Search

PURPOSE OF REVIEW: Recent advancements in big data analytical tools and large patient databases have expanded tremendously the opportunities to track patient and safety outcomes. We discuss the strengths and limitations of large databases and implementation in practice with a focus on the current opportunities to use technological advancements to improve patient safety. RECENT FINDINGS: The most used sources of data for large patient safety observational studies are administrative databases, clinical registries, and electronic health records. These data sources have enabled research on patient safety topics ranging from rare adverse outcomes to large cohort studies of the modalities for pain control and safety of medications. Implementing the insights from big perioperative data research is augmented by automating data collection and tracking the safety outcomes on a provider, institutional, national, and global level. In the near future, big data from wearable devices, physiological waveforms, and genomics may lead to the development of personalized outcome measures. SUMMARY: Patient safety research using large databases can provide actionable insights to improve outcomes in the perioperative setting. As datasets and methods to gain insights from those continue to grow, adopting novel technologies to implement personalized quality assurance initiatives can significantly improve patient care.

To assess the clinicopathological features and prognostic factors of pediatric intracranial ependymomas and to explore the current diagnostic practice, we analyzed clinical data from the Brain Tumor Registry of Japan (BTRJ). Data of fifty children under 18 years of age diagnosed with intracranial ependymoma were extracted from the BTRJ database. Cases were reviewed for overall survival (OS) and progression-free survival (PFS), with attention to gender, preoperative Karnofsky performance status score, location of the tumor, the extent of resection, World Health Organization (WHO) histopathological grading, and adjuvant therapy. The median age at diagnosis was 6.1 years, ranging from 7 months to 17.6 years. Based on the WHO histopathological grading, 27 patients were classified under grade 2 (54%) and 23 patients were classified under grade 3 (46%). Gross total resection (GTR) was achieved in 30 patients (60%). The median follow-up time was 65 months. Five-year PFS and OS were 47.2 ± 7.3% and 73.3 ± 6.7%, respectively. GTR was associated with longer OS (P = 0.02). The histopathological grading was not an independent prognostic factor for the OS. Mitosis and microvascular proliferation were higher among patients with grade 3 than in those with grade 2, which aided in deciding the WHO grade. This nationwide study revealed the characteristics and outcomes of patients with childhood ependymomas. GTR was the factor most consistently associated with improved survival. In contrast, the histopathological grading in this cohort was not a significant prognostic factor. More reproducible and practical criteria for the diagnosis of intracranial ependymomas should be further pursued in future studies.

The preservation of the anterior choroidal artery (AChA) is essential for avoiding neurological sequelae after mesial temporal lobe epilepsy (mTLE) surgery. The purpose of this study is to reveal the anatomical variation in which the perforating branches arise from the plexal segment of the AChA by using a modern neuroimaging modality.This study analyzed 3D rotational angiography (3DRA) images from 56 subjects. The AChA and perforating branches were visualized using slab MIP. We analyzed branching patterns, courses of the perforating arteries arising from the plexal segment of the AChA, and the anastomosis of the AChA with other cerebral arteries.The slab MIP applied to 3DRA visualized one or more perforating branches from the AChA in 92.9% of cases. The presence of perforating branches arising from the AChA plexal segment was 17.3%. Most of the branching points of plexal perforators were likely located in the operative field during hippocampal resection. The course of the AChA plexal perforators included the posterior limb of the internal capsule. Anastomosis with other cerebral arteries was visualized in 25% of the AChA with plexal perforators.3DRA slab MIP was useful for visualizing the perforating branches of the AChA. Our results showed the possibility that surgical manipulation of the choroid plexus may cause infarction in the AChA territory. We suggest that the existence of the AChA plexal perforators should be recognized to further enhance the safety of hippocampal resection for mTLE.

We assessed an intervention aimed at improving adherence to antiretroviral therapy (ART) among pregnant and postpartum women living with HIV (PPWLH). We randomized 133 pregnant women initiating ART in Uganda to receive text reminders generated by real time-enabled electronic monitors and data-informed counseling through 3 months postpartum (PPM3) or standard care. Intention-to-treat analyses found low adherence levels and no intervention impact. Proportions achieving ≥95% adherence in PPM3 were 16.4% vs. 9.1% (t = -1.14, p = 0.26) in intervention vs. comparison groups, respectively; 30.9% vs. 29.1% achieved ≥80% adherence. Additional analyses found significant adherence declines after delivery, and no effect on disease progression (CD4-cell count, viral load), though treatment interruptions were significantly fewer in intervention participants. Per-protocol analyses encompassing participants who used adherence monitors as designed experienced better outcomes, suggesting potential benefit for some PPWLH. The study was registered on ClinicalTrials.Gov (NCT02396394).

This case involved a 65-year-old woman, who had been suffered from weakness in both legs for 10 years. She had not been diagnosed of dystrophia myotonica type 1 (DM1) despite her son's diagnosis of DM and her distinct facial features and gait anomaly. During her son's recent clinical visit, she was finally suspected of having DM. She was sent to our institution, where a distinct muscle atrophy and grip myotonia were observed and a genetical examination was performed. The sequencing data confirmed her diagnosis of DM1 due to the distinct 230-900 CTG repeats found in the dystrophia myotonica protein kinase gene 3' untranslated region. A brain MRI revealed an abnormal lesion with irregular ring-enhancement at the right temporal lobe. Because of the steady growth of the lesion during one month observation, a surgical intervention was performed in our institution. The histopathological examination gave a diagnosis of glioblastoma multiforme (GBM). The clinical management of the patient required special cares during the perioperative periods due to the distinct pathological manifestation of DM. The risk of developing cancer in DM patients has been estimated about twice as much as general population. Since GBM developed in the DM patient is rarely reported, we present this rare case with a few insights: the difficulties of the clinical management of DM patients under the perioperative stress; the pathological contribution of DM to the malignant transformation of the glial cells.

Supplemental Digital Content is Available in the Text., Introduction: Recent studies project thousands of additional AIDS-related deaths because of COVID-19–related disruptions in HIV care. However, the extent to which disruptions in care have materialized since the start of the pandemic is not well understood. Methods: We use electronic health records to investigate how the pandemic has affected clinic visits, patients' antiretroviral therapy (ART) supply, and viral suppression for a cohort of 14,632 HIV clients from a large HIV clinic in Kampala, Uganda. We complement this with an analysis of electronically measured longitudinal ART adherence data from a subcohort of 324 clients. Results: Clinic visits decreased by more than 50% after a national lockdown started. The risk of patients running out of ART on a given day increased from 5% before the lockdown to 25% 3 months later (Relative Risk Ratio of 5.11, 95% confidence interval: 4.99 to 5.24) and remained higher than prelockdown 6 months later at 13% (Relative Risk Ratio of 2.60; 95% confidence interval: 2.52 to 2.70). There was no statistically significant change in electronically measured adherence or viral suppression. Conclusion: We document substantial gaps in HIV care after the start of the COVID-19 pandemic in Uganda. This suggests that measures to improve access should be explored as the pandemic persists. However, ART adherence was unaffected for the subcohort for whom we measured electronic adherence. This suggests that some clients may have stockpiles of ART tablets from previous prescriptions that allowed them to keep taking their medication even when they could not visit the clinic for ART refills.

Background CNS germ cell tumors (GCTs) predominantly develop in pediatric and young adult patients with variable responses to surgery, radiation, and chemotherapy. This study aimed to examine the complex and largely unknown pathogenesis of CNS GCTs. Methods We used a combined transcriptomic and methylomic approach in 84 cases and conducted an integrative analysis of the normal cells undergoing embryogenesis and testicular GCTs. Results Genome-wide transcriptome analysis in CNS GCTs indicated that germinoma had a transcriptomic profile representative of primitive cells during early embryogenesis with high meiosis/mitosis potentials, while nongerminomatous GCTs (NGGCTs) had differentiated phenotypes oriented toward tissue formation and organogenesis. Co-analysis with the transcriptome of human embryonic cells revealed that germinomas had expression profiles similar to those of primordial germ cells, while the expression profiles of NGGCTs were similar to those of embryonic stem cells. Some germinoma cases were characterized by extensive immune-cell infiltration and high expression of cancer-testis antigens. NGGCTs had significantly higher immune-cell infiltration, characterized by immune-suppression phenotype. CNS and testicular GCTs (TGCTs) had similar mutational profiles; TGCTs showed enhanced copy number alterations. Methylation analysis clustered germinoma/seminoma and nongerminoma/nonseminoma separately. Germinoma and seminoma were co-categorized based on the degree of the tumor microenvironment balance. Conclusions These results suggested that the pathophysiology of GCTs was less dependent on their site of origin and more dependent on the state of differentiation as well as on the tumor microenvironment balance. This study revealed distinct biological properties of GCTs, which will hopefully lead to future treatment development.

Glioblastoma is a glioma characterized by highly malignant features. Numerous studies conducted on the relationship between glioblastoma and the microenvironment have indicated the significance of tumor-associated macrophages/microglia (TAMs) in glioblastoma progression. Since interleukin (IL)-1β secreted by TAMs has been suggested to promote glioblastoma growth, we attempted to elucidate the detailed mechanisms of IL-1β in glioblastoma growth in this study. A phospho-receptor tyrosine kinase array and RNA-sequencing studies indicated that IL-1β induced the activation of signal transducer and activator of transcription-3 and nuclear factor-kappa B signaling. Glioblastoma cells stimulated by IL-1β induced the production of IL-6 and CXCL8, which synergistically promoted glioblastoma growth via signal transducer and activator of transcription-3 and nuclear factor-kappa B signaling. By immunohistochemistry, IL-1β expression was seen on TAMs, especially in perinecrotic areas. These results suggest that IL-1β might be a useful target molecule for anti-glioblastoma therapy.

The health and economic threats posed by the COVID-19 pandemic can be sources of great distress among people living with HIV, which in turn can impact the management of their HIV disease. We examined change in depression from pre- to post-lockdown restrictions and correlates of elevated depressive symptoms, including antiretroviral therapy (ART) adherence. Participants enrolled in a randomized controlled trial of an ART adherence intervention in Uganda. The month-12 follow-up assessment was fully administered just prior to the start of the pandemic-related lockdown in March 2020; at the conclusion of the lockdown three months later, we administered a mixed-methods phone-based assessment. ART adherence was electronically monitored throughout the study period, including during and after the lockdown. Depression was assessed with the 8-item Patient health questionnaire (PHQ-8), on which scores > 9 signify a positive screen for elevated depressive symptoms. A sample of 280 participants completed both the month-12 and post-lockdown assessments. Rates of elevated depressive symptoms nearly tripled from month 12 (n = 17, 6.1%) to the post-lockdown assessment (n = 50, 17.9%; McNemar test

Objective The purpose of this study is to investigate changes in autonomic activities and systemic circulation generated by surgical manipulation or electrical stimulation to the human brain stem. Methods We constructed a system that simultaneously recorded microsurgical field videos and heart rate variability (HRV) that represent autonomic activities. In 20 brain stem surgeries recorded, HRV features and sites of surgical manipulation were analyzed in 19 hypertensive epochs, defined as the periods with transient increases in the blood pressure. We analyzed the period during electrical stimulation to the ponto-medullary junction, performed for the purpose of monitoring a cranial nerve function. Results In the hypertensive epoch, HRV analysis showed that sympathetic activity predominated over the parasympathetic activity. The hypertensive epoch was more associated with surgical manipulation of the area in the caudal pons or the rostral medulla oblongata compared to controls. During the period of electrical stimulation, there were significant increases in blood pressures and heart rates, accompanied by sympathetic overdrive. Conclusions Our results provide physiological evidence that there is an important autonomic center located adjacent to the ponto-medullary junction. Significance A large study would reveal a candidate target of neuromodulation for disorders with autonomic imbalances such as drug-resistant hypertension.

OBJECTIVE Traumatic brain injury (TBI) is a major cause of mortality and morbidity in Uganda and other low- and middle-income countries (LMICs). Due to the difficulty of long-term in-person follow-up, there is a paucity of literature on longitudinal outcomes of TBI in LMICs. Using a scalable phone-centered survey, this study attempted to investigate factors associated with both mortality and quality of life in Ugandan patients with TBI. METHODS A prospective registry of adult patients with TBI admitted to the neurosurgical ward at Mulago National Referral Hospital was assembled. Long-term follow-up was conducted between 10.4 and 30.5 months after discharge (median 18.6 months). Statistical analyses included univariable and multivariable logistic regression and Cox proportional hazards regression to elucidate factors associated with mortality and long-term recovery. RESULTS A total of 1274 adult patients with TBI were included, of whom 302 (23.7%) died as inpatients. Patients who died as inpatients received surgery less frequently (p < 0.001), had more severe TBI at presentation (p < 0.001), were older (p < 0.001), and were more likely to be female (p < 0.0001). Patients presenting with TBI resulting from assault were at reduced risk of inpatient death compared with those presenting with TBI caused by road traffic accidents (OR 0.362, 95% CI 0.128–0.933). Inpatient mortality and postdischarge mortality prior to follow-up were 23.7% and 9%, respectively. Of those discharged, 60.8% were reached through phone interviews. Higher Glasgow Coma Scale score at discharge (continuous HR 0.71, 95% CI 0.53–0.94) was associated with improved long-term survival. Tracheostomy (HR 4.38, 95% CI 1.05–16.7) and older age (continuous HR 1.03, 95% CI 1.009–1.05) were associated with poor long-term outcomes. More than 15% of patients continued to suffer from TBI sequelae years after the initial injury, including seizures (6.1%) and depression (10.0%). Despite more than 60% of patients seeking follow-up healthcare visits, mortality was still 9% among discharged patients, suggesting a need for improved longitudinal care to monitor recovery progress. CONCLUSIONS Inpatient and postdischarge mortality remain high following admission to Uganda’s main tertiary hospital with the diagnosis of TBI. Furthermore, posttraumatic sequelae, including seizures and depression, continue to burden patients years after discharge. Effective scalable solutions, including phone interviews, are needed to elucidate and address factors limiting in-hospital capacity and access to follow-up healthcare.

Men’s engagement in the HIV care continuum may be negatively affected by adherence to inequitable gender norms, which may be exacerbated by HIV stigma. This cross-sectional study with 300 male fisherfolk in Uganda examined the independent and interacting effects of inequitable gender norm endorsement and HIV stigma on men’s missed HIV care appointments and missed antiretroviral (ARV) doses. Greater gender inequitable norm endorsement was associated with increased odds of missed HIV clinic visits (Adjusted Odds Ratio [AOR)]: 1.44, 95% CI: 1.16–1.78) and a statistically significant interaction between internalized HIV stigma and inequitable gender norms on missed ARV doses was identified (AOR: 5.32, 95% CI: 2.60–10.86). Adherence to traditional gender norms reduces men’s HIV appointment attendance, and among men with high internalized stigma, increases the likelihood of poor treatment adherence. These findings point to the need for HIV interventions that reconfigure harmful gender norms with a focus on stigma reduction.

Background Carbon monoxide causes electrical, functional, and morphological changes in the heart. It is unclear, however, whether the indicators of myocardial damage can predict the patient’s prognosis after carbon monoxide poisoning. This retrospective study aimed to investigate the relationship between the carboxyhemoglobin level and electrocardiographic (ECG) changes and whether the ECG changes and troponin I levels are related to the patient’s prognosis after carbon monoxide poisoning. Methods Carboxyhemoglobin, troponin I, and ECG parameters were measured in 70 patients with carbon monoxide poisoning. The QT and RR intervals were measured for each ECG lead in all patients, and the corrected QT interval and corrected QT dispersion were calculated. Results The correlation between the maximum corrected QT interval and the carboxyhemoglobin level was significant (P = 0.0072, R2 = 0.1017), as were the relationships between QT dispersion and carboxyhemoglobin (P R2 = 0.2358) and the corrected QT dispersion and carboxyhemoglobin (P R2 = 0.2613). The multivariate logistic analysis showed that the significant predictors of sequential disability were corrected QT dispersion (P = 0.0042), and troponin I level (P = 0.0021). Conclusions Patients’ prognosis following carbon monoxide poisoning can be predicted based on corrected QT dispersion and the troponin I level. Patients with myocardial damage should be monitored not only for their cardiovascular outcome but also for their neurological outcome and their prognosis.

Objective We describe a case of intracranial and extracranial multiple arterial dissecting aneurysms in rheumatoid arthritis (RA). Case Presentation A 29-year-old man with a medical history of RA since 18 years of age was admitted to our hospital for vomiting, dysarthria, and conscious disturbance. At 23, he underwent ligation of the left internal carotid artery (ICA) with superficial temporal artery to middle cerebral artery anastomosis because of acute infarct of the left hemisphere caused by arterial dissection of the left ICA. During the current admission, computed tomography (CT) revealed subarachnoid hemorrhage, and digital subtraction angiography (DSA) demonstrated dissecting aneurysms of the left intracranial vertebral artery (VA) and right extracranial VA. We diagnosed him with a ruptured dissecting aneurysm of the left intracranial VA and performed endovascular parent artery occlusion on the left VA. For the right unruptured VA aneurysm, we performed coil embolization simultaneously. At 2 weeks after the endovascular treatment, follow-up DSA revealed that multiple de novo dissecting aneurysms developed on the origin of the left VA and left and right internal thoracic arteries. Those aneurysms were treated with coil embolization. Other remaining aneurysms on the left thyrocervical trunk, right transverse cervical artery, and both common iliac arteries were treated by conservative therapy. While continuing medical treatment for RA, the patient recovered and was discharged to a rehabilitation hospital. Conclusion Considering that RA-induced vasculitis can be a potential risk of vascular complications including multiple arterial dissections, physicians should carefully perform endovascular interventional procedures for patients with long-term RA.

We investigate the clinical utility of the lactate/albumin (L/A) ratio as an early prognostic marker of ICU mortality in a large cohort of unselected critically ill patients.A retrospective single-center study using data from the Multiparameter Intelligent Monitoring Intensive Care III (MIMIC-III) database collected between 2001 and 2012. We screened adult patients (age ≥ 15) with measured lactate and albumin on the first day of ICU stay to evaluate the prognostic performance of the lactate and lactate/albumin (L/A) ratio for ICU mortality prediction.The overall ICU mortality in the 6414 eligible ICU patients was 16.4%. L/A showed a receiver-operating characteristics area under the curve (ROC-AUC) value of 0.69 (95% CI: 0.67, 0.70) to predict ICU mortality, higher than lactate 0.67 (95%CI: 0.65, 0.69). Regardless of the lactate level, L/A yielded better ROC-AUC compared to the lactate level [normal lactate (2.0 mmol/L): 0.63 vs 0.60; intermediate lactate (2.0 mmol/L ≤ lactate4.0 mmol/L): 0.58 vs 0.56; high lactate (≥4.0 mmol/L): 0.67 vs 0.66]. L/A was a better prognostic marker for ICU mortality in patients with decreased lactate elimination [hepatic dysfunction: 0.72 vs 0.70; renal dysfunction 0.70 vs 0.68]. The L/A ratio ROC-AUC was better in patients with sepsis (0.68 vs 0.66) and those who developed severe sepsis or septic shock (0.68 vs 0.66).The performance of L/A and lactate were equivalent in predicting ICU mortality and can be used as early prognostic markers for ICU patients with different initial lactate level and the presence of hepatic or renal dysfunction.

Erdheim-Chester disease (ECD) is a non-Langerhans form of histiocytosis that occurs in systemic organs, such as bone, the central nervous system, cardiovascular system, lungs, and kidneys. We report the case of a 68-year-old woman with a cranial pharyngeal tumor and a bone lesion in the tibia. The case was diagnosed as ECD. Pathological analysis showed the typical feature of foamy macrophage accumulation. The macrophages were positive for CD68, and negative for CD1a and S100. The BRAF V600E mutation was identified. In addition, immunohistochemistry was performed for the detailed characterization of the macrophages. The macrophages had low proliferative activity and an M2-like phenotype, and they expressed colony-stimulating factor-1 receptor (CSF1R) on the cell surface.

On May 13, 2020, the Wisconsin Supreme Court declared the state's Safer at Home Emergency Order (https://evers.wi.gov/Documents/COVID19/EMO28-SaferAtHome.pdf) "unlawful, invalid, and unenforceable,"* thereby increasing opportunities for social and business interactions. By mid-June, Winnebago County,† Wisconsin experienced an increase in the number of infections with SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), with the largest increase among persons aged 18-23 years (young adults) (1). This age group§ accounts for 12.5% of the population in the county. To identify factors that influence exposure to COVID-19 among young adults in Winnebago County, characteristics of COVID-19 cases and drivers of behaviors in this age group were examined. During March 1-July 18, 2020, 240 young adults received positive SARS-CoV-2 test results, accounting for 32% of all Winnebago County cases. In 30 key informant interviews, most interviewees reported exposure to misinformation, conflicting messages, or opposing views about the need for and effectiveness of masks. Thirteen young adults described social or peer pressure to not wear a mask and perceived severity of disease outcome for themselves as low but high for loved ones at risk. Having low perceived severity of disease outcome might partly explain why, when not in physical contact with loved ones at risk, young adults might attend social gatherings or not wear a mask (2). Exposure to misinformation and unclear messages has been identified as a driver of behavior during an outbreak (3,4), underscoring the importance of providing clear and consistent messages about the need for and effectiveness of masks. In addition, framing communication messages that amplify young adults' responsibility to protect others and target perceived social or peer pressure to not adhere to public health guidance might persuade young adults to adhere to public health guidelines that prevent the spread of COVID-19.

Background Following initiation of MDR-TB treatment, patients have a choice to receive follow up DOT supervision at either the central initiating facility or at a peripheral facility. Objectives We describe the adherence patterns of MDR-TB patients undergoing DOT supervision at the two health facility categories during intensive phase of treatment. Methods We used a retrospective cohort of patients initiated on MDR TB treatment at Mulago National Referral Hospital between 2014 and 2016. We extracted data from the National Tuberculosis and Leprosy Program records and analysed these using STATA V14. Result Majority (84.01%) of the patients received their DOT supervision from the peripheral facilities. Males made up 62.1% of patients, and 91.2% had had their household contacts screened for MDR-TB. 26.5% of the patients on peripheral DOT supervision had good adherence to treatment protocol compared to 0% among patients on central initiating health facility DOT supervision. Among the patients with good adherence, 24.1% had contacts screened for MDR-TB as compared to 3.6% with poor adherence. Conclusion More patients preferred MDR-TB DOT supervision at peripheral facilities, which had better adherence to the treatment protocol compared to the central initiating facility. Younger people and those with household contacts screened had better adherence to the treatment protocol, highlighting areas for targeted interventional programs for MDR-TB in resource limited settingsMore patients preferred MDR-TB DOT supervision at peripheral facilities, which had better adherence to the treatment protocol compared to the central initiating facility. Younger people and those with household contacts screened had better adherence to the treatment protocol, highlighting areas for targeted interventional programs for MDR-TB in resource limited settings.

This study aimed to explore the genetic alterations and to identify good responders in the experimental arm in the tumor samples from newly diagnosed glioblastoma (GBM) patients enrolled in JCOG0911; a randomized phase II trial was conducted to compare the efficacy of interferonβ (IFNβ) plus temozolomide (TMZ) with that of TMZ alone. Of 122 tumors, we performed deep targeted sequencing to determine the somatic mutations, copy number variations, and tumor mutation burden; pyrosequencing for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation; Sanger sequencing for the telomerase reverse transcriptase (TERT) promoter; and microsatellite instability (MSI) testing in 95, 91, 91 and 72 tumors, respectively. We performed a multivariable Cox regression analysis using backward stepwise selection of variables including clinical factors (sex, age, performance status, residual tumor after resection, tumor location) and genetic alterations. Deep sequencing detected an IDH1 mutation in 13 tumors (14%). The MGMT promoter methylation by quantitative pyrosequencing was observed in 41% of the tumors. A mutation in the TERT promoter was observed in 69% of the tumors. While high tumor mutation burden (> 10 mutations per megabase) was seen in four tumors, none of the tumors displayed MSI-high. The clinical and genetic factors considered as independent favorable prognostic factors were gross total resection (hazard ratio [HR]: 0.49, 95% confidence interval, 0.30–0.81, P = 0.0049) and MGMT promoter methylation (HR: 0.43, 0.21–0.88, P = 0.023). However, tumor location at the temporal lobe (HR: 1.90, 1.22–2.95, P = 0.0046) was an independent unfavorable prognostic factor. No predictive factors specific to the TMZ + IFNβ + Radiotherapy (RT) group were found. This additional sub-analytical study of JCOG0911 among patients with newly diagnosed GBM showed that tumor location at the temporal lobe, gross total resection, and MGMT promoter methylation were significant prognostic factors, although no factors specific to IFNβ addition were identified.

Glioblastoma multiforme (GBM), a lethal brain tumor developing in the white matter of the adult brain, contains a small population of GBM stem cells (GSCs), which potentially cause chemotherapeutic resistance and tumor recurrence. However, the mechanisms underlying the pathogenesis and maintenance of GSCs remain largely unknown. A recent study reported that incorporation of ribosomes and ribosomal proteins into somatic cells promoted lineage trans‐differentiation toward multipotency. This study aimed to investigate the mechanism underlying stemness acquisition in GBM cells by focusing on 40S ribosomal protein S6 (RPS6). RPS6 was significantly upregulated in high‐grade glioma and localized at perivascular, perinecrotic, and border niches in GBM tissues. siRNA‐mediated RPS6 knock‐down significantly suppressed the characteristics of GSCs, including their tumorsphere potential and GSC marker expression; STAT3 was downregulated in GBM cells. RPS6 overexpression enhanced the tumorsphere potential of GSCs and these effects were attenuated by STAT3 inhibitor (AG490). Moreover, RPS6 expression was significantly correlated with SOX2 expression in different glioma grades. Immunohistochemistry data herein indicated that RPS6 was predominant in GSC niches, concurrent with the data from IVY GAP databases. Furthermore, RPS6 and other ribosomal proteins were upregulated in GSC‐predominant areas in this database. The present results indicate that, in GSC niches, ribosomal proteins play crucial roles in the development and maintenance of GSCs and are clinically associated with chemoradioresistance and GBM recurrence., We evaluated ribosomal protein S6 (RPS6) that has important roles in developing glioblastoma stem‐like cells. RPS6‐positive cells were highly expressed in glioblastoma stem‐like cell dominant areas. Also, we tested the RPS6 regulated stem cell properties of glioblastoma stem‐like cells. These findings are a break‐through in targeting therapy for ribosomal proteins to downregulate stem cell properties in glioblastoma.

Objective The MD Anderson Symptom Inventory for Brain Tumor (MDASI-BT) module is a widely used instrument for measuring symptom burden and interference of daily activities in brain tumor patients. This study aims to develop and validate its Japanese version (MDASI-BT-Japanese). Methods Following forward and backward translation of the original MDASI-BT into Japanese, understandability and feasibility were assessed by cognitive debriefing. Subsequently, patients with brain tumors were asked to fill out MDASI-BT-Japanese and European Quality of Life-5 Dimensions (EQ-5D). Feasibility, reliability and validity of MDASI-BT-Japanese were assessed. Results Cognitive debriefing confirmed overall ease of completion and good understandability. The study population composed of 140 patients with brain tumors (most commonly gliomas). The mean symptom severity score and mean interference score were 1.9 ± 1.7 and 2.8 ± 2.7, respectively. The top items included distress and drowsiness for symptom severity and general activity and work for interference. The median time required was 4 minutes (range, 0.5–30), and missing values were seen in 1%. Internal consistency was proven by excellent Cronbach’s coefficient alpha (0.94 for symptom severity, 0.92 for interference). Test–retest reliability was assessed with acceptable intra-class correlation coefficient (mean, 0.76). Correlation efficient ranged between 0.7 and 0.9 for convergent validity. Known-group validity was confirmed by significantly different mean symptom severity score and mean interference score among patients with different performance status. As evidence of concurrent validity, MDASI-BT-Japanese correlated with EQ-5D in the hypothesized magnitude and direction. Conclusions The newly developed MDASI-BT-Japanese has demonstrated feasibility, reliability and validity in evaluation of clinical benefit in Japanese-speaking brain tumor patients.

BCORL1 encodes a transcriptional corepressor homolog to BCOR. BCORL1 rearrangements have been previously described as rare events, and among them, CREBBP-BCORL1 has been reported only in 2 cases of ossifying fibromyxoid tumors. Herein, we present the first case of diffusely infiltrating glioma with CREBBP-BCORL1 involving a 17-year-old female patient. Histologically, the tumor was composed of a diffusely infiltrative proliferation of small tumor cells with moderate cellularity showing prominent microcystic formation. DNA methylation analysis revealed that the current case and a previously reported anaplastic ependymoma with EP300-BCORL1 were clustered together in close proximity to but distinct from methylation class high-grade neuroepithelial tumor with BCOR alteration. RNA sequencing demonstrated high mRNA expression of not only BCORL1 but BCOR, and the latter was compatible with diffuse nuclear expression of BCOR detected by immunohistochemistry. Our findings suggest that central nervous system tumors with CREBBP/EP300-BCORL1 may exhibit diverse morphologies but form a distinct DNA methylation group and that BCORL1 fusion genes may lead to upregulation of both BCOR and BCORL1.

To investigate the features associated with rapid growth of vestibular schwannoma using radiomics analysis on magnetic resonance imaging (MRI) together with clinical factors.From August 2005 to February 2019, 67 patients with vestibular schwannoma underwent contrast-enhanced T1-weighted MRI at least twice as part of their diagnosis. After excluding 3 cases with an extremely short follow-up period of 15 days or less, 64 patients were finally enrolled in this study. Ninety-three texture features were extracted from the tumor image data using 3D Slicer software (http://www.slicer.org/). We determined the texture features that significantly affected maximal tumor diameter growth of more than 2 mm/year using Random Forest and Bounty. We also analyzed age and tumor size as clinical factors. We calculated the areas under the curve (AUCs) using receiver operating characteristic analysis for prediction models using texture, clinical, and mixed factors by Random Forest and 5-fold cross-validation.Two texture features, low minimum signal and high inverse difference moment normalized (Idmn), were significantly associated with rapid growth of vestibular schwannoma. The mixed model of texture features and clinical factors offered the highest AUC (0.69), followed by the pure texture (0.67), and pure clinical (0.63) models. The minimum signal was the most important variable followed by tumor size, Idmn, and age.Our radiomics analysis found that texture features were significantly associated with the rapid growth of vestibular schwannoma in contrast-enhanced T1-weighted images. The mixed model offered a higher diagnostic performance than the pure texture or clinical models.

Background The End TB Strategy aims to reduce new tuberculosis (TB) cases by 90% and TB-related deaths by 95% between 2015 – 2035. We determined the trend of case notification rates (CNRs) and treatment outcomes of TB cases with and without HIV co-infection in rural Uganda to provide an interim evaluation of progress towards this global target in rural settings. Methods We extracted retrospective programmatic data on notified TB cases and treatment outcomes from 2015 – 2019 for eight districts in rural Uganda from the District Health Information System 2. We estimated CNRs as the number of TB cases per 100,000 population. Treatment success rate (TSR) was calculated as the sum of TB cure and treatment completion for each year. Trends were estimated using the Mann–Kendall test. Results A total of 11,804 TB cases, of which 5,811 (49.2%) were HIV co-infected, were notified. The overall TB CNR increased by 3.7-fold from 37.7 to 141.3 cases per 100,000 population in 2015 and 2019 respectively. The increment was observed among people with HIV (from 204.7 to 730.2 per 100,000, p = 0.028) and HIV-uninfected individuals (from 19.9 to 78.7 per 100,000, p = 0.028). There was a decline in the TSR among HIV-negative TB cases from 82.1% in 2015 to 63.9% in 2019 (p = 0.086). Conversely, there was an increase in the TSR among HIV co-infected TB cases (from 69.9% to 81.9%, p = 0.807). Conclusion The CNR increased among people with and without HIV while the TSR reduced among HIV-negative TB cases. There is need to refocus programs to address barriers to treatment success among HIV-negative TB cases.

Endovascular treatment is the preferred treatment for acute ischemic stroke (AIS) due to main artery steno-occlusive disease, but it has temporal and technical limitations. Moreover, there is no established treatment for progressive stroke. Superficial temporal artery (STA)-middle cerebral artery (MCA) bypass is sometimes considered as a treatment option.The objective of this paper is to review the treatment outcomes of patients with AIS undergoing urgent STA-MCA bypass.This was a retrospective study including 32 patients diagnosed with AIS treated with urgent STA-MCA bypass at our facility. The patients had small infarct volumes and a large diffusion-perfusion mismatch.New ischemic lesions in postoperative diffusion-weighted images were detected in 15 patients (46.9%), but only four (12.5%) developed paralysis. Hyperperfusion occurred in nine patients (28.1%), and five (15.6%) had bypass occlusion at 1 week. Delayed wound healing were found in four patients (12.5%). Neurological outcome was measured 3 months after onset: Manual Muscle Testing (MMT), 3-5 in 27 patients (84.4%); modified Rankin scale (mRS), 0-2 in 17 patients (53.1%); and 0-3 in 26 patients (81.3%). Prognosis was better in patients who underwent surgery after 24 h of stroke onset (mRS, 0-2 in 56.0% cases and 0-3 in 88.0% at 3 months). Statistical analyses revealed that MMT before surgery had a significant association with favorable outcomes (P = 0.041).Urgent STA-MCA bypass for progressive stroke may result in a good prognosis if the right patients are selected and may play an important role in cases treated 24 h after onset in whom endovascular treatment is ineffective.

The characteristic features of plasticity and heterogeneity in glioblastoma (GB) cells cause therapeutic difficulties. GB cells are exposed to various stimuli from the tumor microenvironment and acquire the potential to resist chemoradiotherapy. To investigate how GB cells acquire stem cell-like phenotypes, we focused on ribosomal proteins, because ribosome incorporation has been reported to induce stem cell-like phenotypes in somatic cells. Furthermore, dysregulation of ribosome biogenesis has been reported in several types of cancer. We focused on ribosomal protein S6, which promotes sphere-forming ability and stem cell marker expression in GB cells. We expect that investigation of dysregulation of ribosome biogenesis and extra-ribosomal function in GB will provide new insights about the plasticity, heterogeneity, and therapeutic resistance of GB cells, which can potentially lead to revolutionary therapeutic strategies.

Tenofovir disoproxil fumarate (TDF) and intramuscular depot medroxyprogesterone acetate (DMPA-IM) are independently associated with reduced bone mineral density (BMD). We aimed to assess the combined effects of DMPA-IM use and TDF initiation on BMD in young adult women living with HIV over two years, compared with age-matched people without HIV.Th BONE: CARE study was a prospective cohort study that recruited women aged 18-35 years from 11 HIV care and general health facilities in Kampala, Uganda. The participants were classified into four groups on the basis of their combination of HIV status, TDF use, and DMPA-IM use, as follows: women living with HIV initiating TDF-containing antiretroviral therapy (ART) with DMPA-IM (HIV positive, DMPA positive, and TDF positive); women living with HIV using DMPA-IM but not eligible for ART as per local guidelines at the time of enrolment into the study (HIV positive, DMPA positive, and TDF negative); women living with HIV initiating TDF-containing ART without DMPA-IM (HIV positive, DMPA negative, and TDF positive); and controls without HIV using non-hormonal contraceptives (HIV negative, DMPA negative, and TDF negative). BMD of the lumbar spine, total hip, and femoral neck were measured using semiannual dual-energy x-ray absorptiometry at enrolment and at intervals every 6 months thereafter. We assessed percentage change in mean BMD.Between March 30, 2016, and Oct 19, 2017, we enrolled 265 women living with HIV initiating ART (159 DMPA-IM users and 106 non-hormonal contraceptive users), 187 women living with HIV using DMPA-IM but not ART, and 69 controls without HIV. Mean age was 26·1 years (SD 4·2). BMD declined significantly from baseline in women living with HIV on TDF with versus without DMPA-IM at the lumbar spine (-3·406% [95% CI -3·969 to -2·844] vs -1·111% [-1·929 to -0·293]; p0·0001), total hip (-3·856% [-4·449 to -3·264] vs -1·714% [-2·479 to -0·949]; p=0·0002), and femoral neck (-4·422% [-5·078 to -3·766] vs -1·999% [-3·022 to -0·976]; p=0·0002), increased in controls at the lumbar spine (1·5% change), and remained unchanged at total hip and femoral neck (-0·1% change). Concurrent use of TDF and DMPA-IM resulted in significantly greater BMD decline (p0·0001) than TDF alone (lumbar spine -2·677% [95% CI -3·743 to -1·611]; p0·0001; total hip -2·518% [-3·575 to -1·461]; p0·0001; and femoral neck -2·907 [-4·132 to -1·683]; p0·0001) or than controls (lumbar spine -4·970% [-6·391 to -3·549]; p0·0001; total hip -4·151% [-5·579 to -2·724]; p0.0001; and femoral neck -4·773% [-6·424 to -3·122]; p0·0001) INTERPRETATION: Concomitant DMPA-IM use resulted in a doubling of BMD loss in women living with HIV initiating TDF-containing ART. Identification of safer contraceptive and bone-sparing ART options should be prioritised for optimal care of women living with HIV.National Institute of Allergy and Infectious Diseases of the US National Institutes of Health.

Several important revisions were made regarding the classification of brain tumors in the newest version(5th edition)of the WHO classification of tumours of the central nervous system published in 2021. Now, most so-called "lower-grade glioma(s)" fall into the category of IDH-mutant diffuse glioma, represented by astrocytoma and oligodendroglioma. For the diagnosis of these IDH-mutant gliomas, the determination of genetic alterations in

Substance use is increasing throughout Africa, with the prevalence of alcohol, tobacco, cannabis, and other substance use varying regionally. Concurrently, sub-Saharan Africa bears the world’s largest HIV burden, with 71% of people living with HIV (PWH) living in Africa. Problematic alcohol, tobacco, and other substance use among PWH is associated with multiple vulnerabilities comprising complex behavioral, physiological, and psychological pathways that include high-risk behaviors (e.g., sexual risk-taking), HIV disease progression, and mental health problems, all of which contribute to nonadherence to antiretroviral therapy. Physiologically, severe substance use disorders are associated with increased levels of biological markers of inflammation; these, in turn, are linked to increased mortality among PWH. The biological mechanisms that underlie the increased risk of substance use among PWH remain unclear. Moreover, the biobehavioral mechanisms by which substance use contributes to adverse health outcomes are understudied in low- and middle-income countries (LMIC). Syndemic approaches to understanding the co-occurrence of substance use and HIV have largely been limited to high-income countries. We propose a syndemic coupling conceptual model to disentangle substance use from vulnerabilities to elucidate underlying disease risk for PWH. This interventionist perspective enables assessment of biobehavioral mechanisms and identifies malleable targets of intervention.

Two phase 3 clinical trials showed that use of a monthly vaginal ring containing 25 mg dapivirine was well tolerated and reduced HIV-1 incidence in women by approximately 30% compared with placebo. We aimed to evaluate use and safety of the dapivirine vaginal ring (DVR) in open-label settings with high background rates of HIV-1 infection, an important step for future implementation.We did a phase 3B open-label extension trial of the DVR (MTN-025/HIV Open-label Prevention Extension [HOPE]). Women who were HIV-1-negative and had participated in the MTN-020/ASPIRE phase 3 trial were offered 12 months of access to the DVR at 14 clinical research centres in Malawi, South Africa, Uganda, and Zimbabwe. At each visit (monthly for 3 months, then once every 3 months), women chose whether or not to accept the offer of the ring. Used, returned rings were tested for residual amounts of dapivirine as a surrogate marker for adherence. HIV-1 serological testing was done at each visit. Dapivirine amounts in returned rings and HIV-1 incidence were compared with data from the ASPIRE trial, and safety was assessed. This study is registered with ClinicalTrials.gov, NCT02858037.Between July 16, 2016, and Oct 10, 2018, of 1756 women assessed for eligibility, 1456 were enrolled and participated in the study. Median age was 31 years (IQR 27-37). At baseline, 1342 (92·2%) women chose to take the DVR; ring acceptance was more than 79% at each visit up until 12 months and 936 (73·2%) of 1279 chose to take the ring at all visits. 12 530 (89·3%) of 14 034 returned rings had residual dapivirine amounts consistent with some use during the previous month (0·9 mg released) and the mean dapivirine amount released was greater than in the ASPIRE trial (by 0·21 mg; p0·0001). HIV-1 incidence was 2·7 per 100 person-years (95% CI 1·9-3·8, 35 infections), compared with an expected incidence of 4·4 per 100 person-years (3·2-5·8) among a population matched on age, site, and presence of a sexually transmitted infection from the placebo group of ASPIRE. No serious adverse events or grade 3 or higher adverse events observed were assessed as related to the DVR.High uptake and persistent use in this open-label extension study support the DVR as an HIV-1 prevention option for women. With an increasing number of HIV-1 prophylaxis choices on the horizon, these results suggest that the DVR will be an acceptable and practical option for women in Africa.The Microbicide Trials Network and the National Institute of Allergy and Infectious Diseases, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health, all components of the US National Institutes of Health.

Spinal arteriovenous (AV) shunts are rare conditions that sometimes present with myelopathy symptoms. The progression of the symptoms is usually gradual; however, some cases show rapid deterioration. We retrospectively investigated the factors that induced the rapid deterioration of myelopathy symptoms in patients with spinal AV shunts. We treated 33 patients with myelopathy with spinal AV shunts at our institutions, eight of whom experienced rapid deterioration (within 24 hours: 24.2%). Of these, three were related to the body movement or particular postures associated with playing golf, 30 minutes of Japanese straight sitting, and massage care. One patient showed deterioration after embolization for a tracheal aneurysm. The remaining four patients received steroid pulse therapy (high-dose steroid infusion) shortly before the rapid deterioration. These symptoms stopped progressing after cessation of steroid use. While positional or physical factors contributing to myelopathy deterioration might exist, we could not identify specific factors in this study. Nevertheless, rapid deterioration was frequently observed after high-dose steroid use. We must take care not to administer high-dose steroids for myelopathy caused by spinal AV shunt disease.

Background Central nervous system (CNS) germ cell tumors (GCTs) are neoplasms predominantly arising in pediatric and young adult populations. While germinomas generally respond to chemotherapy and radiation, non-germinomatous GCTs (NGGCTs) require more intensive treatment. This study aimed to determine whether 12p gain could predict the prognosis of CNS GCTs. Methods Eighty-two CNS GCTs were included in this study. The 12p gain was defined by an additional 12p in the background of potential polyploidy or polysomy. Cases were analyzed using an Illumina methylation 450K array for copy number investigations and validated by fluorescence in situ hybridization (FISH). Results A 12p gain was found in 25-out-of-82 cases (30%) and was more frequent in NGGCTs (12% of germinoma cases and 50% of NGGCT cases), particularly in cases with malignant components, such as immature teratoma, yolk sac tumor, choriocarcinoma, and embryonal carcinoma. 12p gain and KIT mutation were mutually exclusive events. The presence of 12p gain correlated with shorter progression-free (PFS) and overall survival (OS) (10-year OS: 59% vs. 94%, with and without 12p gain, respectively, P = 0.0002), even with histology and tumor markers incorporated in the multivariate analysis. Among NGGCTs, 12p gain still had prognostic significance for PFS and OS (10-year OS: 47% vs. 90%, respectively, P = 0.02). The 12p copy number status was shared among histological components in mixed GCTs. Conclusions 12p gain may predict the presence of malignant components of NGGCTs, and poor prognosis of the patients. It may be associated with early tumorigenesis of CNS GCT.

Background Gender differences among patients with drug resistant tuberculosis (DRTB) and HIV co-infection could affect treatment outcomes. We compared characteristics and treatment outcomes of DRTB/HIV co-infected men and women in Uganda. Methods We conducted a retrospective chart review of patients with DRTB from 16 treatment sites in Uganda. Eligible patients were aged ≥ 18 years, had confirmed DRTB, HIV co-infection and a treatment outcome registered between 2013 and 2019. We compared socio-demographic and clinical characteristics and tuberculosis treatment outcomes between men and women. Potential predictors of mortality were determined by cox proportional hazard regression analysis that controlled for gender. Statistical significance was set at p Results Of 666 DRTB/HIV co-infected patients, 401 (60.2%) were men. The median (IQR) age of men and women was 37.0 (13.0) and 34.0 (13.0) years respectively (p 3 increment). Conclusion Mortality was higher among men than women with DRTB/HIV co-infection which could be explained by several sociodemographic and clinical differences.

The Hepatitis B virus (HBV) is a highly infectious virus and is endemic in Uganda. It is one of the major etiological agents for liver diseases including liver cancer. In this work, we evaluated the prevalence of the HBV serological markers and the associated socio-demographic factors among hepatitis B surface antigen (HBsAg) seronegative persons screened during routine immunization against the virus in eastern Uganda. Data on the socio-demographic characteristics were collected using a structured questionnaire, while that on the serological markers were obtained from serum samples and evaluated by using the 5-panel HBV One Step Hepatitis B Virus Combo Test Device (FastepR, HBV-P43M). The following markers were evaluated by the panel: HBsAg, HBsAb, HBcAb, and HBeAb. Data were analyzed using SPSS (version 26), and multinomial logistic regression was used to elicit the adjusted odds ratio. All the analysis were performed at a 95% confidence limit, and a P value ≤ 0.05 was considered significant. The 424 participants included in this study were mainly female (62.3%), married (55.4%) and aged 30 years and above (54.2%). The seropositivity of the HBsAb, HBeAb, HBcAb marker prevalence rates was 48(11.3%), 73(17.2%) and 45(10.6%) respectively. The majority of the participants (327, 77.1%) did not present with any marker. Married paricipants were significantly associated with reduced HBsAb seropositvity rate, whereas young people aged 18–29 years were associated the with increased odds of HBsAb seropositivity (p

Although glioblastoma (GBM) stem-like cells (GSCs), which retain chemo-radio resistance and recurrence, are key prognostic factors in GBM patients, the molecular mechanisms of GSC development are largely unknown. Recently, several studies revealed that extrinsic ribosome incorporation into somatic cells resulted in stem cell properties and served as a key trigger and factor for the cell reprogramming process. In this study, we aimed to investigate the mechanisms underlying GSCs development by focusing on extrinsic ribosome incorporation into GBM cells. Ribosome-induced cancer cell spheroid (RICCS) formation was significantly upregulated by ribosome incorporation. RICCS showed the stem-like cell characters (number of cell spheroid, stem cell markers, and ability for trans differentiation towards adipocytes and osteocytes). In RICCS, the phosphorylation and protein expression of ribosomal protein S6 (RPS6), an intrinsic ribosomal protein, and STAT3 phosphorylation were upregulated, and involved in the regulation of cell spheroid formation. Consistent with those results, glioma-derived extrinsic ribosome also promoted GBM-RICCS formation through intrinsic RPS6 phosphorylation. Moreover, in glioma patients, RPS6 phosphorylation was dominantly observed in high-grade glioma tissues, and predominantly upregulated in GSCs niches, such as the perinecrosis niche and perivascular niche. Those results indicate the potential biological and clinical significance of extrinsic ribosomal proteins in GSC development.

Cleidocranial dysplasia (CCD) is an autosomal dominant hereditary disease associated with the gene RUNX2. Disease-specific induced pluripotent stem cells (iPSCs) have emerged as a useful resource to further study human hereditary diseases such as CCD. In this study, we identified a novel CCD-specific RUNX2 mutation and established iPSCs with this mutation. Biopsies were obtained from familial CCD patients and mutation analyses were performed through Sanger sequencing and next generation sequencing. CCD-specific human iPSCs (CCD-hiPSCs) were established and maintained under completely defined serum, feeder, and integration-free condition using a non-integrating replication-defective Sendai virus vector. We identified the novel mutation RUNX2_c.371CG and successfully established CCD-hiPSCs. The CCD-hiPSCs inherited the same mutation, possessed pluripotency, and showed the ability to differentiate the three germ layers. We concluded that RUNX2_c.371CG was likely pathogenic because our results, derived from next generation sequencing, are supported by actual clinical evidence, familial tracing, and genetic data. Thus, we concluded that hiPSCs with a novel CCD-specific RUNX2 mutation are viable as a resource for future studies on CCD.

Background Many HIV-positive patients do not appropriately adhere to their antiretroviral medication (ART). This leads to higher viral loads and greater probability of HIV transmission. Present bias—a tendency to give in to short-term temptations at the expense of long-term outcomes—is a potential driver of low adherence. In this study we test a novel intervention rooted in behavioral economics that is designed to overcome present bias and increase ART adherence. Methods/design We will enroll 330 HIV-positive patients at Mildmay Hospital in Kampala, Uganda, into a 2-year randomized controlled trial. Participants will be randomized to one of three groups. The first intervention group (T1, n = 110) will be eligible for small lottery prizes based on timely clinic visits and demonstration of viral suppression. Group 2 (T2, n = 110) will be eligible for the same lottery prizes conditional on high adherence measured by a medication event management system (MEMS) cap. The control group (n = 110) will receive the usual standard of care. Adherence will be measured continuously throughout the intervention period and for 12 months post-intervention to evaluate effect persistence. Surveys will be conducted at baseline and then every 6 months. Viral loads will be measured annually. Primary outcomes are whether the viral load is detectable and MEMS-measured adherence. Secondary outcomes are the log-transformed viral load as a continuous measure and a binary measure for whether the person took at least 90% of their ART pills. Discussion Our study is one of the first to investigate the effectiveness of lottery incentives for improving ART adherence, and in addition, it compares the relative efficacy of using electronically measured adherence versus viral load to determine lottery eligibility. MEMS caps are relatively costly, whereas viral load testing is now part of routine clinical care in Uganda. BEST will test whether directly incentivizing viral suppression (which can be implemented using readily available clinic data) is as effective as incentivizing electronically measured adherence. Cost-effectiveness analyses of the two implementation modes will also be performed. Trial registration ClinicalTrials.gov, NCT03494777. Registered on 11 April 2018.

Medical micro/nanorobots have received tremendous attention over the past decades owing to their potential to be navigated into hard-to-reach tissues for a number of biomedical applications ranging from targeted drug/gene delivery, bio-isolation, detoxification, to nanosurgery. Despite the great promise, the majority of the past demonstrations are primarily under benchtop or in vitro conditions. Many developed micro/nanoscale propulsion mechanisms are based on the assumption of a homogeneous, Newtonian environment, while realistic biological environments are substantially more complex. Moving toward practical medical use, the field of micro/nanorobotics must overcome several major challenges including propulsion through complex media (such as blood, mucus, and vitreous) as well as deep tissue imaging and control in vivo. In this review article, we summarize the recent research efforts on investigating how various complexities in biological environments impact the propulsion of micro/nanoswimmers. We also highlight the emerging technological approaches to enhance the locomotion of micro/nanorobots in complex environments. The recent demonstrations of in vivo imaging, control and therapeutic medical applications of such micro/nanorobots are introduced. We envision that continuing materials and technological innovations through interdisciplinary collaborative efforts can bring us steps closer to the fantasy of "swallowing a surgeon".

As a result of rapid progress in genome medicine technologies, such as the evolution of DNA sequencing and the development of molecular targeted drugs, the era of precision cancer medicine has begun. In 2019, a nationwide genome medicine system was established and cancer gene panel sequencing began being covered by national health insurance in Japan. However, patients with brain tumors have not benefited much from genome medicine, even though gliomas contain many potential molecular targets, such as alterations in EGFR, IDH1/2, BRAF, and Histone H3K27. Targeted therapies for these molecules are currently under enthusiastic development; however, such attempts have not yet achieved remarkable success. To date, only a limited number of targeted drugs for brain tumors such as immune checkpoint, neurotrophic tyrosine receptor kinase (NTRK), and Bruton tyrosine kinase (BTK) inhibitors are available, and only in limited cases. Several obstacles remain in the development of drugs to treat brain tumors, including the difficulties in conducting clinical trials because of the relatively rare incidence and in drug delivery through the blood-brain barrier (BBB). Furthermore, general problems for numerous types of cancer, such as tumor heterogeneity, also exist for brain tumors. We hope that overcoming these issues could enable precision genome medicine to be more beneficial for patients with brain tumors such as malignant gliomas. In addition, careful consideration of ethical, legal, and social issues (ELSIs) is important as it is indispensable for maintaining good relationships with patients, which is one of the keys for genome medicine promotion.

Although Alzheimer's disease (AD) is associated with an increased risk of intracerebral hemorrhage (ICH) caused by hypertension and cerebral amyloid angiopathy, the precise clinical course after hypertensive ICH in AD patients is still unknown. In this study, we investigated how striatal ICH, a frequent site for hypertensive ICH, affected the prognosis of AD. We employed 17- and 18-month-old male 5XFAD (5X) mice and littermate (LT) controls, and striatal ICH was induced by collagenase injection. First, to address the acute effects of ICH on 5X mice, hemorrhagic volume and brain edema were evaluated 3 days after ICH. Next, to address the long-term effects of ICH on 5X mice, morbidity, mortality, neurological function (beam-walking and rotarod tests), and cognitive function (Y-maze and nest-building tests) were monitored. Twenty-eight days later, the animals were euthanized, their brains were isolated, and the cytotoxic alterations were investigated. The results revealed that the acute effects of ICH were not significantly different between 5X and LT mice. In contrast, 5X mice showed significantly higher morbidity and mortality in response to ICH, as well as delayed neurological function recovery, compared to LT mice through 28 days. ICH did not affect cognitive function in either group. Infiltrated macrophages in the perihemorrhagic cortex, gp91phox , p67phox , and COX-2 were significantly increased in 5X mice in response to ICH. We demonstrated that striatal ICH deteriorated prognosis and delayed neurofunctional recovery in 5X mice, which might be associated with enhanced oxidative stress in the presence of AD-like pathology.

A series of recent evidences suggested activated macrophages have broadly two distinct forms that possess opposite functions for the process of inflammation: classically activated macrophages (M1/kill macrophages) and alternatively activated macrophages (M2/repair macrophages) according to their functions and expression markers. To elucidate what roles those two phenotypes of macrophages play in the evolution of cerebral aneurysm, the presence of macrophages inside the aneurysm walls was assessed with an immunohistochemical approach. The portions of the aneurysm domes deflated after neck clipping were utilized for the further histological examinations, including immunostainings with five antibodies to identify macrophage subpopulations. In this study, contrary to the previous reports, the following various ratios of subtypes were observed in the aneurysm walls: M1 M2 (2 cases), M1 M2 (2 cases), M1 = M2 (3 cases). While M1-like macrophages have been typically regarded as a main driver of the degenerating process, these surprisingly richer presences of M2-like macrophages in the aneurysm walls suggests that an unrecognized biological process might be in play in aneurysm development.

Background Uganda has one of the largest unmet neurosurgical needs in the world, but has seen major improvements in neurosurgery—largely centered at Mulago National Referral Hospital (MNRH). This study implements the first long-term follow-up and outcomes analysis of central nervous system tumor patients in Uganda. Methods Inpatient data were collected using a prospective database of patients presenting to the MNRH neurosurgical ward between 2014 and 2015. Follow-up health care status was assessed in the patient's language using phone surveys. Analysis was performed to identify which factors were associated with patient outcomes. Results The MNRH neurosurgical ward saw 112 patients with central nervous system tumors (adult N = 87, female: 70%, median age: 37 years). Meningiomas (21%) comprised the most common tumor diagnosis. In-hospital mortality (18%), 30-day mortality (22%), and 1-year mortality (35%) were high. Thirty percent of patients underwent tumor resection in-patient and had greater median overall survival (66.5 months vs. 5.1 months for nonsurgical patients, P = 0.025). For those with known pathologic diagnoses, patients with glioblastomas had decreased median overall survival (0.83 months vs. 59 months for meningiomas, P = 0.02). Phone interviews yielded an 85% response rate. Of the survivors at the time of follow-up, 55% reported a subjective return to normalcy, and 75% received follow-up care for their tumor with most returning to MNRH. Conclusions We show evidence for improved overall survival with surgical care at MNRH. In addition, phone interviews as a method of measuring health outcomes provided an effective means of follow-up, showing that most patients do seek follow-up care.

Aims Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. Methods We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. Results Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). Conclusions The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.