Hummingbirds are frequently presented to California wildlife rehabilitation centers for medical care, accounting for approximately 5% of overall admissions. Age, sex, and reason for admission could impact hummingbird survivability, therefore identification of these factors could help maximize rehabilitation efforts.Calypte anna, Calypte costa, Selasphorus rufus, Selasphorus sasin, Archilochus alexandri), found in urban settings, and admitted to California wildlife rehabilitation centers over 26 years.Mixed-effects logistic regression models were used to identify specific threats to the survival of 6908 hummingbirds (1645 nestlings and 5263 non-nestlings) consisting of five species  and interactions with domesticated animals (12.9%). Survival odds were lower if a hummingbird was rescued in a “torpor-like state” and were higher if rescued for “nest-related” reasons. Evaluation of treatment regimens administered at wildlife rehabilitation centers identified supportive care, including providing commercial nutrient-rich nectar plus solution, to significantly increase hummingbird survivability.Our results provide evidence of threats to hummingbirds in urban habitats, based on reasons for rescue and presentation to rehabilitation centers. Reasons for hummingbird admissions to three California wildlife rehabilitation centers were anthropogenic in nature  and constituted 25% of total admissions. There was a clear indication that supportive care, such as feeding a commercial nectar solution, and medical treatment significantly increased the odds of survival for rescued hummingbirds. Hummingbirds, found only in the Americas, are often presented to wildlife rehabilitation centers . CommonlWildlife rehabilitation centers play a vital role in rehabilitation efforts and provide valuable data for wildlife commonly found in urban habitats  through To date and to the best of the authors’ knowledge, studies have not yet assessed outcomes for hummingbird rehabilitation. Hummingbird populations in urban settings are known to face a wide variety of anthropogenic threats, including domestic animal interaction, collisions with glass windows, and other manmade structures , and desTo address factors that impact the success of hummingbird rehabilitation, a retrospective study evaluating trends in presentation, treatment, and eventual disposition from data collected by three California wildlife rehabilitation centers was performed. Our objectives were to investigate the demographics of hummingbirds admitted to wildlife rehabilitation centers, to determine common presenting reasons for these hummingbirds being brought to the wildlife rehabilitation centers, to describe seasonal patterns of admission, and to examine whether age, sex, season, treatment administration, and/or reason for admission of a presented hummingbird influenced their rehabilitation outcome.https://www.wrmd.org/). Data used for the current study was imported from this database for the three rehabilitation centers. Admission records for hummingbirds presented to Lindsay Wildlife Experience (data for 1991–2016), Santa Barbara Wildlife Rescue Center (data for 2016), and California Wildlife Center, Malibu (data for 2013–2016), all located in California, were used for analysis. Hummingbirds presented to wildlife rehabilitation centers were reported as nestling/adult on the ground unable to fly, sick, injured, or dead when they were brought into the wildlife rescue centers between January 1st, 1991 and December 31st, 2016. On admission, the rehabilitation center staff collected the following information for each bird: age, sex, species, the reason for admission, date of admission, and the date and place the bird was found. Veterinary technicians or veterinarians completed physical examinations and recorded administered treatments. All data were entered into an online database software called Wildlife Rehabilitation Medical Database (WRMD: Selasphorus spp. and non-Selasphorus spp.) based on known breeding ranges and seasons of hummingbird species in California, and associated information reported by rescuers. The adult-like birds were further classified as “Selasphorus spp.” and “non-Selasphorus spp.” (Selasphorus spp. (Anna’s Hummingbirds (ANHU), Black-Chinned Hummingbirds (BCHU) and Costa’s Hummingbirds (COHU)), records mentioning adult males were assigned “adult-like” and “male” for age and sex respectively. All other non-nestling and non-Selasphorus spp. hummingbirds were categorized as “unknown” and “female-like” for age and sex respectively. Similarly, for Selasphorus spp., records mentioning adult males (Allen’s Hummingbirds [ALHU] and Rufous Hummingbirds [RUHU]) were termed as “adult-like” and “male” for age and sex respectively. All other non-nestling Selasphorus spp. hummingbirds were considered “unknown” and “female-like” for age and sex. Lastly, records for hummingbirds without signalment information were categorized as “unknown” for age, sex, and species.The WRMD data for hummingbird age were initially classified into two main categories: “nestling” and “adult-like bird” hummingbirds. All nestlings were considered unknown for sex and were classified into species groups . Two categories were based on the location where the hummingbirds were found. Hummingbirds that were found on a patio, sidewalk, driveway, road, pool, or grass lawn were classified as “found on the ground” whereas hummingbirds that were found inside a human-built structure  were classified as “found inside”. If a hummingbird was found with a cat, dog, or in one case a chicken, the reason for admission was designated as “associated with domestic animal”. Hummingbirds that were associated with or found in the vicinity of a known nest were identified with the reason of “nest-related”. These included nestlings that were found fallen on the ground but the rescuer had been observing them on a nearby known nest, as well as nestlings that were rescued along with the nest, either where the nest was abandoned by the parents and was easy to extract from the tree/location or where the nesting trees/shrubs were cut down and the nest was found with the nestlings. Hummingbirds that were found at the feeder, usually unresponsive and sitting or hanging upside down, as well as hummingbirds sitting on a bush or fence that people were able to capture with minimal effort, were classified as “torpor-like state”. Another reason for admission included “window collisions” where hummingbirds were brought in after a collision with glass windows, windshields of parked vehicles, and glass doors. Lastly, entries where the reason for admission was not mentioned were classified as “unknown”.Based on the data available for supportive care and treatment provided, a binary variable  was generated. Additional binary variables were created detailing the type of supportive care or treatment including (1) the provision of heat as a supportive measure for possible shock, (2) administration of oral fluids like commercial nectar plus solution as hydration and/or for energy supplementation, and (3) administration of medications like a non-steroidal anti-inflammatory  and steroids (dexamethasone) as well as antibiotic therapy . All treatments included in the study were provided by rehabilitation centers.https://zenodo.org/record/4311820.Since none of the submitted birds had leg bands, all rescued hummingbirds were assumed to be first-time rescues for the purpose of this study. Two mixed-effects logistic regression models were developed to predict the final disposition of hummingbirds  during the rehabilitation process. The first model looked at all the individuals while the second model was developed included only a subset of individuals who received preliminary treatment. Survival was defined when birds were transferred to flight cage facilities for further rehabilitation and/or released, or when nestlings were transferred to nurseries and no death or euthanasia was reported by rehabilitation centers. Species and sex groups were included as random effects. Model candidates were fitted and were compared with each other to identify best-fitting models based on AIC and ANOVA test. For the first model (model 1), factors related to demography and whether treatment was provided were tested, and reasons for admissions were explored. A second model predicting survival was developed that included only a subset of individuals whose records indicated that they received preliminary treatment at rehabilitation centers (model 2). Binary variables for each treatment option  were generated and included in the model. We assumed that reason for admission also accounted for the physical condition of the bird at the time of admission, which may have significantly affected the treatment options. The models were developed in R using the “glmmTMB” package . For botn = 2485) were transferred to the flight cage to be returned to a free-ranging environment while the rest included birds that were dead on arrival , died during the process of rehabilitation , and birds that needed to be euthanized during the process of rehabilitation   either died or were euthanized, with higher nestling deaths reported between March and June  . A totaland June . Similarn = 2950) and at 2.0% (n = 135) the least common was “torpor-like state” . Inclusion of an interaction term between age and season significantly improved the model fit (ANOVA Chisq p > 0.001). Predicted probability of successful release for nestlings based on model with treatment options (model 2) was also significantly higher than adult-like birds , adult-like birds: , while the model evaluating treatment options showed survival odds of 2.61 . Birds rescued in summer also showed similar odds to that of birds rescued in spring, and were twice more likely to be released than birds rescued in fall , model 2 = ). Birds rescued in winter also showed significantly higher odds of survival when compared with birds rescued in fall , model 2 = , p = 0.016)). Season and age interaction terms included in model 1 showed statistically non-significant odds ratios (n = 1067) and spring , and least probability of release for birds rescued in fall .Age was not a significant factor related to survival in the general model . In the s ratios . Model-ps ratios  for birdp < 0.001), model 2 = ). Similarly, within model 1, hummingbirds with a reason for admission related to domestic animals , window hit , and those which were found on the ground  also showed significantly lower odds of release compared to hummingbirds with an unknown reason for admission (n = 575). 45.7% of total nestlings contrary to only 3.62 adult-like birds were admitted due to “nest-related” reasons. Since both the age and reason for admission affect survivability and are associated with each other, they are thought to act as confounders for each other. Hence, the inclusion of both variables in the model was warranted. The least probability of survival was found in birds rescued in “torpor-like state”  followed by “window collisions” . The model-predicted probabilities for release are presented in Hummingbirds that were rescued for reasons related to “torpor-like state” had significantly lower odds of release compared to hummingbirds for which reasons of rescue were unknown  compared to hummingbirds that did not receive antibiotics. Provision of oral fluids also increased the odds of successful release significantly . Even after accounting for reasons for admission, hummingbirds that were administered steroids  and NSAIDs  were found to have reduced odds of survival.Model 1 indicated that provision of supportive treatment, in general, was not found to be significantly associated with improving the odds of successful hummingbird release , it nevertheless cannot be denied that the large number of admissions under this category was concerning. Hunting attempts by cats are known to be lethal for birds  and havep > 0.05). The data showed an increased number of window collisions during early spring that can be associated with the territorial nature of breeding hummingbirds , who realized they hadn’t seen the hen nearby for a “long time” and therefore assumed the nest had been abandoned. Therefore, “nest-related” hummingbirds, especially young ones, raise the question as to whether or not these birds truly needed human interventions, even though rehabilitators do an initial examination for the dependent nestling to check if the crop has nectar or diet items from the hen in the wildlife to determine if reuniting attempts should be made or not. Guidelines that were developed by a hummingbird wildlife rehabilitators for evaluating if a nestling has been abandoned should be consulted before intervention occurs .p < 0.005). All records that mentioned the rescuer was able to capture the hummingbird without the bird attempting to escape were placed under this category. Hummingbirds can enter a state of torpor due to a variety of underlying reasons, such as physiological reasons, systemic illness, traumatic injury, severe dehydration, hypoglycemia, hypothermia, systemic shock, etc., or restricted energy resources  and summer , correlating with the increased number of new nestlings (https://www.audubon.org/bird-guide) and first-year breeding individuals  admitted to wildlife rehabilitation centers remains a challenge due to the complexity in the differentiation of species that are female-like in their appearance. Although overall treatment and rehabilitation protocols were not affected by hummingbird species or sex, unidentified categorization of individuals contributes to skewed demographics . In addition, some of the categories such as “found on ground,” “torpor-like”-state, and “associated with domestic animal”, may have been a secondary rather than the primary cause.A higher degree of ecological awareness and understanding of the impacts of urbanization on hummingbird populations are key to mitigate future anthropogenic threats . With inOur results provide evidence of anthropogenic threats to hummingbirds in urban habitats. Anthropogenic reasons for hummingbird admissions such as physical injures due to domestic animals and collisions with windows constituted more than a quarter of cases reported by three Californian rehabilitation centers. We also highlight treatment options that can significantly help improve the rehabilitation success of hummingbirds and we also saw a clear indication that the provision of supportive treatments and medical aids such as the provision of commercial nectar solution can significantly increase the odds of survival of rescued hummingbirds.10.7717/peerj.11131/supp-1Supplemental Information 1Click here for additional data file.


Prostate cancer (PCa) is the most commonly diagnosed non-skin cancer in men and one of the leading causes of cancer-related death. The driver of PCa proliferation and growth is the androgen receptor (AR) and inhibiting this receptor is the standard of care for patients, following surgery or radiotherapy. Unfortunately, the effectiveness of current therapeutics is temporary, with the cancer eventually developing drug resistance. Among the mechanisms of resistance are the arising mutations in the AR that make the receptor promiscuously activated by drugs or non-specific ligands, thus promoting cancer progression. The aim of this study is to characterize the responses of 44 AR mutants, derived from PCa patients, to available steroids that activate the receptor as well as to various treatments currently used in the clinic. This work will help create a tool to guide the medical team in selecting the best personalized treatment option for each patient.Resistance to drug treatments is common in prostate cancer (PCa), and the gain-of-function mutations in human androgen receptor (AR) represent one of the most dominant drivers of progression to resistance to AR pathway inhibitors (ARPI). Previously, we evaluated the in vitro response of 24 AR mutations, identified in men with castration-resistant PCa, to five AR antagonists. In the current work, we evaluated 44 additional PCa-associated AR mutants, reported in the literature, and thus expanded the study of the effect of darolutamide to a total of 68 AR mutants. Unlike other AR antagonists, we demonstrate that darolutamide exhibits consistent efficiency against all characterized gain-of-function mutations in a full-length AR. Additionally, the response of the AR mutants to clinically used bicalutamide and enzalutamide, as well as to major endogenous steroids , was also investigated. As genomic profiling of PCa patients becomes increasingly feasible, the developed “AR functional encyclopedia” could provide decision-makers with a tool to guide the treatment choice for PCa patients based on their AR mutation status. The emergence of drug resistance in prostate cancer (PCa) is a prominent factor of its progression to castration-resistant PCa (CRPC). Notably, human androgen receptor (AR) remains the main driver in both PCa and CRPC . TherefocBio cancer genomics portal data base [Our group and others have previously demonstrated that the treatment pressure directed at the AR by clinically used AR antagonists leads to drug-induced mutations in the AR androgen-binding site (ABS), changing the pocket characteristics and inducing receptor activation by adrenal/prostate androgens, by steroidal and non-steroidal ligands and, notably, by the AR antagonists themselves ,14,15,16ata base ,19, we fata base . We alsoata base .The remarkable plasticity of the AR under selective pressure of AR pathway inhibition (ARPI), coupled with the marked heterogeneity and negative prognostic significance of its cfDNA mutants, indicates that there is no “one size fits all” treatment for PCa patients. Furthermore, the results of our initial functional characterization of clinically observed AR mutants clearly indicate the need for novel AR antagonist(s) capable of inhibiting all forms of AR mutants.Darolutamide, a structurally distinct AR antagonist compared to ABS antagonists hydroxyflutamide, bicalutamide, enzalutamide and apalutamide , showed Full-length human AR (WT-AR) was encoded on a pcDNA3.1 expression plasmid . The AR point mutations were generated using the QuikChange II Site-Directed Mutagenesis Kit  as per manufacturer’s instructions using WT-AR as the template. The mutagenic oligonucleotide primers were designed individually with the desired mutation in the middle of the primer with ~10–15 bases of correct sequence on both sides  in RPMI 1640 medium with 5% charcoal-stripped serum (CSS) (Hyclone). After 24 h, cells were co-transfected with 25 ng of wild-type or mutated AR and 25 ng of the reporter plasmid pARR3-tk-luciferase using TransIT20/20 transfection reagent (3 μL/μg of DNA)  in Opti-MEM serum-free media (Life Technologies) for 48 h according to manufacturer’s suggested protocol. Cells were stimulated with increasing concentrations of DHT, estradiol, progesterone or hydrocortisone in 100% ethanol (0 to 500 nM). Control cells were treated with 100% ethanol alone. At 24 h after treatment, the medium was aspirated off and the cells were lysed by adding 60 μL of 1× passive lysis buffer  followed by shaking at room temperature for 15 min and two freeze/thaw cycles at −80 °C. Twenty microlitres of lysate from each well was transferred onto a 96-well white flat-bottom plate  and the luminescence signal was measured after adding 50 μL of luciferase assay reagent (Promega). The chemical oxidation of luciferin into oxyluciferin by the luciferase is accompanied by light production that can be quantified as luminescence by a TECAN M200Pro instrument. Each concentration was assayed in quadruplicate, n = 4, with at least 3 biological replicates. For each steroid, results were averaged and normalized by expressing them as a percentage of WT AR activity.PC3 cells lacking the AR and authenticated by Genetica using STR profiling were maintained in RPMI 1640 media (Life Technologies) and 5% FBS  at 37 °C and 5% COn = 4, with at least 3 biological replicates. Results were averaged and normalized by expressing them as a percentage of WT AR activity. Darolutamide was purchased from MedKoo Biosciences .PC3 cells were seeded and transfected as described above. At 48 h after transfection, medium was aspirated and replaced with medium containing 0.1 nM R1881  and either 0.1% DMSO (control) or serial dilutions of increasing concentrations of AR inhibitors ranging from 0 to 25 μM. After 24 h, cells were lysed and AR-dependent luciferase activity was quantified. Each concentration was assayed in quadruplicate, ® Turbo™ Transfer System . The membrane was then blocked for 30 min at room temperature with 5% non-fat skim milk in TBS, followed by incubation with 1/1000 dilution of AR (441) mouse monoclonal antibody  and GAPDH Antibody (G-9) HRP mouse monoclonal antibody  overnight at 4 °C. Membranes were then washed and incubated with 1/1000 dilution of Donkey Anti-Mouse IgG Polyclonal Antibody  for 1 h at room temperature, washed 3 times with TBS 0.1% Tween 20  and bands visualized using Odyssey Li-Cor Scanner.Twenty microlitres of each of 8 replicates of DMSO/control-treated lysate from the luciferase assay were pooled and the total amount of protein was assayed by bicinchoninic acid assay (BCA) . Equal amounts of protein samples were loaded on a 10% SDS-PAGE gel and electrophoresed at 120 V for 90 min. Proteins were transferred to PVDF membrane  at 25 V for 15 min using a TransBlotCharacterization of resistance-associated AR mutants is critically important for predicting and monitoring patients’ response to therapy and ultimately, for the development of evidence-based precision oncology practices ,23. In tThe response of AR mutants to increasing concentrations of DHT was measured using a luciferase reporter transcription assay in PC3 cells transiently transfected with either wild-type (WT) or mutated AR. The expression level of all of the mutants was evaluated by Western blotting . Some muWe further evaluated the response of 44 studied AR variants to activation by estradiol, progesterone and hydrocortisone. The wild-type AR was only mildly stimulated by progesterone with EC50 in the range of 150 nM and was not activated with estradiol or hydrocortisone at concentrations as high as 500 nM . NotablyOf the 44 studied AR mutants, eight exhibited slightly higher levels of activation by progesterone compared to WT-AR  . NeitherWe previously characterized CRPC-associated AR mutants that were mainly located in the vicinity of the receptor’s ligand-binding site ,21. All Acquired drug resistance represents a paramount danger for PCa patients. There are different mechanisms underlying the development of such resistance , yet AR Ten of the studied mutants—C620Y, L723F, G725D, L745F, M750I, N757D, S760P, S792P, S866P and V867M—did not demonstrate any detectible transcriptional activity in the presence of 0.1 nM of the synthetic active anabolic androgenic steroid, the standard AR agonist R1881, in our transcriptional inhibition assay. Out of those ten mutants, C620Y, M750I and S866P did not show any transcriptional activation also in the presence of 500 nM DHT, while the other mutants  required higher concentrations of DHT to reach and surpass the wild-type level of stimulation . Only foIn recent studies where patients were exposed to CYP17A1 inhibitor abiraterone and/or to first- and second-generation antiandrogens, the recurrent mutations were L702H, W742C/L, H875Y, F877L and T878A/S, that gained a significant spotlight and were characterized in our previous study . Herein In summary, out of 68 experimentally evaluated AR mutants (24 reported in the previous works and 44 presented in the current study), 25 demonstrated enhanced activation by DHT, 17 by progesterone, 12 by estradiol and 6 by hydrocortisone, compared to the wild-type receptor . The firEmergent AR mutations in men with advanced PCa treated with ARPI promote CRPC progression. The incidence of AR mutations was estimated to be around 15% for CRPC patients  and the


It is commonly accepted that King George II died of an acute aortic dissection. The origin of this association derives from retelling of the official autopsy performed by Dr. Frank Nicholls. While there is no doubt that King George II did have a Stanford Type A dissection, critical descriptions in the report point to a more likely cause of death. Aortic surgery, as in other medical specialties, has a lore and tradition that include the apocryphal. While Osler's quote “There is no disease more conducive to clinical humility than aneurysms of the aorta” is well documentedFrank Nicholls, MD, FRS, was an English physician, born in 1699. He attended Exeter College at Oxford, obtaining his Bachelor of Arts degree in classics and physics at the age of 19 years, he got his Master's degree at 21 years, a Bachelors of Medicine at 25 years, and his Doctorate at 30 years. Prior to graduating in medicine, he lectured at Oxford in anatomy, mostly devoted to what was then referred to as minute anatomy and demonstrated the structure of small blood vessels. In 1727, he presented to the Royal Society, a paper and demonstration regarding the formation of aneurysms and consequences, including frank rupture and “rupture of the internal coats of the artery,” probably one of the earliest descriptions of an aortic dissection albeit experimentally contrived.As has been described numerous times, on the morning of October 25, 1760, the King arose from bed, had a cup of hot chocolate, and went alone to his privy for a bowel movement. His valet heard a loud crash and found him unresponsive on the floor, his only sign of trauma being a cut on his face presumably related to his fall. The house surgeon, Mr. Andrews, was immediately brought in and as might be expected, was unable to revive the King despite multiple attempts at bloodletting. As it was apparent that the King had died, and as was the custom, an autopsy was ordered to rule out any nefarious cause of death. To this end, Dr. Nicholls was directed to perform the autopsy and embalming the following day.The abdomen was opened first, with no abnormalities noted with the exception “… some hydatides (or watery bladders) were found between the substance of each kidney, and its internal coat.” Upon opening the chest, hemopericardium was discovered, the blood coagulated, “… nearly sufficient to fill a pint cup … upon removing this blood, a round orifice appeared in the middle of the upper side of the right ventricle of the heart, large enough to admit the extremity of the little finger” . Dr. NiAs opposed to the lore that King George II died of aortic dissection that ruptured into the pericardial sac,The possibility that King George II did not die from an acute aortic dissection is suggested by the following considerations. First, as noted in the description of the autopsy, the aorta did not rupture, the right ventricle ruptured. Surgeons have long observed bleeding from the epicardial surface of either ventricle associated with an acute aortic dissection, typically originating from tracking of subadventitial blood from the aorta onto the surface of the heart, not as the result of a hole in the ventricle. Second, contrary to Dr. Nicholls' hypothesis, with modern experience with pulmonary hypertension , we know that systemic pulmonary artery pressure or a pressure surge in the artery will not result in rupture or perforation of the right ventricle. Instead, such high pulmonary artery pressures result in acute failure of the ventricle, for example, the pathophysiology seen with a large pulmonary embolism. Third, King George II had been having cardiac symptoms for some time with Dr. Nicholls noting in his report that “… his Majesty had, for some years, complained of frequent distresses and sinkings about the region of the heart … his pulse was, of late years, observed to fall very much upon bleeding.”While acknowledging that the King did have a Stanford Type A aortic dissection, from the autopsy report, the possibility arises that his demise was due to coronary artery disease. Angina would not be described by HeberdenAs an aside, there are two other historical notations in the autopsy report. First, the “hydatides” as noted by Dr. Nicholls, while at the time just a curiosity, is the earliest description of an association between renal cystic disease and aortic disease. This entity was recently described by Brownstein et alWe appreciate Dr. Nicholls' precise and detailed description of the autopsy that allows us to make a scientific reconsideration of the cause of death of King George II, using our current understanding of pathophysiology which evolved over the past 260 years since this momentous event.


H-indole-2-carbonitriles and 1-benzyl-3-iodo-1H-indole-2-carbonitriles is described. The reactivity of indole derivatives with iodine at position 3 was studied using cross-coupling reactions. The Sonogashira, Suzuki–Miyaura, Stille and Heck cross-couplings afforded a variety of di-, tri- and tetra-substituted indole-2-carbonitriles.An approach for the preparation of polysubstituted indole-2-carbonitriles through a cross-coupling reaction of compounds 1-(but-2-ynyl)-1 A . Th. Th45]. (71–92%) .7a–d as substrates , and this reaction was carried out with various substituents, either in ortho , meta (Me) or para  and also with pyridine derivatives. These products were purified either by crystallization or by chromatography on silica gel.Sonogashira cross-coupling was performed using bstrates  47,48].,48.7a–d 2 through a 6-endo-dig cyclization .,55.54,55purities .1H NMR and 13C NMR spectra ; 13C NMR and J-mod spectra were referenced to the central peak of CDCl3 at 77.0 ppm (39.52 ppm for DMSO-d6). 19F NMR was recorded at 282 MHz on the same instrument, using the CFCl3 as internal reference (δ 0.0). Chemical shifts were reported in parts per million , and coupling constants (J) were given in Hertz (Hz). Abbreviations for signal coupling are as follows: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; sextuplet; sext, dd, doublet of doublets; dq, doublet of quartets; m, multiplet. High-resolution mass spectra (HRMS) were obtained by the electrospray ionization time-of-flight (ESI) mass spectrometry. Thin-layer chromatography (TLC) was performed on TLC silica gel 60 F254. Compounds were visualized under UV light (λ = 254 nm) and/or by immersion in a KMnO4 solution followed by heating. Products were purified by flash column chromatography on silica gel (0.04–0.063 mm) using various mixtures of EtOAc and petroleum ether (35–60 °C fraction) as eluent. Heating was performed using a magnetic stirrer hotplate and an appropriate-sized heating block. Tributyl(vinyl)stannane was prepared from vinylmagnesium bromide and bis(tributyltin) oxide dioxin-6-1-Benzyl-3--1H-indole-2-carbonitrile (9l): Brown solid, 84%, 272 mg. mp 147–149 °C. 1H NMR : δ = 8.13 , 7.96–7.81 , 7.41–7.19 , 5.52 , 3.94  ppm. 13C NMR : δ = 158.3 (Cquat), 138.0 (Cquat), 136.2 (Cquat), 134.3 (Cquat), 129.8 (Ar-CH), 129.2 (Cquat), 129.1 (2Ar-CH), 128.7 (Cquat), 128.2 (Ar-CH), 127.8 (Ar-CH), 127.7 (Ar-CH), 127.2 (Ar-CH), 127.1 (Cquat), 127.0 (2Ar-CH), 126.6 (Ar-CH), 125.4 (Cquat), 121.9 (Ar-CH), 121.8 (Ar-CH), 119.5 (Ar-CH), 114.4 (Cquat), 111.0 (Ar-CH), 107.6 (Cquat), 105.8 (Ar-CH), 55.5 (OCH3), 49.2 (CH2) ppm. HRMS (ESI): calcd. for C27H21N2O (M + H)+ 389.16484; found 389.16527.1-Benzyl-3-(2-methoxypyridin-3-yl)-1H-indole-2-carbonitrile (9m): Brown liquid, 86%, 241 mg. 1H NMR : δ = 8.27 , 7.83 , 7.63 , 7.39–7.37 , 7.34–7.29 , 7.27–7.19 , 7.05 , 5.54 , 4.03  ppm. 13C NMR : δ = 161.3 (Cquat), 147.0 (Ar-CH), 139.9 (Ar-CH), 137.6 (Cquat), 136.1 (Cquat), 129.1 (2Ar-CH), 128.3 (Ar-CH), 127.1 (2Ar-CH), 126.4 (Ar-CH), 125.8 (Cquat), 122.8 (Cquat), 122.1 (Ar-CH), 121.8 (Ar-CH), 117.0 (Ar-CH), 115.3 (Cquat), 113.7 (Cquat), 111.0 (Ar-CH), 109.4 (Cquat), 53.6 (CH2), 49.4 (OCH3) ppm. HRMS (ESI): calcd. for C22H18N3O (M + H)+ 340.14499; found 340.14471.1-Benzyl-5-methoxy-3-(4-methoxyphenyl)-1H-indole-2-carbonitrile (9n): Brown solid, 89%, 254 mg. mp 152–154 °C. 1H NMR : δ = 7.65 , 7.37–7.27 , 7.26–7.18 , 7.10–7.02 , 5.48 , 3.89 , 3.82  ppm. 13C NMR : δ = 159.5 (Cquat), 155.7 (Cquat), 136.3 (Cquat), 133.3 (Cquat), 129.9 (2Ar-CH), 129.1 (2Ar-CH), 128.2 (Ar-CH), 127.6 (Cquat), 127.0 (2Ar-CH), 125.6 (Cquat), 124.5 (Cquat), 118.0 (Ar-CH), 114.7 (2Ar-CH), 114.5 (Cquat), 111.9 (Ar-CH), 107.5 (Cquat), 101.6 (Ar-CH), 55.9 (OCH3), 55.5 (OCH3), 49.3 (CH2) ppm. HRMS (ESI): calcd. for C24H21N2O2 (M + H)+ 369.15975; found 369.16033.1-Benzyl-6-methoxy-3-(3-methoxyphenyl)-1H-indole-2-carbonitrile (9o): Brown solid, 93%, 264 mg. mp 150–152 °C. 1H NMR : δ = 7.78 , 7.46 , 7.41–7.22 , 6.99 , 6.93 , 6.75 , 5.49 , 3.91 , 3.84  ppm. 13C NMR : δ = 160.2 (Cquat), 159.8 (Cquat), 139.1 (Cquat), 136.1 (Cquat), 133.3 (Cquat), 130.2 (Ar-CH), 129.1 (2Ar-CH), 128.8 (Cquat), 128.2 (Ar-CH), 127.0 (2Ar-CH), 122.6 (Ar-CH), 121.2 (Ar-CH), 119.5 (Cquat), 114.6 (Cquat), 114.2 (Ar-CH), 114.0 (Ar-CH), 113.1 (Ar-CH), 106.4 (Cquat), 93.1 (Ar-CH), 55.7 (OCH3), 55.5 (OCH3), 49.1 (CH2) ppm. HRMS (ESI): calcd. for C24H21N2O2 (M + H)+ 369.15975; found 369.16017.1-Benzyl-5-fluoro-3-(3-methoxyphenyl)-1H-indole-2-carbonitrile (9p): Yellow viscous liquid, 98%, 279 mg. 1H NMR : δ = 7.51 , 7.44 , 7.36–7.23 , 7.16–7.08 , 5.52 , 3.90  ppm. 13C NMR : δ = 158.7 , 156.9 (Cquat), 136.0 (Cquat), 134.1 (Cquat), 131.4 (Ar-CH), 130.0 (Ar-CH), 129.1 (2Ar-CH), 128.3 (Ar-CH), 127.0 (2Ar-CH), 126.4 , 124.2 , 121.0 (Ar-CH), 120.1 (Cquat), 115.2 , 113.7 (Cquat), 111.8, , 111.5 (Ar-CH), 110.8 (Cquat), 106.8 , 55.4 (OCH3), 49.5 (CH2) ppm. 19F NMR : δ = −121.7 ppm. HRMS (ESI): calcd. for C23H18FN2O (M + H)+ 357.14032; found 357.14081.7a , alkene , KOAc , Pd(OAc)2 , tBuNH4Cl and DMF (5 mL) were introduced in a sealed tube. The tube was vacuumed and backfilled with argon. The reaction mixture was stirred at 80 °C for 24 h and then cooled to room temperature. The reaction mixture was quenched with water, filtered through a Celite© pad and washed with EtOAc (100 mL). Then, the resulting organic layer was washed with sat. aq. NH4Cl (2 × 40 mL) and brine (3 × 40 mL). The organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using petroleum ether/EtOAc as eluent (70:30).Compound (E)-Methyl-3-(1-benzyl-2-cyano-1H-indol-3-yl) acrylate (10a): Brown solid, 92%, 244 mg. 1H NMR : δ = 7.99 , 7.95 , 7.46–7.30 , 7.18 , 6.76 , 5.50 , 3.85  ppm. 13C NMR : δ = 167.5 (Cquat), 138.1 (Cquat), 135.3 (Cquat), 134.0 (CH=CH), 129.2 (2Ar-CH), 128.5 (Ar-CH), 127.1 (Ar-CH), 127.0 (2Ar-CH), 124.9 (Cquat), 123.2 (Ar-CH), 121.8 (Cquat), 121.6 (Ar-CH), 119.1 (CH=CH), 112.8 (Cquat), 111.7 (Cquat), 111.5 (Ar-CH), 52.0 (OCH3), 49.6 (CH2) ppm. HRMS (ESI): calcd. for C20H17N2O2 (M + H)+ 317.12900; found 317.12946.E)-1-Benzyl-3-styryl-1H-indole-2-carbonitrile (10b): Brown solid, 89%, 257 mg. 1H NMR : δ = 8.06 , 7.66–7.58 , 7.51 , 7.45–7.29 , 7.23–7.20 , 5.45  ppm. 13C NMR : δ = 138.1 (Cquat), 137.3 (Cquat), 135.9 (Cquat), 131.2 (CH=CH), 129.1 (2Ar-CH), 128.9 (2ArCH), 128.2 (Ar-CH), 128.1 (Ar-CH), 126.9 (2Ar-CH), 126.6 (Ar-CH), 126.5 (2Ar-CH), 125.2 (Cquat), 124.6 (Cquat), 122.0 (CH=CH), 121.7 (Ar-CH), 118.4 (Ar-CH), 113.9 (Cquat), 111.0 (Ar-CH), 108.6 (Cquat), 49.1 (CH2) ppm. HRMS (ESI): calcd. for C24H19N2 (M + H)+ 335.15482; found 335.15532.(1-Benzyl-3-(3-cyanoprop-1-en-1-yl)-1H-indole-2-carbonitrile (10c): Brown solid, 81%, 192 mg. 1H NMR : δ = 8.09 , 7.79 , 7.61 , 7.52–7.29 , 7.23–7.18 , 6.14 , 5.64 , 5.48  ppm. 13C NMR E-isomer : δ = 139.5 (CH=CH), 137.9 (Cquat), 134.9 (Cquat), 129.2 (2Ar-CH), 128.6 (Ar-CH), 127.4 (Ar-CH), 126.9 (2Ar-CH), 124.1 (Cquat), 123.7 (Ar-CH), 120.8 (Ar-CH), 120.7 (Cquat), 118.3 (Cquat), 111.2 (Cquat), 111.7 (Ar-CH), 111.3 (Cquat), 96.9 (CH=CH), 49.6 (CH2) ppm. HRMS (ESI): calcd. for C19H14N3 (M + H)+ 284.11877; found 284.11842.(E)-Methyl-3-(1-benzyl-2-cyano-5-methoxy-1H-indol-3-yl) acrylate (10d): Brown solid, 88%, 236 mg. 1H NMR : δ = 7.97 , 7.36–7.28 , 7.27–7.23 , 7.16 , 7.06 , 6.69  5.46 , 3.88 , 3.85  ppm. 13C NMR : δ = 167.6 (Cquat), 156.6 (Cquat), 135.3 (Cquat), 134.1 (CH=CH), 133.2 (Cquat), 129.2 (2Ar-CH), 128.5 (Ar-CH), 126.9 (2Ar-CH), 125.5 (Cquat), 120.8 (Cquat), 118.4 (Ar-CH), 118.1 (Ar-CH), 112.9 (Cquat), 112.4 (Ar-CH), 111.3 (Cquat), 101.6 (Ar-CH), 55.9 (OCH3), 51.9 (OCH3), 49.7 (CH2) ppm. HRMS (ESI): calcd. for C21H19N2O3 (M + H)+ 347.13957; found 347.14053.(E)-Methyl-3-(1-benzyl-2-cyano-6-methoxy-1H-indol-3-yl) acrylate (10e): Brown solid, 92%, 247 mg. 1H NMR : δ = 7.90 , 7.76 , 7.35–7.28 , 7.21–7.13 ,6.94 , 6.71 , 6.68 , 5.40 , 3.83 , 3.80  ppm. 13C NMR : δ = 167.4 (Cquat), 159.9 (Cquat), 139.3 (Cquat), 135.2 (Cquat), 134.6 (Cquat), 133.9 (CH=CH), 129.2 (2Ar-CH), 128.4 (Ar-CH), 126.9 (2Ar-CH), 122.2 (Ar-CH), 122.0 (Cquat), 118.8 (Ar-CH), 113.9 (Ar-CH), 113.0 (Cquat), 110.4 (Cquat), 93.6 (CH=CH), 55.6 (OCH3), 51.8 (OCH3), 49.3 (CH2) ppm. HRMS (ESI): calcd. for C21H19N2O3 (M + H)+ 347.13957; found 347.14046.(E)-Methyl-3-(1-benzyl-2-cyano-5-fluoro-1H-indol-3-yl)acrylate (10f): Brown solid, 81%, 215 mg. 1H NMR : δ = 7.92 , 7.57 , 7.40–7.27 , 7.22–7.12 , 6.67 , 5.48 , 3.85  ppm. 13C NMR : δ = 167.3 (Cquat), 159.6 , 134.6 (Cquat), 133.5 (CH=CH), 129.3 (2Ar-CH), 128.7 (Ar-CH), 126.9 (2Ar-CH), 125.2 , 121.4 , 119.2 (CH=CH), 116.2 , 112.9 (Cquat), 112.7 , 112.4 (Cquat), 106.5 , 52.0 (OCH3), 49.9 (CH2) ppm. 19F NMR : δ = −118.71 ppm. HRMS (ESI): calcd. for C20H16FN2O2 (M + H)+ 335.11958; found 335.12021.7a , DMF (5 mL), vinyl tin derivatives  and PdCl2(MeCN)2  under argon. The mixture was stirred at 40 °C for 1 week. Then, the reaction mixture was added to a mixture of KF (2 M) and ethyl acetate (50:50), stirred for 30 min at room temperature and filtered through a Celite© pad. Solvents were removed under reduced pressure, and the crude product was purified by column chromatography with a stationary phase composed of 10% powdered anhydrous K2CO3 and silica, using petroleum ether/ethyl acetate as eluent (99.9:0.1).A Schlenk flask was charged with compound (E)-1-Benzyl-3-(3-methylbut-1-en-1-yl)-1H-indole-2-carbonitrile (11b): Brown oil, 35%, 88 mg. 1H NMR : δ = 7.90 , 7.39–7.26 , 7.25–7.13 , 6.63 , 6.54 , 5.44 , 2.56 2), 1.16  ppm. 13C NMR : δ = 141.8 (CH=CH), 138.1 (Cquat), 136.2 (Cquat), 129.1 (2Ar-CH), 128.2 (Ar-CH), 127.0 (Cquat), 126.9 (2Ar-CH), 126.5 (Ar-CH), 125.8 (Cquat), 124.8 (Cquat), 121.8 (Ar-CH), 121.6 (CH=CH), 116.9 (Ar-CH), 114.1 (Cquat), 110.9 (Ar-CH), 49.0 (CH2), 32.5 (CH(CH3)2), 22.6 (2xCH3) ppm. HRMS (ESI): calcd. for C21H21N2 (M + H)+ 301.17047; found 301.17038.E)-1-Benzyl-3-(2-(trimethylsilyl)vinyl)-1H-indole-2-carbonitrile (11c): Orange oil, 40%, 111 mg. 1H NMR : δ = 8.01 , 7.41–7.23 , 7.17 , 7.16 , 6.82 , 5.45 , 0.22  ppm. 13C NMR : δ = 138.0 (Cquat), 135.9 (Cquat), 133.6 (CH=CH), 133.0 (Ar-CH), 129.0 (2Ar-CH), 128.2 (Ar-CH), 126.8 (2Ar-CH), 126.5 (Ar-CH), 124.7 (Cquat), 117.0 (Cquat), 113.8 (Cquat), 110.9 (Ar-CH), 108.5 (Cquat), 49.0 (CH2), −1.16 (3xCH3) ppm. HRMS (ESI): calcd. for C21H23N2Si (M + H)+ 331.16305; found 335.16298. in THF (15 mL) was introduced into a dry, single-necked, round-bottomed flask under argon. The suspension was vigorously stirred, and n-BuLi  was added at −78 °C. The mixture was stirred magnetically under argon for 4h at room temperature. Then, ZnI2  and I2  were added at −78 °C, and the suspension was stirred overnight under argon at rt. The mixture was basified with 2 N aq NaOH (10 mL), extracted with EtOAc (10 mL) and washed with 5% aq Na2S2O3 (10 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel.A suspension of compound 1-(1-Benzyl-3-(p-tolylethynyl)-1H-indol-2-yl)pentan-1-one (8b’): Orange solid, 78.0%, 281 mg. 1H NMR : δ = 7.95 , 7.51–7.40 , 7.30–7.20 , 7.05–7.02 , 5.84 , 3.39 , 2.41 , 1.72 , 1.37 , 0.91  ppm. 13C NMR : δ = 195.2 (Cquat), 138.8 (Cquat), 138.7 (Cquat), 138.2 (Cquat), 135.8 (Cquat), 131.3 (2Ar-CH), 129.4 (2Ar-CH), 128.7 (2Ar-CH), 128.5 (Cquat), 127.3 (Ar-CH), 126.9 (Ar-CH), 126.5 (2Ar-CH), 122.2 (Ar-CH), 121.8 (Ar-CH), 120.5 (Cquat), 111.1 (Ar-CH), 105.9 (Cquat), 98.5 (Cquat), 85.8 (Cquat), 48.7 (CH2), 42.4 (CH2), 27.0 (CH2), 22.6 (CH2), 21.7 (CH3), 14.1 (CH3) ppm. HRMS (ESI): calcd. for C29H28NO (M + H)+ 406.21709; found 406.21720.In summary, we have developed a palladium-catalyzed homocoupling reaction of heteroatoms through C–I bond functionalization using different alkynes, alkenes and aryl derivatives. This approach offers a simple strategy and alternative route for the preparation of heteroaryl nitriles from easily available precursors in good to excellent yields. The present work allows access to novel diversely polysubstituted cyanoindoles via Sonogashira, Suzuki–Miyaura, Heck and Stille cross-coupling reactions.


To identify where and how trauma survivors’ rehabilitation needs are met after trauma, to map rehabilitation across five UK major trauma networks, and to compare with recommended pathways.Qualitative study  using soft-systems methodology to map usual care across trauma networks and explore service gaps. Publicly available documents were consulted. CATWOE  was used as an analytic framework to explore the relationship between stakeholders in the pathway.Five major trauma networks across the UK.n = 46), focus groups  and workshops .106 key rehabilitation stakeholders  were recruited to interviews  lack of vocational/psychological support particularly for musculoskeletal injuries; (2) inconsistent service provision in areas located further from major trauma centres; (3) lack of communication between acute and community care; (4) long waiting lists (up to 12 months) for community rehabilitation; (5) most well-established pathways were neurologically focused.The trauma rehabilitation pathway is complex and varies across the UK with few, if any patients following the recommended pathway. Services have developed piecemeal to address specific issues, but rarely meet the needs of individuals with multiple impairments post-trauma, with a lack of vocational rehabilitation and psychological support for this population. Survivors of such injuries may experience physical, social and psychological problems, such as pain, fatigue, depression and anxiety, interpersonal difficulties, or hidden disabilities, such as cognitive problems. A significant number of people experiencing trauma have residual problems affecting their ability to return to, and remain in, work.3 Therefore, it is important that rehabilitation to support these individuals addresses all issues long-term.Traumatic injuries in working age adults are a global public health problem. Traumatic injury or ‘major trauma’ describes serious and often multiple injuries where there is a strong possibility of death or disability46 back pain7 and mental health problems.8 However, moderate to severe trauma can affect single or several body regions, which frequently leads to long-term psychological problems.9 Whilst there is evidence that effective vocational rehabilitation for some types of injuries such as brain and spinal cord injury addresses both physical and psychological problems,10 evidence of this for orthopaedic injury is lacking.12 Previous studies have not evaluated vocational rehabilitation in complex multi-organisational settings, such as UK National Health Service (NHS) major trauma centres, which receive traumatic injury patients from large geographical areas and repatriate patients to a wide range of local services.Systematic reviews suggest that vocational rehabilitation improves return-to-work for some conditions, such as brain and spinal cord injury,14 Although published standards highlight the need for support to return-to-work following trauma, there is limited evidence describing the consistency and quality of service provision across the UK. Studies mapping vocational rehabilitation for specific conditions, such as stroke15 and long-term neurological conditions17 highlight the disparity between service provision in different regions of the UK.Rehabilitation service organisation is in most countries, complex with multiple organisations involved. This means that rehabilitation pathways are not always consistent and are challenging to standardise and evaluate, even in the UK, which has a universal integrated healthcare system. The British Society of Rehabilitation Medicine core standards for specialist rehabilitation following major trauma state that individuals should have access to specialist vocational rehabilitation services in the UK.In this study, we aimed to: (1) understand where and how trauma survivors’ rehabilitation needs are currently met in the UK trauma pathway in terms of vocational and psychological support and; (2) map current UK NHS rehabilitation  across five trauma networks. A trauma network is the collaboration between providers commissioned to deliver trauma care services in a geographical area.www.ROWTATE.org.uk). Ethical approval was obtained from the University of Nottingham Faculty of Medicine and Health Sciences Research Ethics Committee (Ref: FMHS 150-1811) and Leicester South NHS Research Ethics Committee (Ref 19/EM/0114). Recruitment lasted 12 months, starting in February 2019.This study feeds into a larger programme of work funded by the National Institute for Health Research . Findings will inform the development and implementation of a return-to-work intervention , participants were given the time and opportunity to opt out, otherwise consent was assumed.n = 4 focus groups, total of 17 participants) with stakeholders to obtain qualitative data about the rehabilitation pathways. Workshops  with service providers and trauma survivors  were also conducted by researchers  at five UK major trauma centres to understand more about their trauma pathway. For further information about the pathways, appropriate service providers  were consulted through informal interviews (n = 8) about current referral processes and usual care within these centres. The data were used to map current rehabilitation pathways and create a rich description of usual care across the five major trauma centres. Publicly available documents/online resources (n = 10) and relevant NHS Trust website were also consulted. These included the National Clinical Audit of Specialist Rehabilitation for Patients with Complex Need following Major Injury reports, British Society of Rehabilitation Medicine recommendations for best practice and the Trauma Audit & Research Network website. Summary of resources are shown in Supplemental Appendix 1.Researchers  conducted semi-structured interviews (n = 38) and focus groups , to guide the interview questions and inform data coding and analysis , such as vocational rehabilitation therapists and those receiving usual care (customers), such as trauma survivors.We followed Sinclair’sanalysis .18 This 19 approach, informed by the a priori constructs of CATWOE. The transcripts were independently analysed by authors (JK and KB) and main themes identified were discussed with other authors  for agreement. Data were also used to inform the mapping of service pathways.Most interviews and focus groups were audio recorded where possible and transcribed, otherwise notes were taken. Workshops were recorded using contemporaneous notes by a researcher. All data were analysed thematically following Braun and Clarke’sRehabilitation pathways were visually mapped across five major trauma networks, which were informed by consultation with stakeholders , as previously mentioned. In order to highlight the complexity of the system, ensure consistency of reporting and enable comparison across the different trauma networks, the pathways were mapped against the British Society of Rehabilitation Medicine ‘Core Standards for Specialist Rehabilitation following Major Trauma’. This ‘ideal’ pathway post-trauma is shown in n = 106) including trauma survivors, carers, NHS service providers  private service providers and solicitors. Some participants participated in interviews and focus groups. A summary of the characteristics of participants is shown in We recruited a variety of key stakeholders  inconsistent transition from acute care to community services due to a lack of communication between different services and healthcare providers when a patient is discharged from hospital; (2) geographical barriers (e.g. postcode lottery); (3) a lack of expertise in areas located further from the major trauma centre; and (4) a clear gap in vocational and psychological support for trauma survivors, particularly those with musculoskeletal injuries.Supplemental Appendices 2 to 6. It is clear that the ‘ideal’ flow of patients through the rehabilitation system as depicted by the British Society of Rehabilitation Medicine guidelines  facilitated the understanding of the implementation context for trauma rehabilitation services and the issues within the current pathway.Customers: Customers are anyone that could benefit from vocational rehabilitation/psychological support, which could be the trauma survivor, their family, or their employer. Individuals often have unrealistic expectations of their recovery post-trauma, which causes stress to the patient and in some cases, the employer:‘I’ve got many, many patients who they ignore our [rehabilitation experts] advice and go back to work earlier, and they go a step backwards’ (Rehabilitation consultant)‘I think I should have taken on some reduced duties or something first. That was my choice. They [employer] offered that and I said I’d be fine and then it turned out pretty bad for me.’ ‘There is that big question around disclosure, head injuries, trauma, for ‘Joe Bloggs’ employers it’s quite a hard thing to get their heads round, well hang on a minute how is this [injury] going to impact on you [patient]?. . . sometimes a lot of employers, they don’t know, they haven’t got a clue, they have never had to deal with it, they don’t know where to go, they don’t know where to ask [for support].’ (Disability employment advisor)There is also a general lack of knowledge outside of the healthcare system about the impact of trauma, which makes the return-to-work process even more challenging:‘With orthopaedic, complex orthopaedic stuff, which is going to be the vast majority I think of what you’re seeing here, occupational therapy provision is difficult I think, it’d be fair to say. . .and there isn’t an occupational therapy vocational rehab service for these people.’ (Rehabilitation consultant)‘Unless you have quite a bad head injury, they [commissioners] just don’t see musculoskeletal injuries as a problem or amputee people don’t think they need help to go back to work because they just crack on, but actually there may be things [that are required], like worksite assessment.’ There is a clear gap in vocational support for individuals with certain types of injuries, especially traumatic amputations, and musculoskeletal injuries:Supplemental Appendices 2–5). Thus, service providers perceive that more patients with brain injury tend to get back to work than those with spinal injury, even though the latter typically have no cognitive impairment:‘Because I think there’s actually a lower percentage of spinal clients that get back to work than there is brain injury. . .where you have targeted neuro rehab but focused on vocational, you could be looking to get sort of 30, 33% back to work whereas I think spinal is something like 19 or 20%, which is interesting when they’re cognitively intact in the main. So, you would think that the barriers would be more physical in nature but they don’t get returned’ (Case manager)A number of service providers were unaware of specific support for amputees and people with burns, by comparison with the well-known charities for brain and spinal injuries. The majority of vocational rehabilitation teams across the five major trauma pathways only offer return-to-work support to individuals with acquired or traumatic brain injury Some individuals do not want their employers to know about psychological issues or outcomes of injury that are not obvious, such as fatigue, incontinence, cognitive problems and anxiety. This makes it particularly challenging for therapists when supporting someone in their return-to-work, as such issues, if unaddressed, may act as barriers to a sustainable return-to-work:Actors: The individuals delivering care play an important part in the success of rehabilitation and an individual’s return-to-work. However, referrals are impacted by lack of knowledge about which services currently exist and service providers’ understanding of the whole rehabilitation pathway:‘One of the discussions that we’ve just had is, we, as a service, are very unaware of exactly what’s available in the county. . .We met recently with representatives from some of these teams, the brain injury team, etc, and I think the issue at the moment is that actually it’s very much a patchwork of availability. Although some stakeholders had better knowledge of service provision in their local area, this tended to be condition-specific and relevant to their position in the pathway . There is a general lack of knowledge about vocational rehabilitation and psychological services across the different trauma networks.‘Managing those very difficult conversations because employers will say, can this person do the job or not, and they’re asking you as a clinician to make that decision. And I think one of the useful things I’ve learnt from our work psychologist was, you don’t say, yes or not, because you’re not the employer. . .sometimes I have said, you’re the employer, these are the things that would support this person to be able to do this job.’ Employers face similar challenges and may not always recognise psychological or hidden issues, making it difficult for them to understand how to support an employee in their return-to-work. They often require the help of a therapist to make workplace adjustments:‘I think part of the difficulty is trying to work out how you can change work and getting the employers to think differently about why they should support somebody going back to work, particularly I think in high demand and highly technical jobs or very physical jobs. You often find that the employee needs an alternative job that they don’t have the skills to do anything else and that’s very difficult.’ Another challenge raised by stakeholders was the difficulty in finding an appropriate role for someone after traumatic injury and the importance of the NHS service provider  in supporting the employer with this process:‘. . .depending on the client, we word it different ways but it’s essentially how’s your mood? But as you know, people can’t engage in therapy if they – if we’re not addressing their mental health because they might be so depressed that they’re not opening their letters, so they don’t know when their appointment is. They can’t organise themselves to get out of bed to arrange transport to get in here. It’s [addressing mental health needs] like the nuts and bolts of what we do; we can’t do what we do without being aware of that.’ (Speech and language therapist)Some stakeholders stated that patients are not routinely asked about mood. One therapist highlighted the challenge of supporting someone with psychological needs who does not want to engage with therapy and the issue of not always being aware of such needs:‘I think it depends if you’ve got an interest in it [vocational rehabilitation] as well. . .If you feel confident. And what we’re [senior therapists] finding. . .is a lot of OTs aren’t feeling confident about asking that question [about returning to work], they find it quite scary.’ A common reason for not asking patients about their mental health or return-to-work plans was a lack of confidence in dealing with these issues (i.e. not wanting to probe these important issues in case they cannot support the patient), or limited referral options should individuals require more specific support even when feeling confident about asking:‘There’s just not really the [vocational or psychological] services out there to then signpost people on to. So, you almost feel like you’re opening a Pandora’s box where you can’t actually then put those pieces back in.’ Lack of service provision means that therapists are avoiding addressing issues that they cannot deal with:Transformations: Stakeholders suggested that there is a lack of effective communication between service providers, patients, and employers when a patient moves from the acute setting to the community. Trauma survivors felt there was poor continuity of care and consistency in support after they left the major trauma centre. Multiple service providers described the system as a lottery. This means that some individuals fall through gaps in the system, receiving little or no support:‘I mean it’s part of the problem, it’s not coordinated, it’s a bit of a lottery as to what the pathway was when you came through the service, what your injuries were, which directorate you came through, what your postcode is, it’s a lottery to what you can access. Some get really good stuff; seen some really good UKROC [UK specialist Rehabilitation Outcomes Collaborative] rehab. . .but then people have to wait four months to see an OT. It’s good when you get it.’ (Rehabilitation consultant)‘When I was a ward therapist, you’d refer them [patients] and you didn’t know if they were then accepted, or if that referral had got missed. So, you’d just refer them in good faith, and you don’t know then what happened or if you’re referring to somewhere else’ ‘There’s just nobody to take on that role for even making sure referrals have actually gone through to these places [community teams]. And again, the numbers change from week to week and the services change week to week. There’s no central point of access for any of it [referral success]. In addition, therapists stated how hard it was to keep track of whether onward referrals for trauma survivors were successful and concerns over whether their patients were receiving appropriate rehabilitation following discharge:‘. . .and again it’s about the time scale and it’s about the availability of resources. A health care district might only have one neuro psychologist to deal with everything so it’s how thin can they spread themselves really?’ (Case manager)The issue of limited resources causing long waiting lists was raised by the majority of stakeholders as one of the barriers to patients receiving vocational rehabilitation. Waiting lists for community rehabilitation are long across the five trauma networks, and in some areas, up to 12 months. Along with extended waiting lists, there are few services providing vocational support within each trauma network, meaning that these community teams are overloaded with referrals and do not have the resources to deal with the many individuals requiring vocational and psychological rehabilitation, and are not receiving the timely support they require:World view: The public and professional view of vocational rehabilitation has an influence on the delivery and funding of such services, which ultimately has a large impact on whether individuals are supported in their return-to-work following trauma.2025:‘People don’t know their rights about return to work or remaining in work. It’s a big problem. People don’t even mention work in an acute hospital. It just doesn’t even get discussed.’ ‘I think that focus is not in the mind of acute trauma team. I think in order to get it – keep that focus this [do you want to get back to work] needs to be said from day one and day two and we keep that over time, this chap is a driver, this chap is a butcher or something. We don’t do that in the NHS unfortunately.’ (Rehabilitation consultant)Various service providers discussed the view that delivering vocational rehabilitation in the acute setting is often seen as unimportant by acute physicians and therapists. Attitudes among some healthcare providers suggests that starting vocational rehabilitation in acute setting is ‘too early’ and is not discussed, even though some are aware of the evidence supporting the benefit of early interventionIn the initial stages post-injury, the focus is primarily on treating the medical issues and ensuring the patient can be discharged from the major trauma centre as safely and as soon as possible. However, this means that often the biopsychosocial factors that are important to an individual’s recovery are sometimes overlooked, especially their need to return-to-work.‘Return to work is a luxury not a necessity’ ‘If people can’t get back to work within four to six weeks, they [employers] will not start a phased return. . . people pull their hair out when they get hospitals or GPs say, this person can only work two hours a week. They’re like, there’s no point. There’s no job that can be done for two hours a week.’ A ‘world view’ where supporting return-to-work is seen as an extravagance and not routinely provided, shows poor understanding of why vocational rehabilitation can be appropriate for those who want to work, but may struggle in their pre-injury role. Some service providers suggested that employers do not know how or are unwilling to support someone whose abilities have radically altered and can only, for example, work a few hours per week. Being able to gradually reintegrate into work and accomplish a meaningful amount of work whilst there is even more of a challenge when an employer is not willing to support their employee:Owners: The provision of vocational rehabilitation, or any rehabilitation services are strongly influenced by government policies and those commissioning such services. This could include policy makers, service managers and commissioners  but may also include managers in an employing organisation and Occupational Health or Human Resources departments.‘That’s one of the problems, constant change. And we used to have a super vocational rehab service in our community team and they got rid of it because they [commissioners] didn’t think people needed to return to work’ One of the issues with ensuring an individual receives appropriate support post-trauma is keeping track of services which are constantly changing in response to funding alterations and service developments. Even when good services exist, service providers frequently expressed their frustration over instances of the decommissioning of vocational rehabilitation services, which are already limited. One occupational therapist explained that decommissioning often happens if the need of such a service is not recognised from a commissioning perspective:‘There’s a lot of need, and not a lot of provision. . . [rehabilitation] is the first thing to get axed when budget cuts come in.’ (Rehabilitation consultant)This view was corroborated by others:‘So I think that’s another thing I notice. . . is that hospitals are forever trying to get rid of follow-up clinics. . . you’re not going to spot recurrence [of psychological issues] when you see someone in an outpatient clinic so let’s just get rid of them. It’s just so expensive in doctor time. . .But obviously psychologically, it’s really important time for continuity of relationships.’ The perceived value for money of the service can determine which services are funded . This can impact especially those with more severe trauma who need longer term support, including with psychological issues:‘As resources have become more limited within the NHS, you find that things have become much more streamlined so people are only offered so many weeks of service intervention or in order to qualify for some brain injury services you have to have more than two different problems. So, if you need cognitive rehab and you need speech and language therapy you’ll get a service. But if you only need cognitive rehab it’s more difficult.’ (Case manager)There was a perception that those responsible for making service delivery plans do not always understand the medical diagnoses leading to poor service design and funding decisions, ineffective rehabilitation, and non-individualised care. One stakeholder highlighted the challenges for trauma survivors where needs are not met because services are designed to match resources. Some people fall outside the service referral criteria, but have rehabilitation needs that require support, some are only able to receive rehabilitation for a finite period but is required for a longer duration:Environmental context: The major trauma centres across the UK are located in major cities and tend to be surrounded by multiple community-based teams, with easier access to support. However, further away from the trauma centre, service provision becomes patchy and there is greater inconsistency in the availability of psychological and vocational support. Each major trauma centre is considered the hub of its trauma network and repatriating hospitals are seen as the spokes. However, between the hub and the spokes can be up to two hours travelling distance, making it challenging for patients to access the major trauma outpatient services. There is also geographical disparity across the country in terms of what is available for individuals post-trauma. Often those located in more rural areas receive the least support or must travel long distances to receive support. One trauma survivor highlighted their experience of leaving the acute setting:‘One of the areas I struggled with is when you’re in the major trauma centre, you very quickly become aware that you are getting the best treatment that is available, but of course as soon as you become well enough, they want to move you to either your local hospital or something like that, which is what I did. I actually did feel – I actually feel that the physio and everything just went down a notch, not in a bad way but in a noticeable way.’ ‘So, in terms of geographical area, [county name] is split into North and South [county name] for a lot of services, and some services cover both parts, some just the north, some just the south. The service that they do offer is often very different in terms of assessment, treatment, how long people can be treated for, things like that. . .So it’s a real patchwork. . .there’s a lot of uncertainty.’ Inconsistent service provision across the country and constantly changing services means that the system is challenging for service providers to navigate. Stakeholders stated that services either do not exist, had been recently decommissioned, or the team was spread so thinly across the region that they were unable to see new patients:‘The community services are very fragmented, and again a lot of what I see is sort of more specialist neuro rehab stuff, but similarly, you know, we end up bringing people back to physio in [city name] sometimes, if they’re struggling to access, even just for orthopaedic physio, and particularly the less experienced, if they’ve got really complex, like pelvic injury, all those kind of things.’ (Rehabilitation consultant)As service provision is limited in some areas, stakeholders frequently stated that patients are often offered outpatient appointments at their major trauma centre, so that they receive timely support, even if it is a significant distance to travel. Often no local services are available, so patients opt to return to the major trauma centre, which may be difficult for individuals:14 Although individual services aim to deliver effective rehabilitation, the lack of communication between acute and community services has an impact on the continuity of care being provided.Our findings support the hypothesis that the rehabilitation pathways followed by patients after trauma are extremely complex, with few, if any patients following the proposed ideal pathway put forward by the British Society of Rehabilitation Medicine.There are several well-established pathways, particularly for people with neurological injuries, however there are clear gaps in service provision for those with musculoskeletal injuries and amputations. There is a consistent lack of vocational rehabilitation and psychological services across the major trauma networks, and in areas where they do exist, the waiting lists are too long to provide timely support. Although some of the issues within the pathway are common knowledge among trauma stakeholders, there is limited evidence explicitly highlighting the disparity in service provision across different regions of the UK.26 and gaps identified when transitioning from hospital to community.27 Previous research also corroborates our findings in that clinical decisions post-trauma are limited by insufficient resources, gaps in communication, conflicting organisational priorities and unrealistic patient expectations,28 and highlights the value of effective multi-disciplinary input and co-ordinated care.29 However, this study systematically explored these issues and the extent of current provision gaps in five UK major trauma centres, providing a more detailed map of current service provision that no prior research has achieved to date.Our study supports prior UK studies with traumatic injury patients, which highlighted the lack of psychological discussion, support and signposting for trauma patients,30The present work also highlights the geographical nature of the gaps and how these impact on service access. This study contributes to the evidence gap in understanding UK service provision across the pathways and identifies geographical areas and services that require more funding. Until awareness is raised about geographical areas across the UK with limited service provision and service gaps, it is unlikely that change will occur and thus, the system will not improve. In addition, this work may contribute to the understanding of international rehabilitation services with similar integrated systems to the UK NHS, highlighting areas that may require more funding or support, or potentially inform pathway development in other complex healthcare systems.31 particularly when providing vocational and psychological support.33 However, there still appears to be a lack of communication and continuity of care when patients are discharged from an acute setting. Although a known issue among clinicians and reported across the literature,34 our findings suggest that problems still exist. The introduction of the Rehabilitation Prescription in 2013 aimed to improve communication along the pathway and ensure that all information concerning injury management  is transferred across all relevant services/sectors. The 2019 NSCASRI report stated that even though the Rehabilitation Prescription was completed for 89% patients, the mandated data collection was limited  providing little useful information about rehabilitation needs.35 An updated version of the Rehabilitation Prescription was released in 2019 and hopes to address this gap in continuity of care following discharge, by requiring a summary of rehabilitation needs on leaving the acute setting.36Crossing boundaries  and multidisciplinary delivery of rehabilitation is important,37Geographical barriers are an issue within the current rehabilitation pathway, and service provision tends to become more limited the further a patient is located from a major trauma centre. Some major trauma centres have up to two-hour repatriation distances and trauma networks can have catchment areas of up to six million people, it is not surprising therefore that current pathways differ from the ‘ideal’ British Society of Rehabilitation Medicine pathway. However, clinical guidelines suggest that all trauma patients should have access to timely and appropriate rehabilitation, including vocational rehabilitation and psychological support.2025 The importance of timely psychological support post-trauma is also recognised in the literature39 and patients should have access to these services to reduce long-term psychological problems. Occupational therapists and other allied health professionals may benefit from training to increase confidence in addressing vocational and psychological issues. However, services and resources need to be available in order that any problems identified can be addressed for the trauma population.Not only is there limited vocational rehabilitation service provision across the major trauma networks, there are long waiting lists in areas where there is good support. This means that early and timely rehabilitation after trauma is not always feasible. Evidence supports the benefit of early vocational rehabilitation, which should be delivered as soon as possible post-trauma.This study had several strengths and provides new evidence to highlight gaps in current service provision post-traumatic injuries. We interviewed a wide range of stakeholders across a variety of trauma networks and obtained a broad perspective of the current pathways across five diverse  trauma networks. To ensure pathway maps were as accurate as possible, they were amended as necessary following stakeholder engagements and their development was an iterative process. We also drew on clinical guidelines to identify missing information and guide questioning when finalising our diagrams against all stakeholder feedback. However, there were also some limitations. We did not manage to recruit any commissioners or employers, and only spoke to a small number of carers, meaning that we were unable to obtain their perspectives on the rehabilitation pathway.In summary, while there are many examples of rehabilitation identified especially for specific injury groups , our research shows also there are many gaps in service provision, which were more pronounced for other injury groups  and for patients located further from major trauma centres. The gaps and/or inconsistencies in care were especially problematic in relation to vocational rehabilitation and psychological services across the major trauma networks. Guidelines and literature consistently recommend a multidisciplinary approach to rehabilitation; however, it appears that the system is not as co-ordinated as it could be.Rehabilitation services in the UK (and likely in other countries) have developed piecemeal, usually in response to specific identified problems such as stroke, spinal cord injury, amputations. This means the system is fragmented and has not developed with a strong theoretical framework, nor has it developed in a patient-centred way. Consequently, there is a complex set of individual services which address specific injury types or problems, but rarely consider the multifaceted rehabilitation needs of a patient. In contrast, patients who have suffered major trauma often present with a broad range of problems which usually require input from multiple individual services. This means that patients frequently have problems for which there is no identified specific service, leading to issues and poor rehabilitation support. A timely example is patients with long-term rehabilitation needs following COVID-19, in which individuals may require pulmonary rehabilitation, but may also need additional input relating to emotional and psychological problems, and possibly fatigue and cognitive issues. Given the complexity of the rehabilitation pathway, it is unlikely a patient will be able to access support for all issues in a timely manner.Further research is required to map vocational rehabilitation provision and identify service gaps across all major trauma networks in the UK. This should be informed by interviews with a wider range of stakeholders, including carers, employers and commissioners. Research is also required to evaluate the use of the Rehabilitation Prescription and its impact on vocational rehabilitation and psychological support received by trauma patients. Commissioners and providers of rehabilitation services should use our findings to assess how well services are meeting patient need and ensure provision of services addressing the gaps we identified.Rehabilitation pathways followed by patients after trauma are extremely complex, with few, if any patients following an ‘ideal’ pathway.There is a lack of vocational rehabilitation and psychological support, particularly for individuals with musculoskeletal injuries.Continuity of care on discharge from acute to community services is hampered by a lack of communication.Click here for additional data file.Supplemental material, sj-pdf-1-cre-10.1177_0269215520971777 for A study of mapping usual care and unmet need for vocational rehabilitation and psychological support following major trauma in five health districts in the UK by Jade Kettlewell, Stephen Timmons, Kay Bridger, Denise Kendrick, Blerina Kellezi, Jain Holmes, Priya Patel and Kate Radford in Clinical Rehabilitation