Single-Cell Tracing Dissects Regulation of Maintenance and Inheritance of Transcriptional Reinduction Memory.

Transcriptional memory of gene expression enables adaptation to repeated stimuli across many organisms. However, the regulation and heritability of transcriptional memory in single cells and through divisions remains poorly understood. Here, we combined microfluidics with single-cell live imaging to monitor Saccharomyces cerevisiae galactokinase 1 (GAL1) expression over multiple generations. By applying pedigree analysis, we dissected and quantified the maintenance and inheritance of transcriptional reinduction memory in individual cells through multiple divisions. We systematically screened for loss- and gain-of-memory knockouts to identify memory regulators in thousands of single cells. We identified new loss-of-memory mutants, which affect memory inheritance into progeny. We also unveiled a gain-of-memory mutant, elp6Δ, and suggest that this new phenotype can be mediated through decreased histone occupancy at the GAL1 promoter. Our work uncovers principles of maintenance and inheritance of gene expression states and their regulators at the single-cell level.

Results of a Randomized Clinical Trial of Speech After Early Neurostimulation in Parkinson's Disease.

BACKGROUND: The EARLYSTIM trial demonstrated for Parkinson's disease patients with early motor complications that deep brain stimulation of the subthalamic nucleus (STN-DBS) and best medical treatment (BMT) was superior to BMT alone. OBJECTIVE: This prospective, ancillary study on EARLYSTIM compared changes in blinded speech intelligibility assessment between STN-DBS and BMT over 2 years, and secondary outcomes included non-speech oral movements (maximum phonation time [MPT], oral diadochokinesis), physician- and patient-reported assessments. METHODS: STN-DBS (n = 102) and BMT (n = 99) groups underwent assessments on/off medication at baseline and 24 months (in four conditions: on/off medication, ON/OFF stimulation-for STN-DBS). Words and sentences were randomly presented to blinded listeners, and speech intelligibility rate was measured. Statistical analyses compared changes between the STN-DBS and BMT groups from baseline to 24 months. RESULTS: Over the 2-year period, changes in speech intelligibility and MPT, as well as patient-reported outcomes, were not different between groups, either off or on medication or OFF or ON stimulation, but most outcomes showed a nonsignificant trend toward worsening in both groups. Change in oral diadochokinesis was significantly different between STN-DBS and BMT groups, on medication and OFF STN-DBS, with patients in the STN-DBS group performing slightly worse than patients under BMT only. A signal for clinical worsening with STN-DBS was found for the individual speech item of the Unified Parkinson's Disease Rating Scale, Part III. CONCLUSION: At this early stage of the patients' disease, STN-DBS did not result in a consistent deterioration in blinded speech intelligibility assessment and patient-reported communication, as observed in studies of advanced Parkinson's Disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Influence of different CCD angles on osseointegration and radiological changes after total hip arthroplasty of a triple wedge shape cementless femoral stem: a prospective cohort study.

PURPOSE: The purpose of this study was to evaluate the osseointegration and radiological outcomes in patients after total hip arthroplasty, hypothesizing different load patterns with one cementless stem design and different CCD angles (CLS Spotorno femoral stem 125° vs 135°). METHODS: All cases of degenerative hip osteoarthritis fulfilling strict inclusion criteria were treated with cementless hip arthroplasty between 2008 and 2017. Ninety-two out of one hundred six cases were clinically and radiologically examined three and 12 months after implantation. Two groups with each 46 patients were rendered prospectively and compared in clinical (Harris Hip Score) and radiological outcome. RESULTS: At final follow-up, no significant difference regarding Harris Hip Score was detected between the two groups (mean 99.2 ± 3.7 vs. 99.3 ± 2.5; p = 0.73). Cortical hypertrophy was found in none of the patients. Stress shielding was seen in a total of 52 hips (n = 27 vs. n = 25; 57% of the 92 hips). No significant difference regarding stress shielding was detected when comparing both groups (p = 0.67). Significant bone density loss was detected in Gruen zone one and two in the 125° group. The 135° group showed significant radiolucency in Gruen zone seven. No overall radiological loosening or subsidence of the femoral component was observed. CONCLUSION: According to our results, the use of a femoral component with a 125° CCD angle versus a 135° CCD did not result in a different osseointegration and load transfer with a clinically relevant significance.

Impact of keel saw blade design and thickness on the incidence of tibial plateau fracture and tibial implant-loosening in cementless medial UKR.

BACKGROUND: Tibial plateau fractures and tibial implant- loosening are severe complications in cementless unicompartmental knee replacement (UKR). The tibial keel preparation is particularly demanding and different saw blades can be used. It was hypothesized that different blade designs and thickness have an influence on the frequency of tibial plateau fractures and implant-loosening in cementless medial UKR. METHODS: 1258 patients with cementless medial UKR were included in this retrospective study between 2013 and 2020. The tibial keel cut was performed either with a double keel saw blade (DKS; 2.8 mm) and added hand guided pick or a mono reciprocating saw blade (RKB) of different thickness (2.5 mm; 2.65 mm; 2.75 mm). Tibial plateau fracture and loosening were demonstrated by standard two-plane radiographs. Tibial implant-loosening was defined as complete radiolucency and implant migration. Fracture and loosening were combined with pain and loss of function. RESULTS: In 126 patients (10%) the tibial keel was prepared with DKS, in 407 patients (32.4%) with RKB 2.5 mm, in 330 patients (26.2%) with RKB 2.65 mm and in 395 patients (31.4%) with 2.75 mm. In 4 patients (3.17%) with DKS tibial plateau fracture occurred, in 4 patients (0.99%) with 2.5 mm RKB, in 3 patients (0.92%) with 2.65 mm RKB and in 1 patient (0.25%) with 2.75 mm RKB. Significantly fewer fractures occurred with a RKB design (p = 0.007). A negative correlation between fracture incidence and RKB saw blade thickness was found (Spearman-r = - 0.93). No difference for tibial implant-loosening was shown (p = 0.51). CONCLUSION: Different blade designs and thickness have a significant influence on the incidence of tibial plateau fractures and aseptic tibial implant-loosening. The incidence of tibial plateau fractures in cementless medial UKR can be reduced by changing the design and thickness of the tibial keel saw blade. Greater thickness of RKB leads to significantly fewer tibial plateau fractures while the incidence of implant-loosening is not increasing. TRIAL REGISTRATION: This study was retrospectively registered and ethical approval was waived by the local ethical committee (No. 2020-1174).

The acetabular roof reinforcement plate for the treatment of displaced acetabular fractures in the elderly: results in 59 patients.

INTRODUCTION: Open reduction and internal fixation is considered the gold standard of treatment for displaced acetabular fractures in younger patients. For elderly patients with osteoporotic bone quality, however, primary total hip arthroplasty (THA) with the advantage of immediate postoperative mobilization might be an option. The purpose of this study was to evaluate the clinical and radiological outcomes of surgical treatment of displaced osteoporotic acetabular fractures using the acetabular roof reinforcement plate (ARRP) combined with THA. MATERIALS AND METHODS: Between 2009 and 2019, 84 patients were operated using the ARRP combined with THA. Inclusion criteria were displaced osteoporotic fractures of the acetabulum with or without previous hemi- or total hip arthroplasty, age above 65 years, and pre-injury ability to walk at least with use of a walking frame. Of the 84 patients, 59 could be followed up after 6 months clinically and radiographically. Forty-nine (83%) were primary fractures and 10 (17%) periprosthetic acetabular fractures. RESULTS: The mean age was 80.5 years (range 65-98 years). The average time from injury to surgery was 8.5 days (range 1-28). Mean time of surgery was 167 min (range 100-303 min). Immediate postoperative full weight bearing (FWB) was allowed for 51 patients (86%). At the 6-month follow-up, all 59 patients except one showed bony healing and incorporation of the ARRP. One case developed a non-union of the anterior column. No disruption, breakage or loosening of the ARRP was seen. Additional CT scans performed in 18 patients confirmed bony healing. Twenty-six patients (44%) had regained their pre-injury level of mobility. Complications requiring revision surgery occurred in 8 patients. Five of them were suffering from a prosthetic head dislocation, one from infection, one from hematoma and one from a heterotopic ossification. CONCLUSIONS: The ARRP has proven to provide sufficient primary stability to allow for immediate FWB in most cases and represents a valuable option for the surgical management of displaced acetabular fractures in this challenging patient group.

Comparison of two reinforcement rings for primary total hip arthroplasty addressing displaced acetabular fractures: a biomechanical analysis.

INTRODUCTION: Aim of this study was to biomechanically compare two different acetabular cup fixation constructs in terms of fracture fixation for displaced acetabular fractures involving the anterior column with hemitransverse fracture under partial and full weight-bearing conditions. METHODS: Two different reinforcement rings designed as cages for primary THA were biomechanically tested in terms of managing a complex acetabular fracture. Single-leg stance cyclic loading was performed to assess fracture gap movement and fragment rotation. Twelve hemi pelvis Sawbones were divided into two groups: primary THA with acetabulum roof reinforcement plate (ARRP) (n = 6) and primary THA with Burch-Schneider reinforcement cage (BSRC) (n = 6). RESULTS: During loading under partial weight-bearing (250 N) fracture gap movement tended to be larger in the BSRC group as compared to the ARRP group. Under full weight-bearing conditions, the ARRP showed 60% significantly less motion (p = 0.035) of the os ilium to os ischii gap compared to BSRC. Fracture gap movements between the os ilium and spina iliaca fragments were significantly reduced by 76% (p = 0.048) for ARRP in contrast to BSRC. The ARRP group also demonstrated significantly less movement in the fracture gaps os ischii to quadrilateral plate (62% reduction, p = 0.009) and quadrilateral plate to spina iliaca (87% reduction, p < 0.001). Significantly less rotational movement of the quadrilateral plate to the os ilium was exhibited by the ARRP group (p = 0.015). CONCLUSIONS: The presented acetabulum roof-reinforcement plate (ARRP) provides stable conditions at the acetabular component with adequate stabilization of a displaced acetabular fracture.

Correction to: Comparison of two reinforcement rings for primary total hip arthroplasty addressing displaced acetabular fractures: a biomechanical analysis.

The original version of this article unfortunately contained a mistake.

The pararectus approach for internal fixation of acetabular fractures involving the anterior column: evaluating the functional outcome.

INTRODUCTION: Aim of this retrospective analysis of prospectively collected data was to evaluate the functional mid-term outcome two years after open reduction and internal fixation of acetabular fractures involving the anterior column with affection of the quadrilateral plate using the pararectus approach on a large cohort. METHOD: Fifty-two patients (12 female, 40 male) with a median age of 55 (range 18-90) years and displaced acetabular fractures involving the anterior column were surgically treated in a single level I trauma centre between July 2012 and February 2016 using the pararectus approach. Thirty-four patients (8 female and 26 male) with a median age of 58 (range 20-85) years were available for complete clinical follow-up at regular intervals, finally 24 months post-operatively. Functional outcome was evaluated according to modified Merle d'Aubigné score, Lower Extremity Functional Scale, WOMAC, and SF-36. RESULTS: Range of time between trauma and surgical treatment was three (range 0-19) days. Operation time was 140 (range 60-240) minutes, and duration of hospital treatment was 19 (range 7-38) days. Functional results in 34 patients available for final follow-up demonstrated 68 points (median; range 39-80) according to the Lower Extremity Functional Scale, 6% according to the WOMAC (mean; SD ± 14.5%), and 69% (mean; SD ± 20.1%) according to the SF-36. The modified Merle d'Aubigné score was excellent in 22 patients, good in eight patients, and fair in four patients. DISCUSSION/CONCLUSION: Based on the good to excellent functional mid-term follow-up results of this study, the pararectus approach can be recommended as sufficient alternative single access to address displaced acetabular fractures involving the anterior column, independent of patients' age.

Ecotoxicological characterization of the antiepileptic drug carbamazepine using eight aquatic species: baseline study for future higher tier tests.

Ecotoxicological effects of the antiepileptic drug carbamazepine (CBZ) were investigated in one primary producer (Desmodesmus subspicatus) and seven invertebrate species (Daphnia magna, Daphnia pulex, Ceriodaphnia dubia, Gammarus fossarum, Potamopyrgus antipodarum, Lumbriculus variegatus and Chironomus riparius) using OECD and US EPA guidelines for chronic toxicity testing. The present data set was used to conduct a hazard assessment for CBZ including confirmatory data. While most of our results were in accordance with previous studies, published effect data for C. dubia and D. pulex could not be confirmed, even though they have previously been considered to be the most sensitive invertebrate species to CBZ exposure. The non-biting midge, C. riparius, was the most sensitive test organism in the present study. From an EC10 of 406 µg/L and a no observed effect concentration (NOEC) of 400 µg/L, a predicted no effect concentration (PNEC) of 8 µg/L was calculated. With regard to realistic predicted and measured environmental concentrations, the environmental risk can be considered as low for CBZ when the assessment is based on laboratory-based effect data. To conduct a refined and more realistic assessment, this study provides foundational data for two future, higher tier studies: one multiple-stressor experiment and one mesocosm study.

The Effect of Uni- and Bilateral Thalamic Deep Brain Stimulation on Speech in Patients With Essential Tremor: Acoustics and Intelligibility.

BACKGROUND: Deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) is performed to suppress medically-resistant essential tremor (ET). However, stimulation induced dysarthria (SID) is a common side effect, limiting the extent to which tremor can be suppressed. To date, the exact pathogenesis of SID in VIM-DBS treated ET patients is unknown. OBJECTIVE: We investigate the effect of inactivated, uni- and bilateral VIM-DBS on speech production in patients with ET. We employ acoustic measures, tempo, and intelligibility ratings and patient's self-estimated speech to quantify SID, with a focus on comparing bilateral to unilateral stimulation effects and the effect of electrode position on speech. METHODS: Sixteen German ET patients participated in this study. Each patient was acoustically recorded with DBS-off, unilateral-right-hemispheric-DBS-on, unilateral-left-hemispheric-DBS-on, and bilateral-DBS-on during an oral diadochokinesis task and a read German standard text. To capture the extent of speech impairment, we measured syllable duration and intensity ratio during the DDK task. Naïve listeners rated speech tempo and speech intelligibility of the read text on a 5-point-scale. Patients had to rate their "ability to speak". RESULTS: We found an effect of bilateral compared to unilateral and inactivated stimulation on syllable durations and intensity ratio, as well as on external intelligibility ratings and patients' VAS scores. Additionally, VAS scores are associated with more laterally located active contacts. For speech ratings, we found an effect of syllable duration such that tempo and intelligibility was rated worse for speakers exhibiting greater syllable durations. CONCLUSION: Our data confirms that SID is more pronounced under bilateral compared to unilateral stimulation. Laterally located electrodes are associated with more severe SID according to patient's self-ratings. We can confirm the relation between diadochokinetic rate and SID in that listener's tempo and intelligibility ratings can be predicted by measured syllable durations from DDK tasks.

Quantum Chemical-Based Protocol for the Rational Design of Covalent Inhibitors.

We propose a structure-based protocol for the development of customized covalent inhibitors. Starting from a known inhibitor, in the first and second steps appropriate substituents of the warhead are selected on the basis of quantum mechanical (QM) computations and hybrid approaches combining QM with molecular mechanics (QM/MM). In the third step the recognition unit is optimized using docking approaches for the noncovalent complex. These predictions are finally verified by QM/MM or molecular dynamic simulations. The applicability of our approach is successfully demonstrated by the design of reversible covalent vinylsulfone-based inhibitors for rhodesain. The examples show that our approach is sufficiently accurate to identify compounds with the desired properties but also to exclude nonpromising ones.

A chemostat array enables the spatio-temporal analysis of the yeast proteome.

Observing cellular responses to perturbations is central to generating and testing hypotheses in biology. We developed a massively parallel microchemostat array capable of growing and observing 1,152 yeast-GFP strains on the single-cell level with 20 min time resolution. We measured protein abundance and localization changes in 4,085 GFP-tagged strains in response to methyl methanesulfonate and analyzed 576 GFP strains in five additional conditions for a total of more than 10,000 unique experiments, providing a systematic view of the yeast proteome in flux. We observed that processing bodies formed rapidly and synchronously in response to UV irradiation, and in conjunction with 506 deletion-GFP strains, identified four gene disruptions leading to abnormal ribonucleotide-diphosphate reductase (Rnr4) localization. Our microchemostat platform enables the large-scale interrogation of proteomes in flux and permits the concurrent observation of protein abundance, localization, cell size, and growth parameters on the single-cell level for thousands of microbial cultures in one experiment.

Short to mid-term results of stemless reverse shoulder arthroplasty in a selected patient population compared to a matched control group with stem.

PURPOSE: Little scientific evidence on the clinical and radiological outcome after stemless reverse shoulder arthroplasty (RSA) exists. The hypothesis of this study was that stemless RSA has an inferior outcome compared to RSA with stem. METHODS: All cases of cuff-arthropathy fullfilling strict selection criteria (selection rate 18.4 %) were treated with stemless RSA between 2009 and 2013. Twenty nine of 37 cases (78.4 %) were clinically and radiologically examined by an independent observer. Twenty four of the 29 cases could be matched with 24 patients that underwent conventional stemmed RSA at a different institution based on the following criteria: indication (cuff-arthropathy), age (within 5 years), gender, and time of follow-up (within 2 years). Clincial and radiological outcomes of both groups were compared. RESULTS: After mean follow-up of 35 months (range 24-75) no significant difference regarding constant score, ASES, subjective shoulder value, pain score, patient satisfaction, strength, and range of motion was detected. One case of traumatic dislocation was observed in the stemless RSA group. Scapular notching grade 1 was detected in two cases of the stemless group while in the stemmed group five cases with grade 1 and four cases with grade 2 notching were observed. Average post-operative humeral component inclination (neck-shaft angle) in the stemless RSA group (134.4°) was significantly steeper than in the stemmed RSA group (155°) (p < 0.001). No loosening of the humeral component was observed in both groups. CONCLUSION: At short to mid-term follow-up, stemless RSA does not feature inferior clinical or radiological outcomes in a strictly selected patient population.

Estimating source terms for far field dredge plume modelling.

Far field modelling of dredging induced suspended sediment plumes is important while assessing the environmental aspects of dredging. Realistic estimation of source terms, that define the suspended sediment input for far field dredge plume modelling, is key to any assessment. This paper describes a generic method for source term estimation as it is used in practice in the dredging industry. It is based on soil characteristics and dredge production figures, combined with empirically derived, equipment and condition specific 'source term fractions'. A source term fraction relates the suspended fine sediment that is available for dispersion, to the amount of fine sediment that is present in the soil and the way it is dredged. The use of source term fractions helps to circumvent modelling of complicated near field processes, at least initially, enabling quick assessments. When further detail is required and extra information is available, the applicability of the source term fractions can/should be evaluated by characterisation monitoring and/or near field modelling. An example of a fictitious yet realistic dredging project demonstrates how two different work methods can trigger two distinctly different types of stress to the environmental system in terms of sediment concentration and duration.

CAST: a new program package for the accurate characterization of large and flexible molecular systems.

The presented program package, Conformational Analysis and Search Tool (CAST) allows the accurate treatment of large and flexible (macro) molecular systems. For the determination of thermally accessible minima CAST offers the newly developed TabuSearch algorithm, but algorithms such as Monte Carlo (MC), MC with minimization, and molecular dynamics are implemented as well. For the determination of reaction paths, CAST provides the PathOpt, the Nudge Elastic band, and the umbrella sampling approach. Access to free energies is possible through the free energy perturbation approach. Along with a number of standard force fields, a newly developed symmetry-adapted perturbation theory-based force field is included. Semiempirical computations are possible through DFTB+ and MOPAC interfaces. For calculations based on density functional theory, a Message Passing Interface (MPI) interface to the Graphics Processing Unit (GPU)-accelerated TeraChem program is available. The program is available on request.

QM/MM investigations of organic chemistry oriented questions.

About 35 years after its first suggestion, QM/MM became the standard theoretical approach to investigate enzymatic structures and processes. The success is due to the ability of QM/MM to provide an accurate atomistic picture of enzymes and related processes. This picture can even be turned into a movie if nuclei-dynamics is taken into account to describe enzymatic processes. In the field of organic chemistry, QM/MM methods are used to a much lesser extent although almost all relevant processes happen in condensed matter or are influenced by complicated interactions between substrate and catalyst. There is less importance for theoretical organic chemistry since the influence of nonpolar solvents is rather weak and the effect of polar solvents can often be accurately described by continuum approaches. Catalytic processes (homogeneous and heterogeneous) can often be reduced to truncated model systems, which are so small that pure quantum-mechanical approaches can be employed. However, since QM/MM becomes more and more efficient due to the success in software and hardware developments, it is more and more used in theoretical organic chemistry to study effects which result from the molecular nature of the environment. It is shown by many examples discussed in this review that the influence can be tremendous, even for nonpolar reactions. The importance of environmental effects in theoretical spectroscopy was already known. Due to its benefits, QM/MM can be expected to experience ongoing growth for the next decade.In the present chapter we give an overview of QM/MM developments and their importance in theoretical organic chemistry, and review applications which give impressions of the possibilities and the importance of the relevant effects. Since there is already a bunch of excellent reviews dealing with QM/MM, we will discuss fundamental ingredients and developments of QM/MM very briefly with a focus on very recent progress. For the applications we follow a similar strategy.

Young adults with dyskinetic cerebral palsy improve subjectively on pallidal stimulation, but not in formal dystonia, gait, speech and swallowing testing.

BACKGROUND: Pharmacological treatment of dyskinetic cerebral palsy (CP) is often ineffective. Data about outcome of deep brain stimulation (DBS) in these patients remains scarce. METHODS: Eight patients with dyskinetic CP and DBS of the Globus Pallidus internus were investigated. Using pre- and postoperative videos the severity of dystonia and changes thereof during standardized settings ('on') and after the stimulator had been switched off ('off') were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). Furthermore, subjective impression (SI) of the extent of postoperative change as well as gait (Leonardo Mechanograph® Gangway), speech (Frenchay Dysarthria) and swallowing performances (fiberoptic laryngoscopy) were assessed during 'on' and 'off'. RESULTS: When comparing pre- and postoperative as well as 'on' and 'off', the BFMDRS and most of the gait, speech, and swallowing parameters did not differ significantly. In contrast, patients reported significant improvement of their SI postoperatively (3.1 on a 10-point-scale). CONCLUSION: Data show that our CP-patients did not benefit from GPi-DBS when tested formally for dystonia, gait, speech and swallowing. In stark contrast, these patients reported significant subjective improvement. Taken together, and in light of current unsatisfactory medical treatment options, our data suggest that further assessment of the effects of GPi-DBS in dyskinetic CP is warranted.

A prospective study of downhill mountain biking injuries.

BACKGROUND: Downhill mountain biking (DMB) has become an increasingly popular extreme sport in the last few years with high velocities and bold manoeuvres. The goal of this study was to provide information on the pattern and causes of injuries in order to provide starting points for injury prevention measures. METHODS: We performed a monthly e-mail-based prospective survey of 249 riders over one summer season ranging from April until September 2011. RESULTS: A total of 494 injuries occurred during the 29 401 h of downhill exposure recorded, of these 65% were mild, 22% moderate and 13% severe, of which 41% led to a total restriction greater than 28 days. The calculated overall injury rate was 16.8 injuries per 1000 h of exposure. For experts it was 17.9 injuries per 1000 h of exposure, which is significantly higher than the 13.4 for professional riders (OR 1.34; 95% CI, 1.02 to 1.75; p=0.03). A significantly higher rate of injury was reported during competition (20 per 1000 h) than during practice (13 per 1000 h) (OR 1.53; 95% CI, 1.16 to 2.01; p=0.0022). The most commonly injured body site was the lower leg (27%) followed by the forearm (25%). Most frequent injury types were abrasions (64%) and contusions (56%). Main causes of injury reported by the riders were riding errors (72%) and bad trail conditions (31%). CONCLUSIONS: According to our data DMB can be considered an extreme sport conveying a high risk of serious injury. Strategies of injury prevention should focus on improvements in riders' technique, checking of local trail conditions and protective equipment design.

A New Score Based on the International Standards for Neurological Classification of Spinal Cord Injury for Integrative Evaluation of Changes in Sensorimotor Functions.

Sensorimotor function of patients with spinal cord injury (SCI) is commonly assessed according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). From the ISNCSCI segmental motor and sensory assessments, upper and lower extremity motor scores (UEMS and LEMS), sum scores of pinprick (PP) and light touch (LT) sensation, the neurological level of injury (NLI) and the classification of lesion severity according to the American Spinal Injury Association Impairment Scale (AIS) grade are derived. Changes of these parameters over time are used widely to evaluate neurological recovery. Evaluating recovery based on a single ISNCSCI scoring or classification variable, however, may misestimate overall recovery. Here, we propose an Integrated Neurological Change Score (INCS) based on the combination of normalized changes between two time points of UEMS, LEMS, and total PP and LT scores. To assess the agreement of INCS with clinical judgment of meaningfulness of neurological changes, changes of ISNCSCI variables between two time points of 88 patients from an independent cohort were rated by 20 clinical experts according to a five-categories Likert Scale. As for individual ISNCSCI variables, neurological change measured by INCS is associated with severity (AIS grade), age, and time since injury, but INCS better reflects clinical judgment about meaningfulness of neurological changes than individual ISNCSCI variables. In addition, INCS is related to changes in functional independence measured by the Spinal Cord Independence Measure (SCIM) in patients with tetraplegia. The INCS may be a useful measure of overall neurological change in clinical studies.

Efficiency of tabu-search-based conformational search algorithms.

Efficient conformational search or sampling approaches play an integral role in molecular modeling, leading to a strong demand for even faster and more reliable conformer search algorithms. This article compares the efficiency of a molecular dynamics method, a simulated annealing method, and the basin hopping (BH) approach (which are widely used in this field) with a previously suggested tabu-search-based approach called gradient only tabu search (GOTS). The study emphasizes the success of the GOTS procedure and, more importantly, shows that an approach which combines BH and GOTS outperforms the single methods in efficiency and speed. We also show that ring structures built by a hydrogen bond are useful as starting points for conformational search investigations of peptides and organic ligands with biological activities, especially in structures that contain multiple rings.