questions with ‘do not know’, ‘other (please specify),’ and open text boxes included where appropriate. For items that had a ‘yes’, ‘no’, or ‘do not know’ option, data were scored as 1 for ‘yes’, 0 for ‘no’ and ‘do not know’ was scored as missing data. For Likert scale items  data were scored as 1 for ‘extremely dissatisfied’, 2 for ‘somewhat dissatisfied’, 3 for ‘neither satisfied nor dissatisfied’, 4 for ‘somewhat satisfied’ and 5 for ‘extremely satisfied. Survey items can be found in Statistical analyses were performed using R Version 4.0.2 using the miceadds v3.11‐6 package to run the adjusted standard errors regressions  = 20·61, p > 0·001.Ninety‐three legal professionals consented to take part in the survey and reported on 93 cases involving autistic individuals. Fifty‐three of the same professionals reported on a nonautistic client they had defended who was charged with a similar offense within the same period (since January 2015). See Table Only 25% (15/60) of autistic clients were given reasonable adjustments with 38% (23/60) not given any even though lawyers stated that this would have been beneficial. 3% (2/60) stated that their autistic client had not needed adjustments at the police stage while 33% (20/60) did not receive any adjustments because their autism diagnosis was unknown at this time. This means that 75% of autistic clients did not receive any reasonable adjustments at the police station. Of the autistic clients whose case went to trial, 60% (40/67) were given reasonable adjustments in court, and 22% (15/67) were not given any, even though their lawyers stated that this would have been helpful. Only 18% (12/67) were considered not to have needed any adjustments during their trial.B = 2·02, z = 5·64, p < 0·001) times more likely to be concerned about their autistic client's effective participation in court compared with their nonautistic clients. 62% (58/94) received their autism diagnosis before the trial, 29% (27/94) were diagnosed during the criminal proceedings, and 10% (9/94) received their diagnosis after proceedings had ended. These data need to be considered in light of the fact that not all the autistic defendants were diagnosed prior to involvement with the CJS.Lawyers were 7·58  the jury or tribunal of fact were informed the defendant was autistic alongside information about how this may have affected their presentation and communication in court. Lawyers indicated that 59% (42/71) of prosecution barristers and 46% (33/71) of judges or magistrates said or did something during the trial that made them concerned that they did not have an adequate understanding of autism. In cases where their client was found to have committed a crime, 60% (30/50) of judges saw their client's autism as a mitigating factor, the majority of whom were given a suspended or reduced sentence  times more likely to be concerned that their autistic clients would engage in self‐harm behaviors compared with their nonautistic clients and were 5·73 (95% CI = 2·46–13·35) times more likely to report that their autistic clients experienced meltdowns as a result of their involvement in the CJS  of autistic defendants were not given an AA during police investigations and a further 18% (16/88) did not have an AA present because their diagnosis was not known to the police. The use of AAs to assist vulnerable adults at the police station is only available in the UK, so these results are not generalisable to other jurisdictions. However, the concept of reasonable adjustments is a requirement under the ADA (1990) in the USA and the Equality Act (2010) in the UK. The identification of vulnerable defendants is a vital first step in ensuring that their right to a fair investigation is upheld. Our data suggest that a proportion of autistic defendants are not identified as vulnerable adults and that this is even evident in cases where an existing diagnosis is present. Shockingly, 38% (23/60) of the autistic defendants in this study were not given any reasonable adjustments at the police station even though their lawyers stated that this would have been beneficial, and 33% (20/60) did not receive any adjustments during police questioning because their autism diagnosis was not known at the time. The current literature on intellectual disabilities and policing demonstrates a more general, global problem with accurately identifying vulnerable people within the CJS  of autistic clients who had a trial were given reasonable adjustments in court compared with only 25% (15/60) at the police station suggesting that more autistic defendants were given reasonable adjustments in court than when they were in police custody. These findings could be a reflection of the lawyers and barristers in our sample being more experienced at identifying autistic defendants' support needs once they are instructed, which is typically following a police investigation. Autistic clients may need reasonable adjustments at every stage of the CJS to ensure that they are able to participate effectively in the justice process. Our research suggests a failure to identify all autistic defendants as vulnerable adults as they enter the CJS, which undoubtedly leads to poor access to justice.Identifying a defendant as autistic and as a vulnerable adult is the first step in ensuring effective participation throughout the CJS. There are three possible barriers to identification: First, many autistic people do not disclose their diagnosis at the point of police contact  of prosecution barristers and 46% (33/71) of judges said or did something during the trial that made the defense lawyers concerned that they did not have an adequate understanding of autism. In only about half of the cases that had a trial by jury, the jury were informed that the defendant was autistic alongside information about how this may have affected the defendant's presentation and communication in court. Not giving jurors adequate information about a defendant's autism may lead to jurors misinterpreting the autistic behavior of a defendant in court. Education about autism for judges and jurors would likely avoid discriminatory biases arising from ‘odd’ or atypical behavior exhibited by the defendant. Previous research has shown that providing mock jurors with diagnostic information about an autistic witness affected credibility ratings  to address shocking reports on the incidence of suicide and self‐harm in prisons. A Council of Europe  report shttps://www.autism.org.uk/advice-and-guidance/topics/criminal-justice/criminal-justice/professionals). Some police services have opted in to the National Autistic Society's autism‐awareness training, however this is not mandatory and many CJS professionals in the UK receive no training in autism. Our data strongly suggests that all police services should have mandatory autism training, with a focus on identifying autistic traits. Screening tools may also help police to identify when someone might be vulnerable in the absence of a diagnosis. However, we do acknowledge the limited resources available to police services and the CJS more broadly, which may make implementing screening measures difficult.A key policy implication of this study is the importance of autism awareness training across the CJS. Autism awareness training for CJS professionals would help staff identify more subtle social and communication difficulties and equip professionals with practical advice on how to adjust practices to support autistic people. Some states in the USA, such as New Jersey . While steps were taken to address this limitation, such as keeping items broad and relevant to multiple jurisdictions and recruiting lawyers from social media with an international usership, it is nevertheless important to note that the implications of these findings may not be relevant to other nations with differing CJS structures.Autistic clients included in this study were more likely to have a co‐occurring mental health condition than nonautistic clients. It is difficult to be sure which problems these clients faced were due to their autism and how much stems from their co‐occurring mental health conditions. However, the current study presents real‐world cases where a high rate of co‐morbidity is expected, particularly given that living with autism increases ones' risk of depression and anxiety (Nah, Brewer, Young, & Flower, These data provide an insight into the injustices autistic people face following arrest and identifies a number of situations at each stage of the justice process in which there is a failure to identify, acknowledge and address autistic peoples' disability. Policy changes are needed to address issues such as the systematic identification of autism among police detainees and widespread autism awareness training for police officers, the Judiciary, and other legal professionals. Data are needed from autistic defendants themselves to fully understand their experiences at each stage of the CJS and its impact on their mental health. There is currently no evidence that autistic people are more likely to offend than nonautistic people. Data are needed on whether autistic people are more likely to be noticed by law enforcement and are more vulnerable to offending. Whilst the data presented here are preliminary, it is hoped that this study will be a catalyst for future research in this area. An important area for future study includes understanding how autistic people who are victims of crime navigate the CJS and whether their support needs are met.Table S1 Offense categories for autistic and control clientsTable S2. Diagnoses given by a clinician for autistic and control clientsTable S3. Coefficients and standard errors for regressions shown in Table 6Table S4. Lawyers survey questionsClick here for additional data file.