Synchronous Well-Differentiated Papillary Mesothelioma and Endometrioid Adenocarcinoma Arising From Endometriosis.

Well-differentiated papillary mesothelioma (WDPM) is a rare mesothelial tumor of uncertain malignant potential. We present a unique case of a woman with synchronous WDPM and well-differentiated endometrioid adenocarcinoma (EA) arising from extraovarian endometriosis. A 56-year-old postmenopausal woman presented with a several-month history of right lower quadrant abdominal pain. She had a history of supracervical hysterectomy and bilateral salpingo-oophorectomy secondary to endometriosis. Imaging reported a mass in the right lower quadrant originating from the distal ileum. At laparotomy, the patient underwent a right colectomy with resection of the terminal ileum and excision of a solitary peritoneal nodule. Pathology was consistent with a diagnosis of well-differentiated EA (arising from extraovarian endometriosis) and WDPM. Further treatment consisted of complete surgical staging/debulking and adjuvant chemotherapy directed toward metastatic well-differentiated EA. Surgeons should be familiar with WDPM as a potential finding in women of reproductive age undergoing abdominal surgery for any indication.

Targeting interleukin-6 as a treatment approach for peritoneal carcinomatosis.

Peritoneal carcinomatosis (PC) is a complex manifestation of abdominal cancers, with a poor prognosis and limited treatment options. Recent work identifying high concentrations of the cytokine interleukin-6 (IL-6) and its soluble receptor (sIL-6-Rα) in the peritoneal cavity of patients with PC has highlighted this pathway as an emerging potential therapeutic target. This review article provides a comprehensive overview of the current understanding of the potential role of IL-6 in the development and progression of PC. We discuss mechansims by which the IL-6 pathway may contribute to peritoneal tumor dissemination, mesothelial adhesion and invasion, stromal invasion and proliferation, and immune response modulation. Finally, we review the prospects for targeting the IL-6 pathway in the treatment of PC, focusing on common sites of origin, including ovarian, gastric, pancreatic, colorectal and appendiceal cancer, and mesothelioma.

Viral airway injury promotes cell engraftment in an in vitro model of cystic fibrosis cell therapy.

Cell therapy is a potential treatment for cystic fibrosis (CF). However, cell engraftment into the airway epithelium is challenging. Here, we model cell engraftment in vitro using the air-liquid interface (ALI) culture system by injuring well-differentiated CF ALI cultures and delivering non-CF cells at the time of peak injury. Engraftment efficiency was quantified by measuring chimerism by droplet digital PCR and functional ion transport in Ussing chambers. Using this model, we found that human bronchial epithelial cells (HBECs) engraft more efficiently when they are cultured by conditionally reprogrammed cell (CRC) culture methods. Cell engraftment into the airway epithelium requires airway injury, but the extent of injury needed is unknown. We compared three injury models and determined that severe injury with partial epithelial denudation facilitates long-term cell engraftment and functional CFTR recovery up to 20% of wildtype function. The airway epithelium promptly regenerates in response to injury, creating competition for space and posing a barrier to effective engraftment. We examined competition dynamics by time-lapse confocal imaging and found that delivered cells accelerate airway regeneration by incorporating into the epithelium. Irradiating the repairing epithelium granted engrafting cells a competitive advantage by diminishing resident stem cell proliferation. Intentionally, causing severe injury to the lungs of people with CF would be dangerous. However, naturally occurring events like viral infection can induce similar epithelial damage with patches of denuded epithelium. We found that viral preconditioning promoted effective engraftment of cells primed for viral resistance.NEW & NOTEWORTHY Cell therapy is a potential treatment for cystic fibrosis (CF). Here, we model cell engraftment by injuring CF air-liquid interface cultures and delivering non-CF cells. Successful engraftment required severe epithelial injury. Intentionally injuring the lungs to this extent would be dangerous. However, naturally occurring events like viral infection induce similar epithelial damage. We found that viral preconditioning promoted the engraftment of cells primed for viral resistance leading to CFTR functional recovery to 20% of the wildtype.

Clinical practice patterns for assessing children with learning difficulties: survey of eye health care professionals.

CLINICAL RELEVANCE: Understanding what aspects of vision or binocular vision may affect learning, and how these are assessed, is important for the eye health care professional assessing children with learning difficulties. It is vital that visual dysfunction is identified or excluded in these patients to ensure targeted and timely intervention. BACKGROUND: The aim of this study was to investigate similarities and differences between eye care professionals in the knowledge, attitudes and practice patterns, when evaluating children with learning difficulties. METHODS: This study was a cross-occupational, cross-sectional, predominantly quantitative internet-based survey. Ophthalmologists, optometrists, and orthoptists working in Australia were eligible to participate. A questionnaire comprising of 31 multiple-choice questions with up to 19 additional branching questions was distributed using REDCap in September 2022. RESULTS: A total of 130 responses were analysed (6 ophthalmologists, 84 orthoptists and 40 optometrists of whom 9 were practicing behavioural vision care). Most respondents assessed distance visual acuity (95%), near stereoacuity (85%), presence of strabismus (88%) and ocular movements (91%). Near vision was assessed less often (65%). Optometrists were most likely to measure colour vision (p < 0.002), accommodation and undertake a subjective refraction (each p < 0.001). Ophthalmologists were least likely to measure convergence (p = 0.041) but more likely to undertake a cycloplegic refraction (p = 0.044). More optometrists practicing behavioural vision care reported testing binocular vision (p = 0.026), fusional vergence (p < 0.001), saccades (p = 0.066), and smooth pursuit (p = 0.050) than other professions. There was a positive correlation between frequency and confidence level when assessing children with learning difficulties (ρ = 0.64). Respondents referred to paediatricians (39%), speech pathologists (30%), educational psychologists (29%) and general practitioners (29%). CONCLUSION: Despite similarities across occupations, there were differences in testing the vision and binocular functions of children with learning difficulties. Future research should aim to establish minimum standards for assessing this patient cohort to ensure consistent and relevant assessment.

A histone deacetylase network regulates epigenetic reprogramming and viral silencing in HIV-infected cells.

A long-lived latent reservoir of HIV-1-infected CD4 T cells persists with antiretroviral therapy and prevents cure. We report that the emergence of latently infected primary CD4 T cells requires the activity of histone deacetylase enzymes HDAC1/2 and HDAC3. Data from targeted HDAC molecules, an HDAC3-directed PROTAC, and CRISPR-Cas9 knockout experiments converge on a model where either HDAC1/2 or HDAC3 targeting can prevent latency, whereas all three enzymes must be targeted to achieve latency reversal. Furthermore, HDACi treatment targets features of memory T cells that are linked to proviral latency and persistence. Latency prevention is associated with increased H3K9ac at the proviral LTR promoter region and decreased H3K9me3, suggesting that this epigenetic switch is a key proviral silencing mechanism that depends on HDAC activity. These findings support further mechanistic work on latency initiation and eventual clinical studies of HDAC inhibitors to interfere with latency initiation.

Regional Immunotherapy for Peritoneal Carcinomatosis in Gastroesophageal Cancer: Emerging Strategies to Re-Condition a Maladaptive Tumor Environment.

Peritoneal carcinomatosis originating from gastric/gastroesophageal junction cancer (GC-PC) occurs in a defined subset of gastric cancer patients with unique clinical, pathologic, molecular and immunologic characteristics that create significant obstacles to effective treatment with modern therapy. Although systemic chemo- and immuno- therapy have yielded disappointing results in GC-PC, recent advances in the characterization of GC-PC and peritoneal immune biology present new opportunities for targeted therapeutics. In this review article, we discuss the distinct properties of GC-PC and the peritoneal immune environment as they pertain to current and investigative treatment strategies. We discuss pre-clinical studies and clinical trials relevant to the modulation of the peritoneal environment as a therapeutic intervention in GC-PC. Finally, we present a road map for future combinatorial strategies based on the conception of the peritoneal cavity as a bioreactor. Within this isolated compartment, prevailing immunosuppressive conditions can be altered through regional interventions toward an adaptive phenotype that would support the effectiveness of regionally delivered cellular therapy products. It is hoped that novel combination strategies would promote efficacy not only in the sequestered peritoneal environment, but also via migration into the circulation of tumor-reactive lymphocytes to produce durable systemic disease control, thereby improving oncologic outcome and quality of life in patients with GC-PC.

Mesenteric embryonal rhabdomyosarcoma in an adolescent: a case report.

Rhabdomyosarcoma (RMS) is a soft tissue sarcoma that histologically resembles embryonic skeletal muscle. It can occur anywhere in the body, including tissues devoid of skeletal muscles. RMS is a common malignancy in children, and it accounts for ˃50% of all soft tissue sarcomas in children. Embryonal rhabdomyosarcoma (ERMS) mostly affects children younger than 10 years of age. The head and neck area, the genitourinary tract and the retroperitoneum are described as the preferred anatomic sites for ERMS development. However, the mesentery location is extremely rare. We report a rare case of an ERMS occurring in the mesentery of a 17-year-old male.

Race and Ethnic Categories: A Brief Review of Global Terms and Nomenclature.

Terminology regarding descriptors of race and ethnicity have been constantly evolving. Due to differences in terminology, data collection, demographics, and group identity, there are numerous challenges in determining what descriptors are suitable and acceptable to all individuals. The National Institutes of Health (NIH) has defined six racial and ethnic categories that should be used for reporting purposes. This review gives a historical background of the definition of the different racial and ethnic categories. This review also aims to define acceptable categories of race and ethnicity to provide guidelines for reports and best practices.

New Concepts in Therapeutic Manipulation of HIV-1 Transcription and Latency: Latency Reversal versus Latency Prevention.

Antiretroviral therapy (ART) has dramatically improved the prognosis for people living with HIV-1, but a cure remains elusive. The largest barrier to a cure is the presence of a long-lived latent reservoir that persists within a heterogenous mix of cell types and anatomical compartments. Efforts to eradicate the latent reservoir have primarily focused on latency reversal strategies. However, new work has demonstrated that the majority of the long-lived latent reservoir is established near the time of ART initiation, suggesting that it may be possible to pair an intervention with ART initiation to prevent the formation of a sizable fraction of the latent reservoir. Subsequent treatment with latency reversal agents, in combination with immune clearance agents, may then be a more tractable strategy for fully clearing the latent reservoir in people newly initiating ART. Here, we summarize molecular mechanisms of latency establishment and maintenance, ongoing efforts to develop effective latency reversal agents, and newer efforts to design latency prevention agents. An improved understanding of the molecular mechanisms involved in both the establishment and maintenance of latency will aid in the development of new latency prevention and reversal approaches to ultimately eradicate the latent reservoir.

Medical Training in Uganda: A Critical but Neglected Part of the Healthcare System.

Quality healthcare is dependent upon the structure of healthcare and/or healthcare facilities in a country. In Uganda, the healthcare system has had drastic changes over the last 50 years. Medical students, interns, and medical officers play an invaluable role in the function of hospitals and the overall quality of the healthcare system of Uganda, particularly in government facilities. Demands for better working conditions and payment of arrears have forced the graduate medical students and upcoming medical interns to strike, causing disruption in the fulfillment of basic health services. In order to prioritize the care of patients in the country, there should be fair treatment of the medical workers to boost and maintain morale and ultimately lead to continued quality patient care.

Rectal prolapse associated with intussusception and malignancy.

Rectal prolapse associated with intussusception is when the intestine slides into the adjacent part causing a protrusion through the anus. It is also referred to as recto-anal intussusception or trans-anal protrusion of intussusception. Pre-operative diagnosis of the associated intussusception is usually hard to make. We present a case of a patient who presented with a rectal prolapse. Surgical exploration also noted an intussusception and rectal malignancy. We demonstrate the importance of surgical management in patients with rectal prolapse to avoid progression of a malignancy or intussusception.

Areas of enduring COVID-19 prevalence: drivers of prevalence and mitigating strategies.

BACKGROUND: UK local authorities that experienced sustained high levels of COVID-19 between 1st March 2020 and 28th February 2021 were described by the UK Scientific Advisory Group for Emergencies as areas of enduring prevalence. This research was carried out in order to examine the views of local authority Directors of Public Health, who played a crucial role in the local response to COVID-19, on reasons for sustained high levels of prevalence in some areas, alongside an investigation of the mitigation strategies that they implemented during the course of the pandemic. METHODS: Interviews were conducted with Directors of Public Health in 19 local authority areas across England, between July and November 2021. This included nine areas identified as areas of enduring prevalence and ten 'comparison' areas. RESULTS: The outcomes of this study suggests that the geographical differences in prevalence rates are strongly influenced by health inequalities. Structural factors including deprivation, employment, and housing, due to their disproportionate impact on specific groups, converged with demographic factors, including ethnicity and age, and vaccination rates, and were identified as the main drivers of enduring prevalence. There are key differences in these drivers both within and, to a lesser extent, between local authorities. Other than these structural barriers, no major differences in facilitators or barriers to COVID-19 mitigation were identified between areas of varying prevalence. The main features of successful mitigation strategies were a locally tailored approach and partnership working involving local authority departments working with local health, community, voluntary and business organisations. CONCLUSIONS: This study is the first to add the voices of Directors of Public Health, who played a crucial role in the local COVID-19 response. Areas of enduring prevalence existed during the pandemic which were caused by a complex mix of structural factors related to inequalities. Participants advised that more research is needed on the effectiveness of mitigation strategies and other measures to reduce the impact of structural inequalities, to better understand the factors that drive prevalence. This would include an assessment of how these factors combine to predict transmission and how this varies between different areas.

Cost Analysis of Orthoptist-Led Neurofibromatosis Type 1 Screening Clinics.

Purpose: To conduct a costing study comparing orthoptist-led with consultant-led clinics screening for optic pathway gliomas (OPGs) in children with neurofibromatosis Type 1 (NF1) attending the Royal Children's Hospital (RCH), Melbourne. Methods: Patients with NF1 examined in the orthoptist-led NF1 screening clinic and/or consultant-led clinics during the study period were identified. The workflow management software Q-Flow 6® provided data documenting patient's time spent with the orthoptist, nurse, and ophthalmologist. Time points were converted into minutes and multiplied by the cost-per-minute for each profession. A bottom-up micro-costing approach was used to estimate appointment level costs. Bootstrap simulations with 1000 replications were used to estimate 95% confidence intervals (CIs) for the difference in mean appointment time and cost between clinics. Results: Data for 130 consultant-led clinic appointments and 234 orthoptist-led clinic appointments were extracted for analysis. The mean time per appointment for the consultant-led clinic was 45.11 minutes, and the mean time per appointment for the orthoptist-led clinic was 25.85 minutes. The mean cost per appointment for the consultant-led clinic was A $84.15 (GBP £39.60) compared to the orthoptist-led clinic at A $20.40 (GBP £9.60). This represents a mean reduction of 19.25 minutes per appointment (95% CI, -24.85 to -13.66) and a mean reduction of A $63.75 (GBP £30.00) per appointment (95% CI, (A $-75.40 to $-52.10 [GBP £ -35.48 to £ -24.52]). Conclusion: An orthoptist-led clinic screening for OPGs in patients with NF1 can be a more cost-efficient model of care for ophthalmic screening in this patient group.

Caustic esophageal stenosis: A case report of endoscopic dilatation with nasogastric tubes.

The management of the esophageal strictures that may result from caustic ingestion has evolved over time, from surgical to endoscopic management. Dilation with nasogastric tubes may be a valuable alternative in places with limited resources.

Duodenal Mucinous Adenocarcinoma in a Patient With Immunodeficiency: A Case Report.

Duodenal mucinous adenocarcinoma is a rare type of small bowel carcinoma. It is not commonly encountered; hence little knowledge exists about its presentation, diagnosis, and management. The diagnosis is mostly made by either esophagogastroduodenoscopy (EGD) or intra-operatively. Some of the main symptoms are abdominal pain, nausea, vomiting, weight loss, or signs and symptoms of upper gastrointestinal bleeding. Therefore, this is a serious condition that healthcare providers and patients should be aware of to reduce its severity and improve prognosis. We present a case of duodenal mucinous adenocarcinoma in a patient with immunodeficiency virus.

Small-molecule eRF3a degraders rescue CFTR nonsense mutations by promoting premature termination codon readthrough.

The vast majority of people with cystic fibrosis (CF) are now eligible for CF transmembrane regulator (CFTR) modulator therapy. The remaining individuals with CF harbor premature termination codons (PTCs) or rare CFTR variants with limited treatment options. Although the clinical modulator response can be reliably predicted using primary airway epithelial cells, primary cells carrying rare CFTR variants are scarce. To overcome this obstacle, cell lines can be created by overexpression of mouse Bmi-1 and human TERT (hTERT). Using this approach, we developed 2 non-CF and 6 CF airway epithelial cell lines, 3 of which were homozygous for the W1282X PTC variant. The Bmi-1/hTERT cell lines recapitulated primary cell morphology and ion transport function. The 2 F508del-CFTR cell lines responded robustly to CFTR modulators, which was mirrored in the parent primary cells and in the cell donors' clinical response. Cereblon E3 ligase modulators targeting eukaryotic release factor 3a (eRF3a) rescued W1282X-CFTR function to approximately 20% of WT levels and, when paired with G418, rescued G542X-CFTR function to approximately 50% of WT levels. Intriguingly, eRF3a degraders also diminished epithelial sodium channel (ENaC) function. These studies demonstrate that Bmi-1/hTERT cell lines faithfully mirrored primary cell responses to CFTR modulators and illustrate a therapeutic approach to rescue CFTR nonsense mutations.

Association of research timing with surgery resident perceptions of operative autonomy and satisfaction: A multi-institutional study.

BACKGROUND: General surgery residents commonly engage in research years after the second (Post-postgraduate year 2 [PostPGY2]) or third (PostPGY3) clinical training year. The impact of dedicated research training timing on training experience is unknown. Our aim was to examine the progression of residents' perceived meaningful operative autonomy and evaluate career satisfaction, in relation to research timing. METHODS: Categorical surgery residents with 2-year research requirements were surveyed regarding perceived autonomy for laparoscopic appendectomy, laparoscopic cholecystectomy, and right hemicolectomy and satisfaction with the impact of dedicated research training on professional development. Meaningful operative autonomy was defined as Zwisch scores ≥3 (passive help or supervision only). RESULTS: Residents from 17 programs participated (n = 233, 30.6%); 48% were PostPGY2. PostPGY3 residents were more likely to perceive meaningful operative autonomy when starting dedicated research training (laparoscopic appendectomy: 98% vs 74%, P < .001; laparoscopic cholecystectomy: 87% vs 48%, P < .001; right hemicolectomy: 27% vs 3%, P < .001). Meaningful operative autonomy declined during dedicated research training but was still higher for PostPGY3 residents for laparoscopic appendectomy (84% vs 42%, P < .001) and laparoscopic cholecystectomy (68% vs 30%, P < .001). By PGY4, PostPGY2 residents reported rates of meaningful operative autonomy comparable to PostPGY3 through training completion. A higher proportion of PostPGY3 residents reported dedicated research training satisfaction (90% vs 78%, P = .01). Training at PostPGY3 programs (odds ratio, 3.06, 95% confidence interval, 1.38-6.80) and postresearch training stage (compared with preresearch residents, odds ratio, 3.25, 95% confidence interval, 1.06-10.0) were independently associated with satisfaction. CONCLUSION: Significant differences existed in the progression of perceived operative autonomy and dedicated research training satisfaction between PostPGY2 and PostPGY3 residents. These results could help surgical educators make individualized decisions regarding research timing to promote surgical skill acquisition and resident well-being.

Ileosigmoid Knotting: A Case Series.

Ileosigmoid knotting is a rare case of intestinal obstruction that later leads to bowel necrosis. This is more common in males than females and seen more in areas with increased rates of sigmoid volvulus. The main clinical presentations are abdominal distention, abdominal pain and tenderness, vomiting, and obstipation. Definitive diagnosis is challenging due to its rarity and overlapping symptoms with other more common abdominal conditions. Delay in diagnosis and management can lead to peritonitis, necrosis of the bowel, sepsis, and eventually septic shock. Surgeons should consider ileosigmoid knotting in cases of acute abdomen, as it requires fast decision-making and intervention for a good prognosis. We present two cases of ileosigmoid knotting presenting with acute abdomen requiring emergent laparotomy with resection of necrotic bowel.

An fMRI investigation of neural activation predicting memory formation in children with fetal alcohol spectrum disorders.

Prenatal alcohol exposure (PAE) is associated with physical anomalies, growth restriction, and a range of neurobehavioral deficits. Although declarative memory impairment has been documented extensively in individuals with fetal alcohol spectrum disorders (FASD), this cognitive process has been examined in only one functional magnetic resonance imaging (fMRI) study, and mechanisms underlying this impairment are not well understood. We used an event-related fMRI design to examine neural activations during visual scene encoding that predict subsequent scene memory in 51 right-handed children (age range = 10-14 years, M = 11.3, SD = 1.3) whose mothers had been recruited and interviewed prospectively about their alcohol use during pregnancy. Following examination by expert dysmorphologists, children were assigned to one of three FASD diagnostic groups: FAS/PFAS (nFAS = 7; nPFAS = 4), nonsyndromal heavily exposed (HE; n = 14), and Controls (n = 26). Subsequent memory was assessed in a post-scan recognition test, and subsequent memory activations were examined by contrasting activations during encoding of scenes that were subsequently remembered (hits) to those for incorrectly judged as 'new' (misses). Recognition accuracy did not differ between groups. Pooled across groups, we observed extensive bilateral subsequent memory effects in regions including the hippocampal formation, posterior parietal cortex, and occipital cortex-a pattern consistent with previous similar studies of typically developing children. Critically, in the group of children with FAS or PFAS, we observed activations in several additional regions compared to HE and Control groups. Given the absence of between-group differences in recognition accuracy, these data suggest that in achieving similar memory compared to children in the HE and Control groups, children with FAS and PFAS recruit more extensive neural resources to achieve successful memory formation.

Standardized Multi-Institutional Mock Oral Examination: A Feasible and Valuable Educational Experience for General Surgery Residents.

INTRODUCTION: Mock oral examinations (MOE) are used to prepare residents and assess their readiness for the American Board of Surgery Certifying Exam (ABSCE). Delivery of MOEs varies by institution and previous studies have demonstrated significant implementation barriers such as availability of faculty examiners and exam scenarios. OBJECTIVE: To assess the value and participant satisfaction of a standardized multi-institutional MOE for general surgery residents. PARTICIPANTS: Thirty-three general surgery residents and 37 faculty members from 3 institutions participated in a regional MOE. Residents were examined in three 20-minute sessions. Faculty examiners were given a wide selection of prescripted exam scenarios and instructed to use standardized grading rubrics during a brief orientation on the day of the exam. All participants were surveyed on their overall experience. RESULTS: Of 33 participating residents, 26 (79%) passed the MOE (92% of R5, 91% R4, and 50% of R3). Response rates were 91% for residents, and 57% for faculty members respectively. Most respondents were satisfied with the overall exam experience (88%), standardized question quality (86%) and question variety (82%). A total of 92% of respondents agreed that the time, effort, and cost of the MOE was justified by its educational value to residents. Higher medical knowledge ratings assigned by faculty examiners correlated with stronger trainee performance (ß = 0.48; 95% confidence interval [CI] 0.29-0.66), while patient care and interpersonal communication skill ratings were not associated with trainee performance. The standardized grading rubric achieved moderate inter-rater reliability among examiner pairs with 70.6% agreement (Kappa 0.47). CONCLUSIONS: General Surgery residents and faculty perceived the standardized multi-institutional MOE to be a highly satisfactory educational experience and valuable assessment tool. Developing a repertoire of scripted exam scenarios made it feasible to recruit sufficient faculty participants, and standardizing grading rubrics allowed for a consistent exam experience with moderate inter-rater reliability.