Treatment of the neck in residual/recurrent disease after chemoradiotherapy for advanced primary laryngeal cancer.

Concomitant chemoradiotherapy (CRT) is extensively used as primary organ preservation treatment for selected advanced laryngeal squamous cell carcinomas (LSCC). The oncologic outcomes of such regimens are comparable to those of total laryngectomy followed by adjuvant radiotherapy. However, the management of loco-regional recurrences after CRT remains a challenge, with salvage total laryngectomy being the only curative option. Furthermore, the decision whether to perform an elective neck dissection (END) in patients with rN0 necks, and the extent of the neck dissection in patients with rN + necks is still, a matter of debate. For rN0 patients, meta-analyses have reported occult metastasis rates ranging from 0 to 31 %, but no survival advantage for END. In addition, meta-analyses also showed a higher incidence of complications in patients who received an END. Therefore, END is not routinely recommended in addition to salvage laryngectomy. Although some evidence suggests a potential role of END for supraglottic and locally advanced cases, the decision to perform END should weigh benefits against potential complications. In rN + patients, several studies suggested that selective neck dissection (SND) is oncologically safe for patients with specific conditions: when lymph node metastases are not fixed and are absent at level IV or V. Super-selective neck dissection (SSND) may be an option when nodes are confined to one level. In conclusion, current evidence suggests that in rN0 necks routine END is not necessary and that in rN + necks with limited nodal recurrences SND or a SSND could be sufficient.

Final 5-year report of BIONYX comparing the thin-composite wire-strut zotarolimus-eluting stent versus ultrathin-strut sirolimus-eluting stent.

BACKGROUND: The BIONYX randomized trial is the first study to evaluate the Resolute Onyx durable polymer-coated zotarolimus-eluting stent (ZES) in all-comers. Furthermore, it is the first trial to assess safety and efficacy of this stent versus the Orsiro biodegradable-polymer sirolimus-eluting stent (SES) in all-comers, paying particular attention to patients with diabetes. It has previously shown promising results until 3 years of follow-up. AIMS: We aimed to assess long-term clinical outcome after percutaneous coronary intervention (PCI) with Onyx ZES versus Orsiro SES at 5-year follow-up. METHODS: The main composite endpoint was target vessel failure (TVF): cardiac death, target vessel myocardial infarction, or target vessel revascularization. Time to primary and secondary endpoints was assessed using Kaplan-Meier methods, applying the log-rank test for between-group comparison. RESULTS: Follow-up was available in 2414/2488 (97.0%) patients. After 5 years, TVF showed no significant difference between Onyx ZES and Orsiro SES (12.7% vs. 13.7%, hazard ratio [HR] 0.94, 95% confidence interval [CI] [0.75-1.17], plog-rank = 0.55). Landmark analysis between 3- and 5-year follow-up found a lower target lesion revascularization rate for Onyx ZES (1.1% vs. 2.4%, HR 0.47, 95% CI [0.24-0.93], plog-rank = 0.026). A prespecified subgroup analysis showed no significant between-stent difference in clinical outcome among patients with diabetes. After treatment with Onyx ZES, patients aged ≥75 years had significantly lower rates of TVF (13.8% vs. 21.9%, HR 0.60, 95% CI [0.39-0.93], plog-rank = 0.023). CONCLUSIONS: The final 5-year analysis of the randomized BIONYX trial showed favorable and similar long-term outcomes of safety and efficacy for Onyx ZES and Orsiro SES in both all-comers and patients with diabetes.

Unswitched memory B cell deficiency in children with sickle cell disease and response to pneumococcal polysaccharide vaccine.

Early mortality in sickle cell disease (SCD) is attributed to increased infections due to loss of splenic function. Marginal zone B cells are important for initial opsonization of pathogens and can be absent in spleen histopathology in SCD. The frequency of unswitched memory B cells (UMBC), the circulating correlate of marginal zone B cells, reflects the immunologic function of the spleen. We hypothesized that asplenia in SCD is associated with alterations in the peripheral blood lymphocyte population and explored whether UMBC deficiency was associated with a clinical phenotype. We analyzed B cell subsets and clinical history for 238 children with SCD and 63 controls. The median proportion of UMBCs was lower in children with SCD compared with controls (4.7% vs. 6.6%, p < .001). Naïve B cells were higher in SCD compared with controls (80.6 vs. 76.3%, respectively, p = .02). UMBC frequency declined by 3.4% per year increase in age in SCD (95% CI: 2%, 4.7%, p < .001), but not in controls. A majority of children in all cohorts had an IgM concentration in the normal range for age and there were no differences between groups (p = .13). Subjects developed titers adequate for long-term protection to fewer serotypes in the polysaccharide vaccine than controls (14.7 vs. 19.4, p < .001). In this cohort, bacteremia was rare and specific clinical complications were not associated with UMBC proportion. In summary, UMBC deficiency occurs in SCD and is associated with age. Future studies should investigate B cell subsets prospectively and identify the mechanism of B cell loss in the spleen.

A reference quality genome assembly for the Jewel scarab Chrysina gloriosa.

The jewel scarab Chrysina gloriosa is one of the most charismatic beetles in the United States and is found from the mountains of West Texas to the Southeastern Arizona sky islands. This species is highly sought by professional and amateur collectors worldwide due to its gleaming metallic coloration. However, the impact of the large-scale collection of this beetle on its populations is unknown, and there is a limited amount of genetic information available to make informed decisions about its conservation. As a first step, we present the genome of C. gloriosa, which we reconstructed using a single female specimen sampled from our ongoing effort to document population connectivity and the demographic history of this beetle. Using a combination of long-read sequencing and Omni-C data, we reconstructed the C. gloriosa genome at a near-chromosome level. Our genome assembly consisted of 454 scaffolds spanning 642 MB, with the ten largest scaffolds capturing 98% of the genome. The scaffold N50 was 72 MB, and the BUSCO score was 95.5%. This genome assembly will be an essential tool to accelerate understanding C. gloriosa biology and help make informed decisions for the conservation of Chrysina and other species with similar distributions in this region. This genome assembly will further serve as a community resource for comparative genomic analysis.

Langerhans cell histiocytosis: NACHO update on progress, chaos, and opportunity on the path to rational cures.

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.

Accuracy of routinely collected hospital administrative discharge data and death certificate ICD-10 diagnostic coding in progressive supranuclear palsy and corticobasal syndrome: a systematic review and validation study.

BACKGROUND: We conducted a systematic review to identify existing ICD-10 coding validation studies in progressive supranuclear palsy and corticobasal syndrome [PSP/CBS]) and, in a new study, evaluated the accuracy of ICD-10 diagnostic codes for PSP/CBS in Scottish hospital inpatient and death certificate data. METHODS: Original studies that assessed the accuracy of specific ICD-10 diagnostic codes in PSP/CBS were sought. Separately, we estimated the positive predictive value (PPV) of specific codes for PSP/CBS in inpatient hospital data (SMR01, SMR04) compared to clinical diagnosis in four regions. Sensitivity was assessed in one region due to a concurrent prevalence study. For PSP, the consistency of the G23.1 code in inpatient and death certificate coding was evaluated across Scotland. RESULTS: No previous ICD-10 validation studies were identified. 14,767 records (SMR01) and 1497 records (SMR04) were assigned the candidate ICD-10 diagnostic codes between February 2011 and July 2019. The best PPV was achieved with G23.1 (1.00, 95% CI 0.93-1.00) in PSP and G23.9 in CBS (0.20, 95% CI 0.04-0.62). The sensitivity of G23.1 for PSP was 0.52 (95% CI 0.33-0.70) and G31.8 for CBS was 0.17 (95% CI 0.05-0.45). Only 38.1% of deceased G23.1 hospital-coded cases also had this coding on their death certificate: the majority (49.0%) erroneously assigned the G12.2 code. DISCUSSION: The high G23.1 PPV in inpatient data shows it is a useful tool for PSP case ascertainment, but death certificate coding is inaccurate. The PPV and sensitivity of existing ICD-10 codes for CBS are poor due to a lack of a specific code.

The pairwise approximate spatiotemporal symmetry algorithm: A method for segmenting time series pairs.

Methods that measure the association between two intensively measured time series are of interest to researchers studying the symmetry of behaviors during social interaction. Such methods have historically focused on aggregating the amount of symmetry across all measurement occasions. However, it is rarely expected that symmetry is present at all measurement occasions. The current method, the pairwise approximate spatiotemporal symmetry (PASS) algorithm, is an approach that may be used to determine which measurement occasions in pairwise time series are indicative of symmetry and which are not. This process thus divides time series into symmetric and nonsymmetric segments. The PASS algorithm is demonstrated here on representative simulated data and naturalistic psychotherapy data. Results suggest that the PASS algorithm has the potential to extract meaningful symmetry segments from human signals. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

MRD at the End of Induction and EFS in T-cell Lymphoblastic Lymphoma: Children's Oncology Group Trial AALL1231.

Defining prognostic variables in T-lymphoblastic lymphoma (T-LL) remains a challenge. AALL1231 was a COG phase 3 clinical trial for newly diagnosed with T Acute Lymphoblastic leukemia or T-LL patients randomizing children and young adults to a modified augmented BFM backbone to receive standard therapy (Arm A) or with addition of bortezomib (Arm B). Optional bone marrow (BM) samples to assess minimal residual disease (MRD) at the end of induction (EOI) were collected in T-LL analyzed to assess the correlation of MRD at the EOI to event-free survival (EFS). Eighty-six (41%) of the 209 T-LL patients accrued to this trial submitted samples for MRD assessment. Patients with MRD <0.1% (n= 75) at EOI had a superior 4-year EFS versus those with MRD >0.1% (n= 11), (89.0±4.4% versus 63.6±17.2%, p= 0.025). Overall survival did not significantly differ between the two groups. Cox regression for EFS using Arm A as a reference demonstrated that MRD EOI ≥0.1% was associated with a greater risk of inferior outcome (Hazard Ratio, HR= 3.73 (1.12-12.40, p= 0.032), which was independent of treatment arm assignment. Consideration to incorporate MRD at EOI into future trials will help establish its value in defining risk groups. CT# NCT02112916.

Timing of Complete Multivessel Revascularization in Patients Presenting With Non-ST-Segment Elevation Acute Coronary Syndrome.

BACKGROUND: Complete revascularization of the culprit and all significant nonculprit lesions in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and multivessel disease (MVD) reduces major adverse cardiac events, but optimal timing of revascularization remains unclear. OBJECTIVES: This study aims to compare immediate complete revascularization (ICR) and staged complete revascularization (SCR) in patients presenting with NSTE-ACS and MVD. METHODS: This prespecified substudy of the BIOVASC (Percutaneous Complete Revascularization Strategies Using Sirolimus Eluting Biodegradable Polymer Coated Stents in Patients Presenting With Acute Coronary Syndrome and Multivessel Disease) trial included patients with NSTE-ACS and MVD. Risk differences of the primary composite outcome of all-cause mortality, myocardial infarction (MI), unplanned ischemia-driven revascularization (UIDR), or cerebrovascular events and its individual components were compared between ICR and SCR at 1 year. RESULTS: The BIOVASC trial enrolled 1,525 patients; 917 patients presented with NSTE-ACS, of whom 459 were allocated to ICR and 458 to SCR. Incidences of the primary composite outcome were similar in the 2 groups (7.9% vs 10.1%; risk difference 2.2%; 95% CI: -1.5 to 6.0; P = 0.15). ICR was associated with a significant reduction of MIs (2.0% vs 5.3%; risk difference 3.3%; 95% CI: 0.9 to 5.7; P = 0.006), which was maintained after exclusion of procedure-related MIs occurring during the index or staged procedure (2.0% vs 4.4%; risk difference 2.4%; 95% CI: 0.1 to 4.7; P = 0.032). UIDRs were also reduced in the ICR group (4.2% vs 7.8%; risk difference 3.5%; 95% CI: 0.4 to 6.6; P = 0.018). CONCLUSIONS: ICR is safe in patients with NSTE-ACS and MVD and was associated with a reduction in MIs and UIDRs at 1 year.

Clinical, radiological and molecular responses to combination chemotherapy with MAPK pathway inhibition in relapsed and refractory Langerhans cell histiocytosis.

Optimal therapeutic approaches for advanced Langerhans cell histiocytosis (LCH) are not known. We assessed the safety and efficacy of combined chemotherapy with MAPK pathway inhibition in 10 patients with refractory systemic disease and/or LCH-associated neurodegeneration. Overall response rate was 9/10 (90%) for the entire cohort: 5/5 (100%) for patients with systemic disease and 6/7 (86%) for patients with central nervous system disease. BRAFV600E+ peripheral blood fraction decreased in 5/6 (83%). Toxicities included fever, skin rash, myalgias, neuropathy, cytopenias and hypocalcaemia. Prospective trials are required to optimize combination strategies, determine potential to achieve cure and compare outcomes to chemotherapy or MAPK inhibitor monotherapy.

Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis.

Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.

Paradoxical Exception to Island Tameness: Increased Defensiveness in an Insular Population of Rattlesnakes.

Island tameness results largely from a lack of natural predators. Because some insular rattlesnake populations lack functional rattles, presumably the consequence of relaxed selection from reduced predation, we hypothesized that the Santa Catalina Island, California, USA, population of the southern Pacific rattlesnake (Crotalus helleri, which possesses a functional rattle), would exhibit a decrement in defensive behavior relative to their mainland counterparts. Contrary to our prediction, rattlesnakes from the island not only lacked tameness compared to mainland snakes, but instead exhibited measurably greater levels of defensiveness. Island snakes attempted to bite 4.7 times more frequently as we endeavored to secure them by hand, and required 2.1-fold more time to be pinned and captured. When induced to bite a beaker after being grasped, the island snakes also delivered 2.1-fold greater quantities of venom when controlling for body size. The additional venom resulted from 2.1-fold larger pulses of venom ejected from the fangs. We found no effects of duration in captivity (2-36 months), which suggests an absence of long-term habituation of antipredator behaviors. Breeding bird surveys and Christmas bird counts indicated reduced population densities of avian predators on Catalina compared to the mainland. However, historical estimates confirmed that populations of foxes and introduced mammalian predators (cats and pigs) and antagonists (herbivorous ungulates) substantially exceeded those on the mainland in recent centuries, and therefore best explain the paradoxically exaggerated defensive behaviors exhibited by Catalina's rattlesnakes. These findings augment our understanding of anthropogenic effects on the behaviors of island animals and underscore how these effects can negatively affect human safety.

Real-world treatment patterns and outcomes in patients with primary hemophagocytic lymphohistiocytosis treated with emapalumab.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, hyperinflammatory syndrome. Emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon-gamma, is approved in the United States to treat primary HLH (pHLH) in patients with refractory, recurrent, progressive disease or intolerance with conventional HLH. REAL-HLH, a retrospective study, conducted across 33 US hospitals, evaluated real-world treatment patterns and outcomes in patients treated with ≥1 dose of emapalumab between November 20, 2018, and October 31, 2021. Forty-six patients met the pHLH classification criteria. Median (range) age at diagnosis was 1.0 (0.3-21.0) year. Emapalumab was initiated for treating refractory (19/46), recurrent (14/46), or progressive (7/46) pHLH. At initiation, 15/46 patients were in the intensive care unit and 35/46 had received prior HLH-related therapies. Emapalumab treatment resulted in normalization of key laboratory parameters, including chemokine ligand 9 (CXCL9) (24/33; 72.7%), ferritin (20/45; 44.4%), fibrinogen (37/38; 97.4%), platelets (39/46; 84.8%), and absolute neutrophil count (40/45; 88.9%). Forty-two (91.3%) patients were considered eligible for transplant. Pre-transplant survival was 38/42 (90.5%). Thirty-one (73.8%) transplant-eligible patients proceeded to transplant and 23/31 (74.2%) of those transplanted were alive at the end of the follow-up period. Twelve-month survival probability from emapalumab initiation for the entire cohort (n=46) was 73.1%. There were no discontinuations due to adverse events. In conclusion, results from the REAL-HLH study, which describes treatment patterns, effectiveness, and outcomes in patients with pHLH treated with emapalumab in real-world settings, are consistent with the emapalumab pivotal phase 2/3 pHLH trial.

Total Patient Delay: A Comparison of Patient and Clinician/Health System Delays in the Diagnosis of Progressive Supranuclear Palsy and Corticobasal Syndrome.

BACKGROUND: Early diagnosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) is important for clinical care and key to developing successful disease-modifying agents. The patient-dependent phases of decision-making made before contact with a healthcare professional have been inadequately studied. OBJECTIVES: To evaluate the patient-dependent phases of decision-making from symptom onset, comparing this to clinician and/or health system delays within the overall diagnostic pathway. METHODS: Using the Anderson General Model of Total Patient Delay and a mixed-methods approach in participants with PSP/CBS and their caregivers recruited to the Scottish PSP and CBS cohort, we quantified and evaluated the determinants of "appraisal", "illness," and "behavioral" delay, comparing this to the clinician and/or health system delays ("treatment" delay) within the overall time from symptom onset to diagnosis. RESULTS: The time from index symptom onset to diagnosis was 3.26 (interquartile range [IQR] = 2.42, 4.75) years in PSP and 2.58 (IQR = 1.69, 4.08) years in CBS. Patient appraisal delay was 24 (IQR = 6, 60) weeks in PSP and 8 (IQR = 5, 24) weeks in CBS, illness delay 0 (IQR = -14, 0) weeks in PSP and 0 (IQR = -4, 0) weeks in CBS, with little perceived behavioral delay. Determinants of delay included the non-specificity of symptoms, normalization of symptoms within the context of age or normal physiological variability, and the extent of insight into new somatic symptoms. CONCLUSIONS: Although patient appraisal delay contributes to overall diagnostic delay in PSP/CBS, the greater proportion of overall diagnostic delay arises after contact with a healthcare professional (treatment delay).

High Doses of ANA12 Improve Phenobarbital Efficacy in a Model of Neonatal Post-Ischemic Seizures.

Phenobarbital (PB) remains the first-line medication for neonatal seizures. Yet, seizures in many newborns, particularly those associated with perinatal ischemia, are resistant to PB. Previous animal studies have shown that in postnatal day P7 mice pups with ischemic stroke induced by unilateral carotid ligation, the tyrosine receptor kinase B (TrkB) antagonist ANA12 (N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide, 5 mg/kg) improved the efficacy of PB in reducing seizure occurrence. To meet optimal standards of effectiveness, a wider range of ANA12 doses must be tested. Here, using the unilateral carotid ligation model, we tested the effectiveness of higher doses of ANA12 (10 and 20 mg/kg) on the ability of PB to reduce seizure burden, ameliorate cell death (assessed by Fluoro-Jade staining), and affect neurodevelopment (righting reflex, negative geotaxis test, open field test). We found that a single dose of ANA12 (10 or 20 mg/kg) given 1 h after unilateral carotid ligation in P7 pups reduced seizure burden and neocortical and striatal neuron death without impairing developmental reflexes. In conclusion, ANA12 at a range of doses (10-20 mg/kg) enhanced PB effectiveness for the treatment of perinatal ischemia-related seizures, suggesting that this agent might be a clinically safe and effective adjunctive agent for the treatment of pharmacoresistant neonatal seizures.

Early Developmental Exposure to Triclosan Impacts Fecal Microbial Populations, IgA and Functional Activities of the Rat Microbiome.

Triclosan (TCS), a broad-spectrum antibacterial chemical, is detected in human urine, breast milk, amniotic fluid, and feces; however, little is known about its impact on the intestinal microbiome and host mucosal immunity during pregnancy and early development. Pregnant female rats were orally gavaged with TCS from gestation day (GD) 6 to postpartum (PP) day 28. Offspring were administered TCS from postnatal day (PND) 12 to 28. Studies were conducted to assess changes in the intestinal microbial population (16S-rRNA sequencing) and functional analysis of microbial genes in animals exposed to TCS during pregnancy (GD18), and at PP7, PP28 and PND28. Microbial abundance was compared with the amounts of TCS excreted in feces and IgA levels in feces. The results reveal that TCS decreases the abundance of Bacteroidetes and Firmicutes with a significant increase in Proteobacteria. At PND28, total Operational Taxonomic Units (OTUs) were higher in females and showed correlation with the levels of TCS and unbound IgA in feces. The significant increase in Proteobacteria in all TCS-treated rats along with the increased abundance in OTUs that belong to pathogenic bacterial communities could serve as a signature of TCS-induced dysbiosis. In conclusion, TCS can perturb the microbiome, the functional activities of the microbiome, and activate mucosal immunity during pregnancy and early development.

No benefit of the trochanteric stabilizing plate on loss of fracture reduction in AO/OTA 31-A2 trochanteric fractures.

Aims: Despite limited clinical scientific backing, an additional trochanteric stabilizing plate (TSP) has been advocated when treating unstable trochanteric fractures with a sliding hip screw (SHS). We aimed to explore whether the TSP would result in less post operative fracture motion, compared to SHS alone. Methods: Overall, 31 patients with AO/OTA 31-A2 trochanteric fractures were randomized to either a SHS alone or a SHS with an additional TSP. To compare postoperative fracture motion, radiostereometric analysis (RSA) was performed before and after weightbearing, and then at four, eight, 12, 26, and 52 weeks. With the "after weightbearing" images as baseline, we calculated translations and rotations, including shortening and medialization of the femoral shaft. Results: Similar migration profiles were observed in all directions during the course of healing. At one year, eight patients in the SHS group and 12 patients in the TSP group were available for analysis, finding a clinically non-relevant, and statistically non-significant, difference in total translation of 1 mm (95% confidence interval -4.7 to 2.9) in favour of the TSP group. In line with the migration data, no significant differences in clinical outcomes were found. Conclusion: The TSP did not influence the course of healing or postoperative fracture motion compared to SHS alone. Based on our results, routine use of the TSP in AO/OTA 31-A2 trochanteric fractures cannot be recommended. The TSP has been shown, in biomechanical studies, to increase stability in sliding hip screw constructs in both unstable and intermediate stable trochanteric fractures, but the clinical evidence is limited. This study showed no advantage of the TSP in unstable (AO 31-A2) fractures in elderly patients when fracture movement was evaluated with radiostereometric analysis.

Addressing Comorbidities in People with Parkinson's Disease: Considerations From An Expert Panel.

In the UK, guidance exists to aid clinicians and patients deciding when treatment for Parkinson's disease (PD) should be initiated and which therapies to consider. National Institute for Health and Care Excellence (NICE) guidance recommends that before starting PD treatment clinicians should discuss the following: the patient's individual clinical circumstances; lifestyle; preferences; needs and goals; as well as the potential benefits and harms of the different drug classes. Individualization of medicines and management in PD significantly improves patients' outcomes and quality of life. This article aims to provide simple and practical guidance to help clinicians address common, but often overlooked, co-morbidities. A multi-disciplinary group of PD experts discussed areas where clinical care can be improved by addressing commonly found co-morbidities in people with Parkinson's (PwP) based on clinical experience and existing literature, in a roundtable meeting organized and funded by Bial Pharma UK Ltd. The experts identified four core areas (bone health, cardiovascular risk, anticholinergic burden, and sleep quality) that, if further standardized may improve treatment outcomes for PwP patients. Focusing on anticholinergic burden, cardiac risk, sleep, and bone health could offer a significant contribution to personalizing regimes for PwP and improving overall patient outcomes. Within this opinion-based paper, the experts offer a list of guiding factors to help practitioners in the management of PwP.

Durable immunity to EBV after rituximab and third-party LMP-specific T cells: a Children's Oncology Group study.

ABSTRACT: Posttransplant lymphoproliferative disease (PTLD) in pediatric solid organ transplant (SOT) recipients is characterized by uncontrolled proliferation of Epstein-Barr virus-infected (EBV+) B cells due to decreased immune function. This study evaluated the feasibility, safety, clinical and immunobiological outcomes in pediatric SOT recipients with PTLD treated with rituximab and third-party latent membrane protein-specific T cells (LMP-TCs). Newly diagnosed (ND) patients without complete response to rituximab and all patients with relapsed/refractory (R/R) disease received LMP-TCs. Suitable LMP-TC products were available for all eligible subjects. Thirteen of 15 patients who received LMP-TCs were treated within the prescribed 14-day time frame. LMP-TC therapy was generally well tolerated. Notable adverse events included 3 episodes of rejection in cardiac transplant recipients during LMP-TC therapy attributed to subtherapeutic immunosuppression and 1 episode of grade 3 cytokine release syndrome. Clinical outcomes were associated with disease severity. Overall response rate (ORR) after LMP-TC cycle 1 was 70% (7/10) for the ND cohort and 20% (1/5) for the R/R cohort. For all cohorts combined, the best ORR for LMP-TC cycles 1 and 2 was 53% and the 2-year overall survival was 70.7%. vßT-cell receptor sequencing showed persistence of adoptively transferred third-party LMP-TCs for up to 8 months in the ND cohort. This study establishes the feasibility of administering novel T-cell therapies in a cooperative group clinical trial and demonstrates the potential for positive outcomes without chemotherapy for ND patients with PTLD. This trial was registered at www.clinicaltrials.gov as #NCT02900976 and at the Children's Oncology Group as ANHL1522.

Evaluating Injury Severity in Neonatal Encephalopathy Using Automated Quantitative Electroencephalography Analysis: A Pilot Study.

Quantitative analysis of electroencephalography (qEEG) is a potential source of biomarkers for neonatal encephalopathy (NE). However, prior studies using qEEG in NE were limited in their generalizability due to individualized techniques for calculating qEEG features or labor-intensive pre-selection of EEG data. We piloted a fully automated method using commercially available software to calculate the suppression ratio (SR), absolute delta power, and relative delta, theta, alpha, and beta power from EEG of neonates undergoing 72 h of therapeutic hypothermia (TH) for NE between April 20, 2018, and November 4, 2019. We investigated the association of qEEG with degree of encephalopathy (modified Sarnat score), severity of neuroimaging abnormalities following TH (National Institutes of Child Health and Development Neonatal Research Network [NICHD-NRN] score), and presence of seizures. Thirty out of 38 patients met inclusion criteria. A more severe modified Sarnat score was associated with higher SR during all phases of TH, lower absolute delta power during all phases except rewarming, and lower relative delta power during the last 24 h of TH. In 21 patients with neuroimaging data, a worse NICHD-NRN score was associated with higher SR, lower absolute delta power, and higher relative beta power during all phases. QEEG features were not significantly associated with the presence of seizures after correction for multiple comparisons. Our results are consistent with those of prior studies using qEEG in NE and support automated qEEG analysis as an accessible, generalizable method for generating biomarkers of NE and response to TH. Additionally, we found evidence of an immature relative frequency composition in neonates with more severe brain injury, suggesting that automated qEEG analysis may have a use in the assessment of brain maturity.