A randomized controlled trial evaluating a theory driven, complex intervention centered on task sharing and mobile health to improve selfcare and outcomes in heart failure - The PANACEA-HF RCT: Design and rationale.

Background: We developed a three-pronged complex intervention to improve selfcare and deliver whole person care for patients with heart failure, underpinned by the 'extant cycle' theory - a theory based on our formative work. Methods: This is a 3 centre, 2-arm, 1:1, open, adaptive stratified, randomized controlled trial. We included patients aged ≥ 18 years with heart failure, taking any of the key guideline directed medical treatments, with a history of or currently on a high ceiling diuretic. We excluded end stage renal disease, clinically diagnosed severe mental illness or cognitive dysfunction and having no caregivers. Interventions included, (i) trained hospital based lay health worker mediated assessment of patients' current selfcare behaviour, documenting barriers and facilitators and implementing a plan to 'transition' the patient toward optimal selfcare. (ii) m-health mediated remote monitoring and (iii) dose optimization through a 'physician supervisor'. Results: We recruited 301 patients between Jan 2021 and Jan 2022. Mean age was 59.8 (±11.7) years, with 195 (64.8 %) from rural or semi-urban areas and 67.1 % having intermediate to low health literacy. 190 (63.1 %) had an underlying ischemic cardiomyopathy. In the intervention arm, 142 (94.1 %) had a Selfcare in Heart Failure Index (SCHFI) score of ≤70, with significant barriers being 'lack of knowledge' 105 (34.5 %) and 'behavioural passivity' 23 (7.5 %). Conclusion: This is the first South Asian trial evaluating a complex intervention underpinned by behaviour change theory for whole person heart failure care. These learnings can be applied to heart failure patient care in other resource constrained health systems.

Patient and caregiver reported facilitators of self-care among patients with chronic heart failure: report from a formative qualitative study.

Background: Adherence to a complex, yet effective medication regimen improves clinical outcomes in patients with chronic heart failure (CHF). However, patient adherence to an agreed upon plan for medication-taking is sub-optimal and continues to hover at 50% in developed countries. Studies to improve medication-taking have focused on interventions to improve adherence to guideline-directed medication therapy, yet few of these studies have integrated patients' perceptions of what constitutes effective strategies for improved medication-taking and self-care in everyday life. The purpose of this formative study was to explore patient perceived facilitators of selfcare and medication-taking. Methods: We conducted in-depth interviews of patients with long standing heart failure admitted to the cardiology and internal medicine wards of a South Indian tertiary care hospital. We purposively sampled using the following criteria: sex, socio-economic status, health literacy and patient reported medication adherence in the month prior to hospitalization. We employed inductive coding to identify facilitators. At the end of 15 interviews (eight patients and seven caregivers; seven patient-caregiver dyads), we arrived at theoretical saturation for facilitators. Results: Facilitators could be classified into intrinsic (patient traits - situational awareness, self-efficacy, gratitude, resilience, spiritual invocation and support seeking behavior) and extrinsic (shaped by the environment - financial security and caregiver support, company of children, ease of healthcare access, trust in provider/hospital, supportive environment and recognizing the importance of knowledge). Conclusions: We identified and classified a set of key patient and caregiver reported self-care facilitators among Indian CHF patients. The learnings from this study will be incorporated into an intervention package to improve patient engagement, overall self-care and patient-caregiver-provider dynamics.

Combinatorial regulation of phospholipid biosynthetic gene expression by the UME6, SIN3 and RPD3 genes.

The Ume6p-Sin3p-Rpd3p complex negatively regulates expression of genes containing a Ume6p binding site. However, these regulatory proteins also function independently to regulate gene expression both negatively and positively. The model system for this combinatorial regulation is the yeast phospholipid biosynthetic pathway. Sin3p negatively regulates the INO1, CHO1, CHO2 and OPI3 genes while Ume6p negatively regulates the INO1 gene and positively regulates the other genes. We have suggested that the positive regulation results from indirect effects on expression of the INO2 transcriptional activator gene. Here, we demonstrate that the effect of Ume6p on INO2 gene expression is also indirect. We also show that Rpd3p is a negative regulator of phospholipid biosynthetic gene expression. The ability of Ume6p, Sin3p and Rpd3p to differentially regulate expression of the phospholipid biosynthetic genes affects phospholipid composition. A sin3 mutant strain lacks detectable levels of phosphatidylethanolamine and elevated levels of phosphatidylcholine (PC) and a rpd3 mutant strain has reduced levels of PC. These alterations in membrane composition suggest that there may exist additional differences in regulation of phospholipid biosynthetic gene expression and that membrane compositions may be coordinated with other biological processes regulated by Ume6p, Sin3p and Rpd3p.

Cutaneous lymphatic drainage in patients with grossly involved nodal basins.

BACKGROUND: The development of lymphatic mapping techniques has facilitated the identification of the sentinel lymph node (SLN), the first node in the regional basin into which cutaneous lymphatics flow from a particular skin area. Previous studies have shown that SLN histology reflects the histology of the entire basin, because melanoma metastases progress in an orderly fashion, involving the SLN before higher nodes in the basin become involved with metastatic disease. It is uncertain whether these orderly cutaneous lymphatic flow patterns are maintained in grossly involved basins. Lymphatic mapping was performed in a population of melanoma patients with clinically palpable lymphadenopathy to address this question. We aimed to determine whether the presence of gross nodal disease in the basin alters lymphatic flow into that basin so that lymphatic mapping techniques are not applicable, and, in patients referred with a grossly involved basin, whether preoperative lymphoscintigraphy should be performed to identify other regional basins at risk for metastases. METHODS: Eight patients presented with grossly palpable disease in the regional basin and underwent preoperative lymphoscintigraphy. All patients with palpable disease and all basins indicated by lymphoscintigraphy to be at risk were dissected. Three patients presented with clinically palpable nodes at the time of diagnosis, and five developed nodal disease on clinical follow-up after undergoing initial wide local excision only. A total of 10 basins in the eight patients were dissected. Of these, eight of the basins had grossly palpable regional nodal disease, and the other two basins were identified by preoperative lymphoscintigraphy as being at risk for metastases. The SLN was identified with intraoperative mapping, harvested, and submitted to pathology. Complete therapeutic lymph node dissections were performed following the SLN harvest in the basins with grossly palpable disease. SLN biopsy alone was performed in the two basins that did not have clinically palpable adenopathy but showed cutaneous lymphatic flow from the scintigram. RESULTS: Sixteen SLNs were harvested from these eight basins with grossly palpable disease, and 14 (87.5%) contained tumor. In each case, one of the SLNs was the grossly palpable node, and in six of the basins (75%) it was the only site of melanoma metastases. An additional 190 higher level, non-SLNs were removed, 32 (16.8%) of which contained microscopic foci of metastatic melanoma (P = .015). The null hypothesis that melanoma nodal metastasis is a random event is rejected. Two patients with trunk melanoma primary sites were identified to have other basins at risk for metastatic disease on lymphoscintigraphy. SLN biopsies were performed in these two patients, and one had microscopic nodal disease in the SLN. CONCLUSIONS: These data support the fact that cutaneous lymphatic drainage patterns are maintained in patients with grossly involved basins, thus buttressing the idea that the SLN is the node most likely to develop metastatic disease. Gross disease in the basin does not significantly alter cutaneous lymphatic flow into the regional basin, as the sentinel lymph node identified under these circumstances is the same as with the grossly involved node. Preoperative lymphoscintigraphy in patients who present with grossly involved nodes in one basin may identify other regional basins with micrometastatic disease and deserves further study in this setting.

The clinical relevance of sentinel lymph nodes identified with radiolymphoscintigraphy.

BACKGROUND: The purpose of this case report is to illustrate the utility of radio-guided mapping of sentinel lymph nodes (SLN's) as demonstrated by the technique's successful identification of nodes containing metastatic disease that would have been left behind if only the visual-oriented vital blue dye mapping technique had been used. METHOD: The patient underwent preoperative lymphoscintigraphy and intra-operative lymphatic mapping using vital blue dye and radiolymphoscintigraphy using the Neoprobe (handheld gamma probe). Nodes which were blue and/or "hot" (i.e., radioactive counts were three times the background count) were considered SLN's. RESULTS: Four SLN's were harvested, all of which were "hot" but only one of which was both "hot" and blue. Pathology revealed that the two SLN's positive for metastatic disease were not blue. CONCLUSION: While the blue dye lymphatic mapping technique provides the surgeon with a visual road map in the identification of SLN's, the Neoprobe increases the success rate of localization when compared to vital blue dye mapping due to the reliable migration of radiocolloid to the SLN's in the regional basin. Radiolymphoscintigraphy also increases the accuracy and efficiency of the SLN harvest by providing a directed dissection to the level of the nodes in the basin. The Neoprobe increases the yield of SLN's, some of which are clinically relevant since they contain metastatic disease.

Florida's undeclared epidemic: malignant melanoma.

Contrary to the trend of early diagnosis observed in other parts of the world, in Florida melanoma is still being discovered in the more advanced stages. This is characterized by thicker lesions at diagnosis, which are hallmarked by bleeding, itching, ulceration, and increased vertical growth. In a study of 1,626 cutaneous melanoma patients at the H. Lee Moffitt Cancer Center in Florida, three prognostic factors, tumor thickness, Clark level, and presence of ulceration in the primary tumor, have remained relatively constant over an eight-year period (1987-1994). Despite the lack of change in tumor thickness in the last four years, mortality rate is decreasing, possibly due to more effective treatments. Regardless of these apparent improvements in mortality rates, definite progress must be made in the early detection of malignant melanoma through the initiation of statewide programs of lay public and professional education. In addition, it is proposed that the establishment of statewide screening programs of the Caucasian population with skin phenotypes 1 and 2 will also facilitate the early diagnosis of melanoma in the future, improve the outlook for these patients, and begin to address a major public health problem in the state of Florida.

Redefining cutaneous lymphatic flow: the necessity of preoperative lymphoscintigraphy in the management of malignant melanoma.

OBJECTIVE: The purpose of this study is to emphasize the instrumental role of preoperative lymphoscintigraphy in the surgical treatment of patients with malignant melanoma. SUMMARY BACKGROUND DATA: The efficacy of lymphoscintigraphy is reflected in its ability to reveal cutaneous lymphatic drainage to regional nodal basins that are at risk for melanoma metastases but not necessarily discernable to be at risk through standard historical anatomical guidelines or clinical experience. This preoperative lymphatic mapping technique has contributed greatly to the accuracy and efficiency of staging procedures including sentinel node biopsy and elective lymph node dissection. PATIENTS AND METHODS: After informed consent, a selected series of four patients with primary melanomas located in watershed areas of the body (left neck, right mid-abdomen, right scapula, left back) and two patients with extremity melanomas (right distal forearm and left ankle) underwent pre-operative lymphoscintigraphy to identify all basins for metastases. RESULTS: In all of the cases, lymphatic drainage occurred in an unusual and unexpected basin that could not have been predicted clinically and in three of the cases the resected basins contained positive sentinel nodes. If not for the preoperative lymphoscintigraphy, these nodal basins would not have been resected and metastatic disease would have been left behind. In addition, the staging of the melanoma patient would have been inaccurate. CONCLUSION: If the sentinel node biopsy of elective lymph node dissection (ELND) were based on clinical predictions only, nodes equally at risk for metastatic disease would not have been resected and in some cases, nodal basins not at risk for metastases would have been resected unnecessarily. Without lymphoscintigraphy, the validity and efficacy of the ELND or the sentinel node biopsy for nodal staging is greatly compromised. These six case studies illustrate the difficulty of predicating lymphatic drainage from primary sites located on the head and neck, truck and even the extremities and demonstrate the indispensability of preoperative lymphoscintigraphy in the management of malignant melanoma.

Lymphatic Mapping for Melanoma: Long-term Results of Regional Nodal Sampling With Radioguided Surgery.

BACKGROUND: Lymphatic mapping and sentinel lymph node (SLN) biopsy are new techniques used in the surgical treatment of patients with malignant melanoma. These procedures have the potential to change the surgical treatment of the disease to provide a more rational approach to adjuvant therapy. METHODS: A prospective database of melanoma patients undergoing lymphatic mapping and SLN biopsy was reviewed to identify prognostic factors for overall and disease-free survival in this patient population. RESULTS: Five-year overall and disease-free survival was 92.3% and 79.0%, with a median follow-up of 17 months. The number of histologically positive SLNs was the most powerful predictor of overall and disease-free survival. Patients with no histologically positive SLNs had a five-year overall and disease-free survival of 97.9% and 93.3%, respectively. Tumor ulceration and Clark level greater than or equal to III were the significant prognostic factors for survival. CONCLUSIONS: The use of lymphatic mapping and SLN biopsy effectively stages patients with primary cutaneous melanoma. Additionally, the presence of histologically positive SLNs is the most powerful indicator of overall and disease-free survival for these patients.