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Objectives: This study aimed to compare demographic and surgical characteristics between patients who do and do not achieve minimal important change (MIC) in the Knee injury and Osteoarthritis Outcome Score (KOOS) Sports and Recreation (Sport/Rec) and Quality of Life (QoL) subscales 1 year after anterior cruciate ligament reconstruction., Design: Comparative cross-sectional., Setting: The MIC for the KOOS Sport/Rec subscale was ≥12.1 and ≥18.3 for the KOOS QoL subscale from before surgery to 1-year follow-up using data from the Swedish National Knee Ligament Registry., Participants: In total 16 131 patients were included: 11 172 (69%) with no MIC for the Sport/Rec scale, and 10 641 (66%) for the QoL., Results: Patients with no MIC for Sport/Rec and QoL had a higher body mass index (BMI) (24.8±3.5 vs 24.6±3.3 and 24.7±3.5 vs 24.6±3.2, respectively, p<0.0001), were younger (years) at time of surgery (28.5±10.3 vs 29.1±10.8 and 27.4±9.8 vs 29.7±11.0, respectively, p=0.0002 and <0.0001), had longer time from injury to surgery (months) (Sports/Rec 22.0±38.5 vs 19.3±36.6, respectively, p=0.0002), and greater rates of concomitant cartilage injuries especially to the lateral femoral condyle (22.7% vs 19.4% and 23.3% vs 19.0%, respectively, p=0.001 and p=0.005) compared with patients who achieved the MIC. A smaller proportion of patients treated with a hamstring tendon autograft had no MIC (91.4%) compared with patients with MIC (94.1%)., Conclusions: Patients with no MIC for KOOS Sport/Rec and QoL subscales had a higher BMI, longer time from injury to surgery and were younger at the time of surgery compared with patients who did achieve MIC. Although differences were small, they may reframe management strategies with patients who have these characteristics., Competing Interests: Competing interests: JI is President-Elect of the Board of Directors for the Journal of Orthopaedic and Sports Physical Therapy. VM reports educational grants, consulting fees and speaking fees from Smith & Nephew, educational grants from Arthrex and DePuy/Synthes, is a board member of the International Society of Arthroscopy, Knee Surgery and Orthopaedic Sports Medicine (ISAKOS) and deputy editor-in-chief of Knee Surgery, Sports Traumatology, Arthroscopy (KSSTA). KS is a board member at Getinge AB. EHS is the associate editor of Journal of Orthopeadic and Sports Physical Therapy., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rehabilitation after an anterior cruciate ligament (ACL) reconstruction requires patience, devotion, and discipline. Rehabilitation should be individualized to each patient's specific need and sport. Return to sport is a continuum throughout the rehabilitation, and patients should not return to performance before passing a battery of muscle function tests and patient-reported outcomes, as well as change of direction-specific tests. Return to full participation should be an agreement between the patient, physical therapist, surgeon, and coach. For minimal risk for second ACL injury, patients should continue with maintenance and prevention training even after returning to sport., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The relationship between hamstring strength and hop performance after anterior cruciate ligament (ACL) reconstruction with hamstring tendon (HT) autografts has not been well elucidated. The aim was to investigate the relationship between eccentric hamstring strength, assessed with the NordBord, and concentric hamstring strength, assessed with the Biodex, with hop performance at 8 and 12 months after ACL reconstruction., Methods: Registry study. Patients ≥ 16 years who had undergone primary ACL reconstruction with HT autograft, followed by muscle strength and hop tests at 8 and 12 months were included. Correlations of the relative hamstring strength (Nm/kg or N/kg) and limb symmetry index (LSI) with hop performance were analyzed. Pearson's correlation coefficient, and coefficient of determination (r 2 ) were used for statistical analysis., Results: A total of 90 patients were included, of which 48 (53%) were women. The mean age at ACL reconstruction was 27.0 ± 8.0 years. Relative hamstring strength had significant positive correlations with hop performance, ranging from r = 0.25-0.66, whereas hamstring strength LSI had significant positive correlations which ranged from r = 0.22-0.37 at 8 and 12 months after ACL reconstruction. At 12 months, the relative hamstring strength in the Biodex explained 32.5-43.6% of the hop performance in vertical hop height, hop for distance relative to height, and the total number of side hops, whereas the relative hamstring strength in the NordBord explained 15.2-23.0% of the hop performance., Conclusion: The relative hamstring strength in the Biodex test explained 32.5-43.6% of the hop performance, whereas the relative hamstring strength in the NordBord explained 15.2-23.0%. Thus, our findings suggest that relative hamstring strength, especially in the hip-flexed position may be a better indicator of hop performance at 8 and 12 months after ACL reconstruction in patients treated with HT autograft., (© 2024. The Author(s).)

Objective: Comparison of knee flexor strength limb symmetry index (LSI) between the NordBord-test and the Biodex-test, and to determine the relationship between knee flexor strength and function in patients 2 and 5 years after anterior cruciate ligament reconstruction (ACL-R) with hamstring tendon (HT) autografts., Design: Observational registry study., Setting: Primary care., Patients: Cross-sectional data from 96 patients (55% women) participating in a rehabilitation-registry after ACL-R with HT autografts., Main Outcome Measures: Comparison of knee flexor strength symmetry between the Biodex-test and the NordBord-test. Secondly, the relationship between knee flexor strength test and perceived knee function, activity level, and hop performance., Results: The NordBord-test demonstrated greater strength deficits compared to the Biodex-test with a mean difference of 12.5% ± 15.1% 95 % CI [8.1; 16.9%] at 2 years, and 11.1% ± 11.9% 95 % CI [7.7; 14.6 %] at 5 years after ACL-R. Relative concentric knee flexor strength (Nm/kg) in the Biodex demonstrated significant weak-to-moderate correlations with activity level and hop performance (r = 0.33-0.67) at 2 and 5 years., Conclusion: The NordBord-test identified deficits in knee flexor strength LSI not seen with the Biodex-test at 2 and 5 years after ACL-R. No significant correlations were found between the persistent knee flexor strength asymmetry and perceived function, activity level or hop performance., Competing Interests: Declaration of Competing interest KS is a board member of Getinge AB. The authors declare that they have no conflict of interest in the content of the present study., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: About 50% of patients who sustain an anterior cruciate ligament (ACL) injury are treated without ACL reconstruction (ACL-R). A significant proportion of these patients opt for late ACL-R. Patients' experience of changing treatment has not yet been investigated and presented in the scientific literature., Aim: To explore patients' experiences before and after changing treatment from ACL rehabilitation alone to ACL-R., Method: Fifteen patients were interviewed in semi-structured interviews, which were recorded, transcribed, and analyzed with qualitative content analysis, based on the method described by Graneheim and Lundman. Patients were between 26 and 58 years old, and had tried rehabilitation for a minimum of 9 months prior to ACL-R., Results: Two themes, "Expecting what could not be achieved: the struggle to recover and not becoming stable", and "Internal completeness: expectations can be achieved", emerged from the analysis. Each theme was supported by three main categories and 5-6 subcategories. The first theme represents the journey before ACL-R, where patients experienced getting stronger, but perceived the knee as unstable. The second theme represents the journey after ACL-R, where patients expressed that they felt whole after their ACL-R, and where able to achieve their expections. Patients experienced a greater support from the healthcare system, and ultimately expressed a feeling of having achieved the unachievable after ACL-R., Summary: Patients who cross over from ACL rehabilitation to ACL-R experienced rehabilitation alone as insufficient to achieve the desired outcomes, which resulted in a need to opt for delayed ACL-R. Healthcare providers need to support patients, who primarily choose to undergo rehabilitation alone and later opt for ACL-R, throughout the whole rehabilitation process., (© 2024 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Background: The stress on the anterior cruciate ligament (ACL) induced by the quadriceps can be attenuated by activation of the hamstrings by exerting an opposing torque to the anterior translation of tibia. Consequently, considering the ratio between strength of the hamstrings-to-quadriceps (HQ-ratio) may be of value to reduce the odds of second ACL injuries. The objective was therefore to evaluate (1) the association between HQ-ratio and the occurrence of a second ACL injury in patients after ACL-reconstruction within 2 years of return to preinjury sport level and (2) to compare the HQ-ratio between males and females after ACL reconstruction., Methods: Patients who had undergone primary ACL reconstruction and participated in knee-strenuous activity preinjury were included. Demographics, the occurrence of a second ACL injury, and muscle strength test results before returning to preinjury sport level were extracted from a rehabilitation registry. The endpoint was set at a second ACL injury or 2 years after return to preinjury sport level. A multivariable logistic regression was used to analyze the association between the HQ-ratio and a second ACL injury., Results: A total of 574 patients (50.0% female) with a mean age of 24.0 ± 9.4 years at primary ACL reconstruction were included. In the univariable logistic regression analysis, the odds of sustaining a second ACL injury decreased by 3% for every 1% increase in the HQ-ratio (OR 0.97 [95% CI 0.95-1.00], p = 0.025). After adjusting for the time from reconstruction to return to preinjury sport level, sex, preinjury sport level, graft choice, age, and body mass index, the results were no longer significant (OR 0.98 [95% CI 0.95-1.01], p = 0.16). Females had a higher HQ-ratio compared with males for both the ACL-reconstructed and uninjured side (3.7% [95% CI 5.7; 1.8%], p = 0.0002 and 3.3% [95% CI 4.6; 2.1], p < 0.001, respectively)., Conclusion: The HQ-ratio did not significantly affect the odds for sustaining a second ACL injury upon return to preinjury sports level after primary ACL reconstruction. Females had a significant higher HQ-ratio than males for both the ACL reconstructed and uninjured side., (© 2024. The Author(s).)

Background: Treatment volume can impact outcomes after surgical procedures of the knee between surgeons with high- and low-patient-volumes. However, the difference between physical therapeutic clinics with high- and low-volumes has not been widely researched. This registry study aims to investigate how patient volume affects knee function outcomes after anterior cruciate ligament (ACL) reconstruction at physical therapy (PT) clinics in terms of odds for a second ACL injury, return to pre-injury level of activity, perceived knee function, and recovery of strength and hop performance., Method: Data were extracted from the Project ACL, a local rehabilitation registry. High- and low-volume clinics were defined based on the number of patients who attended different clinics. High-volume clinics were defined as those with > 100 patient registrations in Project ACL during the study period while low-volume clinics were those with ≤ 100 patient registrations. High- and low-volume clinics were compared, based on muscle function and patient-reported outcomes across 4 follow-ups, 2-, 4-, 8-, and 12 months, during the first year after ACL reconstruction, and odds of second ACL injury up to 2 years after ACL reconstruction., Result: Of the 115 rehabilitation clinics included, 111 were classified as low-volume clinics and included 733 patients, and 4 as high-volume clinics which included 1221 patients. There were 31 (1.6%) second ACL injuries to the ipsilateral or contralateral side within the first 12 months and 68 (4.0%) within 2 years. No difference in the incidence of a second ACL injury, within 12 months follow-up odds ratio (OR) 0.95 [95% CI 0.46-1.97] or within 2 years follow-up OR 1.13 [95% CI 0.68-1.88], was found between high- and low-volume clinics. There were early (2 months) and non-clinically relevant differences in patient-reported outcomes (PROs) and physical activity levels early after ACL reconstruction in favor of high-volume clinics. One year after ACL reconstruction, no differences were observed between high- and low-volume clinics in terms of PROs, muscle function, and return to pre-injury level of activity., Conclusion: No clinically relevant difference in the incidence of secondary ACL injuries in patients who underwent rehabilitation after ACL reconstruction at high- or low-volume physical therapist clinics was found. In addition, no clinically relevant differences in outcomes were found during the first year in terms of patient-reported outcomes, recovery of muscle function, or return to pre-injury level of activity., (© 2023. The Author(s).)

An AstraZeneca effort to identify a 5-lipoxygenase activating protein inhibitor with good drug-like properties resulted in the identification of AZD6642. To further understand its drug metabolism and pharmacokinetic properties, it was required labeled with tritium. The tritiation of AZD6642 was effected by Ir-catalyzed exchange chemistry to give an average of one tritium per molecule. Additionally, a stable isotope labeled version of AZD6642 was required to support bioanalytical studies. The synthesis originated from [(2) H6 ]acetone which was converted to the trimethylsilyl cyanide adduct and subsequently reduced to give 2-(aminomethyl)-[1,1,1,3,3,3-(2) H6 ]propan-2-ol in good yield. Carbonylation to give an amide adduct resulted in an intermediate that was converted to the final compound in four steps., (Copyright © 2016 John Wiley & Sons, Ltd.)

In support of a study designed to better understand the liver toxicity of ximelagatran, ximelagatran, and melagatran, hydroxymelagatran and ethylmelagatran were prepared in tritium labeled form. Incorporation of tritium was achieved by hydrogen isotope exchange using Crabtree's catalyst and later with N-heterocyclic containing Ir catalyst. The tritiated product was then converted into the four target compounds to afford them in high purity and specific activity., (Copyright © 2013 John Wiley & Sons, Ltd.)

We investigated the enzyme kinetic basis for the stereoselective disposition of R- and S-omeprazole (OME) and racemic OME in human liver microsomes. OME is primarily metabolized by the hepatic cytochrome P450 enzyme system (CYP2C19 and 3A4). The metabolism of each enantiomer and pseudoracemic OME was studied using unlabeled and (13)C(7)-labeled enantiomers. The enantiomers inhibited each other's metabolism competitively in human liver microsomes and in recombinant CYP2C19 and 3A4. The results obtained with the individual enantiomers allowed successful prediction of the enzyme kinetics for the pseudoracemate. The intrinsic clearance of each enantiomer in a pseudoracemic mixture remained the same as those of the individually incubated enantiomers, although K(m) and V(max) decreased. In the pseudoracemate, the relative contribution of CYP2C19 and 3A4 to 5-hydroxylation and 5'-O-demethylation of R-OME was comparable to that obtained for the incubation of R-OME alone. For S-OME, however, the presence of its antipode greatly increased the contribution of CYP3A4, with increasing concentrations, compared with that obtained when incubating S-OME alone. The results of our in vitro study clearly show metabolic interactions between the OME enantiomers, which may also occur in vivo. Because the enantiomers of OME produce similar pharmacological effects, the enantiomer interactions should not significantly affect the pharmacodynamics. On the other hand, the use of the S-enantiomer results in less complex enzyme kinetics than those of the racemate; thus, the outcome of its clinical use is more predictable.

The excretion and metabolism of [14C]omeprazole given orally as a suspension was studied in 10 healthy male subjects. An average of 79% of the dose was recovered in the urine in 96 hr, with most of the radioactivity (76% of dose) being eliminated in the first 24 hr. Pooled urine (0-2 hr) from five subjects, containing about 47% of the dose, was analyzed by reverse phase gradient elution LC with radioisotope detection. Omeprazole was completely metabolized to at least six metabolites. The two major metabolites were extensively purified by LC and their structures were determined by MS with derivatization and use of stable isotopes, 1H NMR, and comparison with synthetic references. They were formed by hydroxylation of a methyl group in the pyridine ring, followed by further oxidation of the alcohol to the corresponding carboxylic acid. Both metabolites retained the sulfoxide group of omeprazole, rendering them as unstable as the parent compound at pH less than 7. They accounted for approximately 28% (hydroxyomeprazole) and 23% (omeprazole acid) of the amount excreted in the 0-2-hr collection interval. Based on in vitro studies with the synthetic metabolites in isolated gastric glands, it is unlikely that M1 and M2 will contribute to the pharmacological effect of omeprazole in humans.

The factor Xa-sensitive substrate BZ-Ile-Glu-Gly-Arg-p-nitroanilide has been made more sensitive by making ester and amide derivatives of the gamma-carboxyl group of the glutamyl residue. The morpholinyl and piperidyl amides react 2.5 times more rapidly with factor Xa.

The kinetic behaviour of human thrombin has been studied with 26 tripeptidyl-p-nitroanilide substrates protected at the N terminus and with 9 unprotected ones. By the regression analysis of experimentally determined 1/Km, kcat and kcat/Km values the individual contribution of each side chain of the various substrates to the kinetic parameters was calculated. The contributions to the kinetic parameters of the best substrates provide information about the structure of the binding site. The interaction of subsites S1 and P1, which determines primary specificity, proved to be marginal on the basis of contribution values, though it depends upon this contact whether the substrate is hydrolyzed at all. At subsite S2 proline appeared to be favourable. Subsite S3 plays an important role in efficiency. The best parameters were obtained here with the D configurations of bulky amino acid residues. The aromatic protecting groups applied did not improve the properties of substrates. BZDPhe-Pro-Arg-Nan was predicted by calculation to be better than the protected substrates assayed. The compound was synthesized and tested. Its experimentally determined 1/Km, 55.1 mM-1, was in good agreement with 50.9 mM-1 found by calculation.

A new synthesis of 4-methoxy-2,3,5-trimethylpyridine (2), an important building block for the preparation of gastric-acid inhibiting compounds, is described. Condensation of ethyl 3-amino-2-methyl-2-butenoate (3) and diethyl 2-methylmalonate (4) gives 4-hydroxy-3,5,6-trimethyl-2(1H)-pyridone 5. Reaction of 5 with phosphoryl chloride affords 2,4-dichloro-3,5,6-trimethylpyridine (9a), which, upon hydrogenolysis with palladium on charcoal, gives 2,3,5-trimethylpyridine (10). However, selective hydrogenolysis in acidic solution yields 4-chloro-2-3-5-trimethylpyridine (11). Substitution of the chlorine in 11 with methoxide ion gives 4-methoxy-2,3,5-trimethylpyridine (2), which can be oxidized to the corresponding N-oxide (13). This constitutes a new and efficient route to compound 2 in an overall yield of 43%.

The carbonyl terminal tripeptide sequence of bradykinin (Pro-Phe-Arg) is molecularly manipulated to obtain agents with potent antagonistic activity towards the smooth muscle contractile activity of bradykinin. Screening of various peptide derivatives revealed that heptyl amides or esters of H-D-Pro-Phe-Arg, and H-D-Phe-Phe-Arg possessed relatively stronger antibradykinin activity on the isolated smooth muscle preparation. The parent tripeptides, H-D-Pro-Phe-Arg-OH, and H-D-Phe-Phe-Arg-OH, and their amino acid components, i.e. D-Proline, D-Phenylalanine, L-Phenylalanine and Arginine, did not possess any antibradykinin activity in concentrations of up to 10(-4) M. When the heptyl derivatives of these peptides were incubated with either heparinized or citrated whole blood or plasma, the antibradykinin activity was not lost. Incubation of these peptide derivatives with either carboxypeptidase A or B did not result in any loss of the pharmacological effect. However, pancreatic protease extract produced a significant loss of the anti-oxytocic action on the isolated rat uterus preparation. H-D-Pro-Phe-Arg-NH-lauryl derivative also blocked the action of bradykinin and this effect sustained for a longer period of time comparative to the blockade with H-D-Pro-Phe-Arg-NH-heptyl derivative. In concentrations of 10(-7) M and 10(-8) M and 1 min incubation, which blocked the contractile action of bradykinin (1 nmole) on the isolated guinea pig ileum, these peptide derivatives did not block the action of acetylcholine, histamine, and serotonin. However, in concentrations of about 10(-6) M and higher with 5 min. incubation histamin is also blocked. On the isolated rat uterus preparation the contractile action of acetylcholine, angiotensin, oxytocin and vasopressin was blocked at concentrations of 10(-6) M. These findings warrant a differential pharmacological evaluation and in vivo testing of these peptide derivatives to investigate their therapeutic potential.

[3H]-Felodipine and high-intensity ultraviolet irradiation were used in the photoaffinity labeling of soluble proteins prepared from porcine mesenteric vascular smooth muscle. Irradiation of the soluble proteins in the presence of [3H]-felodipine resulted in the labeling of a protein with an apparent molecular weight of 62 kDa when analyzed by SDS-polyacrylamide gel electrophoresis. Labeling of the protein did not occur without ultraviolet irradiation. An [3H]-azido analog of felodipine was found to show less specificity than felodipine in its protein labeling when irradiated, since proteins with apparent molecular weights of 44, 29, and 14, as well as 62 kDa, were labeled. The photoaffinity labeling of the proteins were inhibited by excess of unlabeled felodipine.

The kinetic parameters of the tryptic hydrolysis of tripeptidyl-p-nitroanilide substrates were determined and the data were studied by regression analysis. The sequence of substrates optimal from the viewpoint of kinetic constants 1/Km, kcat and kcat/Km was established and the influence of amino acid side chains on the binding and reactivity of substrates was calculated. At subsite P3 [notation of Schechter and Berger (1967) Biochem. Biophys, Res. Commun. 27, 157] polar side chains (Asn, D-Arg) are favourable as regards 1/Km, whereas hydrophobic side chains are preferred definitely from the viewpoint of catalytic efficiency, just as at subsite P2. In the side chain contributions, calculated for the kinetic parameters, the P3-S3 interaction predominates, in spite of the fact that the properties of the residue at subsite P1 decide whether hydrolysis occurs at all. The ZAsn-Ile-Arg-Nan sequence was predicted as a better substrate than those tested experimentally. The compound was synthesized, and the calculated value of its 1/Km (116.4 mM-1) was in a good agreement with the measured value (100.2 mM-1). Comparing the data obtained with trypsin with those observed with thrombin, elastase and subtilisin, we can establish that the homology of these enzymes can be characterized at each binding subsite by the aid of tripeptidyl-p-nitroanilide substrates. The quantities derived allow one to envisage a novel type of comparison of the proteases.