Risk Assessment and Prevention of Falls in Older Community-Dwelling Adults: A Review.

Importance: Falls are reported by more than 14 million US adults aged 65 years or older annually and can result in substantial morbidity, mortality, and health care expenditures. Observations: Falls result from age-related physiologic changes compounded by multiple intrinsic and extrinsic risk factors. Major modifiable risk factors among community-dwelling older adults include gait and balance disorders, orthostatic hypotension, sensory impairment, medications, and environmental hazards. Guidelines recommend that individuals who report a fall in the prior year, have concerns about falling, or have gait speed less than 0.8 to 1 m/s should receive fall prevention interventions. In a meta-analysis of 59 randomized clinical trials (RCTs) in average-risk to high-risk populations, exercise interventions to reduce falls were associated with 655 falls per 1000 patient-years in intervention groups vs 850 falls per 1000 patient-years in nonexercise control groups (rate ratio [RR] for falls, 0.77; 95% CI, 0.71-0.83; risk ratio for number of people who fall, 0.85; 95% CI, 0.81-0.89; risk difference, 7.2%; 95% CI, 5.2%-9.1%), with most trials assessing balance and functional exercises. In a meta-analysis of 43 RCTs of interventions that systematically assessed and addressed multiple risk factors among individuals at high risk, multifactorial interventions were associated with 1784 falls per 1000 patient-years in intervention groups vs 2317 falls per 1000 patient-years in control groups (RR, 0.77; 95% CI, 0.67-0.87) without a significant difference in the number of individuals who fell. Other interventions associated with decreased falls in meta-analysis of RCTs and quasi-randomized trials include surgery to remove cataracts (8 studies with 1834 patients; risk ratio [RR], 0.68; 95% CI, 0.48-0.96), multicomponent podiatry interventions (3 studies with 1358 patients; RR, 0.77; 95% CI, 0.61-0.99), and environmental modifications for individuals at high risk (12 studies with 5293 patients; RR, 0.74; 95% CI, 0.61-0.91). Meta-analysis of RCTs of programs to stop medications associated with falls have not found a significant reduction, although deprescribing is a component of many successful multifactorial interventions. Conclusions and Relevance: More than 25% of older adults fall each year, and falls are the leading cause of injury-related death in persons aged 65 years or older. Functional exercises to improve leg strength and balance are recommended for fall prevention in average-risk to high-risk populations. Multifactorial risk reduction based on a systematic clinical assessment for modifiable risk factors may reduce fall rates among those at high risk.

The influence of the environment and lifestyle on myopia.

BACKGROUND: Myopia, commonly known as near-sightedness, has emerged as a global epidemic, impacting almost one in three individuals across the world. The increasing prevalence of myopia during early childhood has heightened the risk of developing high myopia and related sight-threatening eye conditions in adulthood. This surge in myopia rates, occurring within a relatively stable genetic framework, underscores the profound influence of environmental and lifestyle factors on this condition. In this comprehensive narrative review, we shed light on both established and potential environmental and lifestyle contributors that affect the development and progression of myopia. MAIN BODY: Epidemiological and interventional research has consistently revealed a compelling connection between increased outdoor time and a decreased risk of myopia in children. This protective effect may primarily be attributed to exposure to the characteristics of natural light (i.e., sunlight) and the release of retinal dopamine. Conversely, irrespective of outdoor time, excessive engagement in near work can further worsen the onset of myopia. While the exact mechanisms behind this exacerbation are not fully comprehended, it appears to involve shifts in relative peripheral refraction, the overstimulation of accommodation, or a complex interplay of these factors, leading to issues like retinal image defocus, blur, and chromatic aberration. Other potential factors like the spatial frequency of the visual environment, circadian rhythm, sleep, nutrition, smoking, socio-economic status, and education have debatable independent influences on myopia development. CONCLUSION: The environment exerts a significant influence on the development and progression of myopia. Improving the modifiable key environmental predictors like time spent outdoors and engagement in near work can prevent or slow the progression of myopia. The intricate connections between lifestyle and environmental factors often obscure research findings, making it challenging to disentangle their individual effects. This complexity underscores the necessity for prospective studies that employ objective assessments, such as quantifying light exposure and near work, among others. These studies are crucial for gaining a more comprehensive understanding of how various environmental factors can be modified to prevent or slow the progression of myopia.

Quality of life of patients and caregivers affected by bronchopulmonary dysplasia: a systematic review.

PURPOSE: To synthesize evidence on the impact of bronchopulmonary dysplasia (BPD) on the Quality of Life (QoL) of affected individuals from three perspectives: (i) QoL of caregiver; (ii) caregiver's perception of BPD patient's QoL; and (iii) BPD patient's self-reported QoL. METHODS: Quantitative studies (case-control, cohort, and case series) on the QoL of BPD patients or their caregivers were considered. We conducted a systematic literature search of 6 databases (PubMed, Embase, World of Science, CINAHL, PsycINFO, and Chinese National Knowledge Infrastructure) for relevant studies. All databases were searched from the date of inception of the databases to 31 March 2022. Populations of interest were caregivers with preterm babies with BPD, or children/adults who were born premature and diagnosed with BPD. The main outcome measures were total and subdomain QoL scores, and factors affecting QoL. RESULTS: A total of 1078 articles were found; 10 were eligible for analysis, which included 247 caregivers and 1632 patients with BPD. The QoL of patients differed by domains-some were poorer or similar, but none of the QoL domains was better than QoL of healthy controls. Poor sleep and acute care needs of BPD patients negatively affected caregiver's QoL, while increasing illness acuity negatively affected the QoL of BPD patients. The QoL of BPD patients and their caregivers was most adversely affected during the immediate post-discharge period and tended to improve with time. The physical QoL of BPD patients was similar to that of preterm babies without BPD when assessed during late childhood and early adulthood. CONCLUSION: QoL assessment should be performed as an outcome measure and incorporated in the care plan for BPD patients and their caregivers. Systematic Review Registration PROSPERO CRD42021292253.

Can we accurately diagnose endometriosis without a diagnostic laparoscopy?

Endometriosis is a progressive, estrogen-dependent, chronic inflammatory disease that affects approximately 6-10% of reproductive age women. Patients usually presents with symptoms, such as non-menstrual pelvic and abdominal pain, ovulatory pain, dyspareunia, dysmenorrhea, dyschezia, and/or changes to bowel or bladder function, which can be exacerbated during ovulation or menses. Endometriosis is a leading cause of unexplained infertility, accounting for up to 50-80% of cases. Currently, altered endometrial receptivity and progesterone resistance are some of the leading theories that could explain endometriosis-related implantation failure. In the endometrium, the B-cell chronic lymphocytic leukemia/lymphoma 6 (BCL-6) protein forms a complex that binds to and inactivates regulators of the progesterone pathway, leading to progesterone resistance, aberrant decidualization, implantation failure, and recurrent miscarriages in women diagnosed with endometriosis. Surgical diagnosis consisting of laparoscopy, with or without histologic confirmation, is still considered the gold standard for diagnosis of endometriosis. Development of noninvasive screening and diagnostic tests to accurately identify patients with endometriosis has become increasing popular. A screening test for endometriosis has been developed to detect endometrial BCL-6 overexpression in asymptomatic women with unexplained infertility or recurrent pregnancy loss. Positive endometrial BCL-6 testing has been associated with recurrent miscarriages and poor in vitro fertilization outcomes. When the underlying cause of endometrial inflammation secondary to endometriosis was treated, an improvement in subsequent live birth rates was seen. Endometrial BCL-6 testing has a high positive predictive value that could help physicians and patients undergoing infertility treatment to seek surgical evaluation for endometriosis, to improve their reproductive outcomes.

Elucidation of the Interactions of Reactive Oxygen Species and Antioxidants in Model Membranes Mimicking Cancer Cells and Normal Cells.

Photosensitizers (PSs) used in photodynamic therapy (PDT) have been developed to selectively destroy tumor cells. However, PSs recurrently reside on the extracellular matrix or affect normal cells in the vicinity, causing side effects. Additionally, the membrane stability of tumor cells and normal cells in the presence of reactive oxygen species (ROS) has not been studied, and the effects of ROS at the membrane level are unclear. In this work, we elucidate the stabilities of model membranes mimicking tumor cells and normal cells in the presence of ROS. The model membranes are constructed according to the degree of saturation in lipids and the bilayers are prepared either in symmetric or asymmetric form. Interestingly, membranes mimicking normal cells are the most vulnerable to ROS, while membranes mimicking tumor cells remain relatively stable. The instability of normal cell membranes may be one cause of the side effects of PDT. Moreover, we also show that ROS levels are controlled by antioxidants, helping to maintain an appropriate amount of ROS when PDT is applied.

Anticipating PTSD in severe COVID survivors: the case for screen-and-treat.

Based on research from previous pandemics, studies of critical care survivors, and emerging COVID-19 data, we estimate that up to 30% of survivors of severe COVID will develop PTSD. PTSD is frequently undetected across primary and secondary care settings and the psychological needs of survivors may be overshadowed by a focus on physical recovery. Delayed PTSD diagnosis is associated with poor outcomes. There is a clear case for survivors of severe COVID to be systematically screened for PTSD, and those that develop PTSD should receive timely access to evidence-based treatment for PTSD and other mental health problems by multidisciplinary teams.

Basados en la investigación de pandemias previas, los estudios de los sobrevivientes a cuidados críticos, y los datos emergentes de COVID-19, estimamos que hasta un 30% de los sobrevivientes del COVID grave desarrollarán TEPT. El TEPT es frecuentemente subdetectado en los servicios de salud primarios y secundarios y las necesidades psicológicas de los sobrevivientes puede verse eclipsadas por un enfoque en la recuperación física. El diagnóstico tardío de TEPT se asocia con pobres resultados. Existe un caso claro para que los sobrevivientes del COVID grave sean evaluados sistemáticamente para detectar el TEPT, y aquellos que desarrollan un TEPT deben tener acceso oportuno a tratamientos basados en la evidencia para el TEPT y para otros problemas de salud mental por equipos multidisciplinarios.

Disease Surveillance Among U.S.-Bound Immigrants and Refugees - Electronic Disease Notification System, United States, 2014-2019.

PROBLEM/CONDITION: Each year, approximately 500,000 immigrants and tens of thousands of refugees (range: 12,000-85,000 during 2001-2020) move to the United States. While still abroad, immigrants, refugees, and others who apply for admission to live permanently in the United States must undergo a medical examination. This examination identifies persons with class A or B conditions. Applicants with class A conditions are inadmissible. Infectious conditions that cause an applicant to be inadmissible include infectious tuberculosis (TB) disease (class A TB), infectious syphilis, gonorrhea, and infectious Hansen's disease. Applicants with class B conditions are admissible but might require treatment or follow-up. Class B TB includes persons who completed successful treatment overseas for TB disease (class B0), those with signs or symptoms suggestive of TB but whose overseas laboratory tests and clinical examinations ruled out current infectious TB disease (class B1), those with a diagnosis of latent TB infection (LTBI) (class B2), and the close contacts of persons known to have TB disease (class B3). Voluntary public health interventions might also be offered during the overseas examination. After arriving in the United States, a follow-up TB examination is recommended for persons with class B TB. PERIOD COVERED: This report summarizes health information that was reported to CDC's Electronic Disease Notification (EDN) system for refugees, immigrants, and eligible others who arrived in the United States during 2014-2019. Eligible others are persons who although not classified as refugees (e.g., certain parolees, special immigrant visa holders, and follow-to-join asylees) are eligible for the same services and benefits as refugees. DESCRIPTION OF SYSTEM: The EDN system has both surveillance and programmatic components. The surveillance component is a centralized database that collects 1) health-related data from the overseas medical examination for immigrants with class A or B conditions and for all refugees and eligible others and 2) TB-related data from the postarrival TB examination. The programmatic component is a reporting system that sends arrival notifications to state and local health agencies in the jurisdiction where newly arriving persons have reported intending to live and provides state and local health agencies and other authorized users with medical data from overseas examinations. RESULTS: During 2014-2019, approximately 3.5 million persons moved to the United States from abroad, including 3.2 million immigrants, 313,890 refugees, and 95,993 eligible others. Among these, the overseas examination identified 139,683 persons (3,903 per 100,000 persons examined) with class B TB, 54 with primary or secondary syphilis (30 per 100,000 persons tested), 761 with latent syphilis (415 per 100,000 persons tested), and, after laboratory testing for gonorrhea was added in 2016, a total of 131 with gonorrhea (374 per 100,000 persons tested). Refugees were offered additional, voluntary interventions, including vaccinations and presumptive treatment for parasites. By 2019, first- and second-dose coverage with measles-containing vaccine were 96% and 80%, respectively. In refugee populations for whom presumptive treatment is recommended, up to 96% of refugees, depending on the specific regimen, were offered and accepted treatment. For the 139,683 persons identified overseas with class B TB, EDN sent arrival notifications and overseas medical data to the appropriate state or local health agency to facilitate postarrival TB examinations. Among 101,119 persons identified overseas as having class B0 TB (6,586) or class B1 TB (94,533), a total of 67,432 (67%) had a complete postarrival examination reported to EDN. Among 35,814 children aged 2-14 years identified overseas with class B2 TB, 20,758 (58%) had a complete postarrival examination reported to EDN. (Adults are not routinely tested for immune reactivity to Mycobacterium tuberculosis during the overseas medical examination.) Among those with a complete postarrival examination reported to EDN, the number with a diagnosis of culture-positive TB disease within the first year of arrival was 464 (688 cases per 100,000 persons examined) for those with class B0 or B1 TB and was 11 (53 cases per 100,000 persons examined) for children with class B2 TB. INTERPRETATION: During 2014-2019, the overseas medical examination system prevented importation of 6,586 cases of infectious TB, 815 cases of syphilis, and 131 cases of gonorrhea. When the examination is used to offer public health interventions, most refugees (up to 96%) accept the intervention. Postarrival follow-up examinations, which were completed for 88,190 persons and identified 475 cases of culture-positive TB, represent an important opportunity to further limit spread of TB disease in the United States by identifying and providing, if needed, preventive care for those with LTBI or treatment for those with disease. PUBLIC HEALTH ACTION: Federal, state, and local health departments and agencies should continue to use EDN data to monitor, evaluate, and improve health-related programs and policies aimed at U.S.-bound or recently arrived immigrants, refugees, and eligible others. Additional public health interventions that could be offered during the overseas medical examination should be considered (e.g., treatment for LTBI). Finally, for persons with class B TB, measures should be taken to identify and remove barriers to completing postarrival examinations to reduce risk for TB disease and community transmission, along with measures to encourage reporting of completed examinations for better data-driven decision-making.

Discontinuation of beta-blockers among nursing home residents at end of life.

BACKGROUND: Given limited life expectancy of nursing home (NH) residents, harms of continuing beta-blockers (BBs) may outweigh clinical benefits. Our objective was to describe beta-blocker discontinuation for NH residents during the last year of life, and identify characteristics associated with earlier discontinuation. METHODS: This was a retrospective cohort study that included all long-stay residents in fee-for-service Medicare who died in 2016 and were prescribed oral BBs 1 year before death. Beta-blocker discontinuation was defined as a gap in medication on hand for ≥45 days per Medicare Part D claims, measured from the last date drug was on hand. Comorbidities were obtained from Chronic Condition Warehouse, and other characteristics from the Minimum Data Set. Kaplan-Meier curves were used to describe time to first discontinuation. Findings were stratified by cardiac diagnoses, perceived life expectancy of <6 months, or elevated mortality index. RESULTS: Eighty-eight thousand two hundred and eighty-four residents were prescribed ≥1 daily BB 12 months before death. Mean age was 84.1 years and 69.2% were female. Of these, 60,573 residents (68.6%) remained on a BB in the last 45 days of life, and 57,880 residents (65.6%) had ≥1 cardiac diagnosis. Only 5239 residents (5.9%) had elevated mortality index, whereas 16,798 residents (19.0%) had perceived poor prognosis. In the last year of life, there was no difference in beta-blocker discontinuation pattern between residents with and without cardiac diagnoses. Residents with perceived poor prognosis and elevated mortality index discontinued BBs earlier. For example, mean time until discontinuation among residents with poor perceived prognosis was 245 versus 279 days in residents without such prognosis (p < 0.0001). CONCLUSIONS: BBs are commonly prescribed to NH residents in the final year of life. Overall, discontinuation occurs earlier in residents for whom clinicians perceive limited life expectancy, suggesting that improved prognostication may offer an important opportunity to reduce polypharmacy toward end of life.

Overseas Gonorrhea Screening Among Newly Arrived Refugees During 2018.

We assessed the overseas gonorrhea results reported in the CDC's Electronic Disease Notification (EDN) system among refugees ≥ 15 years old who arrived in the United States during 2018. Of 18,720 refugees, 57 (0.4%) tested positive. Among those with a positive test, 31 (54.5%) were born in the Democratic Republic of the Congo, followed by 12 (21.1%) from Afghanistan. Thirty-three (57.9%) cases were female. Fifty-one cases (89.4%) were between 15 and 44 years of age; 25 (43.9%) were ages 15-24 and 26 (45.6%) were ages 25-44. Among the cases, 56 (98.2%) were treated overseas with the recommended therapy of ceftriaxone and azithromycin. Our findings suggest that the risk of gonorrhea in refugees is similar to that in the U.S. Given recent worldwide increases in gonorrhea, additional monitoring among refugees are necessary to assess the appropriateness of the gonorrhea screening requirement in the overseas medical examination.

Health screening results of Cubans settling in Texas, USA, 2010-2015: A cross-sectional analysis.

BACKGROUND: Protecting the health of refugees and other migrant populations in the United States is key to ensuring successful resettlement. Therefore, to identify and address health concerns early, the US Centers for Disease Control and Prevention (CDC) recommends a domestic medical examination (screening for infectious and noninfectious diseases/conditions) shortly after arrival in the US. However, because refugee/migrant populations often have differing health patterns from one another and the US population, the collection and analysis of health information is key to developing population-specific clinical guidelines to guide the care of resettled individuals. Yet little is known regarding the health status of Cubans resettling in the US. Among the tens of thousands of Cuban migrants who have resettled in the US, some applied as refugees in Cuba, some applied for parole (a term used to indicate temporary US admission status for urgent humanitarian reasons or reasons of public benefit under US immigration law) in Cuba, and others applied for parole status after crossing the border. These groups were eligible for US government benefits to help them resettle, including a domestic medical examination. We reviewed health differences found in these examinations of those who were determined to be refugees or parolees in Cuba and those who were given parole status after arrival. METHODS AND FINDINGS: We conducted a retrospective cross-sectional analysis of the Texas Department of State Health Services database. Cubans who arrived from 2010 to 2015 and received a domestic medical examination in Texas were included. Those granted refugee/parolee status in Cuba were listed in federal databases for US-bound refugees/parolees; those who were paroled after arrival were not listed. Overall, 2,189 (20%) obtained either refugee or parolee status in Cuba, and 8,709 (80%) received parolee status after arrival. Approximately 62% of those who received parolee status after arrival at the border were male, compared with 49% of those who obtained prior refugee/parolee status in Cuba. Approximately one-half (45%) of those paroled after arrival were 19-34 years old (versus 26% among those who obtained refugee/parolee status in Cuba). Separate models were created for each screening indicator as the outcome, with entry route as the main exposure variable. Crude and adjusted prevalence ratios were estimated using PROC GENMOD procedures in SAS 9.4. Individuals paroled after arrival were less likely to screen positive for parasitic infections (9.6% versus 12.2%; adjusted prevalence ratio: 0.79, 0.71-0.88) and elevated blood lead levels (children ≤16 years old, 5.2% versus 12.3%; adjusted prevalence ratio: 0.42, 0.28-0.63). Limitations include potential disease misclassification, missing clinical information, and cross-sectional nature. CONCLUSIONS: Within-country variations in health status are often not examined in refugee populations, yet they are critical to understand granular health trends. Results suggests that the health profiles of Cuban Americans in Texas differed by entry route. This information could assist in developing targeted screenings and health interventions.

Health screenings administered during the domestic medical examination of refugees and other eligible immigrants in nine US states, 2014-2016: A cross-sectional analysis.

BACKGROUND: Refugees and other select visa holders are recommended to receive a domestic medical examination within 90 days after arrival to the United States. Limited data have been published on the coverage of screenings offered during this examination across multiple resettlement states, preventing evaluation of this voluntary program's potential impact on postarrival refugee health. This analysis sought to calculate and compare screening proportions among refugees and other eligible populations to assess the domestic medical examination's impact on screening coverage resulting from this examination. METHODS AND FINDINGS: We conducted a cross-sectional analysis to summarize and compare domestic medical examination data from January 2014 to December 2016 from persons receiving a domestic medical examination in seven states (California, Colorado, Minnesota, New York, Kentucky, Illinois, and Texas); one county (Marion County, Indiana); and one academic medical center in Philadelphia, Pennsylvania. We analyzed screening coverage by sex, age, nationality, and country of last residence of persons and compared the proportions of persons receiving recommended screenings by those characteristics. We received data on disease screenings for 105,541 individuals who received a domestic medical examination; 47% were female and 51.5% were between the ages of 18 and 44. The proportions of people undergoing screening tests for infectious diseases were high, including for tuberculosis (91.6% screened), hepatitis B (95.8% screened), and human immunodeficiency virus (HIV; 80.3% screened). Screening rates for other health conditions were lower, including mental health (36.8% screened). The main limitation of our analysis was reliance on data that were collected primarily for programmatic rather than surveillance purposes. CONCLUSIONS: In this analysis, we observed high rates of screening coverage for tuberculosis, hepatitis B, and HIV during the domestic medical examination and lower screening coverage for mental health. This analysis provided evidence that the domestic medical examination is an opportunity to ensure newly arrived refugees and other eligible populations receive recommended health screenings and are connected to the US healthcare system. We also identified knowledge gaps on how screenings are conducted for some conditions, notably mental health, identifying directions for future research.

Characterization of Internal Validity Threats to Phase III Clinical Trials for Chemotherapy-Induced Peripheral Neuropathy Management: A Systematic Review.

OBJECTIVE: The recent American Society of Clinical Oncology (ASCO) Clinical Guidelines for chemotherapy-induced peripheral neuropathy (CIPN) management (48 Phase III trials reviewed) only recommend duloxetine. However, before concluding that a CIPN intervention is ineffective, scientists and clinicians should consider the risk of Type II error in Phase III studies. The purpose of this systematic review was to characterize internal threats to validity in Phase III CIPN management trials. METHODS: The PubMed, CINAHL, EMBASE®, and Scopus databases were searched for Phase III clinical trials testing interventions for CIPN management between 1990 and 2018. The key search terms were neoplasms, cancer, neuropathy, and CIPN. Two independent researchers evaluated 24 studies, using a modified Joanna Briggs Institute Checklist for Randomized Control Trials developed by the authors specific for CIPN intervention trials. RESULTS: Two studies exhibited minimal or no design flaws. 22/24 Phase III clinical trials for CIPN have two or greater design flaws due to sample heterogeneity, malapropos mechanism of action, malapropos intervention dose, malapropos timing of the outcome measurement, confounding variables, lack of a valid and reliable measurement, and suboptimal statistical validity. CONCLUSIONS: Numerous CIPN interventions have been declared ineffective based on the results of Phase III trials. However, internal validity threats to numerous studies may have resulted in Type II error and subsequent dismissal of a potentially effective intervention. Patients may benefit from rigorous retesting of several agents (e.g., alpha-lipoic acid, duloxetine, gabapentin, glutathione, goshajinkigan, lamotrigine, nortriptyline, venlafaxine, and Vitamin E) to expand and validate the evidence regarding ASCO's recommendations for CIPN management.

Fidelity is fundamental: intervention predictors in advance care plans in terminal cancer.

OBJECTIVES: Assessing whether interventions are implemented as intended (fidelity) is critical to establishing efficacy in clinical research yet rarely applied in advance care planning (ACP) interventions. We aimed to develop and implement a fidelity audit tool for an ACP intervention. METHODS: We developed a fidelity audit tool assessing: (A) content; (B) quality (general communication, eliciting EOL preferences and prognostic communication); and (C) family/caregiver involvement. We audited (double-coded) 55 audio-recordings of ACP discussions delivered to advanced cancer patients and caregivers, within a clinical trial. RESULTS: Fidelity to content was high: mean=9.38/11 but lower for the quality of general communication (mean=12.47/20), discussion of patient preferences (mean=4.67/7), prognosis (mean=3.9/6) and family/caregiver involvement (mean=2.67/4). Older patient age and caregiver religiosity were associated with higher fidelity. Higher fidelity to content was associated with the trial primary outcome of family caregiver report of patient wishes being discussed and met. CONCLUSIONS: Fidelity to content, but not quality, of the ACP intervention is strong. Communication skills training is critical for ACP interventionists. Adherence was higher with older patients and religious carers, factors that may influence acceptance of death and readiness to undertake ACP, making the discussion easier. TRIAL REGISTRATION NUMBER: ACTRN12613001288718.

Radioluminescent nanoparticles for radiation-controlled release of drugs.

The present work demonstrates a novel concept for intratumoral chemo-radio combination therapy for locally advanced solid tumors. For some locally advanced tumors, chemoradiation is currently standard of care. This combination treatment can cause acute and long term toxicity that can limit its use in older patients or those with multiple medical comorbidities. Intratumoral chemotherapy has the potential to address the problem of systemic toxicity that conventional chemotherapy suffers, and may, in our view, be a better strategy for treating certain locally advanced tumors. The present study proposes how intratumoral chemoradiation can be best implemented. The enabling concept is the use of a new chemotherapeutic formulation in which chemotherapy drugs (e.g., paclitaxel (PTX)) are co-encapsulated with radioluminecsnt nanoparticles (e.g., CaWO4 (CWO) nanoparticles (NPs)) within protective capsules formed by biocompatible/biodegradable polymers (e.g., poly(ethylene glycol)-poly(lactic acid) or PEG-PLA). This drug-loaded polymer-encapsulated radioluminescent nanoparticle system can be locally injected in solution form into the patient's tumor before the patient receives normal radiotherapy (e.g., 30-40 fractions of 2-3 Gy daily X-ray dose delivered over several weeks for locally advanced head and neck tumors). Under X-ray irradiation, the radioluminescent nanoparticles produce UV-A light that has a radio-sensitizing effect. These co-encapsulated radioluminescent nanoparticles also enable radiation-triggered release of chemo drugs from the polymer coating layer. The non-toxic nature (absence of dark toxicity) of this drug-loaded polymer-encapsulated radioluminescent nanoparticle ("PEG-PLA/CWO/PTX") formulation was confirmed by the MTT assay in cancer cell cultures. A clonogenic cell survival assay confirmed that these drug-loaded polymer-encapsulated radioluminescent nanoparticles significantly enhance the cancer cell killing effect of radiation therapy. In vivo study validated the efficacy of PEG-PLA/CWO/PTX-based intratumoral chemo-radio therapy in mouse tumor xenografts (in terms of tumor response and mouse survival). Results of a small-scale NP biodistribution (BD) study demonstrate that PEG-PLA/CWO/PTX NPs remained at the tumor sites for a long period of time (> 1 month) following direct intratumoral administration. A multi-compartmental pharmacokinetic model (with rate constants estimated from in vitro experiments) predicts that this radiation-controlled drug release technology enables significant improvements in the level and duration of drug availability within the tumor (throughout the typical length of radiation treatment, i.e., > 1 month) over conventional delivery systems (e.g., PEG-PLA micelles with no co-encapsulated CaWO4, or an organic liquid, e.g., a 50:50 mixture of Cremophor EL and ethanol, as in Taxol), while it is capable of maintaining the systemic level of the chemo drug far below the toxic threshold limit over the entire treatment period. This technology thus has the potential to offer a new therapeutic option that has not previously been available for patients excluded from conventional chemoradiation protocols.

Renal Cell Carcinoma (RCC) Tumors Display Large Expansion of Double Positive (DP) CD4+CD8+ T Cells With Expression of Exhaustion Markers.

Checkpoint inhibitors target the inhibitory receptors expressed by tumor-infiltrating T cells in order to reinvigorate an anti-tumor immune response. Therefore, understanding T cell composition and phenotype in human tumors is crucial. We analyzed by flow cytometry tumor-infiltrating lymphocytes (TILs) from two independent cohorts of patients with different cancer types, including RCC, lung, and colon cancer. In healthy donors, peripheral T cells are usually either CD4+ or CD8+ with a small percentage of CD4+ CD8+ DP cells (<5%). Compared to several other cancer types, including lung, and colorectal cancers, TILs from about a third of RCC patients showed an increased proportion of DP CD4+CD8+ T cells (>5%, reaching 30-50% of T cells in some patients). These DP T cells have an effector memory phenotype and express CD38, 4-1BB, and HLA-DR, suggesting antigen-driven expansion. In fact, TCR sequencing analysis revealed a high degree of clonality in DP T cells. Additionally, there were high levels of PD-1 and TIM-3 expression on DP T cells, which correlated with higher expression of PD-1 and TIM-3 in conventional single positive CD8 T cells from the same patients. These results suggest that DP T cells could be dysfunctional tumor-specific T cells with the potential to be reactivated by checkpoint inhibitors.

In Search of a Gold Standard Patient-Reported Outcome Measure for Use in Chemotherapy- Induced Peripheral Neuropathy Clinical Trials.

PURPOSE: To test a reduced version-CIPN15-of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy scale (QLQ-CIPN20) to establish a possible gold-standard patient-reported outcome measure for chemotherapy-induced peripheral neuropathy (CIPN). METHODS: Using a prospective, longitudinal, case-control design, patients (n = 121) receiving neurotoxic chemotherapy completed the CIPN15 at baseline and 12 weeks and underwent objective neurological assessment using the 5-item Total Neuropathy Score-Clinical (TNSc). Healthy controls (n = 30) completed the CIPN15 once. Structural validity was evaluated using factor analysis. Because a stable factor structure was not found, a sum score was used to evaluate measures of the CIPN15's psychometric properties-reliability, validity, sensitivity, and responsiveness-as follows: internal consistency via Cronbach's α and item-item correlations; test-retest reliability via correlation between 2 CIPN15 scores from each patient; concurrent validity via correlation between CIPN15 and 5-item TNSc scores; contrasting group validity via comparison of CIPN15 scores from patients and healthy controls; sensitivity via descriptive statistics (means, standard deviation, ranges); and responsiveness via Cohen's d effect size. RESULTS: Most patients received single agent oxaliplatin (33.7%), paclitaxel (21.2%), or more than 1 neurotoxic drug concurrently (29.8%). Factor analysis revealed no stable factor structure. Cronbach's α for the CIPN15 sum score was 0.91 (confidence interval [CI] = 0.89-0.93). Test-retest reliability was demonstrated based on strong correlations between the 2 scores obtained at the 12-week time point ( r = 0.86; CI = 0.80-0.90). The CIPN15 and 5-item TNSc items reflecting symptoms (not signs) were moderately correlated ( r range 0.57-0.72): concurrent validity. Statistically significant differences were found between patient and healthy control CIPN15 mean scores ( P < .0001): contrasting group validity. All items encompassed the full score range but the CIPN15 linearly converted sum score did not: sensitivity. The CIPN15 was responsive based on a Cohen's d of 0.52 (CI = 0.25-0.79). CONCLUSION: The sum-scored CIPN15 is reliable, valid, sensitive, and responsive when used to assess taxane- and platinum-induced CIPN.

Examining the Impact of a Web-Based Intervention to Promote Patient Activation in Chemotherapy-Induced Peripheral Neuropathy Assessment and Management.

Lack of activation in self-care can compromise a patient's ability to monitor and manage cancer treatment-related side effects, such as chemotherapy-induced peripheral neuropathy (CIPN). The web-based Carevive® Care Planning System (CPS) was developed to promote evidence-based symptom assessment and treatment by enhancing patients' involvement in their own care. The purpose of this single-arm, pre-test/post-test, prospective study was to examine whether the CPS can promote patient activation in CIPN symptom assessment and management. Seventy-five women with breast cancer receiving neurotoxic chemotherapy were recruited from a Comprehensive Cancer Center. Using standardized neuropathy measures embedded within the CPS, patients reported their CIPN symptoms over three consecutive clinical visits and completed the Patient Activation Measure (PAM) at the first and third visits. Mean changes in PAM scores between visits were compared using repeated measure analysis of covariance, adjusting for age. At baseline, patients were diagnosed with cancer within the past year (94.7%), highly activated (85% Level III/IV), and had a mean age of 51.3. PAM scores improved significantly from 67.15 (SD = 13.5; range = 47-100) at visit one to 69.29 (SD = 16.18; range = 47-100) (p = 0.02) (n = 62) at visit three. However, patients perceived the CPS to be of minimal value because it solely focused on CIPN and, for many, CIPN was not severe enough to motivate them to seek out symptom management information. Further research is needed to assess the utility of the CPS in promoting activation in the assessment and management of varying cancer treatment-related symptoms.

Impact of Enhanced Health Interventions for United States-Bound Refugees: Evaluating Best Practices in Migration Health.

With an unprecedented number of displaced persons worldwide, strategies for improving the health of migrating populations are critical. United States-bound refugees undergo a required overseas medical examination to identify inadmissible conditions (e.g., tuberculosis) 2-6 months before resettlement, but it is limited in scope and may miss important, preventable infectious, chronic, or nutritional causes of morbidity. We sought to evaluate the feasibility and health impact of diagnosis and management of such conditions before travel. We offered voluntary testing for intestinal parasites, anemia, and hepatitis B virus infection, to U.S.-bound refugees from three Thailand-Burma border camps. Treatment and preventive measures (e.g., anemia and parasite treatment, vaccination) were initiated before resettlement. United States refugee health partners received overseas results and provided post-arrival medical examination findings. During July 9, 2012 to November 29, 2013, 2,004 refugees aged 0.5-89 years enrolled. Among 463 participants screened for seven intestinal parasites overseas and after arrival, helminthic infections decreased from 67% to 12%. Among 118 with positive Strongyloides-specific antibody responses, the median fluorescent intensity decreased by an average of 81% after treatment. The prevalence of moderate-to-severe anemia (hemoglobin < 10 g/dL) was halved from 14% at baseline to 7% at departure (McNemar P = 0.001). All 191 (10%) hepatitis B-infected participants received counseling and evaluation; uninfected participants were offered vaccination. This evaluation demonstrates that targeted screening, treatment, and prevention services can be conducted during the migration process to improve the health of refugees before resettlement. With more than 250 million migrants globally, this model may offer insights into healthier migration strategies.