To realize the medicinal potential of peptide toxins, naturally occurring disulfide-rich peptides, as ion channel antagonists, more efficient pharmaceutical optimization technologies must be ...developed. Here, we show that the therapeutic properties of multiple cysteine toxin peptides can be rapidly and substantially improved by combining direct chemical strategies with high-throughput electrophysiology. We applied whole-molecule, brute-force, structure-activity analoging to ShK, a peptide toxin from the sea anemone Stichodactyla helianthus that inhibits the voltage-gated potassium ion channel Kv1.3, to effectively discover critical structural changes for 15× selectivity against the closely related neuronal ion channel Kv1.1. Subsequent site-specific polymer conjugation resulted in an exquisitely selective Kv1.3 antagonist (>1000× over Kv1.1) with picomolar functional activity in whole blood and a pharmacokinetic profile suitable for weekly administration in primates. The pharmacological potential of the optimized toxin peptide was demonstrated by potent and sustained inhibition of cytokine secretion from T cells, a therapeutic target for autoimmune diseases, in cynomolgus monkeys.
Molecular routes to metastatic dissemination are critical determinants of aggressive cancers. Through in vivo CRISPR-Cas9 genome editing, we generated somatic mosaic genetically engineered models ...that faithfully recapitulate metastatic renal tumors. Disruption of 9p21 locus is an evolutionary driver to systemic disease through the rapid acquisition of complex karyotypes in cancer cells. Cross-species analysis revealed that recurrent patterns of copy number variations, including 21q loss and dysregulation of the interferon pathway, are major drivers of metastatic potential. In vitro and in vivo genomic engineering, leveraging loss-of-function studies, along with a model of partial trisomy of chromosome 21q, demonstrated a dosage-dependent effect of the interferon receptor genes cluster as an adaptive mechanism to deleterious chromosomal instability in metastatic progression. This work provides critical knowledge on drivers of renal cell carcinoma progression and defines the primary role of interferon signaling in constraining the propagation of aneuploid clones in cancer evolution.
Cervical spinal cord injury (SCI) causes devastating loss of upper extremity function and independence. Nerve transfers are a promising approach to reanimate upper limbs; however, there remains a ...paucity of high-quality evidence supporting a clinical benefit for patients with tetraplegia.
To evaluate the clinical utility of nerve transfers for reanimation of upper limb function in tetraplegia.
In this prospective case series, adults with cervical SCI and upper extremity paralysis whose recovery plateaued were enrolled between September 1, 2015, and January 31, 2019. Data analysis was performed from August 2021 to February 2022.
Nerve transfers to reanimate upper extremity motor function with target reinnervation of elbow extension and hand grasp, pinch, and/or release.
The primary outcome was motor strength measured by Medical Research Council (MRC) grades 0 to 5. Secondary outcomes included Sollerman Hand Function Test (SHFT); Michigan Hand Outcome Questionnaire (MHQ); Disabilities of Arm, Shoulder, and Hand (DASH); and 36-Item Short Form Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS) scores. Outcomes were assessed up to 48 months postoperatively.
Twenty-two patients with tetraplegia (median age, 36 years range, 18-76 years; 21 male 95%) underwent 60 nerve transfers on 35 upper limbs at a median time of 21 months (range, 6-142 months) after SCI. At final follow-up, upper limb motor strength improved significantly: median MRC grades were 3 (IQR, 2.5-4; P = .01) for triceps, with 70% of upper limbs gaining an MRC grade of 3 or higher for elbow extension; 4 (IQR, 2-4; P < .001) for finger extensors, with 79% of hands gaining an MRC grade of 3 or higher for finger extension; and 2 (IQR, 1-3; P < .001) for finger flexors, with 52% of hands gaining an MRC grade of 3 or higher for finger flexion. The secondary outcomes of SHFT, MHQ, DASH, and SF36-PCS scores improved beyond the established minimal clinically important difference. Both early (<12 months) and delayed (≥12 months) nerve transfers after SCI achieved comparable motor outcomes. Continual improvement in motor strength was observed in the finger flexors and extensors across the entire duration of follow-up.
In this prospective case series, nerve transfer surgery was associated with improvement of upper limb motor strength and functional independence in patients with tetraplegia. Nerve transfer is a promising intervention feasible in both subacute and chronic SCI.
Background Globus pallidus interna (GPi) deep brain stimulation (DBS) is an established surgical procedure that confers a benefit in medication refractory dystonia. Patients with generalized dystonia ...require general anesthesia (GA) for the surgery as their movements may hinder the surgical procedure. General anesthetics tend to dampen the microelectrode recordings (MERs) from the GPi. Methods We describe our experience with a series of consecutive patients with dystonia who underwent bilateral GPi DBS using standard DBS and MER under GA using sevoflurane as the maintenance general anesthetic drug. All patients had Medtronic 3,387 leads implanted and connected to an RC battery. Patients underwent sequential programming of the DBS after the surgery. Results The mean age of the 13 patients who underwent DBS of the GPi for dystonia was 46.5 years with a range from 29 to 71 years. Every patient in our case series received various doses of (1.37% to 2.11%) inhaled sevoflurane for anesthesia maintenance. Sevoflurane provided adequate anesthesia and allowed accurate MERs from the GPi. No adverse effects were encountered. On follow-up and sequential DBS programming, patients had significant improvements in dystonia attesting to the accuracy of the electrode placements. Conclusions We report our experience using sevoflurane for maintenance of GA for bilateral GPi DBS for dystonia. The main benefits identified have been adequate anesthesia and reduction of dystonia-related movements to allow the performance of the DBS surgery. The MER signals from the GPi were not suppressed by sevoflurane. This allowed accurate mapping and placement of the DBS implants in the GPi.
Prospective cohort study.
Apply a machine learning clustering algorithm to baseline imaging data to identify clinically relevant cervical spondylotic myelopathy (CSM) patient phenotypes.
A major ...shortcoming in improving care for CSM patients is the lack of robust quantitative imaging tools to guide surgical decision-making. Advanced diffusion-weighted magnetic resonance imaging (MRI) techniques, such as diffusion basis spectrum imaging (DBSI), may help address this limitation by providing detailed evaluations of white matter injury in CSM.
Fifty CSM patients underwent comprehensive clinical assessments and diffusion-weighted MRI, followed by DBSI modeling. DBSI metrics included fractional anisotropy, axial and radial diffusivity, fiber fraction, extra-axonal fraction, restricted fraction, and nonrestricted fraction. Neurofunctional status was assessed by the modified Japanese Orthopedic Association, myelopathic disability index, and disabilities of the arm, shoulder, and hand. Quality-of-life was measured by the 36-Item Short Form Survey physical component summary and mental component summary. The neck disability index was used to measure self-reported neck pain. K-means clustering was applied to baseline DBSI measures to identify 3 clinically relevant CSM disease phenotypes. Baseline demographic, clinical, radiographic, and patient-reported outcome measures were compared among clusters using one-way analysis of variance (ANOVA).
Twenty-three (55%) mild, 9 (21%) moderate, and 10 (24%) severe myelopathy patients were enrolled. Eight patients were excluded due to MRI data of insufficient quality. Of the remaining 42 patients, 3 groups were generated by k-means clustering. When compared with clusters 1 and 2, cluster 3 performed significantly worse on the modified Japanese Orthopedic Association and all patient-reported outcome measures (P<0.001), except the 36-Item Short Form Survey mental component summary (P>0.05). Cluster 3 also possessed the highest proportion of non-Caucasian patients (43%, P=0.04), the worst hand dynamometer measurements (P<0.05), and significantly higher intra-axonal axial diffusivity and extra-axonal fraction values (P<0.001).
Using baseline imaging data, we delineated a clinically meaningful CSM disease phenotype, characterized by worse neurofunctional status, quality-of-life, and pain, and more severe imaging markers of vasogenic edema.
II.
Hong Kong contained COVID-19 for two years but experienced a large epidemic of Omicron BA.2 in early 2022 and endemic transmission of Omicron subvariants thereafter. We reflected on pandemic ...preparedness and responses by assessing COVID-19 transmission and associated disease burden in the context of implementation of various public health and social measures (PHSMs).
We examined the use and impact of pandemic controls in Hong Kong by analysing data on more than 1.7 million confirmed COVID-19 cases and characterizing the temporal changes non-pharmaceutical and pharmaceutical interventions implemented from January 2020 through to 30 December 2022. We estimated the daily effective reproductive number (Rt) to track changes in transmissibility and effectiveness of community-based measures against infection over time. We examined the temporal changes of pharmaceutical interventions, mortality rate and case-fatality risks (CFRs), particularly among older adults.
Hong Kong experienced four local epidemic waves predominated by the ancestral strain in 2020 and early 2021 and prevented multiple SARS-CoV-2 variants from spreading in the community before 2022. Strict travel-related, case-based, and community-based measures were increasingly tightened in Hong Kong over the first two years of the pandemic. However, even very stringent measures were unable to contain the spread of Omicron BA.2 in Hong Kong. Despite high overall vaccination uptake (>70% with at least two doses), high mortality was observed during the Omicron BA.2 wave due to lower vaccine coverage (42%) among adults ≥65 years of age. Increases in antiviral usage and vaccination uptake over time through 2022 was associated with decreased case fatality risks.
Integrated strict measures were able to reduce importation risks and interrupt local transmission to contain COVID-19 transmission and disease burden while awaiting vaccine development and rollout. Increasing coverage of pharmaceutical interventions among high-risk groups reduced infection-related mortality and mitigated the adverse health impact of the pandemic.
Health and Medical Research Fund.
Background:
Ventriculoperitoneal (VP) shunts are the preferred surgical treatment for hydrocephalus, and rarely, these operations may be complicated by catheter migration to ectopic sites. We present ...the case of an asymptomatic VP shunt patient with delayed peritoneal catheter migration into the pulmonary artery shunt catheter migration into the pulmonary artery (SCMPA) complicated by knotting and indolent thrombosis, necessitating open-heart surgery for system retrieval.
Methods:
We conducted a literature review in PubMed, Scopus, and Web of Science of prior similar reported cases and present the results of 24 cases of SCMPA.
Results:
An asymptomatic 12-year-old male presented with SCMPA noted on routine annual follow-up imaging. Preoperative CT angiogram indicated extensive catheter looping into the pulmonary artery without evidence of thrombosis. Less invasive attempts to retrieve the retained catheter were unsuccessful, and open-heart surgery was required. Intraoperatively, a nonocclusive pulmonary arterial thrombus surrounding the knotted catheter was discovered that was lysed successfully before system retrieval.
Conclusion:
VP shunt catheter migration into the pulmonary artery (SCMPA) with concurrent large vessel thrombosis can develop in pediatric patients incidentally without any clinical symptoms. Our report suggests that preoperative CT angiogram may be insufficient to detect arterial thrombosis in the presence of extensive intravascular catheter knotting. An open-chest approach may be the only viable surgical option for catheter retrieval in the presence of complex catheter coiling. The use of anticoagulation following open-heart surgery for retrieval of a migrated VP shunt catheter remains unclear, we here propose that continuation of long-term therapeutic anticoagulation may successfully prevent thrombus relapse.
Focal adhesions (FAs) control cell shape and motility, which are important processes that underlie a wide range of physiological functions. FA dynamics is regulated by cytoskeleton, motor proteins ...and small GTPases. Kinectin is an integral endoplasmic reticulum (ER) membrane protein that extends the ER along microtubules. Here, we investigated the influence of the ER on FA dynamics within the cellular lamella by disrupting the kinectin-kinesin interaction by overexpressing the minimal kinectin-kinesin interaction domain on kinectin in cells. This perturbation resulted in a morphological change to a rounded cell shape and reduced cell spreading and migration. Immunofluorescence and live-cell imaging demonstrated a kinectin-dependent ER extension into the cellular lamella and ER colocalisation with FAs within the cellular lamella. FRAP experiments showed that ER contact with FAs was accompanied with an increase in FA protein recruitment to FAs. Disruption of the kinectin-kinesin interaction caused a reduction in FA protein recruitment to FAs. This suggests that the ER supports FA growth within the cellular lamella. Microtubule targeting to FAs is known to promote adhesion disassembly; however, ER contact increased FA size even in the presence of microtubules. Our results suggest a scenario whereby kinectin-kinesin interaction facilitates ER transport along microtubules to support FA growth.
Chronic entrapment neuropathy results in a clinical syndrome ranging from mild pain to debilitating atrophy. There remains a lack of objective metrics that quantify nerve dysfunction and guide ...surgical decision-making. Mechanomyography (MMG) reflects mechanical motor activity after stimulation of neuromuscular tissue and may indicate underlying nerve dysfunction.
To evaluate the role of MMG as a surgical adjunct in treating chronic entrapment neuropathies.
Patients 18 years or older with cubital tunnel syndrome (n = 8) and common peroneal neuropathy (n = 15) were enrolled. Surgical decompression of entrapped nerves was performed with intraoperative MMG of the hypothenar and tibialis anterior muscles. MMG stimulus thresholds (MMG-st) were correlated with compound muscle action potential (CMAP), motor nerve conduction velocity, baseline functional status, and clinical outcomes.
After nerve decompression, MMG-st significantly reduced, the mean reduction of 0.5 mA (95% CI: 0.3-0.7, P < .001). On bivariate analysis, MMG-st exhibited significant negative correlation with common peroneal nerve CMAP (P < .05), but no association with ulnar nerve CMAP and motor nerve conduction velocity. On preoperative electrodiagnosis, 60% of nerves had axonal loss and 40% had conduction block. The MMG-st was higher in the nerves with axonal loss as compared with the nerves with conduction block. MMG-st was negatively correlated with preoperative hand strength (grip/pinch) and foot-dorsiflexion/toe-extension strength (P < .05). At the final visit, MMG-st significantly correlated with pain, PROMIS-10 physical function, and Oswestry Disability Index (P < .05).
MMG-st may serve as a surgical adjunct indicating axonal integrity in chronic entrapment neuropathies which may aid in clinical decision-making and prognostication of functional outcomes.
Traumatic cervical spinal cord injury (SCI) can result in debilitating paralysis. Following cervical SCI, accurate early prediction of upper limb recovery can serve an important role in guiding the ...appropriateness and timing of reconstructive therapies.
To develop a clinical prediction rule to prognosticate upper limb functional recovery after cervical SCI.
This prognostic study was a retrospective review of a longitudinal cohort study including patients enrolled in the National SCI model systems (SCIMS) database in US. Eligible patients were 15 years or older with tetraplegia (neurological level of injury C1-C8, American Spinal Cord Injury Association ASIA impairment scale AIS A-D), with early (within 1 month of SCI) and late (1-year follow-up) clinical examinations from 2011 to 2016. The data analysis was conducted from September 2021 to June 2022.
The primary outcome was a composite of dependency in eating, bladder management, transfers, and locomotion domains of functional independence measure at 1-year follow-up. Each domain ranges from 1 to 7 with a lower score indicating greater functional dependence. Composite dependency was defined as a score of 4 or higher in at least 3 chosen domains. Multivariable logistic regression was used to predict the outcome based on early neurological variables. Discrimination was quantified using C statistics, and model performance was internally validated with bootstrapping and 10-fold cross-validation. The performance of the prediction score was compared with AIS grading. Data were split into derivation (2011-2014) and temporal-validation (2015-2016) cohorts.
Among 2373 patients with traumatic cervical SCI, 940 had complete 1-year outcome data (237 patients 25% aged 60 years or older; 753 men 80%). The primary outcome was present in 118 patients (13%), which included 92 men (78%), 83 (70%) patients who were younger than 60 years, and 73 (62%) patients experiencing AIS grade A SCI. The variables significantly associated with the outcome were age (age 60 years or older: OR, 2.31; 95% CI, 1.26-4.19), sex (men: OR, 0.60; 95% CI, 0.31-1.17), light-touch sensation at C5 (OR, 0.44; 95% CI, 0.44-1.01) and C8 (OR, 036; 95% CI, 0.24-0.53) dermatomes, and motor scores of the elbow flexors (C5) (OR, 0.74; 95% CI, 0.60-0.89) and wrist extensors (C6) (OR, 0.61; 95% CI, 0.49-0.75). A multivariable model including these variables had excellent discrimination in distinguishing dependent from independent patients in the temporal-validation cohort (C statistic, 0.90; 95% CI, 0.88-0.93). A clinical prediction score (range, 0 to 45 points) was developed based on these measures, with higher scores increasing the probability of dependency. The discrimination of the prediction score was significantly higher than from AIS grading (change in AUC, 0.14; 95% CI, 0.10-0.18; P < .001).
The findings of this study suggest that this prediction rule may help prognosticate upper limb function following cervical SCI. This tool can be used to set patient expectations, rehabilitation goals, and aid decision-making regarding the appropriateness and timing for upper limb reconstructive surgeries.
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