Cervical cancer treatment in Rwanda: Resource-driven adaptations, quality indicators, and patient outcomes.

OBJECTIVE: Most cervical cancer cases and deaths occur in low- and middle-income countries, yet clinical research from these contexts is significantly underrepresented. We aimed to describe the treatment quality, resource-driven adaptations, and outcomes of cervical cancer patients in Rwanda. METHODS: A retrospective cohort study was conducted of all patients with newly diagnosed cervical cancer enrolled between April 2016 and June 2018. Data were abstracted from medical records and analyzed using descriptive statistics, Kaplan Meier methods, and Cox proportional hazards regression. RESULTS: A total of 379 patients were included; median age 54 years, 21% HIV-infected. A majority (55%) had stage III or IV disease. Thirty-four early-stage patients underwent radical hysterectomy. Of 254 patients added to a waiting list for chemoradiation, 114 ultimately received chemoradiation. Of these, 30 (26%) received upfront chemoradiation after median 126 days from diagnosis, and 83 (73%) received carboplatin/paclitaxel while waiting, with a median 56 days from diagnosis to chemotherapy and 207 days to chemoradiation. There was no survival difference between the upfront chemoradiation and prior chemotherapy subgroups. Most chemotherapy recipients (77%) reported improvement in symptoms. Three-year event-free survival was 90% with radical hysterectomy (95% CI 72-97%), 66% with chemoradiation (95% CI 55-75%), and 12% with chemotherapy only (95% CI 6-20%). CONCLUSIONS: Multi-modality treatment of cervical cancer is effective in low resource settings through coordinated care and pragmatic approaches. Our data support a role for temporizing chemotherapy if delays to chemoradiation are anticipated. Sustainable access to gynecologic oncology surgery and expanded access to radiotherapy are urgently needed.

Climate Change and Cardiovascular Health: A Systematic Review.

Importance: Climate change may increase the risk of adverse cardiovascular outcomes by causing direct physiologic changes, psychological distress, and disruption of health-related infrastructure. Yet, the association between numerous climate change-related environmental stressors and the incidence of adverse cardiovascular events has not been systematically reviewed. Objective: To review the current evidence on the association between climate change-related environmental stressors and adverse cardiovascular outcomes. Evidence Review: PubMed, Embase, Web of Science, and Cochrane Library were searched to identify peer-reviewed publications from January 1, 1970, through November 15, 2023, that evaluated associations between environmental exposures and cardiovascular mortality, acute cardiovascular events, and related health care utilization. Studies that examined only nonwildfire-sourced particulate air pollution were excluded. Two investigators independently screened 20 798 articles and selected 2564 for full-text review. Study quality was assessed using the Navigation Guide framework. Findings were qualitatively synthesized as substantial differences in study design precluded quantitative meta-analysis. Findings: Of 492 observational studies that met inclusion criteria, 182 examined extreme temperature, 210 ground-level ozone, 45 wildfire smoke, and 63 extreme weather events, such as hurricanes, dust storms, and droughts. These studies presented findings from 30 high-income countries, 17 middle-income countries, and 1 low-income country. The strength of evidence was rated as sufficient for extreme temperature; ground-level ozone; tropical storms, hurricanes, and cyclones; and dust storms. Evidence was limited for wildfire smoke and inadequate for drought and mudslides. Exposure to extreme temperature was associated with increased cardiovascular mortality and morbidity, but the magnitude varied with temperature and duration of exposure. Ground-level ozone amplified the risk associated with higher temperatures and vice versa. Extreme weather events, such as hurricanes, were associated with increased cardiovascular risk that persisted for many months after the initial event. Some studies noted a small increase in cardiovascular mortality, out-of-hospital cardiac arrests, and hospitalizations for ischemic heart disease after exposure to wildfire smoke, while others found no association. Older adults, racial and ethnic minoritized populations, and lower-wealth communities were disproportionately affected. Conclusions and Relevance: Several environmental stressors that are predicted to increase in frequency and intensity with climate change are associated with increased cardiovascular risk, but data on outcomes in low-income countries are lacking. Urgent action is needed to mitigate climate change-associated cardiovascular risk, particularly in vulnerable populations.

Mechanisms of left ventricular systolic dysfunction in light chain amyloidosis: a multiparametric cardiac MRI study.

Background: Cardiac systolic dysfunction is a poor prognostic marker in light-chain (AL) cardiomyopathy, a primary interstitial disorder; however, its pathogenesis is poorly understood. Purpose: This study aims to analyze the effects of extracellular volume (ECV) expansion, a surrogate marker of amyloid burden on myocardial blood flow (MBF), myocardial work efficiency (MWE), and left ventricular (LV) systolic dysfunction in AL amyloidosis. Methods: Subjects with biopsy-proven AL amyloidosis were prospectively enrolled (April 2016-June 2021; Clinicaltrials.gov ID NCT02641145) and underwent cardiac magnetic resonance imaging (MRI) to quantify rest MBF by perfusion imaging, LV ejection fraction (LVEF) by cine MRI, and ECV by pre- and post-contrast T1 mapping. The MWE was estimated as external cardiac work from the stroke volume and mean arterial pressure normalized to the LV myocardial mass. Results: Rest MBF in 92 subjects (62 ± 8 years, 52 men) with AL amyloidosis averaged 0.87 ± 0.21 ml/min/g and correlated with MWE (r = 0.42; p < 0.001). Rest MBF was similarly low in subjects with sustained hematologic remission after successful AL amyloidosis therapy (n = 21), as in those with recently diagnosed AL amyloidosis. Both MBF and MWE decreased by ECV tertile (p < 0.01 for linear trends). The association of ECV with MWE comprised a direct effect (84% of the total effect; p < 0.001) on MWE from adverse interstitial remodeling assessed by ECV and an indirect effect (16% of the total effect; p < 0.001) mediated by MBF. There was a significant base-to-apex gradient of rest MBF in subjects with higher amyloid burden. Conclusions: In AL amyloidosis, both MBF and MWE decrease as cardiac amyloid burden and ECV expansion increase. Both structural and vascular changes from ECV expansion and myocardial amyloid burden appear to contribute to lower MWE.

Physiologic and molecular characterization of a murine model of right ventricular volume overload.

Pulmonary insufficiency (PI) is a common long-term sequel after repair of tetralogy of Fallot, causing progressive right ventricular (RV) dilation and failure. We describe the physiologic and molecular characteristics of the first murine model of RV volume overload. PI was created by entrapping the pulmonary valve leaflets with sutures. Imaging, catheterization, and exercise testing were performed at 1, 3, and 6 mo and compared with sham controls. RNA from the RV free wall was hybridized to Agilent whole genome oligonucleotide microarrays. Volume overload resulted in RV enlargement, decreased RV outflow tract shortening fraction at 1 mo followed by normalization at 3 and 6 mo (39 ± 2, 44 ± 2, and 41 ± 2 vs. 46 ± 3% in sham), early reversal of early and late diastolic filling velocities (E/A ratio) followed by pseudonormalization (0.87 ± 0.08, 0.82 ± 0.08, and 0.96 ± 0.08 vs. 1.04 ± 0.03; P < 0.05), elevated end-diastolic pressure (7.6 ± 0.7, 6.9 ± 0.8, and 7 ± 0.5 vs. 2.7 ± 0.2 mmHg; P < 0.05), and decreased exercise duration (26 ± 0.4, 26 ± 1, and 22 ± 1.3 vs. 30 ± 1.1 min; P < 0.05). Subendocardial RV fibrosis was evident by 1 mo. At 1 mo, 372 genes were significantly downregulated. Mitochondrial pathways and G protein-coupled receptor signaling were the most represented categories. At 3 mo, 434 genes were upregulated and 307 downregulated. While many of the same pathways continued to be downregulated, TNF-α, transforming growth factor-ß(1) (TGF-ß(1)), p53-signaling, and extracellular matrix (ECM) remodeling transitioned from down- to upregulated. We describe a novel murine model of chronic RV volume overload recapitulating aspects of the clinical disease with gene expression changes suggesting early mitochondrial bioenergetic dysfunction, enhanced TGF-ß signaling, ECM remodeling, and apoptosis.

Myocardial Characterization for Early Diagnosis, Treatment Response Monitoring, and Risk Assessment in Systemic Light-Chain Amyloidosis.

Aims: In systemic light-chain (AL) amyloidosis, cardiac involvement portends poor prognosis. Using myocardial characteristics on magnetic resonance imaging (MRI), this study aimed to detect early myocardial alterations, to analyze temporal changes with plasma cell therapy, and to predict risk of major adverse cardiac events (MACE) in AL amyloidosis. Methods and Results: Participants with recently diagnosed AL amyloidosis were prospectively enrolled. Presence of AL cardiomyopathy (AL-CMP vs. AL-non-CMP) was determined by abnormal cardiac biomarkers. MRI was performed at baseline and 6 months, with 12-month imaging in AL-CMP cohort. MACE was defined as all-cause death, heart failure hospitalization, or cardiac transplantation. Mayo AL stage was based on troponin T, NT-proBNP, and difference in free light chains. The study cohort included 80 participants (median age 62 years, 58% males). Median left ventricular extracellular volume (ECV) was significantly higher in AL-CMP (53% vs. 30%, p<0.001). ECV was abnormal (>32%) in all AL-CMP and in 47% of AL-non-CMP. ECV tended to increase at 6 months and decreased significantly from 6 to 12 months in AL-CMP (median -3%, p=0.011). ECV was strongly associated with MACE (p<0.001), and improved MACE prediction when added to Mayo AL stage (p=0.002). ECV≤32% identified a cohort without MACE, while ECV>48% identified a cohort with 74% MACE. Conclusions: In AL amyloidosis, ECV detects subclinical cardiomyopathy. ECV tends to increase from baseline to 6 months and decreases significantly from 6 and 12 months of plasma cell therapy in AL-CMP. ECV provides excellent risk stratification and offers additional prognostic performance over Mayo AL stage.

Laboratory-Generated Urine Toxicology Interpretations: A Mixed Methods Study.

BACKGROUND: Clinicians frequently order urine drug testing (UDT) for patients on chronic opioid therapy (COT), yet often have difficulty interpreting test results accurately. OBJECTIVES: To evaluate the implementation and effectiveness of a laboratory-generated urine toxicology interpretation service for clinicians prescribing COT. STUDY DESIGN: Type II hybrid-convergent mixed methods design (implementation) and pre-post prospective cohort study with matched controls (effectiveness). SETTING: Four ambulatory sites (2 primary care, 1 pain management, 1 palliative care) within 2 US academic medical institutions. METHODS: Interpretative reports were generated by the clinical chemistry laboratory and were provided to UDT ordering providers via inbox message in the electronic health record (EHR). The Partners Institutional Review Board approved this study.Participants were primary care, pain management, and palliative care clinicians who ordered liquid chromatography-mass spectrometry UDT for COT patients in clinic. Intervention was a laboratory-generated interpretation service that provided an individualized interpretive report of UDT results based on the patient's prescribed medications and toxicology metabolites for clinicians who received the intervention (n = 8) versus matched controls (n = 18).Implementation results included focus group and survey feedback on the interpretation service's usability and its impact on workflow, clinical decision making, clinician-patient relationships, and interdisciplinary teamwork. Effectiveness outcomes included UDT interpretation concordance between the clinician and laboratory, documentation frequency of UDT results interpretation and communication of results to patients, and clinician prescribing behavior at follow-up. RESULTS: Among the 8 intervention clinicians (median age 58 [IQR 16.5] years; 2 women [25%]) on a Likert scale from 1 ("strongly disagree") to 5 ("strongly agree"), 7 clinicians reported at 6 months postintervention that the interpretation service was easy to use (mean 5 [standard deviation {SD}, 0]); improved results comprehension (mean 5 [SD, 0]); and helped them interpret results more accurately (mean 5 [SD, 0]), quickly (mean 4.67 [SD, 0.52]), and confidently (mean 4.83 [SD, 0.41]). Although there were no statistically significant differences in outcomes between cohorts, clinician-laboratory interpretation concordance trended toward improvement (intervention 22/32 [68.8%] to 29/33 [87.9%] vs. control 21/25 [84%] to 23/30 [76.7%], P = 0.07) among cases with documented interpretations. LIMITATIONS: This study has a low sample size and was conducted at 2 large academic medical institutions and may not be generalizable to community settings. CONCLUSIONS: Interpretations were well received by clinicians but did not significantly improve laboratory-clinician interpretation concordance, interpretation documentation frequency, or opioid-prescribing behavior.

Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection.

Bacteriophage are abundant at sites of bacterial infection, but their effects on mammalian hosts are unclear. We have identified pathogenic roles for filamentous Pf bacteriophage produced by Pseudomonas aeruginosa (Pa) in suppression of immunity against bacterial infection. Pf promote Pa wound infection in mice and are associated with chronic human Pa wound infections. Murine and human leukocytes endocytose Pf, and internalization of this single-stranded DNA virus results in phage RNA production. This triggers Toll-like receptor 3 (TLR3)- and TIR domain-containing adapter-inducing interferon-ß (TRIF)-dependent type I interferon production, inhibition of tumor necrosis factor (TNF), and the suppression of phagocytosis. Conversely, immunization of mice against Pf prevents Pa wound infection. Thus, Pf triggers maladaptive innate viral pattern-recognition responses, which impair bacterial clearance. Vaccination against phage virions represents a potential strategy to prevent bacterial infection.

Demonstration of Infectious Transgression Through the Skull Base Occurring 9 Years After Pituitary Adenoma Resection.

BACKGROUND: Sellar infections represent less than 1% of all sellar lesions and can be life-threatening. These infections occur de novo in up to 70% of patients or can less commonly develop after surgical treatment of another primary lesion, such as a pituitary adenoma. CASE DESCRIPTION: We report a unique case of a 27-year-old woman with a recurrent pituitary adenoma treated with 2 previous transsphenoidal resections. She ultimately presented with hypopituitarism, followed by headaches, malaise, chills, and visual-field and acuity deficits 9 years after her second transsphenoidal resection. During the second operation, the sellar floor was reconstructed with hydroxyapatite bone cement. On the most recent presentation, magnetic resonance imaging of the brain and pituitary demonstrated a residual sellar mass accompanied by significant enhancement and T2 hyperintensity of the infundibulum, hypothalamus, optic chiasm, and optic tracts. The patient was started on empiric antibiotics and steroids before frank purulence in the sella was discovered and removed by transsphenoidal endoscopy. Cultures were positive for methicillin-sensitive Staphylococcus aureus and Propionibacterium acnes. At her 3-month follow-up evaluation, the patient had complete resolution of her symptoms and radiographic findings. CONCLUSIONS: This case demonstrates the fact that patients with pituitary lesions who have foreign material used for surgical closure can present with infections many years after the initial intervention. Furthermore, with appropriate clinical diagnosis and treatment, the reactive inflammation caused by sellar infection is reversible. We review the literature regarding the risk factors and management strategies for delayed postoperative sellar infections.

Filamentous Bacteriophage Promote Biofilm Assembly and Function.

Biofilms-communities of bacteria encased in a polymer-rich matrix-confer bacteria with the ability to persist in pathologic host contexts, such as the cystic fibrosis (CF) airways. How bacteria assemble polymers into biofilms is largely unknown. We find that the extracellular matrix produced by Pseudomonas aeruginosa self-assembles into a liquid crystal through entropic interactions between polymers and filamentous Pf bacteriophages, which are long, negatively charged filaments. This liquid crystalline structure enhances biofilm function by increasing adhesion and tolerance to desiccation and antibiotics. Pf bacteriophages are prevalent among P. aeruginosa clinical isolates and were detected in CF sputum. The addition of Pf bacteriophage to sputum polymers or serum was sufficient to drive their rapid assembly into viscous liquid crystals. Fd, a related bacteriophage of Escherichia coli, has similar biofilm-building capabilities. Targeting filamentous bacteriophage or the liquid crystalline organization of the biofilm matrix may represent antibacterial strategies.