Reframing prosegment-dependent folding and limits on natural protein folding landscapes from an evolutionary perspective.

In this perspective, we propose that the folding energy landscapes of model proteases including pepsin and alpha-lytic protease (αLP), which lack thermodynamic stability and fold on the order of months to millennia, respectively, should be viewed as not evolved and fundamentally distinct from their extended zymogen forms. These proteases have evolved to fold with prosegment domains and robustly self-assemble as expected. In this manner, general protein folding principles are strengthened. In support of our view, αLP and pepsin exhibit hallmarks of frustration associated with unevolved folding landscapes, such as non-cooperativity, memory effects, and substantial kinetic trapping. The evolutionary implications of this folding strategy are considered in detail. Direct applications of this folding strategy on enzyme design, finding new drug targets, and constructing tunable folding landscapes are also discussed. Together with certain proteases, growing examples of other folding "exceptions"-including protein fold switching, functional misfolding, and prevalent inability to refold-suggests a paradigm shift in which proteins may evolve to exist in a wide range of energy landscapes and structures traditionally thought to be avoided in nature.

Outcomes of anterior interosseous nerve transfer to restore intrinsic muscle function after high ulnar nerve injury.

Traumatic high ulnar nerve injuries have historically resulted in long-term loss of hand function due to the long re-innervation distance to the intrinsic muscles. Transfer of the anterior interosseous nerve (AIN) to the deep motor branch of the ulnar nerve (MUN) is proving promising in these patients. The purpose of this study was to evaluate the outcomes and efficacy of this procedure in our series. Eligible high ulnar nerve injury patients who underwent AIN to MUN nerve transfer were evaluated with a mean follow-up of 17 months. Data including demographics, injury details, surgical procedures, and outcomes were collected. A review of the current literature was performed for comparison. Sixteen patients had AIN to MUN transfer, mean age of 39.4 years, and a median delay from injury to nerve transfer of 0.8 months. The injury site was above the elbow in 5 cases, at the elbow in 8 cases, and in the proximal forearm in 3 cases. The majority were sharp transection, with the remaining from blast injuries, traumatic traction, and one post-traumatic neuroma resection. Transfer was performed end-to-end in 7 cases, hemi end-to-end in 7 cases, and supercharged end-to-side in 2 cases. Five patients achieved intrinsic muscle recovery of MRC 4+ and thirteen gained MRC 3 or above. The AIN to MUN nerve transfer provides meaningful intrinsic recovery in the majority of traumatic high ulnar nerve injuries. This procedure should be routinely considered, however, warrants further research to validate the optimum technique.

The management of failed cubital tunnel decompression.

Cubital tunnel decompression is a commonly performed operation with a much higher failure rate than carpal tunnel release.Failed cubital tunnel release generally occurs due to an inadequate decompression in the primary procedure, new symptoms due to an iatrogenic cause, or development of new areas of nerve irritation.Our preferred technique for failed release is revision circumferential neurolysis with medial epicondylectomy, as this eliminates strain, removes the risk of subluxation, and avoids the creation of secondary compression points.Adjuvant techniques including supercharging end-to-side nerve transfer and nerve wrapping show promise in improving the results of revision surgery.Limited quality research exists in this subject, compounded by the lack of consensus on diagnostic criteria, classification, and outcome assessment. Cite this article: EFORT Open Rev 2021;6:735-742. DOI: 10.1302/2058-5241.6.200135.

Cubital tunnel syndrome.

Cubital tunnel syndrome (CuTS) is the second most common compression neuropathy of the upper limb, presenting with disturbance of ulnar nerve sensory and motor function.The ulnar nerve may be dynamically compressed during movement, statically compressed due to reduction in tunnel volume or compliance, and tension forces may cause ischaemia or render the nerve susceptible to subluxation, further causing local swelling, compression inflammation and fibrosis.Superiority of one surgical technique for the management of CuTS has not been demonstrated. Different techniques are selected for different clinical situations with simple decompression being the most common procedure due to its efficacy and low complication rate.Adjunctive distal nerve transfer for denervated muscles using an expendable motor nerve to restore the axon population in the distal nerve is in its infancy but may provide a solution for severe intrinsic weakness or paralysis. Cite this article: EFORT Open Rev 2021;6:743-750. DOI: 10.1302/2058-5241.6.200129.

A novel pathway for investigation of colorectal symptoms with colonoscopy or computed tomography colonography.

BACKGROUND: Colorectal cancer (CRC) is a common problem in New Zealand and there is significant pressure on colonoscopy resources. Lower gastrointestinal symptoms are common in the community hence the appropriate selection of patients for colonoscopy is problematic. The Canterbury District Health Board recently developed the Canterbury Colorectal Symptom Pathway (CCrSP) to attempt to improve prioritisation using a combination of presenting clinical features integrated into a scoring tool. This study describes that pathway and its outcomes over a 6-month period. METHOD: Following implementation of the CCrSP, all outpatient referrals receiving colonoscopy or Computerised Tomography Colonography (CTC) over a 6-month period were audited. The clinical features included in the referral, waiting time and outcome of investigation were recorded. Using the scoring tool, a score was calculated for all referrals and compared with outcome. RESULTS: Some 1,369 procedures were performed during the study period. Of the symptomatic patients, 38 CRCs were diagnosed from 633 colonoscopies and 253 CTCs. Individual factors predictive for CRC were rectal bleeding (OR 2.1, 95%CI 1.1-4.2), iron deficiency anaemia (OR 3.2, 95%CI 1.6-6.3) and positive faecal occult blood test (OR 6.1, 95%CI 2.1-16.3). No CRCs were diagnosed in the group scoring below the pre-set threshold for investigation. Multiple logistic regression analysis demonstrated a 1 unit increase in score increased the likelihood of CRC by 7.2% (95%CI 4.4%-10.1%, p<0.001). Of the 11 CRCs suggested by CTC, there was one false positive. The follow up colonoscopy rate after CTC was 11.5% and further radiology was recommended in 7.9%. CONCLUSION: The CCrSP pathway was accurate for predicting CRC and offers a reliable triage tool. The scoring tool was both sensitive for CRC and predictive of the risk of CRC in patients who received colonoscopy or CTC.