Mitochondrial dysfunction and mitophagy defects in LRRK2-R1441C Parkinson's disease models.

Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene have been identified as one of the most common genetic causes of Parkinson's disease (PD). The LRRK2 PD-associated mutations LRRK2G2019S and LRRK2R1441C, located in the kinase domain and in the ROC-COR domain, respectively, have been demonstrated to impair mitochondrial function. Here, we sought to further our understanding of mitochondrial health and mitophagy by integrating data from LRRK2R1441C rat primary cortical and human induced pluripotent stem cell-derived dopamine (iPSC-DA) neuronal cultures as models of PD. We found that LRRK2R1441C neurons exhibit decreased mitochondrial membrane potential, impaired mitochondrial function and decreased basal mitophagy levels. Mitochondrial morphology was altered in LRRK2R1441C iPSC-DA but not in cortical neuronal cultures or aged striatal tissue, indicating a cell-type-specific phenotype. Additionally, LRRK2R1441C but not LRRK2G2019S neurons demonstrated decreased levels of the mitophagy marker pS65Ub in response to mitochondrial damage, which could disrupt degradation of damaged mitochondria. This impaired mitophagy activation and mitochondrial function were not corrected by the LRRK2 inhibitor MLi-2 in LRRK2R1441C iPSC-DA neuronal cultures. Furthermore, we demonstrate LRRK2 interaction with MIRO1, a protein necessary to stabilize and to anchor mitochondria for transport, occurs at mitochondria, in a genotype-independent manner. Despite this, we found that degradation of MIRO1 was impaired in LRRK2R1441C cultures upon induced mitochondrial damage, suggesting a divergent mechanism from the LRRK2G2019S mutation.

Vision loss shifts the balance of feedforward and intracortical circuits in opposite directions in mouse primary auditory and visual cortices.

Loss of a sensory modality leads to widespread changes in synaptic function across sensory cortices, which are thought to be the basis for cross-modal adaptation. Previous studies suggest that experience-dependent cross-modal regulation of the spared sensory cortices may be mediated by changes in cortical circuits. Here, we report that loss of vision, in the form of dark exposure (DE) for 1 week, produces laminar-specific changes in excitatory and inhibitory circuits in the primary auditory cortex (A1) of adult mice to promote feedforward (FF) processing and also strengthens intracortical inputs to primary visual cortex (V1). Specifically, DE potentiated FF excitatory synapses from layer 4 (L4) to L2/3 in A1 and recurrent excitatory inputs in A1-L4 in parallel with a reduction in the strength of lateral intracortical excitatory inputs to A1-L2/3. This suggests a shift in processing in favor of FF information at the expense of intracortical processing. Vision loss also strengthened inhibitory synaptic function in L4 and L2/3 of A1, but via laminar specific mechanisms. In A1-L4, DE specifically potentiated the evoked synaptic transmission from parvalbumin-positive inhibitory interneurons to principal neurons without changes in spontaneous miniature IPSCs (mIPSCs). In contrast, DE specifically increased the frequency of mIPSCs in A1-L2/3. In V1, FF excitatory inputs were unaltered by DE, whereas lateral intracortical connections in L2/3 were strengthened, suggesting a shift toward intracortical processing. Our results suggest that loss of vision produces distinct circuit changes in the spared and deprived sensory cortices to shift between FF and intracortical processing to allow adaptation.

Five-year mortality for patients with end-stage renal disease who undergo upper extremity amputation.

PURPOSE: To compare the 5-year survival rate of patients on dialysis requiring an upper extremity amputation with those who did not require such surgery and to analyze whether such an amputation was prognostic for mortality. METHODS: The medical records of 20 consecutive patients with end-stage renal disease who received upper extremity amputations were reviewed. Control patients (n = 40) were matched based on age, sex, and duration of dialysis treatment. A Kaplan-Meier survival analysis was performed. RESULTS: The mean survival time after the index surgery for the surgical group was 4.95 years ± 0.90 years, and the mean survival for the control group was 8.40 years ± 0.61 years. The probability of death (the event) was statistically greater in the surgical group. The overall 5-year survival rates for the surgical and the nonsurgical groups were 35% (7 of 20) and 70% (28 of 40), respectively. Patients with diabetes in the surgical group had a significantly lower 5-year survival rate, a greater number of amputations, and a greater number of wound-healing failures. CONCLUSIONS: The 5-year survival rate from the index surgery of the surgical group was half that of the nonsurgical group. Increased mortality may be partially attributed to the poor vascular health of the patient. This analysis may help the hand surgeon to more effectively counsel patients with end-stage renal disease about the prognosis associated with an upper extremity amputation and, more importantly, supports the goal of timely intervention by the multidisciplinary team to optimize care planning and to improve surgical outcomes and quality of life. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic III.

Predictors of residual disease after breast conservation surgery for ductal carcinoma in situ: A retrospective study.

BACKGROUND: Breast-conserving therapy is the standard of care for ductal carcinoma in situ (DCIS). Debate on what constitutes a satisfactory margin persists. This study aimed to identify predictors of residual disease at re-excision. METHODS: This is a population-based retrospective cohort study of women with DCIS who underwent a lumpectomy between 2007 and 2017 in Manitoba, with close (≤2 mm) or positive margins that led to re-excision. RESULTS: The DCIS re-excision rate was 29.3% for 1001 patients. 63.2% of patients were found to have residual disease on re-excision. On univariable analysis, the size, margin status, number of positive margins, type of second surgery, and Van Nuys Prognostic Index score were associated with residual disease on re-excision. The size of DCIS and the number of positive margins remained statistically significant on multivariable analysis. CONCLUSIONS: Re-excision should be rationalized by considering the predictors of residual disease in conjunction with other factors.

Evaluating Mortality Outcomes, Transfusion Characteristics, and Risk Factors Associated With Cirrhotic Trauma Patients Undergoing Emergency Laparotomy Versus Non-Operative Management: A National Analysis.

BACKGROUND: Patients with liver cirrhosis (LC) demonstrate significantly elevated mortality rates following a traumatic event. This study aims to examine and compare the clinical outcomes in adult trauma patients with pre-existing LC undergoing laparotomy or non-operative management (NOM). Additionally, the study aims to investigate various patient outcomes, including mortality rate based on transfusion needs and timing. METHODS: This retrospective cohort study utilized the American College of Surgeons Trauma Quality Program Participant Use File (ACS-TQIP-PUF) 2017-21 to compare laparotomy vs NOM in adults (≥18 years) with pre-existing LC who presented to trauma facilities with isolated blunt solid organ abdominal injuries (Injury Severity Score ≥16, Abbreviated Injury Scale solid organ abdomen ≥3). RESULTS: Among 929 patients, 38.2% underwent laparotomy, while 61.7% received NOM. The in-hospital mortality rate was lower for patients who received NOM (52.3% vs 20.0%, P < .01). The risk of in-hospital mortality was significantly associated with laparotomy (OR 5.22, 95% CI: 2.06-13.18, P < .01) and sepsis (OR 99.50, 95% CI: 6.99-1415.28, P < .01). On average an increase in blood units in 4 hours was observed among those who experienced an in-hospital mortality (OR 5.65, 95% CI: 3.05-8.24, P < .01) and those who underwent laparotomy (OR 3.85, 95% CI: 1.36-6.34, P < .01). CONCLUSION: Trauma patients with moderate to severe isolated organ injury and Liver cirrhosis had significantly higher mortality rates, acute renal failure, whole blood units received, as well as longer ICU-LOS when undergoing laparotomy compared to non-operative management.

Complex regional pain syndrome of the upper extremity.

The diagnosis and management of complex regional pain syndrome is often challenging. Early diagnosis and intervention improve outcomes in most patients; however, some patients will progress regardless of intervention. Multidisciplinary management facilitates care in complex cases. The onset of signs and symptoms may be obvious or insidious; temporal delay is a frequent occurrence. Difficulty sleeping, pain unresponsive to narcotics, swelling, stiffness, and hypersensitivity are harbingers of onset. Multimodal treatment with hand therapy, sympatholytic drugs, and stress loading may be augmented with anesthesia blocks. If the dystrophic symptoms are controllable by medications and a nociceptive focus or nerve derangement is correctable, surgery is an appropriate alternative. Chronic sequelae of contracture may also be addressed surgically in patients with controllable sympathetically maintained pain.

Nonvascularized toe phalangeal transfer and distraction lengthening for symbrachydactyly.

Symbrachydactyly describes a spectrum of congenital hand differences consisting of digital loss resulting in fused short fingers. As the principles for distraction lengthening have evolved, the technique of nonvascularized toe phalangeal transfer to the hand with shortened digits has provided patients with improved outcomes. Nonvascularized toe phalanx to hand transplant with distraction lengthening restores functional length to a skeletally deficient, poorly functioning hand while maintaining an overlying layer of vascular and sensate tissue. The primary goal is improvement of digital length to enhance mechanical advantage and prehension. We describe the technique of nonvascularized toe phalangeal transfer and distraction lengthening for symbrachydactyly, including the following steps: nonvascularized proximal toe phalanx harvest, toe phalanx transfer to hand, pin placement, osteotomy, and closure.

Proprioception of the wrist following posterior interosseous sensory neurectomy.

PURPOSE: The posterior interosseous sensory nerve innervates the dorsal capsule of the wrist, which may provide nociceptive and proprioceptive sensation. Posterior interosseous sensory neurectomy (PISN) is commonly used as a primary or adjunctive procedure to provide wrist analgesia for a variety of wrist conditions. Currently, there is little information in the literature regarding the proprioceptive role of the posterior interosseous sensory nerve and the resultant effects of PISN on wrist proprioception. The purpose of our investigation was to examine the effect of PISN on wrist proprioception. METHODS: For 23 consecutive patients who had posterior interosseous sensory neurectomy, proprioception of their surgical wrists was compared to their nonsurgical wrists as well as to the normal wrists of 23 healthy volunteers. Using a custom testing device, wooden dowels were used to set subjects' wrists at specific angles within the testing jig, and then subjects were asked to mimic the position with their other hand at the following angles: neutral (0 degrees ), flexion (20 degrees , 40 degrees , 60 degrees ), extension (20 degrees , 40 degrees , 60 degrees ), 10 degrees of radial deviation, and 10 degrees of ulnar deviation. The following statistical comparisons were made:(1) patients' surgical versus controls' assessed wrists and(2) patients' surgical wrists versus patients' nonsurgical wrists. RESULTS: There were no statistically significant differences in wrist proprioception except in 40 degrees of extension with more accurate estimations by surgical wrists when compared to control wrists. CONCLUSIONS: Posterior interosseous sensory neurectomy does not appear to be associated with decreased proprioception of the wrist as measured by a custom testing device. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Distal biceps tendon reconstruction with tendoachilles allograft: a modification of the endobutton technique utilizing an ACL reconstruction system.

Distal biceps tendon ruptures typically occur with biceps contraction against resistance with the elbow flexed at 90 degrees. Anatomic repair is the gold standard in active patients. Numerous surgical techniques are available; however, the Endobutton might offer several advantages. We describe a novel technique for chronic distal biceps reconstruction using a modification of the Endobutton technique with an anterior cruciate ligament (ACL) drill guide as well as tendoachilles allograft. The Endobutton technique might offer several advantages, including direct tendon-to-bone healing, less bony debris to limit heterotopic ossification, less heating of the bone, ease of use, a biomechanical superiority, and excellent clinical outcomes.

Physician engagement: the Vancouver Medical Staff Association engagement charter.

Engagement of physicians with their healthcare community or institution should be a central issue in healthcare because it can be translated into improved patient care, enhanced well-being for physicians as well as safer, more effective and less costly healthcare. To accomplish the mission/goal of meaningful physician engagement, we set about to establish a 'charter' for physician engagement. We defined our concept of meaningful physician engagement and customised the engagement spectrum construct for physician relationship with their healthcare community or institution. While recognising the importance of physician leaders within the hierarchical system for efficacy of organisational management, relying only on physicians in formal executive positions is insufficient for developing physician engagement. There is a need for widespread physician engagement across the organisation. The objective is both an improvement in patient care and in physician well-being.

Cup arthroplasty for rotator cuff tear arthropathy.

Cup arthroplasty is a conservative bone-sparing option for resurfacing of the humeral head. Earlier reports have shown its effectiveness in appropriately selected patients with osteoarthritis, osteonecrosis, and severe rheumatoid arthritis. Patients with cuff tear arthropathy may also benefit from a modified cup arthroplasty technique. The purpose of this article is to describe the surgical technique involved in humeral cup arthroplasty in cuff tear arthropathy patients. We will review the indications, contraindications, complications, and postoperative rehabilitation.

Complications of anticoagulation for thromboembolism in early postoperative total joint arthroplasty.

In the study reported here, we analyzed the complications associated with anticoagulation in total joint arthroplasty patients treated for venous thromboembolism (VTE) in the early postoperative period. Twenty-nine consecutive cases from a 1-year period were identified and retrospectively reviewed. VTE treatment, which in most instances (79%) consisted of a heparin drip, was begun a mean of 2.3 days after surgery. Patients received a mean (SD) of 4.4 (5.0) units of packed red blood cells. There were no differences in bleeding parameters with respect to timing of initiation of anticoagulation. Local and systemic bleeding complications were common. The proportion of patients who were transfused was significantly (P<.0001) higher for VTE patients than for control patients, and transfused VTE patients received significantly (P = .0004) more blood products. In total joint arthroplasty patients, VTE treatment began 2.3 days after surgery and had a high incidence of complications related to bleeding.

Dorsal approach for open reduction of complex metacarpophalangeal joint dislocations.

The metacarpophalangeal (MP) joint is resistant to injury due to its strong capsuloligamentous structures, which include the volar plate and deep transverse metacarpal and collateral ligaments. Complex MP joint dislocations are, by definition, irreducible by closed means and require open reduction, as the volar plate becomes entrapped between the metacarpal head and proximal phalanx. The dorsal approach may offer the following advantages: 1) reduced risk to palmarly displaced neurovascular structures, 2) facilitated management of osteochondral fractures, and 3) full exposure of the volar plate. However, the dorsal approach requires splitting of the volar plate for adequate reduction, which may delay recovery.