Comparison of feline and human immunodeficiency virus reverse transcriptase enzymes through chemical screening and computational analysis.

Feline immunodeficiency virus (FIV) is a common infection found in domesticated and wild cats worldwide. Despite the wealth of therapeutic understanding of the disease in humans, considerably less information exists regarding the treatment of the disease in felines. Current treatment relies on drugs developed for the related human immunodeficiency virus (HIV) and includes compounds of the popular non-nucleotide reverse transcriptase (NNRTI) class. This is despite FIV-RT being only 67% similar to HIV-1 RT at the enzyme level, increasing to 88% for the allosteric pocket targeted by NNRTIs. The goal of this project was to try to quantify how well the more extensive pharmacological knowledge available for human disease translates to felines. To this end we screened known NNRTIs and 10 diverse pyrimidine analogs identified virtually. We use this chemo-centric probe approach to (a) assess the similarity between the two related RT targets based on the observed experimental inhibition values, (b) try to identify more potent inhibitors at FIV, and (c) gain a better appreciation of the structure-activity relationships (SAR). We found the correlation between IC50s at the two targets to be strong (r2 = 0.87) and identified compound 1 as the most potent inhibitor of FIV with IC50 of 0.030 µM ± 0.009. This compared to FIV IC50 values of 0.22 ± 0.17 µM, 0.040 ± 0.010 µM and >160 µM for known anti HIV-1 RT drugs Efavirenz, Rilpivirine, and Nevirapine, respectively. This knowledge, along with an understanding of the structural origin that give rise to any differences could improve the way HIV drugs are repurposed for FIV.

An acute presentation of Chronic Thromboembolic Pulmonary Hypertension complicated by cerebellar infarction.

Persistent symptoms and features of pulmonary hypertension in a patient with pulmonary embolism suggests chronic thromboembolic pulmonary hypertension (CTEPH) which can be associated with significant morbidity and mortality. A high level of clinical suspicion, including addressing risk factors for recurrent or cgronic thromboemboli and appropriate anticoagulation is required. We present a rare case of a young man presenting late with pulmonary embolism and features consistent with CTEPH complicated by a cerebrovascular event.

The new quinazoline derivative (N2-methyl-N4-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine) vasodilates isolated mesenteric arteries through endothelium-independent mechanisms and has acute hypotensive effects in Wistar rats.

During the screening of new N2,N4-disubstituted quinazoline 2,4-diamines as phosphodiesterase-5 inhibitors and pulmonary artery vasodilators, one N2-methyl-N4-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine (compound 8) presented a greater selectivity for systemic than pulmonary vasculature. The present study aimed to characterize its vasorelaxant and hypotensive effects in Wistar rats. Vasorelaxant effects of compound 8 and underlying mechanisms were evaluated on isolated mesenteric arteries. Acute hypotensive effect was evaluated in anesthetized rats. Additionally, cell viability and cytochrome P450 (CYP) activities were studied in rat isolated hepatocytes. Nifedipine was used as a comparator. Compound 8 induced a strong vasorelaxant effect, similar to nifedipine. This was unaffected by endothelium removal but was decreased by inhibitors of guanylate cyclase (ODQ) and KCa channel (iberiotoxin). Compound 8 enhanced sodium nitroprusside-induced relaxation, but inhibited vasoconstriction evoked by α1-adrenergic receptor activation and extracellular Ca2+ influx via receptor-operated Ca2+ channels. Acute intravenous infusion of compound 8 (0.05 and 0.1 mg/kg) produced hypotension. It showed similar potency to nifedipine for lowering diastolic and mean arterial blood pressure, but less so for the effect on systolic blood pressure. Compound 8 had no effect on hepatocyte viability and CYP activities except at high concentration (10 µM) at which a weak inhibitory effect on CYP1A and 3A was observed. In conclusion, this study identified a N2-methyl-N4-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine with a potent vasodilator effect on resistance vessels, leading to an acute hypotensive effect and a low risk of liver toxicity or drug-drug interactions. These vascular effects were mediated mainly through sGC/cGMP pathway, opening of KCa channels, and inhibition of calcium entry.

Preparation, biological evaluation and QSAR analysis of urea substituted 2,4-diamino-pyrimidine anti-malarials.

The synthesis and evaluation of twenty six new phenylurea substituted 2,4-diamino-pyrimidines against Plasmodium falciparum (Pf) 3D7 are reported. Compounds were prepared to improve both anti-malarial activity and selectivity of the series previously reported by our group. Additional properties have been determined to assess their potential as anti-malarial leads including; HepG2 cytotoxicity, solubility, permeability, and lipophilicity, as well as in vitro stability in human and rat microsomes. We also assess their inhibition profile against a diverse set of 10 human kinases. Molecular docking, cheminformatics and bioinformatics analyses were also undertaken. Compounds 40 demonstrated the best anti-malarial activity at Pf 3D7 (0.09 µM), good selectivity with respect to mammalian cytotoxicity (SI = 54) and low microsomal clearance. Quantitative structure activity relationship (QSAR) analyses point to lipophilicity being a key driver of improved anti-malarial activity. The most active compounds in the series suffered from high lipophilicity, poor aqueous solubility and low permeability. The results provide useful information to guide further chemistry iterations.

Computational design, synthesis and biological evaluation of PDE5 inhibitors based on N2,N4-diaminoquinazoline and N2,N6-diaminopurine scaffolds.

We report the synthesis, and characterization of twenty-nine new inhibitors of PDE5. Structure-based design was employed to modify to our previously reported 2,4-diaminoquinazoline series. Modification include scaffold hopping to 2,6-diaminopurine core as well as incorporation of ionizable groups to improve both activity and solubility. The prospective binding mode of the compounds was determined using 3D ligand-based similarity methods to inhibitors of known binding mode, combined with a PDE5 docking and molecular dynamics based-protocol, each of which pointed to the same binding mode. Chemical modifications were then designed to both increase potency and solubility as well as validate the binding mode prediction. Compounds containing a quinazoline core displayed IC50s ranging from 0.10 to 9.39 µM while those consisting of a purine scaffold ranging from 0.29 to 43.16 µM. We identified 25 with a PDE5 IC50 of 0.15 µM, and much improved solubility (1.77 mg/mL) over the starting lead. Furthermore, it was found that the predicted binding mode was consistent with the observed SAR validating our computationally driven approach.

Quinazoline-based human phosphodiesterase 5 inhibitors exhibited a selective vasorelaxant effect on rat isolated pulmonary arteries involving NO-sGC-cGMP pathway and calcium inhibitory effects.

Phosphodiesterase 5 (PDE5) inhibitors are an attractive option among the currently available therapies in the management of pulmonary arterial hypertension (PAH). Good selectivity for PDE5 is associated with reduced side effects and greater vasorelaxant effect on pulmonary arteries (PA). This study investigated the vasorelaxant effects of a series of quinazoline-based PDE5 inhibitors and their precise mechanisms action using rat isolated PA and aorta, as compared to sildenafil. Their effects on rat hepatocytes (viability and CYP activities) were also evaluated. Compounds 5 and 11 displayed lower human PDE5 IC50 of the analogs studied here and induced a greater relaxant effect on PA (EC50 0.94 ± 0.30 and 1.03 ± 0.23 µM, respectively). As compared to sildenafil (EC50 = 0.05 ± 0.02 µM on PA), the relaxant effect of 5 and 11 on PA was lower but their selectivity for PA compared to aorta was higher. The effects of 5 and 11 were reduced by NG-nitro-L-arginine methyl ester, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one, but not by indomethacin or potassium channels blockers. They also enhanced the relaxant effect of sodium nitroprusside, and inhibited extracellular Ca2+ influx and intracellular Ca2+release. Compounds 5 and 11 did not reduce hepatocyte viability except at concentration > 10 µM, inhibited CYP3A at 10 µM, like sildenafil, but did not induce CYP1A. In conclusion, this study identified 2 quinazoline analogues with good PDE5 inhibitory activity and good selectivity for the pulmonary vasculature. Their relaxant effect involves both the potentiation of nitric oxide-sGC-cGMP pathway and calcium inhibition. These compounds are potential leads for developing new drugs for PAH.

Preparation, biological & cheminformatics-based assessment of N2,N4-diphenylpyrimidine-2,4-diamine as potential Kinase-targeted antimalarials.

Twenty eight new N2,N4-diphenylpyrimidine-2,4-diamines have been prepared in order to expand our understanding of the anti-malarial SAR of the scaffold. The aim of the study was to make structural modifications to improve the overall potency, selectivity and solubility of the series by varying the anilino groups attached to the 2- and 4-position. We evaluated the activity of the compounds against Plasmodium falciparum (Pf) 3D7, cytotoxicity against HepG2, % inhibition at a panel of 10 human kinases, solubility, permeability and lipophilicity, and human and rat in vitro clearance. 11 was identified as a potent anti-malarial with an IC50 of 0.66 µM at the 3D7 strain and a selectivity (SI) of ~ 40 in terms of cytotoxicity against the HepG2 cell line. It also displayed low experimental logD7.4 (2.27), reasonable solubility (124 µg/ml), good metabolic stability, but low permeability. A proteo-chemometric workflow was employed to identify putative Pf targets of the most promising compounds. Ligand-based similarity searching of the ChEMBL database led to the identification of most probable human targets. These were then used as input for sequence-based searching of the Pf proteome. Homology modelling and molecular docking were used to evaluate whether compounds could indeed bind to these targets with valid binding modes. In vitro biological testing against close human analogs of these targets was subsequently undertaken. This allowed us to identify potential Pf targets and human anti-targets that could be exploited in future development.

ABVD and BEACOPP regimens’ effects on fertility in young males with Hodgkin lymphoma

Purpose Considering the increased cancer patient survivorship, the focus is now on addressing the impacts of treatment on quality of life. In young people, altered reproductive function is a major issue and its effects in young males are largely neglected by novel research. To improve clinician awareness, we systematically reviewed side effects of chemotherapy for Hodgkin lymphoma (HL) in young males. Methods The review was prospectively registered (PROSPERO N. CRD42019122868). Three databases (Medline via PUBMED, SCOPUS, and Cochrane Library) were searched for studies featuring males aged 13-51-years who underwent chemotherapy for HL using ABVD (Adriamycin® (doxorubicin), bleomycin, vinblastine, and dacarbazine) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone) regimens. These chemotherapy regimens were compared against each other using sperm characteristics, FSH, and inhibin B levels to measure fertility levels. Results Data were extracted from five studies featuring 1344 patients. 6 months post-ABVD saw marked deterioration in sperm count, further reduced by more cycles (P = 0.05). Patients treated with BEACOPP rather than ABVD were more prone to oligospermia. Receiving fewer cycles of both regimens increased the likelihood of sperm production recovering. Patients treated with 6-8 cycles of BEACOPP did not recover spermiogenesis. Conclusions ABVD and BEACOPP regimens significantly reduce fertility function to varying effects depending on treatment duration. ABVD temporarily causes significant reductions in male fertility, whereas BEACOPP’s effects are more permanent. Therefore, clinicians should discuss fertility preservation with male patients receiving infertility-inducing gonadotoxic therapy. Further high-quality studies are required to more adequality describe the risk to fertility by chemotherapy (AU)

The Effect of the EGFR - Targeting Compound 3-[(4-Phenylpyrimidin-2-yl) Amino] Benzene-1-Sulfonamide (13f) against Cholangiocarcinoma Cell Lines.

OBJECTIVE: Cholangiocarcinoma (CCA) is a noxious malignancy of epithelium of the bile duct with a low response rate to chemotherapy. The epidermal growth factor receptor (EGFR) signaling pathway is implicated in the development of cancerous cells, especially CCA. In this study, we report detailed biological profiling of 13f identified from our earlier hit expansion studies. The aim of this work was to expand our understanding of 13f via more detailed investigations of its mechanism of action against KKU-100, KKU-452 and KKU-M156 CCA cells, as well as in comparison to the EGFR inhibitor Gefitinib and non-specific chemotherapeutic agents such as Cisplatin. METHODS: Inhibiting EGFR-Kinase, cytotoxicity, clonogenic assay, wound healing and apoptosis were performed. Levels of total expression of EGFR and EGFR phosphorylation proteins were detected. RESULTS: 13f was confirmed as an inhibitor of EGFR with an IC50 value against the tyrosine kinase of EGFR of 22 nM and IC50 values for 48 h incubation period were 1.3 ± 1.9, 1.5 ± 0.4 and 1.7 ± 1.1 µM of KKU-100, KKU-452 and KKU-M156, respectively through dose- and time-dependent induction of early apoptosis of CCA cells. The compound also suppressed the clonogenic ability of KKU-100 and KKU-M156 cells stronger than Gefitinib, while potently inhibiting EGF-stimulated CCA cell migratory activity in KKU-452 cells. It was observed that under normal conditions EGFR was activated in CCA cells. EGF-stimulated basal expression of EGFR in KKU-452 cells was suppressed following 13f treatment, which was significantly greater than that of the marketed EGFR inhibitor Gefitinib. CONCLUSION: In summary, our study showed that 13f has potent anti-cancer activities including antiproliferation, clonogenic ability and migration through the modulation of EGFR signaling pathway in CCA for the first time. The compound represents an interesting starting point as a potential chemotherapeutic agent in ongoing efforts to improve response rate in CCA patients.
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QM/MM and molecular dynamics investigation of the mechanism of covalent inhibition of TAK1 kinase.

TAK1 is a serine/threonine kinase which is involved in the moderation of cell survival and death via the TNFα signalling pathway. It is also implicated in a range of cancer and anti-inflammatory diseases. Drug discovery efforts on this target have focused on both traditional reversible ATP-binding site inhibitors and increasingly popular irreversible covalent binding inhibitors. Irreversible inhibitors can offer benefits in terms of potency, selectivity and PK/PD meaning they are increasingly pursued where the strategy exists. TAK1 kinase differs from the better-known kinase EGFR in that the reactive cysteine nucleophile targeted by electrophilic inhibitors is located towards the back of the ATP binding site, not at its mouth. While a wealth of structural and computational effort has been spent exploring EGFR, only limited studies on TAK1 have been reported. In this work we report the first QM/MM study on TAK1 aiming to better understand aspects of covalent adduct formation. Our goal is to identify the general base in the catalytic reaction, whether the process proceeds via a stepwise or concerted pathway, and how the highly flexible G-loop and A-loop affect the catalytic cysteine located nearby.

ABVD and BEACOPP regimens' effects on fertility in young males with Hodgkin lymphoma.

PURPOSE: Considering the increased cancer patient survivorship, the focus is now on addressing the impacts of treatment on quality of life. In young people, altered reproductive function is a major issue and its effects in young males are largely neglected by novel research. To improve clinician awareness, we systematically reviewed side effects of chemotherapy for Hodgkin lymphoma (HL) in young males. METHODS: The review was prospectively registered (PROSPERO N. CRD42019122868). Three databases (Medline via PUBMED, SCOPUS, and Cochrane Library) were searched for studies featuring males aged 13-51-years who underwent chemotherapy for HL using ABVD (Adriamycin® (doxorubicin), bleomycin, vinblastine, and dacarbazine) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone) regimens. These chemotherapy regimens were compared against each other using sperm characteristics, FSH, and inhibin B levels to measure fertility levels. RESULTS: Data were extracted from five studies featuring 1344 patients. 6 months post-ABVD saw marked deterioration in sperm count, further reduced by more cycles (P = 0.05). Patients treated with BEACOPP rather than ABVD were more prone to oligospermia. Receiving fewer cycles of both regimens increased the likelihood of sperm production recovering. Patients treated with 6-8 cycles of BEACOPP did not recover spermiogenesis. CONCLUSIONS: ABVD and BEACOPP regimens significantly reduce fertility function to varying effects depending on treatment duration. ABVD temporarily causes significant reductions in male fertility, whereas BEACOPP's effects are more permanent. Therefore, clinicians should discuss fertility preservation with male patients receiving infertility-inducing gonadotoxic therapy. Further high-quality studies are required to more adequality describe the risk to fertility by chemotherapy.

The development and evaluation of a nationwide training program for oncology health professionals in the provision of genetic testing for ovarian cancer patients.

BACKGROUND: BRCA1/2 mutation status has increasing relevance for ovarian cancer treatments, making traditional coordination of genetic testing by genetic services unsustainable. Consequently alternative models of genetic testing have been developed to improve testing at the initial diagnosis for all eligible women. METHODS: A training module to enable mainstreamed genetic testing by oncology healthcare professionals was developed by genetic health professionals. Oncology healthcare professionals completed questionnaires before and 12 months post-training to assess perceived skills, competence and barriers to their coordinating genetic testing for women with high-grade non-mucinous epithelial ovarian cancer. Genetic health professionals were surveyed 12 months post-training to assess perceived barriers to implementation of mainstreaming. RESULTS: 185 oncology healthcare professionals were trained in 42 workshops at 35 Australasian hospitals. Of the 273 tests ordered by oncology healthcare professionals post-training, 241 (93.1%) met national testing guidelines. The number of tests ordered by genetic health professionals reduced significantly (z = 45.0, p = 0.008). Oncology healthcare professionals' perceived barriers to mainstreamed testing decreased from baseline to follow-up (t = 2.39, p = 0.023), particularly perceived skills, knowledge and attitudes. However, only 58% reported either 'always' or 'nearly always' having ordered BRCA testing for eligible patients at 12 months, suggesting oncology healthcare professionals' perceived barriers were not systematically addressed through training. CONCLUSIONS: Oncology healthcare professionals have demonstrated a willingness to be involved in the provision of genetic testing in a mainstreaming model. If oncology services are to hold responsibility for coordinating genetic testing, their readiness will require understanding of barriers not addressed by training alone to inform future intervention design.

Implementation of Early Intervention Protocol in Australia for 'High Risk' Injured Workers is Associated with Fewer Lost Work Days Over 2 Years Than Usual (Stepped) Care.

Purpose To evaluate whether a protocol for early intervention addressing the psychosocial risk factors for delayed return to work in workers with soft tissue injuries would achieve better long-term outcomes than usual (stepped) care. Methods The study used a controlled, non-randomised prospective design to compare two case management approaches. For the intervention condition, workers screened within 1-3 weeks of injury as being at high risk of delayed returned to work by the Örebro Musculoskeletal Pain Screening Questionnaire-short version (ÖMPSQ-SF) were offered psychological assessment and a comprehensive protocol to address the identified obstacles for return to work. Similarly identified injured workers in the control condition were managed under usual (stepped) care arrangements. Results At 2-year follow-up, the mean lost work days for the Intervention group was less than half that of the usual care group, their claim costs were 30% lower, as was the growth trajectory of their costs after 11 months. Conclusions The findings supported the hypothesis that brief psychological risk factor screening, combined with a protocol for active collaboration between key stakeholders to address identified psychological and workplace factors for delayed return to work, can achieve better return on investment than usual (stepped) care.

Insights into the EGFR SAR of N-phenylquinazolin-4-amine-derivatives using quantum mechanical pairwise-interaction energies.

Protein kinases are an important class of enzymes that play an essential role in virtually all major disease areas. In addition, they account for approximately 50% of the current targets pursued in drug discovery research. In this work, we explore the generation of structure-based quantum mechanical (QM) quantitative structure-activity relationship models (QSAR) as a means to facilitate structure-guided optimization of protein kinase inhibitors. We explore whether more accurate, interpretable QSAR models can be generated for a series of 76 N-phenylquinazolin-4-amine inhibitors of epidermal growth factor receptor (EGFR) kinase by comparing and contrasting them to other standard QSAR methodologies. The QM-based method involved molecular docking of inhibitors followed by their QM optimization within a ~ 300 atom cluster model of the EGFR active site at the M062X/6-31G(d,p) level. Pairwise computations of the interaction energies with each active site residue were performed. QSAR models were generated by splitting the datasets 75:25 into a training and test set followed by modelling using partial least squares (PLS). Additional QSAR models were generated using alignment dependent CoMFA and CoMSIA methods as well as alignment independent physicochemical, e-state indices and fingerprint descriptors. The structure-based QM-QSAR model displayed good performance on the training and test sets (r2 ~ 0.7) and was demonstrably more predictive than the QSAR models built using other methods. The descriptor coefficients from the QM-QSAR models allowed for a detailed rationalization of the active site SAR, which has implications for subsequent design iterations.

Correction to: Implementation of Early Intervention Protocol in Australia for 'High Risk' Injured Workers is Associated with Fewer Lost Work Days Over 2 Years Than Usual (Stepped) Care.

The original version of this article unfortunately contained a spelling error in one of the co-authors's names. The family name of the co-author was incorrectly displayed as "James McCauley" instead of "James McAuley. The original article has been corrected.

Theoretical Investigation of the Enantioselective [4 + 2] Cycloaddition Reaction of o-Hydroxystyrene and Azlactone.

Theoretical studies have been undertaken to rationalize the origin of the enantioselective Diels-Alder reaction (DA) of o-hydroxystyrene and azlactone catalyzed by (a) chiral BINOL-phosphoric acid (CPA) and (b) CPA and chiral guanidine (TBO). The sequence of events leading to increased enantioselectivity under the latter conditions have been studied using density functional theory (DFT) methods. The computational results indicate that both the mono- and co-catalytic processes proceed via stepwise [4 + 2] cycloaddition reactions involving three steps, which are (1) C-C bond formation, (2) C-O bond formation, and (3) the opening of the azlactone ring. This results in the formation of an oxygenous cycle with one chiral center. The origin of greater enantioselectivity under the latter catalytic conditions are discussed in terms of the structural characteristics and energetics of the intermediates and transition states formed on the potential energy surface of the competing reactions.

Elucidation of Vasodilation Response and Structure Activity Relationships of N²,N4-Disubstituted Quinazoline 2,4-Diamines in a Rat Pulmonary Artery Model.

Pulmonary arterial hypertension (PAH) is a rare and progressive disease arising from various etiologies and pathogenesis. PAH decreases life expectancy due to pulmonary vascular remodeling, elevation of mean pulmonary arterial pressure, and ultimately progresses to heart failure. While clinical treatments are available to reduce the associated symptoms, a complete cure has yet to be found. Phosphodiesterase-5 (PDE-5) inhibition has been identified as a possible intervention point in PAH treatment. The functional vasodilation response to N²,N4-diamino quinazoline analogues with differing PDE-5 inhibitory activities and varying physicochemical properties were assessed in both endothelium-intact and denuded rat pulmonary arteries to gain greater insight into their mode of action. All analogues produced vasorelaxant effects with EC50s ranging from 0.58 ± 0.22 µM to ˃30 µM. It was observed that vasodilation response in intact vessels was highly correlated with that of denuded vessels. The ~10% drop in activity is consistent with a loss of the nitric oxide mediated cyclic guanosine monophosphate (NO/cGMP) pathway in the latter case. A moderate correlation between the vasodilation response and PDE-5 inhibitory activity in the intact vessels was observed. Experimental protocol using the alpha-adrenergic (α1) receptor agonist, phenylephrine (PE), was undertaken to assess whether quinazoline derivatives showed competitive behavior similar to the α1 receptor blocker, prazosin, itself a quinazoline derivative, or to the PDE-5 inhibitor, sildenafil. Competitive experiments with the α1-adrenergic receptor agonist point to quinazoline derivatives under investigation here act via PDE-5 inhibition and not the former. The pre-incubation of pulmonary arterial rings with quinazoline test compounds (10 µM) reduced the contractile response to PE around 40⁻60%. The most promising compound (9) possessed ~32 folds higher selectivity in terms of vasodilation to its mammalian A549 cell cytotoxicity. This study provides experi0 0mental basis for PDE-5 inhibition as the mode of action for vasodilation by N²,N4-diamino quinazoline analogues along with their safety studies that may be beneficial in the treatment of various cardiovascular pathologies.

Predicting Return to Work in a Heterogeneous Sample of Recently Injured Workers Using the Brief ÖMPSQ-SF.

Purpose (1) to examine the ability of the Örebro Musculoskeletal Pain Screening Questionnaire-short version (ÖMPSQ-SF) to predict time to return to pre-injury work duties (PID) following a work-related soft tissue injury (regardless of body location); and (2) to examine the appropriateness of 50/100 as a suitable cut-off score for case identification. Methods Injured workers (IW) from six public hospitals in Sydney, Australia, who had taken medically-sanctioned time off work due to their injury, were recruited by insurance case managers within 5-15 days of their injury. Eligible participants (N = 213 in total) were administered the ÖMPSQ-SF over the telephone by the case manager. For objective (1) Cox proportional hazards regression analysis was used to predict days to return to PID using the ÖMPSQ-SF. For objective (2) receiver operator characteristic (ROC) analysis was used to determine the ÖMPSQ-SF total score that optimises sensitivity and specificity in detecting whether or not participants had returned to PID within 2-7 weeks. Results The total ÖMPSQ-SF score significantly predicted number of days to return to PID, such that for every 1-point increase in the total ÖMPSQ-SF score the predicted chance of returning to work reduced by 4% (i.e., hazard ratio = 0.96), p < 0.001. Sensitivity and specificity for the ROC analysis comparing ÖMPSQ-SF total score to return to PID within 2-7 weeks suggested 48 as the optimal cut off (sensitivity = 0.65, specificity = 0.79). Conclusion The results provide strong support for the use of the ÖMPSQ-SF in an applied setting for identifying those IW likely to have delayed RTW when administered within 15 days of the injury. While a score of 48/100 was the optimal cut point for sensitivity and specificity, pragmatically, 50/100 should be acceptable as a cut-off in future studies of this type.