Primary care outreach and decision counseling for lung cancer screening.

INTRODUCTION: Lung cancer screening rates are very low despite a level B recommendation from the United States Preventive Services Task Force since 2013 and clear evidence that lung cancer screening reduces mortality. The Center for Medicare and Medicaid Services requires shared decision-making (SDM) for lung cancer screening reimbursement. The objective of this study was to determine the effect of an SDM intervention on lung cancer screening in primary care. METHODS: The study design was a single-arm clinical trial design. The intervention included phone contact outside of a primary care visit and the use of the Decision Counseling Program ®, an online interactive decision aid focused on determining the factors which influence patients to screen or not screen, prioritizing those factors, and determining a decision preference score. The primary outcome was the completion of low-dose computed tomography scan (LDCT) 1 year after the SDM session compared in participants versus nonparticipants. RESULTS: From six practices, there were 1359 potentially eligible patients in electronic medical record data, and 336 were reached to assess eligibility criteria. A total of 80 patients consented to be in the study, 64 completed a decision counseling session and 16 did not complete a session. Among the 64 people who agreed to have decision counseling, 45% had LDCT, higher than typically seen in routine clinical practice. Although not a comparable group, among the 16 people who declined decision counseling, none had LDCT. CONCLUSIONS: Decision counseling is a promising intervention that might support SDM in the context of improving uptake of lung cancer screening in primary care. However, further, larger studies are needed.

Fast and slow skeletal myosin binding protein-C and aging.

Aging is associated with skeletal muscle strength decline and cardiac diastolic dysfunction. The structural arrangements of the sarcomeric proteins, such as myosin binding protein-C (MyBP-C) are shown to be pivotal in the pathogenesis of diastolic dysfunction. Yet, the role of fast (fMyBP-C) and slow (sMyBP-C) skeletal muscle MyBP-C remains to be elucidated. Herein, we aimed to characterize MyBP-C and its paralogs in the fast tibialis anterior (TA) muscle from adult and old mice. Immunoreactivity preparations showed that the relative abundance of the fMyBP-C paralog was greater in the TA of both adult and old, but no differences were noted between groups. We further found that the expression level of cardiac myosin binding protein-C (cMyBP-C), an important modulator of cardiac output, was lowered by age. Standard SDS-PAGE along with Pro-Q Diamond phosphoprotein staining did not identify age-related changes in phosphorylated MyBP-C proteins from TA and cardiac muscles; however, it revealed that MyBP-C paralogs in fast skeletal and cardiac muscle were highly phosphorylated. Mass spectrometry further identified glycogen phosphorylase, desmin, actin, troponin T, and myosin regulatory light chain 2 as phosphorylated myofilament proteins in both ages. MyBP-C protein-bound carbonyls were determined using anti-DNP immunostaining and found the carbonyl level of fMyBP-C, sMyBP-C, and cMyBP-C to be similar between old and adult animals. In summary, our data showed some differences regarding the MyBP-C paralog expression and identified an age-related reduction of cMyBP-C expression. Future studies are needed to elucidate which are the age-driven post-translational modifications in the MyBP-C paralogs.

Identifying the optimal developmental age of human pluripotent stem cell-derived midbrain dopaminergic progenitors for transplantation in a rodent model of Parkinson's disease.

Donor cell age can have a significant impact on transplantation outcomes. Despite the rapid advancement of human pluripotent stem cell (hPSC)-derived dopaminergic (DA) progenitors to the clinic for transplantation into Parkinson's Disease (PD), surprisingly limited data exists regarding the influence of cellular age on neural graft survival, composition, and integration. Here we examined the impact of transplanting ventral midbrain (VM) progenitors at varying days of differentiation (from day 13-30) into a rodent PD model, comparing two hPSC lines (an embryonic and an induced pluripotent cell line, hESC and hiPSC, respectively). Both hPSC lines expressed GFP under the promoter PITX3 enabling specific tracking of graft-derived DA neurons. Post-mortem analysis at 6 months revealed larger grafts from Day19 (D19), D22 and D25 progenitors, yet contained a higher proportion of non-DA and poorly specified (FOXA2-) cells. While D13 and D30 progenitors yielded smaller grafts. D13-derived grafts had the highest DA neuron proportion and proportionally more GIRK2+ DA neurons, the subpopulation critical for motor function. These younger progenitor grafts maintained their capacity to innervate developmentally relevant DA targets, with increased innervation capacity per DA neuron, collectively resulting in restoration of motor deficits with equal or greater proficiency than older donor cells. While donor age effects were reproducible for a given hPSC line and trends were similar between the two hPSC lines, grafts of D13 hiPSC-derived progenitors showed a 6-fold greater density of DA neurons compared to D13 hESC-derived grafts, highlighting between-line variability. These findings show that hPSC-derived VM donor age has a direct impact on graft survival, composition and maturation, and that careful assessment, on a line-to-line basis is required prior to translation.

Adrenalectomy for incidental and symptomatic phaeochromocytoma: retrospective multicentre study based on the Eurocrine® database.

BACKGROUND: Phaeochromocytoma is sometimes not diagnosed before surgery and may present as an adrenal incidentaloma. The aim of this study was to investigate differences in clinical presentation and perioperative outcome in patients with subclinical and symptomatic phaeochromocytoma, and in patients operated with and without preoperative α-blockade. METHODS: This was a retrospective observational study of patients with a histopathological diagnosis of phaeochromocytoma registered in Eurocrine®, the European registry for endocrine tumours, between 1 January 2015 and 31 March 2020. Patient characteristics, clinical presentation, tumour detection, and perioperative variables were analysed. RESULTS: Some 551 patients were included. Of these, 486 patients (88.2 per cent) had a preoperative diagnosis of phaeochromocytoma. Tumours were detected as incidentalomas in 239 patients (43.4 per cent) and 265 (48.1 per cent) had a preoperative diagnosis of hypertension. Preoperative α-blockade was more frequently used in patients with a known phaeochromocytoma (350, 90.9 per cent) than in patients with other indications for adrenalectomy (16, 31 per cent). Complications did not differ between patients who had surgery because of catecholamine excess compared with those who had other indications for surgery (19 (3.9 per cent) versus 2 (3 per cent); P = 0.785), nor did the conversion rate from minimally invasive to open surgery differ between the groups. There were no obvious differences in complications, according to the Clavien-Dindo classification, based on preoperative α-blockade or not. CONCLUSION: Subclinical phaeochromocytoma detected incidentally is common. A significant proportion of patients with phaeochromocytoma did not have α-blockade before surgery, without an apparent effect on complications.

Phaeochromocytoma is an unusual adrenal tumour with hormonal overproduction of catecholamines leading to a severe condition, including extreme hypertension in some situations. It is treated with surgery. Medical treatment before surgery is used to minimize surgical complications related to high blood pressure. A large proportion of phaeochromocytomas are detected incidentally, without symptoms, on radiological examination for other reasons. The aim of this study was to investigate differences in patient characteristics and surgical results in patients operated with or without symptoms of phaeochromocytoma. Patients registered in the large, European database, Eurocrine®, between 2015 and 2020 were included in the study. The study showed that phaeochromocytoma without symptoms is common. Medical treatment before surgery does not seem to affect complications.

Systemic acidemia impairs cardiac function in critically Ill patients.

BACKGROUND: Acidemia, is associated with reduced cardiac function in animals, but no studies showing an effect of acidemia on cardiac function in humans are reported. In the present study, we examined the effect of acidemia on cardiac function assessed with transpulmonary thermodilution technique with integrated pulse contour analysis (Pulse Contour Cardiac Output, PiCCO™) in a large cohort of critically ill patients. METHODS: This was a prospective multicenter observational cross-sectional study of 297 patients from 6 intensive care units in London, England selected from all patients admitted consecutively between May 2018 and March 2019. Measurements of lowest plasma pH and concurrent assessment of cardiac function were obtained. FINDINGS: There was a significant difference between two pH categories (pH ≤ 7.28 vs. pH > 7.28) for the following variables of cardiac function: SVI (difference in means 32.7; 95% CI: 21 to 45 mL/m2; p < 0.001); GEF (18; 95% CI: 11 to 26%; p < 0.001), dPmax (-331; 95% CI: -510 to -153 mmHg/s; p = 0.001), CFI (0.7; 95% CI: 0.2 to 1.3 1/min; p = 0.01) and CPI (0.09; 95% CI: 0.03 to 0.15 W/m2; p < 0.001). However, there was no significant difference in CI (0.13; 95% CI: -0.20 to 0.47 L/min/m2; p = 0.12) between the pH categories. Also, a significant relationship was found between the quantitative pH and the following variables: SVI (132; 95% CI: 77 to 188 mL/m2; p < 0.001), GEF (74.7; 95% CI: 37.1 to 112.4%; p < 0.001), dPmax (-1587; 95% CI: -2361 to -815 mmHg/s; p < 0.001), CFI (3.5; 95% CI: 0.9 to 6.1 /min; p = 0.009), CPI (0.62; 95% CI: 0.36 to 0.88 W/m2; p < 0.001) and CI (regression coefficient 1.96; 95% CI:0.45 to 3.47 L/min/m2; p = 0.01). INTERPRETATION: Acidemia is associated with impaired cardiac function in seriously ill patients hospitalized in the intensive care unit supporting the potential value of early diagnosis and improvement of arterial pH in these patients. FUNDING: The study was partially supported by unrestricted funds from the UCLA School of Medicine.

Effect of dermatological consultation on survival in patients with checkpoint inhibitor-associated cutaneous toxicity.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) are a common side-effect of immune checkpoint inhibitors (ICIs). However, prior work examining these toxicities in detail has considered only the fraction of events evaluated by dermatologists. Associations between dermatology referral, cirAE treatment and survival outcomes remain underexplored across care settings. OBJECTIVES: To comprehensively categorize cirAE patterns among all patients treated with immunotherapy at our institution, and to evaluate: (i) the effect of dermatology referral on cirAE treatment and (ii) the impact of cirAE treatment on survival. METHODS: This was a retrospective cohort analysis of patients with cancer who initiated ICI therapy between 1 January 2016 and 8 March 2019 and developed one or more cirAEs, as screened for using International Classification of Diseases 10th revision codes and confirmed via manual chart review (n = 358). All relevant information documented prior to 31 March 2020 was included. RESULTS: CirAEs evaluated by dermatologists were significantly more likely to be treated than cirAEs that were not referred (odds ratio 6·08, P < 0·001). Patients who received any cirAE treatment had improved progression-free survival [hazard ratio (HR) 0·59, P = 0·001] and overall survival (HR 0·58, P = 0·007) compared with those who did not. CONCLUSIONS: CirAEs evaluated by dermatologists were significantly more likely to be treated than cirAEs that were not referred, and patients who received any treatment for a cirAE had improved survival outcomes.

Human Health Risk from Consumption of Marine Fish Contaminated with DDT and Its Metabolites in Maputo Bay, Mozambique.

Many countries with incidence of malaria, including those surrounding Maputo Bay, use dichloro-diphenyl-trichloroethane (DDT) to reduce mosquitoes. This study is the first to estimate the human health risk associated with consumption of marine fish from Maputo Bay contaminated with DDTs. The median for ∑DDTs was 3.8 ng/g ww (maximum 280.9 ng/g ww). The overall hazard ratio for samples was 1.5 at the 75th percentile concentration and 28.2 at the 95th percentile. These calculations show increased potential cancer risks due to contamination by DDTs, data which will help policy makers perform a risk-benefit analysis of DDT use in malaria control programs in the region.

Acute intravenous exposure to silver nanoparticles during pregnancy induces particle size and vehicle dependent changes in vascular tissue contractility in Sprague Dawley rats.

The use of silver nanoparticles (AgNP) raises safety concerns during susceptible life stages such as pregnancy. We hypothesized that acute intravenous exposure to AgNP during late stages of pregnancy will increase vascular tissue contractility, potentially contributing to alterations in fetal growth. Sprague Dawley rats were exposed to a single dose of PVP or Citrate stabilized 20 or 110nm AgNP (700µg/kg). Differential vascular responses and EC50 values were observed in myographic studies in uterine, mesenteric arteries and thoracic aortic segments, 24h post-exposure. Reciprocal responses were observed in aortic and uterine vessels following PVP stabilized AgNP with an increased force of contraction in uterine artery and increased relaxation responses in aorta. Citrate stabilized AgNP exposure increased contractile force in both uterine and aortic vessels. Intravenous AgNP exposure during pregnancy displayed particle size and vehicle dependent moderate changes in vascular tissue contractility, potentially influencing fetal blood supply.

Concentrations and human health risk assessment of DDT and its metabolites in free-range and commercial chicken products from KwaZulu-Natal, South Africa.

Organochlorine pesticides such as dichlorodiphenyltrichloroethane (DDT) have been used in agriculture and for disease control purposes over many decades. Reports suggest that DDT exposure may result in a number of adverse effects in humans. In the KwaZulu-Natal Province of South Africa, DDT is sprayed annually in homes (indoor residual spraying) to control the mosquito vector of malaria. In the northern part of the Province, samples of free-range chicken meat (n = 48) and eggs (n = 13), and commercially produced chicken meat (n = 6) and eggs (n = 11), were collected and analysed. Of the free-range chicken meat samples, 94% (45/48) contained DDTs (ΣDDTs median 6.1 ng/g wet weight [ww], maximum 79.1 ng/g ww). Chicken egg contents were also contaminated (ΣDDTs in free-range eggs median 9544 ng/g ww, maximum 96.666 ng/g ww; and in commercial eggs median 1.3 ng/g ww, maximum 4.6 ng/g ww). The predominant DDT congener detected was p,p'-DDE in both free-range meat (>63%) and eggs (>66%), followed by p,p'-DDT and then p,p'-DDD. Based on estimated daily intake values, calculated human risk ratio (carcinogenic) values were >1 for DDTs detected in both free-range chicken products. Consumption of free-range eggs poses a particularly high health risk.

Salivary acinic cell carcinoma: reappraisal and update.

Epidemiologic and clinicopathologic features, therapeutic strategies, and prognosis for acinic cell carcinoma of the major and minor salivary glands are critically reviewed. We explore histopathologic, histochemical, electron microscopic and immunohistochemical aspects and discuss histologic grading, histogenesis, animal models, and genetic events. In the context of possible diagnostic difficulties, the relationship to mammary analog secretory carcinoma is probed and a classification is suggested. Areas of controversy or uncertainty, which may benefit from further investigations, are also highlighted.

Validation and adaptation of rapid neurodevelopmental assessment instrument for infants in Guatemala.

BACKGROUND: Timely detection of neurodevelopmental impairments in children can prompt referral for critical services that may prevent permanent disability. However, screening of impairments is a significant challenge in low-resource countries. We adapted and validated the rapid neurodevelopmental assessment (RNDA) instrument developed in Bangladesh to assess impairment in nine domains: primitive reflexes, gross and fine motor development, vision, hearing, speech, cognition, behaviour and seizures. METHODS: We conducted a cross-sectional study of 77 infants (0-12 months) in rural Guatemala in July 2012 and July 2013. We assessed inter-rater reliability and predictive validity between the 27-item RNDA and the 325-item Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) and concurrent validity based on chronic malnutrition, a condition associated with neurodevelopmental impairments. For both RNDA and BSID-III, standardized scores below 80 were defined as borderline impairment. RESULTS: Children came from rural households (92%), were born to indigenous women of Mayan descent (73%) and had moderate or severe growth stunting (43%). Inter-rater reliability for eight RNDA domains was of moderate to high reliability (weighted κ coefficients, 0.49-0.99). Children screened positive for impairment in fine motor (17%) and gross motor (14%) domains using the RNDA. The RNDA had good concurrent ability; infants who were growth stunted had higher mean levels of impairment in gross motor, speech and cognition domains (all p < 0.001). The RNDA took 20-30 min to complete compared with 45-60 min for BSID-III. CONCLUSIONS: Wide-scale implementation of a simple, valid and reliable screening tool like the RNDA by community health workers would facilitate early screening and referral of infants at-risk for neurodevelopmental impairment.

Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin.

Huntington's disease (HD), a progressive neurodegenerative disease, is caused by an expanded CAG triplet repeat producing a mutant huntingtin protein (mHTT) with a polyglutamine-repeat expansion. Onset of symptoms in mutant huntingtin gene-carrying individuals remains unpredictable. We report that synthetic polyglutamine oligomers and cerebrospinal fluid (CSF) from BACHD transgenic rats and from human HD subjects can seed mutant huntingtin aggregation in a cell model and its cell lysate. Our studies demonstrate that seeding requires the mutant huntingtin template and may reflect an underlying prion-like protein propagation mechanism. Light and cryo-electron microscopy show that synthetic seeds nucleate and enhance mutant huntingtin aggregation. This seeding assay distinguishes HD subjects from healthy and non-HD dementia controls without overlap (blinded samples). Ultimately, this seeding property in HD patient CSF may form the basis of a molecular biomarker assay to monitor HD and evaluate therapies that target mHTT.

The Incorporation of an Advanced Donation Program Into Kidney Paired Exchange: Initial Experience of the National Kidney Registry.

The continued growth of kidney paired donation (KPD) to facilitate transplantation for otherwise incompatible or suboptimal living kidney donors and recipients has depended on a balance between the logistics required for patients and the collaborating transplant centers. The formation of chains for KPD and the shipping of kidneys have permitted networks such as the National Kidney Registry (NKR) to offer KPD to patients over a transcontinental area. However, over the last 3 years, we have encountered patient requests for a more flexible experience in KPD to meet their individual needs often due to rigid time constraints. To accommodate these requests, we have developed an Advanced Donation Program (ADP) in which the donor desires to donate by a specific date, but their paired recipient has not yet been matched to a specific donor or scheduled for surgery. After obtaining careful informed consent from both the donor and paired recipient, 10 KPD chains were constructed using an ADP donor. These 10 ADP donors have facilitated 47 transplants, and thus far eight of their paired recipients have received a kidney within a mean of 178 (range 10-562) days. The ADP is a viable method to support time limited donors in a KPD network.

Antimicrobial management of septic arthritis of the hand and wrist.

PURPOSE: The optimal antimicrobial treatment for patients with hand or wrist septic arthritis is unknown. We report the treatment outcomes in patients with these infections. METHODS: The medical records of 40 consecutive adult patients with hand or wrist septic arthritis treated at our institution from 2000 to 2008 were retrospectively reviewed. The primary outcome measure was treatment failure (histopathologic or microbiologic evidence of relapsed infection from the same joint or a contiguous anatomic area). RESULTS: Involved joints were the wrist (n = 10, 25 %), metacarpal-phalangeal (n = 11, 27.5 %), proximal interphalangeal (n = 8, 20 %), distal interphalangeal (n = 10, 25 %), and thumb interphalangeal (n = 1, 2.5 %). Methicillin-sensitive (n = 15, 45 %) and -resistant (n = 7, 17.5 %) Staphylococcus aureus were the most common pathogens. Surgical therapies included open arthrotomy with debridement (n = 33, 82.5 %), arthroscopic debridement (n = 2, 5 %), and aspiration alone (n = 5, 12.5 %). Most patients (23/40, 58 %) received less than 1 week of parenteral antimicrobial therapy. Only two patients developed definite antimicrobial treatment failure, one of whom had an atypical mycobacterium infection. Patients with subacute to chronic infections were at high risk for finger amputation. CONCLUSIONS: When combined with surgical debridement, relatively short courses of parenteral antimicrobial treatment (<1 week) supplemented with oral therapy for an additional 2-3 weeks is usually sufficient antimicrobial therapy for hand or wrist septic arthritis.

Antibacterial activity of flavonoid 5.7.4’-trimethoxyflavone isolated from Praxelis clematides R.M. King & Robinson / Actividad antibacterial del flavonoide 5.7.4’-trimetoxiflavona aislada dePrexelis clematides R.M. King & Robinson

The flavonoids are a large class of polyphenolic compounds found in plants that are known to exhibit biological effects. In the study, the flavonoid 5.7.4’-trimethoxyflavone (TMF) extracted from Praxelis clematidea was evaluated for its antibacterial activity. Microdilution method was used for antibacterial assay of the flavonoid and eleven bacteria strains were used in the study for activities. The results were also compared with the standard drug, Chloramphenicol (100 ug/mL). The results obtained showed activity of the flavonoid against Gram positive and Gram negative bacteria.

Los flavonoides son una clase importante de compuestos polifenólicos encontrados en las plantas que se sabe que presentan efectos biológicos. En el estudio, el flavonoide 5.7.4 '-trimethoxyflavone (TMF) extraído de Praxelis clematidea fue evaluado por su actividad antibacteriana. Se utilizó el método de microdilución para el ensayo antibacteriano del flavonoide y once cepas de bacterias se usaron en el estudio de las actividades. Los resultados se compararon también con el fármaco estándar, Cloranfenicol (100 ug/mL). Los resultados obtenidos mostraron actividad del flavonoide contra bacterias Gram positivas y Gram negativas.

Phase I/II trial of nanomolecular liposomal annamycin in adult patients with relapsed/refractory acute lymphoblastic leukemia.

BACKGROUND: Treatment options for relapsed/refractory ALL in adult patients remain challenging. Annamycin is a highly lipophilic form of the anthracycline doxorubicin with the ability to bypass multidrug resistance mechanisms of cellular drug resistance. PATIENTS AND METHODS: We performed a phase I/II multicenter, open-label, study to determine the maximally tolerated dose (MTD) of nanomolecular liposomal annamycin in adult patients with refractory ALL. RESULTS: Thirty-one patients were enrolled; the MTD was determined to be 150 mg/m(2)/d for 3 days. Other than tumor lysis syndrome, there were 3 grade 3 mucositis which comprised the MTD determination. There was also 1 case each of grade 3 diarrhea, typhlitis, and nausea. After determining the MTD, a 10-patient phase IIA trial was conducted. Eight of the patients completed 1 cycle of the 3 days of treatment at the MTD. Of these, 5 (62%) had an efficacy signal with complete clearing of circulating peripheral blasts. Three of these subjects also cleared bone marrow blasts with 1 subsequently proceeding onto successful stem cell transplantation. CONCLUSION: Single-agent nanomolecular liposomal annamycin appears to be well tolerated, and shows evidence of clinical activity as a single agent in refractory adult ALL.

Predicting aortic complications after endovascular aneurysm repair.

BACKGROUND: Lifelong surveillance is standard after endovascular repair of abdominal aortic aneurysm (EVAR), but remains costly, heterogeneous and poorly calibrated. This study aimed to develop and validate a scoring system for aortic complications after EVAR, informing rationalized surveillance. METHODS: Patients undergoing EVAR at two centres were studied from 2004 to 2010. Preoperative morphology was quantified using three-dimensional computed tomography according to a validated protocol, by investigators blinded to outcomes. Proportional hazards modelling was used to identify factors predicting aortic complications at the first centre, and thereby derive a risk score. Sidak tests between risk quartiles dichotomized patients to low- or high-risk groups. Aortic complications were reported by Kaplan-Meier analysis and risk groups were compared by log rank test. External validation was by comparison of aortic complications between risk groups at the second centre. RESULTS: Some 761 patients, with a median age of 75 (interquartile range 70-80) years, underwent EVAR. Median follow-up was 36 (range 11-94) months. Physiological variables were not associated with aortic complications. A morphological risk score incorporating maximum aneurysm diameter (P < 0·001) and largest common iliac diameter (measured 10 mm from the internal iliac origin; P = 0·004) allocated 75 per cent of patients to a low-risk group, with excellent discrimination between 5-year rates of aortic complication in low- and high-risk groups at both centres (centre 1: 12 versus 31 per cent, P < 0·001; centre 2: 12 versus 45 per cent, P = 0·002). CONCLUSION: The risk score uses commonly available morphological data to stratify the rate of complications after EVAR. The proposals for rationalized surveillance could provide clinical and economic benefits.