Small Study Research Articles

Patterns of single and multiple HPV infections in female: A systematic review and meta-analysis

BackgroundData on the patterns of single and multiple HPV infections are largely limited to small size studies, and the regional difference have not been systematically examined. MethodsA literature search was conducted using PubMed, Embase, and Web of Science databases up to Sept 22, 2023. The pooled prevalence of HPV infection were calculated using random-effects meta-analysis. Subgroup analysis was used to explore the heterogeneity, and publication bias was evaluated by Egger's test and Begg's test. ResultsThere were 121 studies included with 1,682,422 participants. Globally, the most common genotypes of single HPV infection were HPV16 (7.05 %), 18 (1.94 %), 52 (1.93 %), 58 (1.68 %), and 31 (1.53 %), as well as HPV 16 (4.91 %), 31 (2.68 %), 52 (2.20 %), 51 (1.99 %), and 18 (1.96 %) in multiple HPV infections. Apart from HPV16 and 18, HPV52 and 58 were common in Asia, HPV31 and 51 was in Europe, North and South America, and HPV35 and 45 were in Africa. The prevalence of HPV infection among different age groups (<30, 30–50, >50 years age groups) was 20.93 %, 16.27 %, and 18.69 %, respectively. The single HPV infection prevalence in the No-ILs, LSILs, HSILs, and cervical cancer groups were 16.17 %, 51.60 %, 57.12 %, and 62.88 %, respectively, as well as in multiple infections were 5.09 %, 30.93 %, 32.86 %, and 21.26 % ConclusionDeveloping local HPV vaccines is necessary based on the HPV infection pattern. It is essential to educate young women to get vaccinated and encourage elderly women to have regular cervical cancer screenings to reduce the danger of cervical cancer.

Audio magnetotelluric view of the giant carbonatite-hosted Bayan Obo REE deposit, Inner Mongolia, northern China

As critical minerals in low-carbon economies, rare-earth elements (REEs) are crucial for modern industry, technology, and medicine. The largest known REE resource in the world is the Bayan Obo (BO) deposit in northern China. However, BO features as complicated mineral compositions and has experienced several geological events. As a reuslt, controversy remains about the BO REE genesis and enrichment mechanism, and debates are also ongoing about the controlling structure of this giant deposit. We carried out an multiscale electromagnetism study on BO mineral deposits. The multiscale study consists a microscale on samples, a small scale targeting mineral deposits and a mid scale concerning the mine field. The small and mid scale study were conducted using audio-magnetotelluric (AMT). This study revealed the controlling structure using geoelectrical characteristics. AMT data were acquired from more than 590 stations, and the petro-electromagnetism of several samples was analyzed to understand the geoelectrical features of the ore deposits and their surrounding rocks. The data were interpreted using Bostick transformation and generalized least-squares inversions. We obtained the geoelectrical structure of the BO complex down to a maximum depth of 3500 m, and we present two-dimensional imaging based on the AMT conversion results. The results show that the BO deposit developed at the transition of the high- and low-resistivity geoelectrical structure from south to north. Our AMT results indicate that the tectonic setting of the BO deposit is the transition zone between the rift edge and craton margin slope. The ore geology is presently controlled by the complex slope and the rift remnant, the ore-bearing dolostone in the profiles is Y-shaped. It goes downward from south to north and potentially features a great mineral prospect deep in the BO deposit.

Sustained release of 3D printed bupropion hydrochloride tablets bearing Braille imprints for the visually impaired

3D printing has been introduced as a novel approach for the design of personalized dosage forms and support patient groups with special needs that require additional assistance for enhanced medication adherence. In this study liquid crystal display (LCD) is introduced for the development of sustained release bupropion.HCl printed tablets. The optimization of printing hydrogel inks was combined with the display of Braille patterns on the tablet surface for blind or visually impaired patients. Due to the high printing accuracy, the Braille patterns could be verified by blind patients and provide the required information. Further characterization revealed the presence of BUP in amorphous state within the photopolymerized resins. The selection of poly(ethylene glycol) (PEG)-diacrylate (PEGDA) of different molecular weights and the presence of surfactants or solubilizers disrupted the resin photopolymerization, thus controlling the BUP dissolution rates. A small batch scale-up study demonstrated the capacity of LCD to print rapidly a notable number of tablets within 24 min.

Early Cardiovascular Effects of Indoor Environmental Quality During Sleep in Children: Insights from a Small Cohort Study in Taiwan

Early Cardiovascular Effects of Indoor Environmental Quality During Sleep in Children: Insights from a Small Cohort Study in Taiwan

Mycophenolate Mofetil for the Treatment of Warm Autoimmune Haemolytic Anaemia Post-Rituximab Therapy: A Case Series.

Warm autoimmune haemolytic anaemia (wAIHA) is an acquired haemolytic disorder most commonly treated with a combination of corticosteroids, rituximab and/or splenectomy. Third-line therapies for refractory cases include immunosuppressive agents. Mycophenolate mofetil is frequently used in these scenarios, although its use is supported by small studies and anecdotal evidence rather than large-scale data. We describe three cases of refractory warm autoimmune haemolytic anaemia successfully treated with mycophenolate mofetil. Case 1: A persistent case of autoimmune haemolytic anaemia in a 56-year-old was ultimately managed with mycophenolate mofetil, leading to successful steroid tapering and stable haemoglobin levels without relapse. Case 2: A woman with a complex oncological history, including lymphoma and breast cancer, achieved remission with mycophenolate therapy, maintaining stability post-steroid treatment. Case 3: Mycophenolate proved effective for a 63-year-old with cirrhosis after recurrent autoimmune anaemia and deep vein thrombosis, enabling cessation of steroids and maintaining remission. Management of this condition can be challenging and balancing the available treatments is crucial to reduce potential complications from long-term therapies that appear to be ineffective. Our case series demonstrates anecdotal experience on successful use of mycophenolate mofetil for complex refractory cases of wAIHA. Warm autoimmune haemolytic anaemia can be a challenging condition to manage. Refractory cases that are steroid-dependent can benefit from trialling steroid-sparing agents such as mycophenolate.Anti-CD20 agents such as rituximab can be very effective in refractory cases, however there is a small percentage of patients that might not be responsive to this monoclonal antibody.Autoimmune haemolytic anaemias can be frequently complicated by thrombotic events, and part of the backbone treatment is establishing good thromboprophylaxis.

Rupture as generative of professional agency: narratives from student teachers on placement during school closures

ABSTRACT Existing ways of knowing how to prepare people to become teachers were insufficient when COVID-19 closed schools, and some enduring hierarchies in teacher preparation were unsettled. This re-positioned qualified and student teachers as equally inexperienced in the circumstances. We contribute to post-COVID-19 educational research by considering the impact on student teachers through the historical socio-cultural lenses of phylogenesis (societal), ontogenesis (cultural) and microgenesis (individual). Our small qualitative study conducted interviews with four student teachers from undergraduate and postgraduate programmes whose practical placements, in a range of geographical contexts, were disrupted by school closures. Thematic analysis of student teachers’ narratives during school closures identified how disrupted hierarchies became generative spaces for the development of student teacher professional agency. Though the initial ruptures of social activity have passed, successive global (financial, environmental, political) and personal crises characterise the current era, with implications for teacher education about developing student teachers’ professional agency to cope with ongoing types of disruption in professional practice.

Treatment of hidradenitis suppurativa with adalimumab in the PIONEER I and II trials reduced indices of systemic inflammation, recognised risk factors for cardiovascular disease.

Hidradenitis suppurativa (HS) is associated with increased cardiovascular disease (CVD) risk. Systemic immune inflammation index (SII), neutrophil/lymphocyte (NLR), platelet/lymphocyte (PLR) and monocyte/lymphocyte ratios (MLR) are biomarkers of systemic inflammation and CVD. One small study identified a lower NLR and PLR in patients treated with adalimumab. Our aim was to assess changes in SII, NLR, PLR and MLR in a larger cohort, and to evaluate their association with disease severity and treatment response. This was a post-hoc analysis of PIONEER I and PIONEER II, two phase 3 randomised placebo-controlled clinical trials of adalimumab for HS. SII, NLR, PLR and MLR were log10-transformed and linear mixed model was used to estimate treatment effect. SII, NLR, PLR and MLR reduced from baseline levels with adalimumab treatment by week 12, when the primary response endpoint was assessed. Significant changes first appeared at week 4 and were maintained to week 36. In contrast, no significant changes were observed in placebo-treated patients. In patients re-randomised at week 12 from placebo to adalimumab, SII, NLR, PLR and MLR also reduced within 4 weeks. In patients re-randomised from adalimumab to placebo, these biomarkers returned to baseline by week 36. In addition, SII, NLR and PLR correlated with draining fistula count (r=0.26-0.43, p<0.001). Adalimumab non-responders in PIONEER I had a higher SII, NLR and PLR at baseline and week 12, but this was not significant when adjusted for draining fistulae. Treatment of HS patients with adalimumab results in rapid sustained reduction in systemic inflammation measured by SII, NLR, PLR and MLR which correlate with CVD risk. SII, NLR and PLR may predict adalimumab response, although dependent on their interaction with the number of draining fistulae.

Increasing inter-word spacing reduces migration errors and improves reading comprehension in students with dyslexia.

We report a small study in which we explored the effects of manipulating narrative text on levels of comprehension for students with and without dyslexia. Using two pieces of standardised narrative text deemed to be of similar difficulty and length, we manipulated the texts such that we could present two texts to each participant, one in each condition. The first condition was text using standard inter-word spacing; the second condition used increased inter-word spacing. Scores on standardised comprehension questions were significantly improved for participants with dyslexia. Additionally, given that there is evidence of delayed visual attention disengagement in individuals with specific forms of dyslexia, we hypothesised that the phenomena of migration of letters and words for some readers might be mitigated by increasing inter-word spacing. We did indeed find that incidence of migration was significantly reduced in this condition for all participants.

Impact of a clinical decision support system on identifying drug-related problems and making recommendations to providers during community pharmacist-led medication reviews in Ontario, Canada: A pilot study.

To evaluate the impact of a clinical decision support system (CDSS) to identify drug-related problems (DRPs) during community pharmacist medication reviews. Pilot 3-phase (group), open-label study. Two community pharmacies in Sarnia, Ontario, with pharmacists providing medication reviews to patients. Five pharmacists participated in three phases (groups). During Phase 1, pharmacists conducted medication reviews in 25 adult patients using the usual approaches. In Phase 2, pharmacists were trained to use a CDSS to identify DRPs, and then conducted medication reviews using the tool in a different group of 25 adult patients. In Phase 3, pharmacists conducted medication reviews without the aid of the CDSS in 25 additional adult patients. The primary outcome was recommendation to the primary care physician to alter pharmacotherapy based on medication review, assessed using mean number and frequency (yes/no) of recommendations by patient. Secondary outcomes included number of potential DRPs, actual DRPs, medication review duration time, pharmacist's perceptions of the CDSS and patient satisfaction with medication review. The mean number of recommendations to primary care physicians to alter pharmacotherapy per patient in Phases 1, 2 and 3 did not differ: 1.0 (SD = I.2) versus 1.5 (1.0) versus 1.5 (1.0), respectively; p = 0.223. The percentage of patients with a pharmacy recommendation sent to physicians across the phases, however, differed: 52% versus 80% versus 88%, respectively; p = 0.010, with more in Phases 2 and 3 compared to 1. There were more potential DRPs in group 2 compared to other groups. There were no differences in actual DRPs and medication review time. Pharmacists had positive attitudes about the CDSS. Patients were generally satisfied with their medication review. This small pilot study provides some preliminary evidence for performance and feasibility of a CDSS to identify DRPs that pharmacists will act on. Future research is recommended to validate these findings in a larger sample.

Acute splenic pathology on CT in patients with babesiosis.

To better understand the occurrence of splenic disease as a potential manifestation of babesiosis by retrospectively estimating the frequency of acute splenic injury on abdominal and pelvic CT in a cohort of patients with active babesia infection. In a search of our single institution, suburban teaching community hospital database, 57 patients were found to have positive babesia infection between the years 2021-2023. 29 of these patients underwent abdominal and pelvic CT (22 with and 7 without intravenous contrast), and 3 underwent abdominal ultrasound without any CT. The imaging was reviewed for the presence or absence of splenic abnormalities, and for follow-up imaging. Parasitemia levels at the time of imaging were also reviewed; parasitemia levels < 4% are associated with mild to moderate disease, whereas parasitemia levels > 4% are associated with severe disease. 21/32 (66%) patients who underwent any type of abdominal imaging (ultrasound, MRI, and CT) had splenomegaly. Of the 22 patients who had IV contrast-enhanced CT scans, 6 were found to have splenic infarction (27%). One of these 22 patients had multiple rounded non-peripheral hypoenhancing foci on both CT and MRI which did not meet criteria for infarction, in association with splenomegaly, and which resolved after treatment. 0/6 patients in the splenic infarction group had parasitemia levels greater than 4%, while 4 of the 16 patients (4/16) without infarction had parasitemia levels of greater than 4%. Our study showed that splenic disease in patients with babesiosis mostly took the form of splenomegaly, and in a substantial minority of patients as splenic infarction. There were no cases of splenic rupture and perisplenic hematoma in our case series, likely reflecting a limitation of the relatively small study size. Concordant with prior studies, we found no identifiable association between parasitemia levels and the presence of splenic infarction.

Effect of aluminum hydroxide on serum phosphate and fibroblast growth factor 23 concentrations in young adult cats with surgically induced chronic kidney disease.

To describe serum fibroblast growth factor 23 (FGF-23) concentrations in young adult cats with remnant kidney model-induced chronic kidney disease (CKD) and to evaluate the effects of orally administered aluminum hydroxide (ALOH) on serum phosphate and FGF-23 concentrations in these cats. 17 adult, purpose-bred cats with induced CKD and 13 healthy, age-matched cats. A prospective, randomized study. Cats with induced CKD fed a wet renal diet received treatment with ALOH (90 mg/kg/d, PO) on days 0 to 42 and no treatment on days 43 to 84 (treatment group, n = 9) or no treatment on days 0 to 84 (control group, n = 8). Standard serum and urine biochemical analyses and several parameters reflective of calcium-phosphate balance, including serum parathyroid hormone and FGF-23 concentrations, were evaluated at baseline and various time points, including days 42 and 84. Age-matched, healthy, community-owned cats underwent similar evaluations at a single time point. Baseline data from CKD cats were compared to those of healthy cats. Longitudinal data from CKD cats were compared over time. Serum phosphate, total and ionized calcium, and FGF-23 concentrations were significantly higher in CKD cats at baseline relative to healthy cats (all P ≤ .009). Serum phosphate concentration did not change significantly over time in either CKD group; however, FGF-23 concentrations significantly increased over time in the control group (P < .02) but not the treatment group (P = .059). Aluminum hydroxide did not reduce serum phosphate or FGF-23 concentrations in this small study of cats with induced CKD chronically eating a phosphate-restricted diet.

A worldwide study of white matter microstructural alterations in people living with Parkinson’s disease

The progression of Parkinson’s disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies. Here we performed a large diffusion MRI study in PD, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of white matter differences. Diffusion-weighted MRI data from 1654 participants diagnosed with PD (age: 20–89 years; 33% female) and 885 controls (age: 19–84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate white matter microstructure. Skeletonized maps of fractional anisotropy (FA) and mean diffusivity (MD) were compared across Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter alterations at different stages. We found an enhanced, more widespread pattern of microstructural alterations with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest: Cohen’s d effect sizes reached d = −1.01 for FA differences in the fornix at PD HY Stage 4/5. The early PD signature in HY stage 1 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with motor and non-motor clinical dysfunction. While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA and lower MD in PD, consistent with early compensatory changes associated with the disorder.

The association between road traffic accidents and visual functions: A systematic review and meta-analysis.

Poor visual functions have been reported to be related to the occurrence of road traffic accidents. To review the association between visual function and road traffic accidents (RTAs) from published relevant empirical studies. Worldwide. A random effects (RE) model meta-analysis was conducted using STATA 18. Statistical tests conducted include meta-summary statistics, RE meta-analysis (forest plot), meta-regression (relationship between mean age and effect sizes), funnel plots, Egger's and Begg's tests for publication bias and small study effects. A total of 17 relevant studies, which were either cross-sectional or observational by design, were included in the meta-analysis. Reported effect sizes were within computed confidence intervals (CI) at 95%. The computedQtest of homogeneity was 61.94. The overall mean effect size of 1.43 (95% CI of 0.985-1.883) was statistically significant at a 5% level (Z= 6.26;p 0.001). TheI-squared = 62.17% (p= 0.00) confirmed moderate heterogeneity and theQ-value of 61.94 (p= 0.00) rejected the null hypothesis that the effect size was the same in all the studies. The funnel plot showed that the remaining majority of 13 studies were within the funnel plot on the right-hand side of the line of no effect. These results provide evidence of associations between visual functions and RTAs, and highlight the need for targeted interventions and further research to address the challenges associated with impaired visual functions and road safety.Contributions:The study contributes to the understanding of the implications of visual functions for road safety.

Peripheral Blood TCRβ Repertoire, IL15, IL2 and Soluble Ligands for NKG2D Activating Receptor Predict Efficacy of Immune Checkpoint Inhibitors in Lung Cancer.

The development of immune checkpoint inhibitors (ICIs) has changed the therapeutic paradigm of lung cancer (LC), becoming the standard of treatment for previously untreated advanced non-small cell lung cancer (NSCLC) without actionable mutations. It has allowed the achievement of durable responses and resulted in significant survival benefits. However, not all patients respond; hence, molecular biomarkers are needed to help us predict which patients will respond. With this objective, a prospective observational study was designed, including a cohort of 55 patients with NSCLC who received ICIs. We studied whether biomarkers such as TCRβ and specific cytokines involved in the regulation of T cell activity were related to the immunotherapy response. In the survival analysis, it was found that patients with higher TCRβ clonality, lower TCRβ evenness, higher TCRβ Shannon diversity and lower TCRβ convergence had higher overall survival (OS) and progression-free survival (PFS). However, no statistically significant association was observed. Regarding cytokines, those patients with higher levels of IL-2 and IL-15 presented statistically significantly shorter OS and PFS, respectively. In fact, in the multivariable analysis, the high IL-15 level increased the risk of death by three times. Although the sample size was small and more studies are needed to confirm our results, our study reveals promising markers of responses to ICIs.

Impact of Peripheral Angioplasty on Wound Oxygenation and Healing in Patients with Chronic Limb-Threatening Ischemia Measured by Near-Infrared Spectroscopy.

Managing chronic limb-threatening ischemia (CLTI) is challenging due to difficulties in assessing tissue oxygen saturation in ulcers. Near-infrared spectroscopy (NIRS) is a non-invasive method for measuring tissue oxygen saturation (StO2). This study evaluated the effects of endovascular treatment (EVT) on StO2 and wound healing in CLTI patients, comparing NIRS to standard ankle-brachial index (ABI) measurements. Using the Duesseldorf PTA Registry, 43 CLTI patients were analyzed: 27 underwent EVT, and 16 received conservative treatment. ABI assessed macrocirculation, while NIRS measured wound, wound area, and mean foot StO2 at baseline, post-EVT, and four-month follow-up. Wound severity was classified by wound area and wound, ischemia, and foot infection (WIfI) score. Wound StO2 increased significantly (median (interquartile range (IQR)), 38 (49.3) to 60 (34.5)%, p = 0.004), as did wound area StO2 (median (IQR), 70.9 (21.6) to 72.8 (18.3)%, p < 0.001), with no significant changes in the control group by four-month follow-up. Wound area decreased significantly after EVT (mean ± SD, 343.1 ± 267.8 to 178.1 ± 268.5 mm2, p = 0.01) but not in the control group. Changes in wound StO2, wound area StO2, and WIfI score correlated with wound area reduction, unlike ABI. This small exploratory study shows that NIRS-measured StO2 improvements after EVT correlate with reduced wound area and WIfI scores, highlighting NIRS as a potential enhancement for CLTI wound management in addition to ABI.

Retrospective evaluation of the predictive value of tumour burden at baseline [68 Ga]Ga-DOTA-TOC or -TATE PET/CT and tumour dosimetry in GEP-NET patients treated with PRRT

PurposeThere is a lack of validated imaging biomarkers for prediction of response to peptide receptor radionuclide therapy (PRRT). The primary objective was to evaluate if tumour burden at baseline PET/CT could predict treatment outcomes to PRRT with [177Lu]Lu-DOTA-TATE. Secondary objectives were to evaluate if there was a correlation between tumour burden and mean tumour absorbed dose (AD) during first cycle, and if mean tumour AD or the relative change of tumour burden at first follow-up PET/CT could predict progression free survival (PFS) or overall survival (OS).MethodsPatients with gastroenteropancreatic neuroendocrine tumour (GEP-NET) treated with [177Lu]Lu-DOTA-TATE PRRT were retrospectively included. Tumour burden was quantified from [68 Ga]Ga-DOTA-TOC/TATE PET/CT-images at baseline and first follow-up and expressed as; whole-body somatostatin receptor expressing tumour volume (SRETVwb), total lesion somatostatin receptor expression (TLSREwb), largest tumour lesion diameter and highest SUVmax. The relative change of tumour burden was evaluated in three categories. Mean tumour AD was estimated from the first cycle of PRRT. PFS was defined as time from start of PRRT to radiological or clinical progression. OS was evaluated as time to death. Kaplan Meier survival curves and log-rank test were used to compare PFS and OS between different groups.ResultsThirty-one patients had a baseline PET/CT < 6 months before treatment and 25 had a follow-up examination. Median tumour burden was 132 ml (IQR 61–302) at baseline and 71 ml (IQR 36–278) at follow-up. Twenty-two patients had disease progression (median time to progression 17.2 months) and 9 patients had no disease progression (median follow-up 28.7 months). SRETVwb dichotomized by the median at baseline was not associated with longer PFS (p = 0.861) or OS (p = 0.937). Neither TLSREwb, largest tumour lesion or SUVmax showed significant predictive value. There was a moderately strong correlation, however, between SUVmax and mean tumour AD r = 0.705, p < 0.001, but no significant correlation between SRETVwb nor TLSREwb and mean tumour AD. An increase of SRETVwb, TLSREwb or largest tumour lesion at first follow-up PET/CT was significantly correlated with shorter PFS/OS.ConclusionTumour burden at baseline showed no predictive value of PFS/OS after PRRT in this small retrospective study. An increase of tumour burden was predictive of worse outcome.

From Maps to Models: A Survey on the Reliability of Small Studies of Task-Based fMRI.

Task-based functional magnetic resonance imaging is a powerful tool for studying brain function, but neuroimaging research produces ongoing concerns regarding small-sample studies and how to interpret them. Although it is well understood that larger samples are preferable, many situations require researchers to make judgments from small studies, including reviewing the existing literature, analyzing pilot data, or assessing subsamples. Quantitative guidance on how to make these judgments remains scarce. To address this, we leverage the Human Connectome Project's Young Adult dataset to survey various analyses-from regional activation maps to predictive models. We find that, for some classic analyses such as detecting regional activation or cluster peak location, studies with as few as 40 subjects are adequate, although this depends crucially on effect sizes. For predictive modeling, similar sizes can be adequate for detecting whether features are predictable, but at least an order of magnitude more (at least hundreds) may be required for developing consistent predictions. These results offer valuable insights for designing and interpreting fMRI studies, emphasizing the importance of considering effect size, sample size, and analysis approach when assessing the reliability of findings. We hope that this survey serves as a reference for identifying which kinds of research questions can be reliably answered with small-scale studies.

Antiseizure Medications and Sudden Unexpected Death in Epilepsy: An Updated Review.

Sudden unexpected death in epilepsy (SUDEP) is responsible for most epilepsy-related deaths. It is mainly related to unwitnessed nocturnal convulsions, either focal to bilateral or generalised tonic-clonic seizures (TCS). Targeted preventive strategies are currently lacking as underlying mechanisms are largely unknown. Antiseizure medications (ASMs) modulate SUDEP risk through seizure reduction, but it is yet undetermined whether individual ASMs or other medications could also influence the internal SUDEP cascade. Seizure detection devices (SDD) may offer an alternative strategy by preventing TCS from being unwitnessed. Here, we critically evaluated the current evidence on the influence of ASMs, non-epilepsy concomitant drugs and SDD on SUDEP occurrence. We found no robust evidence for the effect of starting ASMs on SUDEP beyond TCS control, but we found some indications of a protective effect for polytherapy. We found no signs that specific ASMs exert a risk for SUDEP. One study suggested a possible protective effect of levetiracetam requiring further investigation. Only a few small studies addressed the association between non-epilepsy concomitant drugs and SUDEP, with no consistent effect for psychotropic medications and one more extensive study suggesting a lower risk among statin users. We only found indirect evidence indicating a protective effect for enhancing nocturnal supervision without explicitly addressing the impact of SDD on SUDEP occurrence. Further work is needed to explore the potential of ASMs and other interventions to modulate SUDEP risk, and they should accurately account for TCS frequency, polypharmacy and markers of non-adherence.

Tutorial on Firth's Logistic Regression Models for Biomarkers in Preclinical Space.

Preclinical studies are broad and can encompass cellular research, animal trials, and small human trials. Preclinical studies tend to be exploratory and have smaller datasets that often consist of biomarker data. Logistic regression is typically the model of choice for modeling a binary outcome with explanatory variables such as genetic, imaging, and clinical data. Small preclinical studies can have challenging data that may include a complete separation or quasi-complete separation issue that will result in logistic regression inflated coefficient estimates and standard errors. Penalized regression approaches such as Firth's logistic regression are a solution to reduce the bias in the estimates. In this tutorial, a number of examples with separation (complete or quasi-complete) are illustrated and the results from both logistic regression and Firth's logistic regression are compared to demonstrate the inflated estimates from the standard logistic regression model and bias-reduction of the estimates from the penalized Firth's approach. R code and datasets are provided in the supplement.

Integrating electromagnetic cancer stress with immunotherapy: a therapeutic paradigm.

An array of published cell-based and small animal studies have demonstrated a variety of exposures of cancer cells or experimental carcinomas to electromagnetic (EM) wave platforms that are non-ionizing and non-thermal. Overall effects appear to be inhibitory, inducing cancer cell stress or death as well as inhibition in tumor growth in experimental models. A variety of physical input variables, including discrete frequencies, amplitudes, and exposure times, have been tested, but drawing methodologic rationale and mechanistic conclusions across studies is challenging. Nevertheless, outputs such as tumor cytotoxicity, apoptosis, tumor membrane electroporation and leak, and reactive oxygen species generation are intriguing. Early EM platforms in humans employ pulsed electric fields applied either externally or using interventional tumor contact to induce tumor cell electroporation with stromal, vascular, and immunologic sparing. It is also possible that direct or external exposures to non-thermal EM waves or pulsed magnetic fields may generate electromotive forces to engage with unique tumor cell properties, including tumor glycocalyx to induce carcinoma membrane disruption and stress, providing novel avenues to augment tumor antigen release, cross-presentation by tumor-resident immune cells, and anti-tumor immunity. Integration with existing checkpoint inhibitor strategies to boost immunotherapeutic effects in carcinomas may also emerge as a broadly effective strategy, but little has been considered or tested in this area. Unlike the use of chemo/radiation and/or targeted therapies in cancer, EM platforms may allow for the survival of tumor-associated immunologic cells, including naïve and sensitized anti-tumor T cells. Moreover, EM-induced cancer cell stress and apoptosis may potentiate endogenous tumor antigen-specific anti-tumor immunity. Clinical studies examining a few of these combined EM-platform approaches are in their infancy, and a greater thrust in research (including basic, clinical, and translational work) in understanding how EM platforms may integrate with immunotherapy will be critical in driving advances in cancer outcomes under this promising combination.