Higher conversion rate to knee arthroplasty in female patients following medial open-wedge high tibial osteotomy.

PURPOSE: Most studies about medial open-wedge high tibial osteotomy (HTO) reported outcomes without focusing on gender differences. Therefore, the study compared the long-term survival rate and postoperative subjective knee function after HTO in female versus male patients with symptomatic medial compartment knee osteoarthritis. METHODS: The data of three cohorts with long-term outcomes were analysed (n = 245; 32% females; age: 49 ± 7 years; Kellgren Lawrence Grade I 6.1%, II 32.7%, III 42.4%; IV 18.8%). The minimum follow-up was at least 6 years or an earlier conversion to total knee arthroplasty (TKA). The gender-specific survival rate after HTO was calculated after 5 and 10 years and compared using Kaplan-Meier analysis and the logrank test. Baseline characteristics and subjective knee function (International Knee Documentation Committee [IKDC]/Lysholm) were analysed between both genders. RESULTS: Forty of 78 (51.3%) women and 41 of 167 men (24.5%) underwent TKA. HTO survival in females was significantly lower (p = 0.0010). The 5- and 10-year survival rates were 85.9% and 62.6% for females and 93.4% and 77.7% for males. In females and males, from preoperative to the last follow-up, the IKDC (43 ± 15 to 58 ± 17; 47 ± 14 to 67 ± 18) and the Lysholm (42 ± 18 to 72 ± 18; 55 ± 22 to 77 ± 23) improved significantly (all p < 0.0001). Females had significantly lower preoperative and postoperative IKDC (p = 0.0438; p = 0.0035) and Lysholm scores (p = 0.0002; p = 0.0323). But the absolute improvements of the IKDC and Lysholm were not significantly different between genders. CONCLUSIONS: Females had higher conversion rates to TKA and lower knee function at the last follow-up. However, preoperative knee function was lower in females and the absolute improvement following HTO was similar for both genders. In general, females benefit from HTO to treat medial knee arthritis, and TKA could be postponed for half of female patients for more than 10 years. However, surgeons must be aware of the described inferior outcomes in females for realistic patient expectation management. LEVEL OF EVIDENCE: Level II.

Cognitive performance of adult patients with SMA before and after treatment initiation with nusinersen.

BACKGROUND: Spinal muscular atrophy (SMA) is a genetic neuromuscular disease caused by mutations of the SMN1 gene. Deficient SMN protein causes irreversible degeneration of alpha motor neurons characterized by progressive muscle weakness and atrophy. Considering that SMA is a multi-systemic disorder and SMN protein was found to be expressed in cortical structures, the cognitive profile of adult patients with SMA has recently been of particular interest. With nusinersen, a novel, disease-modifying drug has been established, but its effects on neuropsychological functions have not been validated yet. Aim of this study was to investigate the cognitive profile of adult patients with SMA during treatment initiation with nusinersen and to reveal improvement or deterioration in cognitive performance. METHODS: This monocentric longitudinal study included 23 patients with SMA type 2 and 3. All patients were assessed with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) before and after 14 months of treatment initiation with nusinersen. Additionally, motor function was evaluated by Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM) and Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). RESULTS: Of the treatment-naive patients, only three were below the age- and education-matched cut-off for cognitive impairment in the ECAS total score. Significant differences between SMA type 2 and 3 were only detected in the domain of Language. After 14 months of treatment, patients showed significant improvement of absolute scores in all three ALS-specific domains, in the non-ALS-specific domain of Memory, in both subscores and in the ECAS total score. No associations were detected between cognitive and functional outcome measures. CONCLUSIONS: In some adult patients with SMA abnormal cognitive performance in ALS-specific functions of the ECAS was evident. However, the presented results suggest no clinically significant cognitive changes during the observed treatment period with nusinersen.

Serum creatine kinase and creatinine in adult spinal muscular atrophy under nusinersen treatment.

OBJECTIVE: To determine whether serum creatine kinase activity (CK) and serum creatinine concentration (Crn) are prognostic and predictive biomarkers for disease severity, disease progression, and nusinersen treatment effects in adult patients with 5q-associated spinal muscular atrophy (SMA). METHODS: Within this retrospective, multicenter observational study in 206 adult patients with SMA, we determined clinical subtypes (SMA types, ambulatory ability) and repeatedly measured CK and Crn and examined disease severity scores (Hammersmith Functional Motor Scale Expanded, Revised Upper Limb Module, and revised Amyotrophic Lateral Sclerosis Functional Rating Scale). Patients were followed under nusinersen treatment for 18 months. RESULTS: CK and Crn differed between clinical subtypes and correlated strongly with disease severity scores (e.g., for Hammersmith Functional Motor Scale Expanded: (CK) ρ = 0.786/ (Crn) ρ = 0.558). During the 18 months of nusinersen treatment, CK decreased (∆CK = -17.56%, p < 0.0001), whereas Crn slightly increased (∆Crn = +4.75%, p < 0.05). INTERPRETATION: Serum creatine kinase activity and serum creatinine concentration reflect disease severity of spinal muscular atrophy and are promising biomarkers to assess patients with spinal muscular atrophy during disease course and to predict treatment response. The decrease of creatine kinase activity, combined with the tendency of creatinine concentration to increase during nusinersen treatment, suggests reduced muscle mass wasting with improved muscle energy metabolism.

Patient-Reported Prevalence of Non-motor Symptoms Is Low in Adult Patients Suffering From 5q Spinal Muscular Atrophy.

Background: 5q spinal muscular atrophy (SMA) is an autosomal recessive lower motoneuron disease caused by deletion or mutations in the survival motor neuron 1 gene (SMN1) which results in reduced expression of full-length SMN protein. The main symptoms are caused by spinal motor neuron demise leading to muscle atrophy, and medical care mostly refers to motor symptoms. However, new insights of recent studies in severe SMA type I revealed disease involvement of several non-motor regions, for example cardiac, vascular, sensory nerve involvement, and thalamic lesions. Non-motor symptoms (NMS) were previously described in many neurodegenerative diseases i.e., Parkinson's disease and, importantly, also amyotrophic lateral sclerosis. Methods: We screened for NMS in 70 adult patients with SMA type II (SMAII) and type III (SMAIII) and 59 age/sex-matched healthy controls (controls) in a multicenter cross-sectional study including 5 different centers with specialized expertise in medical health care of motoneuron diseases. We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is a validated tool in Parkinson's disease. Results: Total NMS burden was low in adult SMA (median: 3 items) and not significantly different compared to controls (median: 2 items). Total NMS of SMA patients did not correlate with disease severity scores. However, the items "swallowing difficulties," "falling," and particularly "swelling legs" were significantly more frequently reported in SMA. Neuropsychiatric symptoms were reported in a frequency comparable to controls and were not significantly increased in SMA. Conclusion: Patient-reported prevalence of NMS in adult SMA was low, which does not argue for a clinically relevant multisystemic disorder in SMAII/III. Importantly, adult SMA patients do not seem to suffer more frequently from symptoms of depression or adaptive disorders compared to controls. Our results yield novel information on previously underreported symptoms and will help to improve the medical guidance of these patients.

Visible-Light-Mediated Synthesis of ß-Chloro Ketones from Aryl Cyclopropanes.

We report the visible-light-mediated synthesis of ß-chloro ketones from aryl cyclopropanes, oxygen, hydrochloric acid, and nitric acid. The operationally simple and catalyst-free method uses cheap standard laboratory reagents and displays broad functional-group tolerance. Moreover, scale up of the reaction and late-stage functionalization of bioactive compounds is possible, providing the opportunity to utilize the cyclopropane ring as a masked ß-chloro ketone in a reaction sequence. We propose a light-driven radical chain reaction initiated by the reaction of diluted hydrochloric and nitric acid to produce small quantities of molecular chlorine. The mechanistic hypothesis is supported by 18 O labelling and UV/Vis experiments, cyclovoltammetry, and several control reactions.

Visible-Light-Mediated Liberation and In Situ Conversion of Fluorophosgene.

The first example for the photocatalytic generation of a highly electrophilic intermediate that is not based on radical reactivity is reported. The single-electron reduction of bench-stable and commercially available 4-(trifluoromethoxy)benzonitrile by an organic photosensitizer leads to its fragmentation into fluorophosgene and benzonitrile. The in situ generated fluorophosgene was used for the preparation of carbonates, carbamates, and urea derivatives in moderate to excellent yields via an intramolecular cyclization reaction. Transient spectroscopic investigations suggest the formation of a catalyst charge-transfer complex-dimer as the catalytic active species. Fluorophosgene as a highly reactive intermediate, was indirectly detected via its next downstream carbonyl fluoride intermediate by NMR. Furthermore, detailed NMR analyses provided a comprehensive reaction mechanism including a water dependent off-cycle equilibrium.

Motor Unit Number Index (MUNIX) of hand muscles is a disease biomarker for adult spinal muscular atrophy.

OBJECTIVE: There is still insufficient knowledge about natural history in adult spinal muscular atrophy, thus valid markers for treatment and disease monitoring are urgently needed. METHODS: We studied hand muscle innervation pattern of 38 adult genetically confirmed 5q spinal muscular atrophy (SMA) patients by the motor unit number index (MUNIX) method. Data were compared to healthy controls and amyotrophic lateral sclerosis (ALS) patients and systematically correlated to typical disease-relevant scores and other clinical as well as demographic characteristics. RESULTS: Denervation of hand muscles in adult SMA was not evenly distributed. By calculation of the MUNIX ratios, we identified a specific hand muscle wasting pattern for SMA which is different to the split hand in ALS. Furthermore, MUNIX parameters strongly correlated with established disease course parameters independent of disease stages. CONCLUSION: We found a pathophysiological remarkable denervation pattern of hand muscles, a 'reversed split hand'. MUNIX of single hand muscles correlated well with disease severity and thus represents an easily available biomarker for adult SMA. SIGNIFICANCE: Our data show the power of the MUNIX method as a biomarker for upcoming questions in adult SMA.