The copper-linked Escherichia coli AZY operon: Structure, metal binding, and a possible physiological role in copper delivery.

The Escherichia coli yobA-yebZ-yebY (AZY) operon encodes the proteins YobA, YebZ, and YebY. YobA and YebZ are homologs of the CopC periplasmic copper-binding protein and the CopD putative copper importer, respectively, whereas YebY belongs to the uncharacterized Domain of Unknown Function 2511 family. Despite numerous studies of E. coli copper homeostasis and the existence of the AZY operon in a range of bacteria, the operon's proteins and their functional roles have not been explored. In this study, we present the first biochemical and functional studies of the AZY proteins. Biochemical characterization and structural modeling indicate that YobA binds a single Cu2+ ion with high affinity. Bioinformatics analysis shows that YebY is widespread and encoded either in AZY operons or in other genetic contexts unrelated to copper homeostasis. We also determined the 1.8 Å resolution crystal structure of E. coli YebY, which closely resembles that of the lantibiotic self-resistance protein MlbQ. Two strictly conserved cysteine residues form a disulfide bond, consistent with the observed periplasmic localization of YebY. Upon treatment with reductants, YebY binds Cu+ and Cu2+ with low affinity, as demonstrated by metal-binding analysis and tryptophan fluorescence. Finally, genetic manipulations show that the AZY operon is not involved in copper tolerance or antioxidant defense. Instead, YebY and YobA are required for the activity of the copper-related NADH dehydrogenase II. These results are consistent with a potential role of the AZY operon in copper delivery to membrane proteins.

Gradients of response latencies and temporal precision of auditory neurons extend across the whole inferior colliculus.

Neural responses to acoustic stimulation have long been studied throughout the auditory system to understand how sound information is coded for perception. Within the inferior colliculus (IC), a majority of the studies have focused predominantly on characterizing neural responses within the central region (ICC), as it is viewed as part of the lemniscal system mainly responsible for auditory perception. In contrast, the responses of outer cortices (ICO) have largely been unexplored, though they also function in auditory perception tasks. Therefore, we sought to expand on previous work by completing a three-dimensional (3-D) functional mapping study of the whole IC. We analyzed responses to different pure tone and broadband noise stimuli across all IC subregions and correlated those responses with over 2,000 recording locations across the IC. Our study revealed there are well-organized trends for temporal response parameters across the full IC that do not show a clear distinction at the ICC and ICO border. These gradients span from slow, imprecise responses in the caudal-medial IC to fast, precise responses in the rostral-lateral IC, regardless of subregion, including the fastest responses located in the ICO. These trends were consistent at various acoustic stimulation levels. Weaker spatial trends could be found for response duration and spontaneous activity. Apart from tonotopic organization, spatial trends were not apparent for spectral response properties. Overall, these detailed acoustic response maps across the whole IC provide new insights into the organization and function of the IC.NEW & NOTEWORTHY Study of the inferior colliculus (IC) has largely focused on the central nucleus, with little exploration of the outer cortices. Here, we systematically assessed the acoustic response properties from over 2,000 locations in different subregions of the IC. The results revealed spatial trends in temporal response patterns that span all subregions. Furthermore, two populations of temporal response types emerged for neurons in the outer cortices that may contribute to their functional roles in auditory tasks.

Validation of Inertial Measurement Units for Analyzing Golf Swing Rotational Biomechanics.

Training devices to enhance golf swing technique are increasingly in demand. Golf swing biomechanics are typically assessed in a laboratory setting and not readily accessible. Inertial measurement units (IMUs) offer improved access as they are wearable, cost-effective, and user-friendly. This study investigates the accuracy of IMU-based golf swing kinematics of upper torso and pelvic rotation compared to lab-based 3D motion capture. Thirty-six male and female professional and amateur golfers participated in the study, nine in each sub-group. Golf swing rotational kinematics, including upper torso and pelvic rotation, pelvic rotational velocity, S-factor (shoulder obliquity), O-factor (pelvic obliquity), and X-factor were compared. Strong positive correlations between IMU and 3D motion capture were found for all parameters; Intraclass Correlations ranged from 0.91 (95% confidence interval [CI]: 0.89, 0.93) for O-factor to 1.00 (95% CI: 1.00, 1.00) for upper torso rotation; Pearson coefficients ranged from 0.92 (95% CI: 0.92, 0.93) for O-factor to 1.00 (95% CI: 1.00, 1.00) for upper torso rotation (p < 0.001 for all). Bland-Altman analysis demonstrated good agreement between the two methods; absolute mean differences ranged from 0.61 to 1.67 degrees. Results suggest that IMUs provide a practical and viable alternative for golf swing analysis, offering golfers accessible and wearable biomechanical feedback to enhance performance. Furthermore, integrating IMUs into golf coaching can advance swing analysis and personalized training protocols. In conclusion, IMUs show significant promise as cost-effective and practical devices for golf swing analysis, benefiting golfers across all skill levels and providing benchmarks for training.

Titratable transmembrane residues and a hydrophobic plug are essential for manganese import via the Bacillus anthracis ABC transporter MntBC-A.

All extant life forms require trace transition metals (e.g., Fe2/3+, Cu1/2+, and Mn2+) to survive. However, as these are environmentally scarce, organisms have evolved sophisticated metal uptake machineries. In bacteria, high-affinity import of transition metals is predominantly mediated by ABC transporters. During bacterial infection, sequestration of metal by the host further limits the availability of these ions, and accordingly, bacterial ABC transporters (importers) of metals are key virulence determinants. However, the structure-function relationships of these metal transporters have not been fully elucidated. Here, we used metal-sensitivity assays, advanced structural modeling, and enzymatic assays to study the ABC transporter MntBC-A, a virulence determinant of the bacterial human pathogen Bacillus anthracis. We find that despite its broad metal-recognition profile, MntBC-A imports only manganese, whereas zinc can function as a high-affinity inhibitor of MntBC-A. Computational analysis shows that the transmembrane metal permeation pathway is lined with six titratable residues that can coordinate the positively charged metal, and mutagenesis studies show that they are essential for manganese transport. Modeling suggests that access to these titratable residues is blocked by a ladder of hydrophobic residues, and ATP-driven conformational changes open and close this hydrophobic seal to permit metal binding and release. The conservation of this arrangement of titratable and hydrophobic residues among ABC transporters of transition metals suggests a common mechanism. These findings advance our understanding of transmembrane metal recognition and permeation and may aid the design and development of novel antibacterial agents.

Single-molecule probing of the conformational homogeneity of the ABC transporter BtuCD.

ATP-binding cassette (ABC) transporters use the energy of ATP hydrolysis to move molecules through cellular membranes. They are directly linked to human diseases, cancer multidrug resistance, and bacterial virulence. Very little is known of the conformational dynamics of ABC transporters, especially at the single-molecule level. Here, we combine single-molecule spectroscopy and a novel molecular simulation approach to investigate the conformational dynamics of the ABC transporter BtuCD. We observe a single dominant population of molecules in each step of the transport cycle and tight coupling between conformational transitions and ligand binding. We uncover transient conformational changes that allow substrate to enter the transporter. This is followed by a 'squeezing' motion propagating from the extracellular to the intracellular side of the translocation cavity. This coordinated sequence of events provides a mechanism for the unidirectional transport of vitamin B12 by BtuCD.

COVID-19 in pregnancy: creating an outpatient surveillance model in a public hospital system.

Objectives We describe a standardized, scalable outpatient surveillance model for pregnant women with COVID-19 with several objectives: (1) to identify and track known, presumed, and suspected COVID-positive pregnant patients both during their acute illness and after recovery, (2) to regularly assess patient symptoms and escalate care for those with worsening disease while reducing unnecessary hospital exposure for others, (3) to educate affected patients on warning symptoms, hygiene, and quarantine recommendations, and (4) to cohort patient care, isolating stable infected patients at home and later within the same physical clinic area upon their return to prenatal care. Methods Pregnant women in an urban public hospital system with presumed or confirmed COVID-19 were added to a list in our electronic medical record as they came to the attention of providers. They received a series of phone calls based on their illness severity and were periodically assessed until deemed stable. Results A total of 83 patients were followed between March 19 and May 31, 2020. Seven (8%) were asymptomatic, 62 (75%) had mild disease, 11 (13%) had severe disease, and three (4%) had critical illness. Conclusions We encourage others to develop and utilize outpatient surveillance systems to facilitate appropriate care and to optimize maternal and fetal well-being.

The Influence of Obesity on Outcomes After Pediatric Reduction Mammaplasty: A Retrospective Analysis of the Pediatric National Surgical Quality Improvement Program-Pediatric Database.

BACKGROUND: Symptomatic macromastia causes negative physical and psychosocial effects, which support the need for early intervention, even in the adolescent population (Plast Reconstr Surg 2012;130:785-789). Reduction mammaplasty is a proven treatment that reliably addresses symptoms from macromastia. The National Surgical Quality Improvement Program-Pediatric is the leading nationally validated, risk-adjusted, outcomes-based program to measure and improve the quality of surgical care (Pediatrics 2012;130:e339-e346). In adults, obesity is associated with increased early postoperative complications after mammaplasty (Pediatrics 2017;140(5)). We hypothesized that obesity would increase the incidence of postoperative complications in pediatric patients undergoing reduction mammaplasty. METHODS: The National Surgical Quality Improvement Program-Pediatric database was queried for female patients 18 years or younger who underwent reduction mammaplasty from January 2012 to December 2017 using Current Procedural Terminology code 19318. Demographic, clinical, and outcomes data were abstracted from the database. A composite postoperative adverse events variable was created from a list of 21 individual adverse events. Patients were stratified by presence of obesity (body mass index ≥30 kg/m) on univariate analyses. Multivariable logistic regression was used to determine factors associated with any postoperative adverse events. RESULTS: A total of 542 female patients underwent reduction mammaplasty, with 48% of the cohort being obese. Patients were similar in age (median, 17 years) and comorbidities between obese and nonobese groups. Obese patients were more likely to be African American, have higher American Society of Anesthesiologists class, and endure longer operations. Composite adverse event rates were significantly higher in the obese group (7% vs 2%, P = 0.013). Individual adverse events were similar between groups, with the exception of 30-day readmissions, which was higher in the obese group (3% vs 1%, P = 0.04). On multivariable logistic regression, obesity increased the odds of having a postoperative adverse event by 3-fold after adjusting for operative duration. CONCLUSIONS: Obesity was significantly associated with greater postoperative adverse events in obese adolescent females after reduction mammaplasty compared with their nonobese counterparts. Although recorded rates of adverse events after reduction mammaplasty were low, preoperative weight loss programs may further improve outcomes for obese pediatric populations undergoing reduction mammaplasty.

An Analysis of Specialty-Specific Microsurgical Head and Neck Reconstruction: A Look at a Single Institution and National Trends Over a Decade.

INTRODUCTION: Head and neck free flap (HNFF) reconstructions have historically utilized a multidisciplinary approach between otolaryngology head and neck surgery (OHNS) and plastic surgery (PS). However, there seems to be a trend toward both the extirpative and reconstructive portions being performed by OHNS. We aimed to elucidate the volume trend in HNFF reconstruction over the last decade. METHODS: Data were collected by 3 modalities: electronic medical record search of patients who underwent HNFF surgery at our institution (2013-2018), survey data from microsurgery fellowship programs (2007-2017), and National Surgical Quality Improvement Program (NSQIP) query of cases receiving designated HNFF Current Procedural Terminology codes (2011-2016). Data were analyzed with trends in HNFF reconstruction as our primary outcome. RESULTS: At our institution, HNFF reconstructions increased 4-fold (59-227). Percentage of cases by PS decreased from 18.6% to 6.0%, whereas that of OHNS increased 81.4% to 94.0% (P = 0.009). Survey data, completed by microsurgery fellowship program directors (23/81 [27.2%]), revealed the number of OHNS programs in 2007 performing 100 or more HNFF cases compared with PS was 40% (6/15) to 12.5% (1/8) (P = 0.172). By 2016, that number increased significantly for OHNS to 73.3% (11/15), whereas that of PS remained stagnant at 12.5% (1/8) (P = 0.005). According to NSQIP data, the percentage of cases performed by PS in 2011 was 52%, which was greater than OHNS's share of 43%. The other 5% was allotted to either orthopedic, oral and maxillofacial surgery, or general surgery. In 2013, those numbers reached a peak for PS at 55% and a nadir for OHNS at 36%. However, by 2016, the percentage of HNFF cases reversed. where 58% of cases were performed by OHNS and only 38% by PS. When comparing the 2011 data to the 2016 data, OHNS had a 134% increase, whereas PS had a 27% decrease (P = 0.003). CONCLUSIONS: Head and neck free flap reconstruction has grown dramatically over the last 10 years. Plastic surgeons are performing fewer cases, whereas otolaryngology head and neck surgeons perform more as indicated by institutional, microsurgery fellowship program director survey, and NSQIP data.

L-glutamine Induces Expression of Listeria monocytogenes Virulence Genes.

The high environmental adaptability of bacteria is contingent upon their ability to sense changes in their surroundings. Bacterial pathogen entry into host poses an abrupt and dramatic environmental change, during which successful pathogens gauge multiple parameters that signal host localization. The facultative human pathogen Listeria monocytogenes flourishes in soil, water and food, and in ~50 different animals, and serves as a model for intracellular infection. L. monocytogenes identifies host entry by sensing both physical (e.g., temperature) and chemical (e.g., metabolite concentrations) factors. We report here that L-glutamine, an abundant nitrogen source in host serum and cells, serves as an environmental indicator and inducer of virulence gene expression. In contrast, ammonia, which is the most abundant nitrogen source in soil and water, fully supports growth, but fails to activate virulence gene transcription. We demonstrate that induction of virulence genes only occurs when the Listerial intracellular concentration of L-glutamine crosses a certain threshold, acting as an on/off switch: off when L-glutamine concentrations are below the threshold, and fully on when the threshold is crossed. To turn on the switch, L-glutamine must be present, and the L-glutamine high affinity ABC transporter, GlnPQ, must be active. Inactivation of GlnPQ led to complete arrest of L-glutamine uptake, reduced type I interferon response in infected macrophages, dramatic reduction in expression of virulence genes, and attenuated virulence in a mouse infection model. These results may explain observations made with other pathogens correlating nitrogen metabolism and virulence, and suggest that gauging of L-glutamine as a means of ascertaining host localization may be a general mechanism.

Correction: Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection.

[This corrects the article DOI: 10.1371/journal.ppat.1006299.].

Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection.

Human cytomegalovirus (CMV) infection is a substantial cause of morbidity and mortality in immunocompromised hosts and globally is one of the most important congenital infections. The nucleoside analogue ganciclovir (GCV), which requires initial phosphorylation by the viral UL97 kinase, is the mainstay for treatment. To date, CMV decay kinetics during GCV therapy have not been extensively investigated and its clinical implications not fully appreciated. We measured CMV DNA levels in the blood of 92 solid organ transplant recipients with CMV disease over the initial 21 days of ganciclovir therapy and identified four distinct decay patterns, including a new pattern exhibiting a transient viral rebound (Hump) following initial decline. Since current viral dynamics models were unable to account for this Hump profile, we developed a novel multi-level model, which includes the intracellular role of UL97 in the continued activation of ganciclovir, that successfully described all the decline patterns observed. Fitting the data allowed us to estimate ganciclovir effectiveness in vivo (mean 92%), infected cell half-life (mean 0.7 days), and other viral dynamics parameters that determine which of the four kinetic patterns will ensue. An important clinical implication of our results is that the virological efficacy of GCV operates over a broad dose range. The model also raises the possibility that GCV can drive replication to a new lower steady state but ultimately cannot fully eradicate it. This model is likely to be generalizable to other anti-CMV nucleoside analogs that require activation by viral enzymes such as UL97 or its homologues.

The Pediatric Temporal-spatial Deviation Index: quantifying gait impairment for children with cerebral palsy.

AIM: To develop an easily-administered metric to quantify gait impairment in children and to assess its use in children with cerebral palsy (CP). METHOD: The Pediatric Temporal-spatial Deviation Index (TDI) was developed from gait data collected from 75 typically developing children (37 males, 38 females; mean age 9y 4mo; interquartile range [IQR] 8-10y) and 17 children diagnosed with spastic CP (nine males, eight females; mean age 9y 9mo; IQR 9-11y), in Gross Motor Function Classification System (GMFCS) levels I to III, aged 7 to 11 years. Children walked on a pressure-sensitive mat. Children with CP also completed 3D gait analysis. The Kaiser-Meyer-Olkin test of sampling adequacy was used for temporal-spatial feature selection. Principal components obtained from temporal-spatial gait parameters quantified deviation from typically developing gait. Deviation was normalized to a Pediatric TDI score mean (standard deviation [SD]) of 100 (10). The Pediatric TDI for children with CP was compared to 3D motion capture-based Gait Deviation Index (GDI). RESULTS: The Pediatric TDI was significantly lower for children with CP compared to typically developing children (p<0.001), correlated with average GDI (r=0.610, p=0.009), and demonstrated sensitivity (0.78) and specificity (0.88) to gait function, assessed with GDI. INTERPRETATION: The Pediatric TDI is an easily administered, revealing gait metric that can be used in children with CP in pediatric clinics and for research. Detection of gait abnormalities in the clinic can expedite diagnosis and treatment. What this paper adds The Pediatric Temporal-spatial Deviation Index (TDI) is a single-score index of gait deviation, based on nine parameters. The Pediatric TDI was more revealing than single temporal-spatial gait parameters. The Pediatric TDI is quick and simple to administer in the clinic.

Implications of Internal Mammary Lymph Node Sampling During Microsurgical Breast Reconstruction.

INTRODUCTION: Internal mammary lymph node (IMN) chain assessment for breast cancer is controversial; however, current oncologic data have shed new light on its importance. Metastatic involvement of the IMN chain has implications for staging, prognosis, treatment, and survival. Here, we analyzed our data gathered during sampling of the IMN and the oncologic treatment changes that resulted from our findings. METHODS: A retrospective chart review was performed on 581 patients who underwent free-flap breast reconstruction performed by the senior author. All dissected IMNs were submitted for pathological examination. Patient demographics, oncologic data, and the results of IMN sampling were reviewed. RESULTS: 581 patients undergoing 981 free flaps were identified. A total of 400 lymph node basins were harvested from 273 patients. Of these, nine had positive IMNs. Two of these nine patients had positive IMNs of the contralateral nonaffected breast. Five patients had positive axillary lymph nodes. Four patients had multifocal tumors, one of which was bilateral. Seven patients had an increase in cancer stage as a result of having positive IMNs. Six patients had a change in treatment: two patients required additional chemotherapy, one received adjuvant radiation therapy, and three necessitated both supplemental chemotherapy and radiation. CONCLUSIONS: Opportunistic biopsy of the IMN while dissecting the recipient vessels is simple and results in no added morbidity. We recommend that biopsy of the IMN chain be performed whenever internal mammary vessels are dissected for microsurgical anastomosis in breast cancer patients. Positive IMN involvement should encourage thorough oncological workup and treatment reevaluation. LEVEL OF EVIDENCE IV: Case series.

A common data language for clinical research studies: the National Institute of Neurological Disorders and Stroke and American Academy for Cerebral Palsy and Developmental Medicine Cerebral Palsy Common Data Elements Version 1.0 recommendations.

To increase the efficiency and effectiveness of clinical research studies, cerebral palsy (CP) specific Common Data Elements (CDEs) were developed through a partnership between the National Institute of Neurological Disorders and Stroke (NINDS) and the American Academy of Cerebral Palsy and Developmental Medicine (AACPDM). International experts reviewed existing NINDS CDEs and tools used in studies of children and young people with CP. CDEs were compiled, subjected to internal review, and posted online for external public comment in September 2016. Guided by the International Classification of Functioning, Disability and Health framework, CDEs were categorized into six domains: (1) participant characteristics; (2) health, growth, and genetics; (3) neuroimaging; (4) neuromotor skills and functional assessments; (5) neurocognitive, social, and emotional assessments; and (6) engagement and quality of life. Version 1.0 of the NINDS/AACPDM CDEs for CP is publicly available on the NINDS CDE and AACPDM websites. Global use of CDEs for CP will standardize data collection, improve data quality, and facilitate comparisons across studies. Ongoing collaboration with international colleagues, industry, and people with CP and their families will provide meaningful feedback and updates as additional evidence is obtained. These CDEs are recommended for NINDS-funded research for CP. WHAT THIS PAPER ADDS: This is the first comprehensive Common Data Elements (CDEs) for children and young people with CP for clinical research. The CDEs for children and young people with CP include common definitions, the standardization of case report forms, and measures. The CDE guides the standardization for data collection and outcome evaluation in all types of studies with children and young people with CP. The CDE ultimately improves data quality and data sharing.

Nipple viability after nipple-sparing mastectomy in patients with prior circum-areolar incisions.

Nipple-areola-sparing mastectomy (NSM) is becoming more commonplace as it offers a more esthetic breast appearance while still appropriately treating malignancy. However, patients with prior circum-areolar incisions are often considered at risk for nipple viability. The authors present a case series of all patients undergoing NSM at their institution between 2012 and 2016. Eighteen consecutive female nonsmoking patients underwent 32 NSMs. None of the patients had reconstructive failures including those relating to the nipple-areola complex (NAC), such as nipple necrosis. NSM is therefore feasible in cases with prior circum-areolar incisions. These patients can be safely reconstructed with both prosthetic devices and autologous tissue.

Evaluation of the single medial circummuscular perforator DIEP flap: Outcomes and comparison to traditional transmuscular single perforator flap.

INTRODUCTION: Successful breast reconstruction using deep inferior epigastric perforator (DIEP) flaps depends on optimal perforator choice. Circummuscular wraparound medial perforators allow for no rectus dissection and minimal fascial incisions, often presenting as an ideal option. The aim of our study is to evaluate outcomes of the single medial wraparound perforator flap in comparison to more traditional transmuscular single-perforator DIEP flaps. PATIENTS AND METHODS: A retrospective chart review was conducted of all DIEP flaps performed by the senior author from 2011 to 2016, yielding 269 flaps on 157 patients. For this study, we included all patients who underwent reconstruction of the breast(s) and possessed circummuscular perforators arising from the DIE vessels. A control group consisted of all consecutive patients with transmuscular one-perforator DIEP flaps. Patient details and their postoperative outcomes were collected. RESULTS: In our study, eight patients (5.1%) were of the medial wraparound variety. Sixteen control patients (10.2%) with similar comorbidities had flaps that were of the more traditional single perforator transmuscular variety. There was a slight trend toward decreased operative time in the medial wraparound group, however, it was not found to be statistically significant (536 ± 81 vs. 572 ± 84 min, P = .377). Complication profiles were similar between groups (25.0 vs. 18.8%, P = .722), with no increased rates of fat necrosis in the wraparound cohort. CONCLUSION: Based on our findings, using a medial wraparound perforator is a safe and reliable option when compared with a single transmuscular perforator DIEP flap. Choosing the wraparound perforator may show benefit as it eliminates muscular dissection and nerve damage, and tends to minimize fascial incision length.

Genetic characterization of spotted fever group rickettsiae in questing ixodid ticks collected in Israel and environmental risk factors for their infection.

This study aimed to genetically characterize spotted fever group rickettsiae (SFGR) in questing ixodid ticks from Israel and to identify risk factors associated with SFGR-positive ticks using molecular techniques and geographic information systems (GIS) analysis. 1039 ticks from the genus Rhipicephalus were collected during 2014. 109/1039 (10·49%) carried SFGR-DNA of either Rickettsia massiliae (95), 'Candidatus Rickettsia barbariae' (8) or Rickettsia conorii (6). Higher prevalence of SFGR was found in Rhipicephalus turanicus (18·00%) compared with Rhipicephalus sanguineus sensu lato (3·22%). Rickettsia massiliae was the most commonly detected species and the most widely disseminated throughout Israel (87·15% of all Rickettsia-positive ticks). GIS analysis revealed that Central and Northern coastal regions are at high risk for SFGR. The presence of ticks was significantly associated with normalized difference vegetation index and temperature variation over the course of the year. The presence of rickettsiae was significantly associated with brown type soils, higher land surface temperature and higher precipitation. The latter parameters may contribute to infection of the tick with SFGR. Health care professionals should be aware of the possible exposure of local communities and travellers to R. massillae. Molecular and geographical information can help professionals to identify areas that are susceptible to SFGR-infected ticks.

Artificial Walking Technologies to Improve Gait in Cerebral Palsy: Multichannel Neuromuscular Stimulation.

Cerebral palsy (CP) is the most common childhood motor disability and often results in debilitating walking abnormalities, such as flexed-knee and stiff-knee gait. Current medical and surgical treatments are only partially effective in improving gait abnormalities and may cause significant muscle weakness. However, emerging artificial walking technologies, such as step-initiated, multichannel neuromuscular electrical stimulation (NMES), can substantially improve gait patterns and promote muscle strength in children with spastic CP. NMES may also be applied to specific lumbar-sacral sensory roots to reduce spasticity. Development of tablet computer-based multichannel NMES can leverage lightweight, wearable wireless stimulators, advanced control design, and surface electrodes to activate lower-limb muscles. Musculoskeletal models have been used to characterize muscle contributions to unimpaired gait and identify high muscle demands, which can help guide multichannel NMES-assisted gait protocols. In addition, patient-specific NMES-assisted gait protocols based on 3D gait analysis can facilitate the appropriate activation of lower-limb muscles to achieve a more functional gait: stance-phase hip and knee extension and swing-phase sequence of hip and knee flexion followed by rapid knee extension. NMES-assisted gait treatment can be conducted as either clinic-based or home-based programs. Rigorous testing of multichannel NMES-assisted gait training protocols will determine optimal treatment dosage for future clinical trials. Evidence-based outcome evaluation using 3D kinematics or temporal-spatial gait parameters will help determine immediate neuroprosthetic effects and longer term neurotherapeutic effects of step-initiated, multichannel NMES-assisted gait in children with spastic CP. Multichannel NMES is a promising assistive technology to help children with spastic CP achieve a more upright, functional gait.

Neonatal Biomarkers of Inflammation: Correlates of Early Neurodevelopment and Gait in Very-Low-Birth-Weight Preterm Children.

OBJECTIVE: Neonatal biomarkers of inflammation were examined in relation to early neurodevelopment and gait in very-low-birth-weight (VLBW) preterm children. We hypothesized that preterm infants exposed to higher levels of neonatal inflammation would demonstrate lower scores on Bayley Scales of Infant Toddler Development, 3rd ed. (BSID-III) and slower gait velocity at 18 to 22 months adjusted age. STUDY DESIGN: A total of 102 VLBW preterm infants (birthweight [BW] ≤ 1,500 g, gestational age [GA] ≤ 32 weeks) admitted to neonatal intensive care unit [NICU] were recruited. Neonatal risk factors examined were GA at birth, BW, bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy of prematurity, sepsis, and serum C-reactive protein (CRP), albumin, and total bilirubin over first 2 postnatal weeks. At 18 to 22 months, neurodevelopment was assessed with BSID-III and gait was assessed with an instrumented mat. RESULTS: Children with neonatal CRP ≥ 0.20 mg/dL (n = 52) versus < 0.20 mg/dL (n = 37) had significantly lower BSID-III composite cognitive (92.0 ± 13.1 vs. 100.1 ± 9.6, p = 0.002), language (83.9 ± 16.0 vs. 95.8 ± 14.2, p < 0.001), and motor scores (90.0 ± 13.2 vs. 98.8 ± 10.1, p = 0.002), and slower gait velocity (84.9 ± 19.0 vs. 98.0 ± 22.4 cm/s, p = 0.004). Higher neonatal CRP correlated with lower cognitive (rho = - 0.327, p = 0.002), language (rho = - 0.285, p = 0.007), and motor scores (rho = - 0.257, p = 0.015), and slower gait (rho = - 0.298, p = 0.008). Multivariate analysis demonstrated neonatal CRP ≥ 0.20 mg/dL significantly predicted BSID-III cognitive (adjusted R(2) = 0.104, p = 0.008), language (adjusted R(2) = 0.124, p = 0.001), and motor scores (adjusted R(2) = 0.122, p = 0.004). CONCLUSIONS: Associations between low-level neonatal inflammation and neurodevelopment suggest early biomarkers that may inform neuroprotective treatment for preterm children.

Neonatal brain microstructure correlates of neurodevelopment and gait in preterm children 18-22 mo of age: an MRI and DTI study.

BACKGROUND: Near-term brain structure was examined in preterm infants in relation to neurodevelopment. We hypothesized that near-term macrostructural brain abnormalities identified using conventional magnetic resonance imaging (MRI), and white matter (WM) microstructure detected using diffusion tensor imaging (DTI), would correlate with lower cognitive and motor development and slower, less-stable gait at 18-22 mo of age. METHODS: One hundred and two very-low-birth-weight preterm infants (≤1,500 g birth weight; ≤32 wk gestational age) were recruited prior to routine near-term brain MRI at 36.6 ± 1.8 wk postmenstrual age. Cerebellar and WM macrostructure was assessed on conventional structural MRI. DTI was obtained in 66 out of 102 and WM microstructure was assessed using fractional anisotropy and mean diffusivity (MD) in six subcortical brain regions defined by DiffeoMap neonatal atlas. Neurodevelopment was assessed with Bayley-Scales-of-Infant-Toddler-Development, 3rd-Edition (BSID-III); gait was assessed using an instrumented mat. RESULTS: Neonates with cerebellar abnormalities identified using MRI demonstrated lower mean BSID-III cognitive composite scores (89.0 ± 10.1 vs. 97.8 ± 12.4; P = 0.002) at 18-22 mo. Neonates with higher DTI-derived left posterior limb of internal capsule (PLIC) MD demonstrated lower cognitive and motor composite scores (r = -0.368; P = 0.004; r = -0.354; P = 0.006) at 18-22 mo; neonates with higher genu MD demonstrated slower gait velocity (r = -0.374; P = 0.007). Multivariate linear regression significantly predicted cognitive (adjusted r(2) = 0.247; P = 0.002) and motor score (adjusted r(2) = 0.131; P = 0.017). CONCLUSION: Near-term cerebellar macrostructure and PLIC and genu microstructure were predictive of early neurodevelopment and gait.