Seizure Burden and Neurologic Outcomes After Neonatal Encephalopathy.

BACKGROUND AND OBJECTIVES: Seizures are common during neonatal encephalopathy (NE), but the contribution of seizure burden (SB) to outcomes remains controversial. This study aims to examine the relationship between electrographic SB and neurologic outcomes after NE. METHODS: This prospective cohort study recruited newborns ≥36 weeks postmenstrual age around 6 hours of life between August 2014 and November 2019 from a neonatal intensive care unit (NICU). Participants underwent continuous electroencephalography for at least 48 hours, brain MRI within 3-5 days of life, and structured follow-up at 18 months. Electrographic seizures were identified by board-certified neurophysiologists and quantified as total SB and maximum hourly SB. A medication exposure score was calculated based on all antiseizure medications given during NICU admission. Brain MRI injury severity was classified based on basal ganglia and watershed scores. Developmental outcomes were measured using the Bayley Scales of Infant Development, Third Edition. Multivariable regression analyses were performed, adjusting for significant potential confounders. RESULTS: Of 108 enrolled infants, 98 had continuous EEG (cEEG) and MRI data collected, of which 5 were lost to follow-up, and 6 died before age 18 months. All infants with moderate-severe encephalopathy completed therapeutic hypothermia. cEEG-confirmed neonatal seizures occurred in 21 (24%) newborns, with a total SB mean of 12.5 ± 36.4 minutes and a maximum hourly SB mean of 4 ± 10 min/h. After adjusting for MRI brain injury severity and medication exposure, total SB was significantly associated with lower cognitive (-0.21, 95% CI -0.33 to -0.08, p = 0.002) and language (-0.25, 95% CI -0.39 to -0.11, p = 0.001) scores at 18 months. Total SB of 60 minutes was associated with 15-point decline in language scores and 70 minutes for cognitive scores. However, SB was not significantly associated with epilepsy, neuromotor score, or cerebral palsy (p > 0.1). DISCUSSION: Higher SB during NE was independently associated with worse cognitive and language scores at 18 months, even after adjusting for exposure to antiseizure medications and severity of brain injury. These observations support the hypothesis that neonatal seizures occurring during NE independently contribute to long-term outcomes.

Standing, Transition, and Walking Ability in Older Adults: The Case for Independently Evaluating Different Domains of Mobility Function.

BACKGROUND: Independent mobility is a complex behavior that relies on the ability to walk, maintain stability, and transition between postures. However, guidelines for assessment that details what elements of mobility to evaluate and how they should be measured remain unclear. METHODS: Performance on tests of standing, sit-to-stand, and walking were evaluated in a cohort of 135 complex, comorbid, and older adults (mean age 87 ± 5.5 years). Correlational analysis was conducted to examine the degree of association for measures within and between mobility domains on a subset of participants (n = 83) able to complete all tasks unaided. Participants were also grouped by the presence of risk markers for frailty (gait speed and grip strength) to determine if the level of overall impairment impacted performance scores and if among those with risk markers, the degree of association was greater. RESULTS: Within-domain relationships for sit-to-stand and walking were modest (rho = 0.01-0.60). Associations either did not exist or relationships were weak for measures reflecting different domains (rho = -0.35 to 0.25, p > 0.05). As expected, gait speed differed between those with and without frailty risk markers (p < 0.001); however, balance and sit-to-stand measures did not (p ≥ 0.05). CONCLUSIONS: This study highlights the need to independently evaluate different mobility domains within an individual as a standard assessment approach. Modest within-domain relationships emphasize the need to account for multiple, unique control challenges within more complex domains. These findings have important implications for standardized mobility assessment and targeted rehabilitation strategies for older adults.

Nonpeptidic, Polo-Box Domain-Targeted Inhibitors of PLK1 Block Kinase Activity, Induce Its Degradation and Target-Resistant Cells.

PLK1, polo-like kinase 1, is a central player regulating mitosis. Inhibition of the subcellular localization and kinase activity of PLK1 through the PBD, polo-box domain, is a viable alternative to ATP-competitive inhibitors, for which the development of resistance and inhibition of related PLK family members are concerns. We describe novel nonpeptidic PBD-binding inhibitors, termed abbapolins, identified through successful application of the REPLACE strategy and demonstrate their potent antiproliferative activity in prostate tumors and other cell lines. Furthermore, abbapolins show PLK1-specific binding and inhibitory activity, as measured by a cellular thermal shift assay and an ability to block phosphorylation of TCTP, a validated target of PLK1-mediated kinase activity. Additional evidence for engagement of PLK1 was obtained through the unique observation that abbapolins induce PLK1 degradation in a manner that closely matches antiproliferative activity. Moreover, abbapolins demonstrate antiproliferative activity in cells that are dramatically resistant to ATP-competitive PLK1 inhibitors.

Peptidomimetic Polo-Box-Targeted Inhibitors that Engage PLK1 in Tumor Cells and Are Selective against the PLK3 Tumor Suppressor.

The polo-box domain (PBD) of PLK1 determines mitotic substrate recognition and subcellular localization. Compounds that target PLK1 selectively are required due to the tumor-suppressor roles of PLK3. A structure-activity analysis of the PBD phosphopeptide binding motif has identified potent peptides that delineate the determinants required for mimicry by nonpeptidic inhibitors and provide insights into the structural basis for the selectivity of inhibitors for the PLK1 PBD. Fragment-ligated inhibitory peptides (FLIPs) obtained through REPLACE have been optimized to enhance in vitro binding and a systematic analysis of selectivity for PLK1 vs PLK3 has been carried out for peptides and peptidomimetics. Furthermore, these more drug-like non-ATP-competitive inhibitors had on-target engagement in a cellular context, as evidenced by stabilization of PLK1 in a thermal-shift assay and by inhibition of the phosphorylation of TCTP, a target of PLK1. Investigation in cells expressing a mutant PLK1 showed that these cells are sensitive to PBD inhibitors but dramatically resistant to clinically investigated ATP-competitive compounds. These results further validate targeting the PBD binding site in the move towards PLK1 inhibitors that are active against tumors resistant to ATP inhibitors.

Activity in Functional Cortical Networks Temporally Associated with Postural Instability.

Human bipedal balance control is proposed to be the integrated activity of distributed neural areas. There is growing understanding about the cortical involvement in this highly automated behavior. While evidence exists for cortical activity temporally linked to reactive balance control, little is known about the functional interaction of potential cortical regions. Here, we used functional connectivity and graph theoretical analysis to derive functional cortical networks during reactive balance control from an event-related potential evoked by external perturbation known as the perturbation-evoked potential N1 (PEP N1). Fourteen healthy young adults were subjected to temporally unpredictable postural perturbations using a custom-made lean and release cable system. Electroencephalographic signals were recorded using a 64-channel electrode cap and segmented around perturbation onset. Functional connectivity was analyzed in source-space and sensor-space using coherence measures and functional cortical networks were characterized using graph measures. The results suggest that there might exist a balance control cortical network while standing and rapid, transient, and frequency-specific reorganization occurs in this network during reactive balance control events. This reorganization was characterized by an increased number of short-range connections between neighboring areas and increased strength between connections in delta, theta, alpha, and beta frequency bands during PEP N1 compared to baseline. To our knowledge, this is the first study to report the existence of functional cortical networks during reactive balance control with potential implications on assessing impaired balance associated with various neural diseases.

Estimating the sensorimotor components of cybersickness.

The user base of the virtual reality (VR) medium is growing, and many of these users will experience cybersickness. Accounting for the vast interindividual variability in cybersickness forms a pivotal step in solving the issue. Most studies of cybersickness focus on a single factor (e.g., balance, sex, or vection), while other contributors are overlooked. Here, we characterize the complex relationship between cybersickness and several measures of sensorimotor processing. In a single session, we conducted a battery of tests of balance control, vection responses, and vestibular sensitivity to self-motion. Following this, we measured cybersickness after VR exposure. We constructed a principal components regression model using the measures of sensorimotor processing. The model significantly predicted 37% of the variability in cybersickness measures, with 16% of this variance being accounted for by a principal component that represented balance control measures. The strongest predictor was participants' sway path length during vection, which was inversely related to cybersickness [ r(28) = -0.53, P = 0.002] and uniquely accounted for 7.5% of the variance in cybersickness scores across participants. Vection strength reports and measures of vestibular sensitivity were not significant predictors of cybersickness. We discuss the possible role of sensory reweighting in cybersickness that is suggested by these results, and we identify other factors that may account for the remaining variance in cybersickness. The results reiterate that the relationship between balance control and cybersickness is anything but straightforward. NEW & NOTEWORTHY The advent of consumer virtual reality provides a pressing need for interventions that combat sickness in simulated environments (cybersickness). This research builds on multiple theories of cybersickness etiology to develop a predictive model that distinguishes between individuals who are/are not likely to experience cybersickness. In the future this approach can be adapted to provide virtual reality users with curated content recommendations based on more efficient measurements of sensorimotor processing.

Evaluation of interobserver reliability of Nugent score for diagnosis of bacterial vaginosis.

BACKGROUND: Vaginal discharge is the commonly narrated compliant of the female attendees of sexually transmitted infection clinic, among which bacterial vaginosis (BV) is responsible for one-third of the visits. BV is often diagnosed clinically which warrants laboratory confirmation. AIMS: The study aims to detect the reliability of the Nugent scoring system between observers for the diagnosis of BV. MATERIALS AND METHODS: This is a prospective study including 177 high vaginal swabs. The gram-stained smears were examined by three independent microbiologists, and the Nugent scoring was performed. Statistical analysis was performed using IBM-SPSS version-22 statistical package for kappa value. RESULTS: Concordant results were seen in 64.03% of smears, discordant results were given in 4.51% of smears, and partial agreement was observed in 31.63% of smears. CONCLUSION: Interobserver reliability is good for the Nugent score. The Nugent score is a simple and reliable method for the diagnosis of BV that can be adapted even in the resource poor settings.

Perturbation-evoked potentials: Significance and application in balance control research.

Historically, balance control was thought to be mediated solely by subcortical structures based on animal research. However, recent findings provide compelling evidence of cortical involvement during balance reactions evoked by whole-body postural perturbations. In humans, an external perturbation elicits an evoked potential, termed the perturbation-evoked potential (PEP). PEPs are widely distributed over fronto-centro-parietal areas with maximal amplitude at the FCz/Cz electrode. From our literature review it is evident that the PEPs are comprised of a small positive potential (P1) that peaks around 30-90ms after perturbation onset, a large negative potential (N1) that peaks around 90-160ms, followed by positive (P2) and negative (N2) potentials between 200 and 400ms. Converging results across multiple studies suggest that these different PEP components are influenced by perturbation characteristics, postural set, environmental, and psychological factors. This review summarizes and integrates seminal research on the PEP, with a special emphasis on the PEP N1. Implications for future studies in PEP research are discussed to encourage further empirical investigation of PEP characteristics in healthy and patient populations.

Standing still: is there a role for the cortex?

In humans, standing still appears so automatic that high-level cortical processes seem unnecessary. However, by measuring cortical activity time-locked to reactive control events arising from naturally occurring instability while standing still, we detected cortical involvement in the form of an evoked N1 potential prior to the onset of balance reactions. Peak amplitude and spectral power of this event-related activity increased as postural challenges and demand for reactive control increased.

Role of trans vaginal ultrasound and Doppler in diagnosis of pelvic congestion syndrome.

Pelvic congestion syndrome (PCS) is a cause of chronic pelvic pain in women and is defined as pelvic pain lasting for more than six months.The diagnosis of PCS is a challenging task for the gynaecologist. It can be due to many varied causes like endometriosis, adhesions, chronic pelvic inflammatory disease (PID), ovarian cyst, fibroids, pelvic varicosities. Radiology plays an important role in the diagnosis and management of PCS. Pelvic UltraSonography (PUS),transvaginal sonography (TVS) with doppler, Magnetic resonance imaging (MRI), computed tomography (CT) and ovarian venography are usually used in the diagnosis of this condition. We report a case of a 35-year-old multiparous patient with history of pain in lower abdomen, vaginal discharge and general lethargy for past three years who was diagnosed as a case of PCS based on typical TVS and Doppler findings.

Frequency characteristics of cortical activity associated with perturbations to upright stability.

Cortical evoked potentials are evident in the control of whole-body balance reactions in response to transient instability. The focus of this work is to continue to advance understanding of the potential cortical contributions to bipedal balance control. Temporally unpredictable postural perturbations evoke a negative potential (N1), which has drawn parallels to error-related negativity (ERN) as well as visual and auditory evoked N1 responses. The mechanism underlying the generation of event-related potentials (ERPs) has been a matter of debate for the past few decades. While the evoked model proposes that ERPs are generated by the addition of fixed latency and fixed polarity responses, the phase reorganization model suggests that ERPs are the result of stimulus-induced phase reorganization of the ongoing oscillations. Previous studies have suggested phase reorganization as a possible mechanism in auditory N1, visual N1 and error-related negativity (ERN). The purpose of the current study was to explore the frequency characteristics of the cortical responses to whole-body balance perturbations. Perturbations were evoked using a lean and release protocol. The results revealed a significant power increase and phase-locking of delta, theta, alpha, and beta band activity during perturbation-evoked N1. This may suggest that the stimulus-induced phase reorganization of the ongoing electroencephalographic (EEG) activity could account for the features of cortical ERPs in response to perturbation of upright stability.

Antiphospholipid antibodies--our experience.

Antiphospholipid antibodies (APA) have aroused multispeciality interests. In our study of 200 cases worked up for APA, we have used a few simple coagulation tests to detect lupus anticoagulant (LA) and ELISA to detect anticardiolipin antibodies. The positivity rate for LA among cases with recurrent pregnancy loss was 4.16% and for aCL 20.8%. The positivity rate for LA in patients with venous thrombosis was 6.2%, in arterial thrombosis was 7.14% and in SLE patients was 58.3%. In conclusion APAs are to be looked for in cases of recurrent pregnancy loss, thrombosis in people < 45 years of age without risk factors and SLE patients to assess the thrombotic risk and to decide on anti coagulant therapy for further management.

Changing trends in malaria--a decade's experience at a referral hospital.

A 10 year study of malaria during 1989-98 recorded an increase in the incidence of malaria from 0.22 in 1989 to 1.3 in 1996 following which it has reached a plateau. The cases were chiefly from Karnataka, Andhra Pradesh and Tamil nadu. The P. falciparum infection and mixed infections (P. falciparum and vivax) were found to be on the rise. Peak of malaria cases were recorded in the months of June-July and in Oct-Nov coinciding with the rains showing a seasonal pattern. The common haematological findings were anemia, thrombocytopenia, pancytopenia and leucopenia. Complications noted in our study were haemolysis, renal failure, hepatopathy and cerebral malaria. The unusual cases were congenital malaria, malaria with sickle cell anemia, AIHA and G-6PD deficiency. Mortality due to cerebral malaria was found to be 13.5%.