The Impact of Scars After DIEP-Flap Breast Reconstruction on Satisfaction and HR-QoL: A Cross-Sectional Study Comparing BREAST-Q Scores.

BACKGROUND: Although deep inferior epigastric perforator (DIEP) flap breast reconstruction is the most widely used technique for autologous breast reconstruction, this technique leads to large scars in visible areas on breast and abdomen. So far, limited studies have thoroughly addressed the impact of breast and abdominal scars on satisfaction and Health-related Quality of Life (HR-QoL). OBJECTIVES: This research aimed to determine whether women with no/minor scar symptoms after undergoing DIEP-flap breast reconstruction differ in satisfaction and perceived HR-QoL from women with symptomatic scars. MATERIALS AND METHODS: In this cross-sectional survey study, women who had previously undergone DIEP-flap breast reconstruction completed an online survey. Patient-reported scar quality was assessed with the Patient and Observer Scar Assessment Scale (POSAS), and satisfaction and HR-QoL with BREAST-Q. Independent-samples t-tests were conducted to compare BREAST-Q scores between women with no/minor scar symptoms (POSAS overall opinion score 1-3) and women with symptomatic scars (POSAS overall opinion score 4-10). RESULTS: A total of 248 women completed the survey. Women with scar symptoms had significantly worse BREAST-Q scores on 'Satisfaction with breasts,' 'Physical well-being,' 'Psychosocial well-being' and, 'Sexual well-being' compared to women with no/minor scar symptoms (p ≤ 0.001). CONCLUSION: After DIEP-flap breast reconstructions, women with symptomatic breast and abdominal scars had a clinically relevant and statistically significant lower degree of satisfaction and HR-QoL compared to women who had no/minor scar symptoms. We therefore recommend to explicitly and repeatedly address inevitability of visible scars after DIEP-flap breast reconstruction, aiming to improve preoperative patient selection and post-operative expectation management. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Solid waste dumpsite leachate and contiguous surface water contain multidrug-resistant ESBL-producing Escherichia coli carrying Extended Spectrum ß-Lactamase (ESBL) genes.

Dumpsites generate leachates containing bacteria that may carry antibiotic resistance genes, such as extended spectrum ß-lactamase (ESBL). However, the contribution of dumpsite leachates in the environmental spread of ESBL genes has not been investigated in greater detail. This study aimed to quantify the impact of Ajakanga dumpsite leachate on the spread of ESBL genes through surface water. The susceptibility of Escherichia coli isolated from dumpsite leachate and the accompanying surface water to selected antibiotics was assessed by the standardized disc diffusion method. The isolates were evaluated for phenotypic ESBL production using the double disc synergy test (DDST). The detection of ESBL genes in the isolates was carried out using a primer-specific polymerase chain reaction (PCR). Escherichia coli isolates from leachate (n = 26/32) and surface water (n = 9/12) expressed ESBL phenotype. The ESBL-producing isolates showed the highest level of resistance to the 3rd generation cephalosporin antibiotics: cefotaxime (100%), cefpodoxime (97%), ceftazidime (97%), with low resistance observed to imipenem (6%) and azithromycin (3%). All the isolates were multidrug-resistant, showing resistance to three or more classes of antibiotics. All the ESBL-producing E. coli obtained carried blaCTX-M, 21/35 (60%) carried blaTEM while none of the isolates bore blaSHV. This study found that ESBL-producing Escherichia coli from dumpsite leachate and nearby surface water had identical resistance signatures indicating the relatedness of the isolates, and that dumpsite leachate could contribute to the transfer of ESBL-producing bacteria and their genes to receiving surface water. This study has necessitated the need for a review of the guidelines and operational procedures of dumpsites to forestall a potential public health challenge.

Lestaurtinib's antineoplastic activity converges on JAK/STAT signaling to inhibit advanced forms of therapy resistant ovarian cancer.

Ovarian cancer is the deadliest gynecological malignancy, owing to its late-stage diagnosis and high rates of recurrence and resistance following standard-of-care treatment, highlighting the need for novel treatment approaches. Through an unbiased drug screen, we identified the kinase inhibitor, lestaurtinib, as a potent antineoplastic agent for chemotherapy- and PARP-inhibitor (PARPi)-sensitive and -resistant ovarian cancer cells and patient derived xenografts (PDXs). RNA-sequencing revealed that lestaurtinib potently suppressed JAK/STAT signaling and lestaurtinib efficacy was shown to be directly related to JAK/STAT pathway activity in cell lines and PDX models. Most ovarian cancer cells exhibited constitutive JAK/STAT pathway activation and genetic loss of STAT1 and STAT3 resulted in growth inhibition. Lestaurtinib also displayed synergy when combined with cisplatin and olaparib, including in a model of PARPi resistance. In contrast, the most well-known JAK/STAT inhibitor, ruxolitinib, lacked antineoplastic activity against all ovarian cancer cell lines and PDX models tested. This divergent behavior was reflected in the ability of lestaurtinib to block both Y701/705 and S727 phosphorylation of STAT1 and STAT3, whereas ruxolitinib failed to block S727. Consistent with these findings, lestaurtinib additionally inhibited JNK and ERK activity, leading to more complete suppression of STAT phosphorylation. Concordantly, combinatorial treatment with ruxolitinib and a JNK or ERK inhibitor resulted in synergistic antineoplastic effects at dose levels where single agents were ineffective. Taken together, these findings indicate that lestaurtinib, and other treatments that converge on JAK/STAT signaling, are worthy of further pre-clinical and clinical exploration for the treatment of highly aggressive and advanced forms of ovarian cancer. Statement of significance: Lestaurtinib is a novel inhibitor of ovarian cancer, including chemotherapy- and PARPi-resistant models, that acts through robust inhibition of the JAK/STAT pathway and synergizes with standard-of-care agents at clinically relevant concentrations.

Facilitators of and Barriers to the Use of a Digital Self-Management Service for Diagnostic Testing: Focus Group Study With Potential Users.

BACKGROUND: Health care lags in digital transformation, despite the potential of technology to improve the well-being of individuals. The COVID-19 pandemic has accelerated the uptake of technology in health care and increased individuals' willingness to perform self-management using technology. A web-based service, Directlab Online, provides consumers with direct digital access to diagnostic test packages, which can digitally support the self-management of health. OBJECTIVE: This study aims to identify the facilitators, barriers, and needs of Directlab Online, a self-management service for web-based access to diagnostic testing. METHODS: A qualitative method was used from a potential user's perspective. The needs and future needs for, facilitators of, and barriers to the use of Directlab Online were evaluated. Semistructured focus group meetings were conducted in 2022. Two focus groups were focused on sexually transmitted infection test packages and 2 were focused on prevention test packages. Data analysis was performed according to the principles of the Framework Method. The Consolidated Framework for Implementation Research was used to categorize the facilitators and barriers. RESULTS: In total, 19 participants, with a mean age of 34.32 (SD 14.70) years, participated in the focus groups. Important barriers were a lack of privacy information, too much and difficult information, and a commercial appearance. Important facilitators were the right amount of information, the right kind of tests, and the involvement of a health care professional. The need for a service such as Directlab Online was to ensure its availability for users' health and to maintain their health. CONCLUSIONS: According to the participants, facilitators and barriers were comprehension of the information, the goal of the website, and the overall appearance of the service. Although the service was developed in cocreation with health care professionals and users, the needs did not align. The users preferred understandable and adequate, but not excessive, information. In addition, they preferred other types of tests to be available on the service. For future research, it would be beneficial to focus on cocreation between the involved medical professionals and users to develop, improve, and implement a service such as Directlab Online.

"Deficiency in ELF4, X-Linked": a Monogenic Disease Entity Resembling Behçet's Syndrome and Inflammatory Bowel Disease.

Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.

Digital Triage Tools for Sexually Transmitted Infection Testing Compared With General Practitioners' Advice: Vignette-Based Qualitative Study With Interviews Among General Practitioners.

BACKGROUND: Digital triage tools for sexually transmitted infection (STI) testing can potentially be used as a substitute for the triage that general practitioners (GPs) perform to lower their work pressure. The studied tool is based on medical guidelines. The same guidelines support GPs' decision-making process. However, research has shown that GPs make decisions from a holistic perspective and, therefore, do not always adhere to those guidelines. To have a high-quality digital triage tool that results in an efficient care process, it is important to learn more about GPs' decision-making process. OBJECTIVE: The first objective was to identify whether the advice of the studied digital triage tool aligned with GPs' daily medical practice. The second objective was to learn which factors influence GPs' decisions regarding referral for diagnostic testing. In addition, this study provides insights into GPs' decision-making process. METHODS: A qualitative vignette-based study using semistructured interviews was conducted. In total, 6 vignettes representing patient cases were discussed with the participants (GPs). The participants needed to think aloud whether they would advise an STI test for the patient and why. A thematic analysis was conducted on the transcripts of the interviews. The vignette patient cases were also passed through the digital triage tool, resulting in advice to test or not for an STI. A comparison was made between the advice of the tool and that of the participants. RESULTS: In total, 10 interviews were conducted. Participants (GPs) had a mean age of 48.30 (SD 11.88) years. For 3 vignettes, the advice of the digital triage tool and of all participants was the same. In those vignettes, the patients' risk factors were sufficiently clear for the participants to advise the same as the digital tool. For 3 vignettes, the advice of the digital tool differed from that of the participants. Patient-related factors that influenced the participants' decision-making process were the patient's anxiety, young age, and willingness to be tested. Participants would test at a lower threshold than the triage tool because of those factors. Sometimes, participants wanted more information than was provided in the vignette or would like to conduct a physical examination. These elements were not part of the digital triage tool. CONCLUSIONS: The advice to conduct a diagnostic STI test differed between a digital triage tool and GPs. The digital triage tool considered only medical guidelines, whereas GPs were open to discussion reasoning from a holistic perspective. The GPs' decision-making process was influenced by patients' anxiety, willingness to be tested, and age. On the basis of these results, we believe that the digital triage tool for STI testing could support GPs and even replace consultations in the future. Further research must substantiate how this can be done safely.

Factors Predicting Clinically Relevant Pain Relief After Spinal Cord Stimulation for Patients With Chronic Low Back and/or Leg Pain: A Systematic Review With Meta-Analysis and Meta-Regression.

RATIONALE: To optimize results with spinal cord stimulation (SCS) for chronic low back pain (CLBP) and/or leg pain, including persistent spinal pain syndrome (PSPS), careful patient selection based on proved predictive factors is essential. Unfortunately, the necessary selection process required to optimize outcomes of SCS remains challenging. OBJECTIVE: This review aimed to evaluate predictive factors of clinically relevant pain relief after SCS for patients with CLBP and/or radicular leg pain, including PSPS. MATERIALS AND METHODS: In August 2023, PubMed, Cinahl, Cochrane, and EMBASE were searched to identify studies published between January 2010 and August 2023. Studies reporting the percentage of patients with ≥50% pain relief after SCS in patients with CLBP and leg pain, including PSPS at 12 or 24 months, were included. Meta-analysis was conducted to pool results for back, leg, and general pain relief. Predictive factors for pain relief after 12 months were examined using univariable and multivariable meta-regression. RESULTS: A total of 27 studies (2220 patients) were included for further analysis. The mean percentages of patients with substantial pain relief were 68% for leg pain, 63% for back pain, and 73% for general pain at 12 months follow-up, and 63% for leg pain, 59% for back pain, and 71% for general pain at 24 months follow-up assessment. The implantation method and baseline Oswestry Disability Index made the multivariable meta-regression model for ≥50% back pain relief. Sex and pain duration made the final model for ≥50% leg pain relief. Variable stimulation and implantation method made the final model for general pain relief. CONCLUSIONS: This review supports SCS as an effective pain-relieving treatment for CLBP and/or leg pain, and models were developed to predict substantial back and leg pain relief. To provide high-grade evidence for predictive factors, SCS studies of high quality are needed in which standardized factors predictive of SCS success, based on in-patient improvements, are monitored and reported.

Microneedling in Abdominal Scarring after DIEP-flap Breast Reconstruction to Improve Scar Quality: A Randomized Controlled Split Scar Trial.

Background: Deep inferior epigastric perforator (DIEP) flap breast reconstruction leads to large scars in the breast and abdominal region. Common symptoms related to abdominal scarring include changes in color, stiffness, thickness, and irregularity of the skin. The aim of this study was to examine whether microneedling improves the abdominal scar quality after DIEP-flap breast reconstruction. Methods: A prospective randomized controlled within subject comparison design (N = 30) was used to study the effect of microneedling treatments on the abdominal scar, versus no treatment. Three electrically powered microneedling sessions were performed every 4 weeks on one side of the abdominal scar. Abdominal scar assessment was performed at baseline and 3-, 6-, and 9-month follow-up using the Patient and Observer Scar Assessment Scale (POSAS). Treated and untreated sides were compared using a t test or Wilcoxon signed-rank test in case the data were not normally distributed. Results: Twenty-seven women completed the study. Microneedling treatment led to lower POSAS scores compared with the untreated scar side after the 3- and 9-month follow-up. At the 9-month follow-up, the POSAS total score (Mdn = 17, interquartile range = 18.3 versus Mdn = 21.4, interquartile range = 17.5) was statistically lower for the treated side compared with the untreated side, implying a better-appraised scar quality. The observer POSAS total score was statistically lower for the treated side compared with the untreated side. Conclusions: Based on patient and observer ratings, overall abdominal scars after DIEP-flap surgery improve significantly after microneedling treatment. Scar symptoms reduce faster under the influence of microneedling treatment compared with no treatment.

An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma.

Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.

Validation of Longitudinal Progression Examinations for Prediction of APPE Readiness.

OBJECTIVE: To study curricular outcomes for the purpose of holistic improvement of the curriculum. METHODS: A single-institution retrospective cohort study evaluated 3 cohorts of Doctor of Pharmacy students entering the program through performance in Advanced Pharmacy Practice Experience (APPE) rotations. Assessment scores and pass/fail outcomes were collected from the 3 examinations to use as predictors, and the numbers of "needs improvement" (NI) and "unsatisfactory" (U) ratings from preceptors during the APPE rotations served as outcome measures. RESULTS: Pharmacy mathematics competency and Milemarker 1 (MM1) examination first-time scores, but not those from Milemarker 2 (MM2), were significantly associated with NI or U scores on required APPE rotations. Significant correlations for all examinations (pharmacy mathematics competency, MM1, and MM2) were found for the Acute Care/Inpatient APPE rotation for each cohort and the combined cohorts. Significant correlations were also found between all examinations and the APPE rotation courses Advanced Hospital and Ambulatory Care, with the exception of the 2021 cohort. Performance in the Advanced Community rotation was not associated with any of the examinations. MM1 and MM2 are both reliable measures of competence in our didactic curriculum and predictive of scoring an NI or U rating in the APPE Acute Care/Inpatient rotation. CONCLUSION: The longitudinal milestone examinations used in our institution provide a mechanism to identify students likely to struggle in required APPE rotations and target them for remediation activities.

Zika virus antibody-positivity among symptomatic/asymptomatic pregnant women in the Aseer region displays pre-exposure to dengue viruses.

Antibody cross-reactivity among flaviviruses is a major limitation in understanding the prevalence without vector control measures. In this study, we investigated the presence of Zika virus (ZIKV)-specific antibodies and the significance of their cross-reactivity with other flaviviruses, which could affect the serological specificity in both symptomatic and asymptomatic pregnant women. Among the results obtained from 217 serum samples tested for ZIKV-specific IgM and IgG, no specific predictions regarding seropositivity or exposure due to extensive cross-reactivity with dengue virus (DENV) serology could be made. Clear-cut positivity was observed in 1.8% (n = 4) and 1.0% (n = 2) for ZIKV IgM and IgG, respectively. The same samples assessed for DENV showed 1.3% (n = 3) seropositivity each for IgM and IgG levels. None of the samples were positive for ZIKV and DENV IgM or IgG. However, one sample (0.4%) tested positive for ZIKV and DENV IgM. No significant correlation was observed between DENV IgM and IgG when comparing the overlapped serotiters. On the other hand, the ZIKV IgG-positive sample showed higher serotiters for DENV IgG, indicating cross-reactivity with ZIKV but without statistical significance. Therefore, screening for the incidence of ZIKV becomes particularly challenging in a population where the presence or pre-exposure to DENV is observed. Our observations further suggest that unless flavivirus prevalence is properly addressed, determining the prevalence of ZIKV antibodies, which may be confounded with other uninvestigated flaviviruses, will be complicated.

Bone biopsy devices - a patent review.

INTRODUCTION: Bone biopsies have great value for the diagnosis of, amongst others, hematologic diseases. Although the bone biopsy procedure is mostly performed minimally invasive with the use of a slender cannula, the patient may still experience discomfort, especially when the procedure has to be repeated due to an unsuccessful biopsy. AREAS COVERED: This review presents a comprehensive overview of bone biopsy devices presented in the patent literature. The patents were obtained using a classification search combined with keywords in the Espacenet patent database and were subsequently verified using pre-set eligibility criteria. This resulted in 62 unique patents included in this review. EXPERT OPINION: The included patents were categorized based on the used strategies for the three steps that can be identified during a bone biopsy (1) biopsy sampling, (2) biopsy severing and (3) biopsy harvesting. Most patents described strategies for multiple steps. Insight into the used strategies and the comprehensive overview may serve as a source of inspiration for the design of novel bone biopsy devices.

Breathing pattern and pulmonary gas exchange in elderly patients with and without left ventricular dysfunction-modification with exercise-based cardiac rehabilitation and prognostic value.

Background: Inefficient ventilation is an established prognostic marker in patients with heart failure. It is not known whether inefficient ventilation is also linked to poor prognosis in patients with left ventricular dysfunction (LVD) but without overt heart failure. Objectives: To investigate whether inefficient ventilation in elderly patients with LVD is more common than in patients without LVD, whether it improves with exercise-based cardiac rehabilitation (exCR), and whether it is associated with major adverse cardiovascular events (MACE). Methods: In this large multicentre observational longitudinal study, patients aged ≥65 years with acute or chronic coronary syndromes (ACS, CCS) without cardiac surgery who participated in a study on the effectiveness of exCR in seven European countries were included. Cardiopulmonary exercise testing (CPET) was performed before, at the termination of exCR, and at 12 months follow-up. Ventilation (VE), breathing frequency (BF), tidal volume (VT), and end-expiratory carbon dioxide pressure (PETCO2) were measured at rest, at the first ventilatory threshold, and at peak exercise. Ventilatory parameters were compared between patients with and without LVD (based on cardio-echography) and related to MACE at 12 month follow-up. Results: In 818 patients, age was 72.5 ± 5.4 years, 21.9% were women, 79.8% had ACS, and 151 (18%) had LVD. Compared to noLVD, in LVD resting VE was increased by 8%, resting BF by 6%, peak VE, peak VT, and peak PETCO2 reduced by 6%, 8%, and 5%, respectively, and VE/VCO2 slope increased by 11%. From before to after exCR, resting VE decreased and peak PETCO2 increased significantly more in patients with compared to without LVD. In LVD, higher resting BF, higher nadir VE/VCO2, and lower peak PETCO2 at baseline were associated with MACE. Conclusions: Similarly to patients with HF, in elderly patients with ischemic LVD, inefficient resting and exercise ventilation was associated with worse outcomes, and ExCR alleviated abnormal breathing patterns and gas exchange parameters.

Tsetse fly inspired steerable bone drill-a proof of concept.

The fixation strength of pedicle screws could be increased by fixating along the much stronger cortical bone layer, which is not possible with the current rigid and straight bone drills. Inspired by the tsetse fly, a single-plane steerable bone drill was developed. The drill has a flexible transmission using two stacked leaf springs such that the drill is flexible in one plane and can drill along the cortical bone layer utilizing wall guidance. A proof-of-principle experiment was performed which showed that the Tsetse Drill was able to successfully drill through 5, 10 and 15 PCF cancellous bone phantom which has similar mechanical properties to severe osteoporotic, osteoporotic and healthy cancellous bone. Furthermore, the Tsetse Drill was able to successfully steer and drill along the cortical wall utilizing wall guidance for an insertion angle of 5°, 10° and 15°. The experiments conclude that the tsetse fly-inspired drilling method is successful and even allows the drilling along the cortical bone layer. The Tsetse Drill can create curved tunnels utilizing wall guidance which could increase the fixation strength of bone anchors and limit the risk of cortical breach and damage to surrounding anatomy.

A critical appraisal on the treatment of acute appendicitis in pediatric population during the COVID-19 pandemic.

Acute appendicitis is one of the most common causes of abdominal pain in children. During the coronavirus disease 2019 (COVID-19) pandemic, a delay in presentation to the emergency department and a higher rate of complicated appendicitis were observed. Traditionally, operative management (laparoscopic or open appendectomy) was thought to be the best treatment strategy for acute appendicitis. However, nonoperative management with antibiotics has gained popularity in managing pediatric appendicitis during the COVID-19 era. The pandemic has posed significant challenges in the management of acute appendicitis. Cancellation of elective appendectomies, delay in seeking care due to fear of contracting COVID-19 infection, and impact of COVID-19 infection in the pediatric population have resulted in higher rates of complications. Furthermore, multiple studies have reported multisystem inflammatory syndrome in children mimicking acute appendicitis, subjecting patients to unnecessary surgery. Therefore, it is imperative to update the treatment guidelines for the management of acute appendicitis in the pediatric population during and after COVID-19 times.

Targeting mitochondrial energetics reverses panobinostat- and marizomib-induced resistance in pediatric and adult high-grade gliomas.

In previous studies, we demonstrated that panobinostat, a histone deacetylase inhibitor, and bortezomib, a proteasomal inhibitor, displayed synergistic therapeutic activity against pediatric and adult high-grade gliomas. Despite the remarkable initial response to this combination, resistance emerged. Here, in this study, we aimed to investigate the molecular mechanisms underlying the anticancer effects of panobinostat and marizomib, a brain-penetrant proteasomal inhibitor, and the potential for exploitable vulnerabilities associated with acquired resistance. RNA sequencing followed by gene set enrichment analysis (GSEA) was employed to compare the molecular signatures enriched in resistant compared with drug-naïve cells. The levels of adenosine 5'-triphosphate (ATP), nicotinamide adenine dinucleotide (NAD)+ content, hexokinase activity, and tricarboxylic acid (TCA) cycle metabolites required for oxidative phosphorylation to meet their bioenergetic needs were analyzed. Here, we report that panobinostat and marizomib significantly depleted ATP and NAD+ content, increased mitochondrial permeability and reactive oxygen species generation, and promoted apoptosis in pediatric and adult glioma cell lines at initial treatment. However, resistant cells exhibited increased levels of TCA cycle metabolites, which required for oxidative phosphorylation to meet their bioenergetic needs. Therefore, we targeted glycolysis and the electron transport chain (ETC) with small molecule inhibitors, which displayed substantial efficacy, suggesting that resistant cell survival is dependent on glycolytic and ETC complexes. To verify these observations in vivo, lonidamine, an inhibitor of glycolysis and mitochondrial function, was chosen. We produced two diffuse intrinsic pontine glioma (DIPG) models, and lonidamine treatment significantly increased median survival in both models, with particularly dramatic effects in panobinostat- and marizomib-resistant cells. These data provide new insights into mechanisms of treatment resistance in gliomas.

Disruption of estrogen receptor beta's DNA binding domain impairs its tumor suppressive effects in triple negative breast cancer.

Triple negative breast cancer (TNBC) is an aggressive sub-type of the disease which accounts for a disproportionately high percentage of breast cancer morbidities and mortalities. For these reasons, a better understanding of TNBC biology is required and the development of novel therapeutic approaches are critically needed. Estrogen receptor beta (ERß) is a reported tumor suppressor that is expressed in approximately 20% of primary TNBC tumors, where it is associated with favorable prognostic features and patient outcomes. Previous studies have shown that ERß mediates the assembly of co-repressor complexes on DNA to inhibit the expression of multiple growth promoting genes and to suppress the ability of oncogenic transcription factors to drive cancer progression. To further elucidate the molecular mechanisms by which ERß elicits its anti-cancer effects, we developed MDA-MB-231 cells that inducibly express a mutant form of ERß incapable of directly binding DNA. We demonstrate that disruption of ERß's direct interaction with DNA abolishes its ability to regulate the expression of well characterized immediate response genes and renders it unable to suppress TNBC cell proliferation. Loss of DNA binding also diminishes the ability of ERß to suppress oncogenic NFκB signaling even though it still physically associates with NFκB and other critical co-factors. These findings enhance our understanding of how ERß functions in this disease and provide a model system that can be utilized to further investigate the mechanistic processes by which ERß elicits its anti-cancer effects.

The Usability of Homelab, a Digital Self-service at a Dutch General Practice, for Diagnostic Tests: Pilot Study With a Questionnaire.

BACKGROUND: eHealth potentially can make health care more accessible and efficient and help reduce the workload in primary health care. Homelab is an eHealth tool implemented in a general practice environment, and it offers relatively simple laboratory diagnostic tests without the referral of the general practitioner. After logging in this eHealth tool, patients select and order a diagnostic test based on their symptoms. The test results are presented online to the general practitioner and the patient. OBJECTIVE: This study aims to evaluate the use, usability, and user characteristics of Homelab. Further, it aims to evaluate whether Homelab replaces an appointment with the general practitioner. METHODS: Homelab has been implemented since May 2021 as a pilot in a Dutch general practice. The number of requests and the ordered diagnostic packages are monitored. After using Homelab, patients are invited to complete a short questionnaire. The questionnaire contains demographic questions and assesses usability using the System Usability Scale (10 items). In addition, questions about requesting an appointment with the general practitioner without Homelab are included. All data were anonymous. RESULTS: The questionnaire was filled by 74 individual patients. The mean age of the patients was 40.33 (SD 12.11) years, and half of them were females (39/74, 53%). The majority of the patients were highly educated (56/74, 76%) and employed (53/74, 72%). Approximately 81% (60/74) of the patients reported that they would use Homelab again in the future and 66% (49/74) reported that they would have gone to the general practitioner if they had not used Homelab. The usability of Homelab was perceived higher by the younger age group (mean 73.96, SD 14.74) than by the older age group (mean 61.59, SD 14.37). In total, 106 test packages were ordered over 1 year, and the most requested diagnostic package was "Am I still healthy? I want to do my annual health checkup." Homelab was used the most during the months of the COVID-19 lockdown. CONCLUSIONS: The use of Homelab, a digital self-service for ordering diagnostic tests, was monitored in this study, and its usability was perceived as above average. Our findings showed that patients are willing to use Homelab in the future and they would use it most of the time as a replacement for regular consultations. Homelab offers opportunities for more accessible and efficient health care for both the patient and the general practitioner.

Asociación entre el riesgo nutricional, estancia hospitalaria y diagnóstico médico en pacientes de un hospital del seguro social peruano

Objetivo: Determinar la asociación que existe entre el riesgo nutricional, la estancia hospitalaria y el diagnóstico médico en pacientes hospitalizados en el Centro Especializado de Rehabilitación Profesional (CERP) del Hospital Nacional Guillermo Almenara Irigoyen. Materiales y métodos: Se realizó un estudio observacional de cohorte longitudinal, retrospectivo, que incluyó a las personas hospitalizadas durante el periodo comprendido entre el 1 de julio del 2021 y el 27 de febrero del 2022. Hubo un seguimiento de los pacientes hasta su alta del centro hospitalario (egreso). Se excluyeron los individuos menores de 18 años, gestantes o puérperas, y cuya permanencia fue menor a 24 horas. Los datos de interés fueron recogidos a partir de la revisión de las historias clínicas y kárdex de nutrición. La variable principal fue el riesgo nutricional, el cual fue detectado mediante el Nutritional Risk Screening (NRS) 2002; las variables secundarias fueron los grupos etarios, el sexo, la estancia hospitalaria, el diagnóstico médico principal, la condición de egreso y el estado nutricional. En el análisis de los datos, para la comparación de variables cualitativas o categóricas se utilizó la prueba chi-cuadrado y para variables cuantitativas, la prueba t de Student y ANOVA. Se consideró significancia estadística al valor de p < 0,05. Resultados: Se incluyó un total de 1 929 pacientes. La prevalencia del riesgo nutricional fue 33,13 %. Los pacientes con esta condición presentaron tasas de mortalidad más altas (57,51 %). Se observó que la prevalencia del riesgo nutricional está relacionada con una mayor estancia hospitalaria (4,6 días más) (p < 0,001), con el diagnóstico nutricional de delgadez (48,67 %) (p < 0,001) y con el diagnóstico médico, donde la enfermedad oncológica es la más asociada (50,93 %). Conclusiones: El riesgo nutricional se asocia a una evolución negativa de la enfermedad, lo que origina un aumento de la estancia hospitalaria, la tasa de mortalidad y, por ende, los costos intrahospitalarios. Es importante realizar su detección temprana para poder brindar intervenciones nutricionales adecuadas.

Objective: To determine the association between nutritional risk, hospital stay and medical diagnosis among patients admitted at Centro Especializado de Rehabilitación Profesional (CERP) of Hospital Nacional Guillermo Almenara Irigoyen. Materials and methods: An observational retrospective longitudinal cohort study was conducted with inpatients between July 1, 2021 and February 27, 2022. The patients were followed up until they left the hospital (discharge). Individuals under 18 years of age, pregnant or puerperal women, and those whose stay was less than 24 hours were excluded. The data of interest was collected from the patients' medical records and diet cards. The main variable was the nutritional risk, which was detected using the Nutritional Risk Screening (NRS) 2002. The secondary variables were age group, sex, hospital stay, main medical diagnosis, discharge condition and nutritional status. Data analysis was performed using the chi-square test to compare the qualitative or categorical variables, and the Student's t-test and ANOVA for the quantitative variables. A value of p < 0.05 was considered as statistically significant. Results: A total of 1,929 patients were included in the study. Nutritional risk prevalence accounted for 33.13 %. Patients with this condition showed the highest mortality rates (57.51 %). It was found that nutritional risk prevalence was related to a longer hospital stay (4.6 more days) (p < 0.001), a diagnosis of constitutional thinness (48.67 %) (p < 0.001) and the medical diagnosis, being oncology disorders the most associated ones (50.93 %). Conclusions: Nutritional risk is associated with disease progression, resulting in an increased hospital stay, mortality rate and therefore hospital costs. Early detection is important to provide adequate dietary interventions.

Subcutaneous Stimulation as Add-on Therapy to Spinal Cord Stimulation in Patients With Persistent Spinal Pain Syndrome Significantly Increases the Total Electrical Charge per Second: Aspects on Stimulation Parameters and Energy Requirements of the Implanted Neurostimulators.

OBJECTIVE: In our previous multicenter randomized controlled trial, we demonstrated the clinical effectiveness of peripheral nerve field stimulation (PNFS) as add-on therapy to spinal cord stimulation (SCS) for the treatment of chronic back pain in patients with persistent spinal pain syndrome (PSPS) or failed back surgery syndrome (FBSS). To our knowledge, no previous study has investigated the effect of PNFS as an add-on to SCS on the energy consumption of the implanted neurostimulators. Therefore, in this study, we compared the specific stimulation parameters and energy requirements of a previously unreported group of patients with only SCS with those of a group of patients with SCS and add-on PNFS. We also investigated differences that might explain the need for PNFS in the treatment of chronic low back pain. MATERIALS AND METHODS: We analyzed 75 patients with complete sets of stimulation parameters, with 21 patients in the SCS-only group and 54 patients in the SCS + PNFS group. Outcome measures were average visual analog scale score, SCS parameters (voltage, frequency, and pulse width), SCS charge per second, and total charge per second. We analyzed baseline characteristics and differences between and within groups over time. RESULTS: Both groups had comparable patient characteristics at baseline and showed a significant decrease in back and leg pain. SCS charge per second did not significantly differ between the groups at baseline or at 12 months. The total charge per second was significantly higher in the active SCS + PNFS group than in the SCS-only group at baseline; in the SCS + PNFS group, this persisted for up to 12 months, and the SCS charge per second and total charge per second increased significantly over time. CONCLUSIONS: Our results show that add-on PNFS increases the total charge per second compared with SCS alone, as expected. However, further research is needed because our results do not directly explain why some patients require add-on PNFS to treat low back pain.