Effect of Laser-Exposed Volume and Irradiation Position on Nonphotochemical Laser-Induced Nucleation of Potassium Chloride Solutions.

Herein, we study the influences of the laser-exposed volume and the irradiation position on the nonphotochemical laser-induced nucleation (NPLIN) of supersaturated potassium chloride solutions in water. The effect of the exposed volume on the NPLIN probability was studied by exposing distinct milliliter-scale volumes of aqueous potassium chloride solutions stored in vials at two different supersaturations (1.034 and 1.050) and laser intensities (10 and 23 MW/cm2). Higher NPLIN probabilities were observed with increasing laser-exposed volume as well as with increasing supersaturation and laser intensity. The measured NPLIN probabilities at different exposed volumes are questioned in the context of the dielectric polarization mechanism and classical nucleation theory. No significant change in the NPLIN probability was observed when samples were irradiated at the bottom, top, or middle of the vial. However, a significant increase in the nucleation probability was observed upon irradiation through the solution meniscus. We discuss these results in terms of mechanisms proposed for NPLIN.

Design and Validation of a Droplet-based Microfluidic System To Study Non-Photochemical Laser-Induced Nucleation of Potassium Chloride Solutions.

Non-photochemical laser-induced nucleation (NPLIN) has emerged as a promising primary nucleation control technique offering spatiotemporal control over crystallization with potential for polymorph control. So far, NPLIN was mostly investigated in milliliter vials, through laborious manual counting of the crystallized vials by visual inspection. Microfluidics represents an alternative to acquiring automated and statistically reliable data. Thus we designed a droplet-based microfluidic platform capable of identifying the droplets with crystals emerging upon Nd:YAG laser irradiation using the deep learning method. In our experiments, we used supersaturated solutions of KCl in water, and the effect of laser intensity, wavelength (1064, 532, and 355 nm), solution supersaturation (S), solution filtration, and intentional doping with nanoparticles on the nucleation probability is quantified and compared to control cooling crystallization experiments. Ability of dielectric polarization and the nanoparticle heating mechanisms proposed for NPLIN to explain the acquired results is tested. Solutions with lower supersaturation (S = 1.05) exhibit significantly higher NPLIN probabilities than those in the control experiments for all laser wavelengths above a threshold intensity (50 MW/cm2). At higher supersaturation studied (S = 1.10), irradiation was already effective at lower laser intensities (10 MW/cm2). No significant wavelength effect was observed besides irradiation with 355 nm light at higher laser intensities (≥50 MW/cm2). Solution filtration and intentional doping experiments showed that nanoimpurities might play a significant role in explaining NPLIN phenomena.

Microfluidic Platform with Serpentine Geometry Providing Chaotic Mixing in Induction Time Experiments.

We present a droplet microfluidic platform mixing the contents of the droplet chaotically in microfluidic induction time measurements, a promising method for quantifying nucleation kinetics with minute amounts of solute. The nucleation kinetics of aqueous potassium chloride droplets dispersed in mineral oil without surfactants is quantified in the presence and absence of chaotic mixing. We demonstrate the ability of the proposed platform to dictate droplet size, to provide a homogeneous temperature distribution, and to chaotically mix the droplet contents. Chaotic mixing in induction time measurements is facilitated by the motion of droplets through serpentine micromixer bends, while the extent of mixing is controlled by how much droplets move. Different nucleation kinetics are observed in experiments where the droplets are static, mixed, and in motion. We hypothesize that the droplet motion induces formation of a thin-liquid Bretherton film surrounding the droplets. The thin film shields droplets from solid boundaries that are more efficient heteronucleant surfaces compared to liquid-liquid interfaces. We observed that repeated microfluidic induction time measurements, particularly with moving droplets, produce significantly distinct cumulative nucleation probability curves, indicating that the measured nucleation kinetics depend strongly on the details of the experimental procedure, which we discuss in detail. Finally, we compare the microfluidic experiments to well-mixed, milliliter volume, turbidity-based measurements in the context of classic nucleation theory.

Efficacy and Safety of Reirradiation with Stereotactic Body Radiation Therapy for Locally Recurrent Pancreatic Adenocarcinoma.

AIMS: The purpose of this study was to report on outcomes of a cohort of patients who were treated with reirradiation with stereotactic body radiation therapy (SBRT) for locally recurrent pancreatic adenocarcinoma. MATERIALS AND METHODS: Patients treated with SBRT reirradiation for locally recurrent pancreatic adenocarcinoma from December 2009 to April 2020 were included in the study. Descriptive statistics were used to record patient demographics, tumour and treatment characteristics. Kaplan-Meier analysis was used to evaluate overall survival, local progression-free survival (LPFS), distant metastasis-free survival and progression-free survival (PFS). RESULTS: In total, 27 patients were included in the study. The median follow-up time from local recurrence was 19.7 months (range 4.2-43.1 months). Most patients received five-fraction SBRT (26/27, 96%). The median overall survival after local recurrence treatment was 18.3 months (range 3.0-42.6 months), with 6-month, 1-year and 2-year overall survival rates of 88.5%, 73.1% and 33.6%. The median LPFS after local recurrence treatment was 16.2 months (range 2.3-33.6 months), with 6-month, 1-year and 2-year LPFS rates of 95.8%, 62.9% and 27.2%. Peri-SBRT chemotherapy improved LPFS (median 17.5 versus 8.5 months; P = 0.010) and overall survival (median 19.3 versus 5.5 months; P = 0.049). Tumours ≤ 3 cm in the greatest dimension showed better local control (median LPFS 19.2 versus 10.2 months; P = 0.130). There was one case (4%) of acute grade 3 pain and one case (4%) of late grade 3 gastrointestinal toxicity. CONCLUSIONS: Reirradiation with five-fraction SBRT is safe, but local control remains suboptimal. Patients with smaller tumours experienced improved outcomes, as did patients whose treatment plan included the administration of peri-SBRT chemotherapy.

Nucleation kinetics of calcium oxalate monohydrate as a function of pH, magnesium, and osteopontin concentration quantified with droplet microfluidics.

A droplet-based microfluidic platform is presented to study the nucleation kinetics of calcium oxalate monohydrate (COM), the most common constituent of kidney stones, while carefully monitoring the pseudo-polymorphic transitions. The precipitation kinetics of COM is studied as a function of supersaturation and pH as well as in the presence of inhibitors of stone formation, magnesium ions (Mg2+), and osteopontin (OPN). We rationalize the trends observed in the measured nucleation rates leveraging a solution chemistry model validated using isothermal solubility measurements. In equimolar calcium and oxalate ion concentrations with different buffer solutions, dramatically slower kinetics is observed at pH 6.0 compared to pHs 3.6 and 8.6. The addition of both Mg2+ and OPN to the solution slows down kinetics appreciably. Interestingly, complete nucleation inhibition is observed at significantly lower OPN, namely, 3.2 × 10-8 M, than Mg2+ concentrations, 0.875 × 10-4 M. The observed inhibition effect of OPN emphasizes the often-overlooked role of macromolecules on COM nucleation due to their low concentration presence in urine. Moreover, analysis of growth rates calculated from observed lag times suggests that inhibition in the presence of Mg2+ cannot be explained solely on altered supersaturation. The presented study highlights the potential of microfluidics in overcoming a major challenge in nephrolithiasis research, the overwhelming physiochemical complexity of urine.

Novel Design Integrating a Microwave Applicator into a Crystallizer for Rapid Temperature Cycling. A Direct Nucleation Control Study.

The control of nucleation in crystallization processes is a challenging task due to the often lacking knowledge on the process kinetics. Inflexible (predetermined) control strategies fail to grow the nucleated crystals to the desired quality because of the variability in the process conditions, disturbances, and the stochastic nature of crystal nucleation. Previously, the concept of microwave assisted direct nucleation control (DNC) was demonstrated in a laboratory setup to control the crystal size distribution in a batch crystallization process by manipulating the number of particles in the system. Rapid temperature cycling was used to manipulate the super(under)saturation and hence the number of crystals. The rapid heating response achieved with the microwave heating improved the DNC control efficiency, resulting in halving of the batch time. As an extension, this work presents a novel design in which the microwave applicator is integrated in the crystallizer, hence avoiding the external loop though the microwaves oven. DNC implemented in the 4 L unseeded crystallizer, at various count set points, resulted in strong efficiency enhancement of DNC, when compared to the performance with a slow responding system. The demonstrated crystallizer design is a basis for extending the enhanced process control opportunity to other applications.

Solid Separation from a Mixed Suspension through Electric-Field-Enhanced Crystallization.

When applied to a pure component suspension in an apolar solvent, a strong inhomogeneous electric field induces particle movement, and the particles are collected at the surface of one of the two electrodes. This new phenomenon was used to separately isolate two organic crystalline compounds, phenazine and caffeine, from their suspension in 1,4-dioxane. First, crystals of both compounds were collected at different electrodes under the influence of an electric field. Subsequent cooling crystallization enabled the immobilization and growth of the particles on the electrodes, which were separately collected after the experiment with purities greater than 91 %. This method can be further developed into a technique for crystal separation and recovery in complex multicomponent suspensions of industrial processes.

Assessing the potential for improvement of primary care in 34 countries: a cross-sectional survey.

OBJECTIVE: To investigate patients' perceptions of improvement potential in primary care in 34 countries. METHODS: We did a cross-sectional survey of 69 201 patients who had just visited general practitioners at primary-care facilities. Patients rated five features of person-focused primary care - accessibility/availability, continuity, comprehensiveness, patient involvement and doctor-patient communication. One tenth of the patients ranked the importance of each feature on a scale of one to four, and nine tenths of patients scored their experiences of care received. We calculated the potential for improvement by multiplying the proportion of negative patient experiences with the mean importance score in each country. Scores were divided into low, medium and high improvement potential. Pair-wise correlations were made between improvement scores and three dimensions of the structure of primary care - governance, economic conditions and workforce development. FINDINGS: In 26 countries, one or more features of primary care had medium or high improvement potentials. Comprehensiveness of care had medium to high improvement potential in 23 of 34 countries. In all countries, doctor-patient communication had low improvement potential. An overall stronger structure of primary care was correlated with a lower potential for improvement of continuity and comprehensiveness of care. In countries with stronger primary care governance patients perceived less potential to improve the continuity of care. Countries with better economic conditions for primary care had less potential for improvement of all features of person-focused care. CONCLUSION: In countries with a stronger primary care structure, patients perceived that primary care had less potential for improvement.

Effectiveness of cranberry capsules to prevent urinary tract infections in vulnerable older persons: a double-blind randomized placebo-controlled trial in long-term care facilities.

OBJECTIVES: To determine whether cranberry capsules prevent urinary tract infection (UTI) in long-term care facility (LTCF) residents. DESIGN: Double-blind randomized placebo-controlled multicenter trial. SETTING: Long-term care facilities (LTCFs). PARTICIPANTS: LTCF residents (N = 928; 703 women, median age 84). MEASUREMENTS: Cranberry and placebo capsules were taken twice daily for 12 months. Participants were stratified according to UTI risk (risk factors included long-term catheterization, diabetes mellitus, ≥ 1 UTI in preceding year). Main outcomes were incidence of UTI according to a clinical definition and a strict definition. RESULTS: In participants with high UTI risk at baseline (n = 516), the incidence of clinically defined UTI was lower with cranberry capsules than with placebo (62.8 vs 84.8 per 100 person-years at risk, P = .04); the treatment effect was 0.74 (95% confidence interval (CI) = 0.57-0.97). For the strict definition, the treatment effect was 1.02 (95% CI = 0.68-1.55). No difference in UTI incidence between cranberry and placebo was found in participants with low UTI risk (n = 412). CONCLUSION: In LTCF residents with high UTI risk at baseline, taking cranberry capsules twice daily reduces the incidence of clinically defined UTI, although it does not reduce the incidence of strictly defined UTI. No difference in incidence of UTI was found in residents with low UTI risk.

Cost-effectiveness of cranberry capsules to prevent urinary tract infection in long-term care facilities: economic evaluation with a randomized controlled trial.

OBJECTIVES: To investigate whether the preventive use of cranberry capsules in long-term care facility (LTCF) residents is cost-effective depending on urinary tract infection (UTI) risk. DESIGN: Economic evaluation with a randomized controlled trial. SETTING: Long-term care facilities. PARTICIPANTS: LTCF residents (N = 928, 703 female, median age 84), stratified according to UTI risk. MEASUREMENTS: UTI incidence (clinically or strictly defined), survival, quality of life, quality-adjusted life years (QALYs), and costs. RESULTS: In the weeks after a clinical UTI, participants showed a significant but moderate deterioration in quality of life, survival, care dependency, and costs. In high-UTI-risk participants, cranberry costs were estimated at €439 per year (1.00 euro = 1.37 U.S. dollar), which is €3,800 per prevented clinically defined UTI (95% confidence interval = €1,300-infinity). Using the strict UTI definition, the use of cranberry increased costs without preventing UTIs. Taking cranberry capsules had a 22% probability of being cost-effective compared with placebo (at a willingness to pay of €40,000 per QALY). In low-UTI-risk participants, use of cranberry capsules was only 3% likely to be cost-effective. CONCLUSION: In high-UTI-risk residents, taking cranberry capsules may be effective in preventing UTIs but is not likely to be cost-effective in the investigated dosage, frequency, and setting. In low-UTI-risk LTCF residents, taking cranberry capsules twice daily is neither effective nor cost-effective.

Natural course of care dependency in residents of long-term care facilities: prospective follow-up study.

BACKGROUND: Insight in the natural course of care dependency of vulnerable older persons in long-term care facilities (LTCF) is essential to organize and optimize individual tailored care. We examined changes in care dependency in LTCF residents over two 6-month periods, explored the possible predictive factors of change and the effect of care dependency on mortality. METHODS: A prospective follow-up study in 21 Dutch long-term care facilities. 890 LTCF residents, median age 84 (Interquartile range 79-88) years participated. At baseline, 6 and 12 months, care dependency was assessed by the nursing staff with the Care Dependency Scale (CDS), range 15-75 points. Since the median CDS score differed between men and women (47.5 vs. 43.0, P = 0.013), CDS groups (low, middle and high) were based on gender-specific 33% of CDS scores at baseline and 6 months. RESULTS: At baseline, the CDS groups differed in median length of stay on the ward, urine incontinence and dementia (all P < 0.001); participants in the low CDS group stayed longer, had more frequent urine incontinence and more dementia. They had also the highest mortality rate (log rank 32.2; df = 2; P for trend <0.001). Per point lower in CDS score, the mortality risk increased with 2% (95% CI 1%-3%). Adjustment for age, gender, cranberry use, LTCF, length of stay, comorbidity and dementia showed similar results. A one point decrease in CDS score between 0 and 6 months was related to an increased mortality risk of 4% (95% CI 3%-6%).At the 6-month follow-up, 10% improved to a higher CDS group, 65% were in the same, and 25% had deteriorated to a lower CDS group; a similar pattern emerged at 12-month follow-up. Gender, age, urine incontinence, dementia, cancer and baseline care dependency status, predicted an increase in care dependency over time. CONCLUSION: The majority of residents were stable in their care dependency status over two subsequent 6-month periods. Highly care dependent residents showed an increased mortality risk. Awareness of the natural course of care dependency is essential to residents and their formal and informal caregivers when considering therapeutic and end-of-life care options.

Gastrointestinal ostomies and sexual outcomes: a comparison of colorectal cancer patients by ostomy status.

PURPOSE: Research examining effects of ostomy use on sexual outcomes is limited. Patients with colorectal cancer were compared on sexual outcomes and body image based on ostomy status (never, past, and current ostomy). Differences in depression were also examined. METHODS: Patients were prospectively recruited during clinic visits and by tumor registry mailings. Patients with colorectal cancer (N = 141; 18 past ostomy; 25 current ostomy; and 98 no ostomy history) completed surveys assessing sexual outcomes (medical impact on sexual function, Female Sexual Function Index, International Index of Erectile Function), body image distress (Body Image Scale), and depressive symptoms (Center for Epidemiologic Studies Depression Scale-Short Form). Clinical information was obtained through patient validated self-report measures and medical records. RESULTS: Most participants reported sexual function in the dysfunctional range using established cut-off scores. In analyses adjusting for demographic and medical covariates and depression, significant group differences were found for ostomy status on impact on sexual function (p < .001), female sexual function (p = .01), and body image (p < .001). The current and past ostomy groups reported worse impact on sexual function than those who never had an ostomy (p < .001); similar differences were found for female sexual function. The current ostomy group reported worse body image distress than those who never had an ostomy (p < .001). No differences were found across the groups for depressive symptoms (p = .33) or male sexual or erectile function (p values ≥ .59). CONCLUSIONS: Colorectal cancer treatment puts patients at risk for sexual difficulties and some difficulties may be more pronounced for patients with ostomies as part of their treatment. Clinical information and support should be offered.

Impact of a single-day multidisciplinary clinic on the management of patients with liver tumours.

PURPOSE: Multidisciplinary cancer clinics may improve patient care. We examined how a single-day multidisciplinary liver clinic (mdlc) affected care recommendations for patients compared with the recommendations provided before presentation to the mdlc. METHODS: We analyzed the demographic and clinicopathologic data of 343 patients assessed in the Johns Hopkins Liver Tumor Center from 2009 to 2012, comparing imaging and pathology interpretation, diagnosis, and management plan between the outside provider (osp) and the mdlc. RESULTS: Most patients were white (n = 259, 76%); median age was 60 years; and 146 were women (43%). Outside providers referred 182 patients (53%); the rest were self-referred. Patients travelled median of 83.4 miles (interquartile range: 42.7-247 miles). Most had already undergone imaging (n = 338, 99%) and biopsy (n = 194, 57%) at the osp, and a formal management plan had been formulated for about half (n = 168, 49%). Alterations in the interpretation of imaging occurred for 49 patients (18%) and of biopsy for 14 patients (10%). Referral to the mdlc resulted in a change of diagnosis in 26 patients (8%), of management plan in 70 patients (42%), and of tumour resectability in 7 patients (5%). Roughly half the patients (n = 174, 51%) returned for a follow-up, and 154 of the returnees (89%) received treatment, primarily intraarterial therapy (n = 88, 57%), systemic chemotherapy (n = 60, 39%), or liver resection (n = 32, 21%). Enrollment in a clinical trial was proposed to 34 patients (10%), and 21 of the 34 (62%) were accrued. CONCLUSIONS: Patient assessment by our multidisciplinary liver clinic had a significant impact on management, resulting in alterations to imaging and pathology interpretation, diagnosis, and management plan. The mdlc is an effective and convenient means of delivering expert opinion about the diagnosis and management of liver tumours.

Clinically diagnosed infections predict disability in activities of daily living among the oldest-old in the general population: the Leiden 85-plus Study.

BACKGROUND: ageing is frequently accompanied by a higher incidence of infections and an increase in disability in activities of daily living (ADL). OBJECTIVE: this study examines whether clinical infections [urinary tract infections (UTI) and lower respiratory tract infections (LRTI)] predict an increase in ADL disability, stratified for the presence of ADL disability at baseline (age 86 years). DESIGN: the Leiden 85-plus Study. A population-based prospective follow-up study. SETTING: general population. PARTICIPANTS: a total of 154 men and 319 women aged 86 years. METHODS: information on clinical infections was obtained from the medical records. ADL disability was determined at baseline and annually thereafter during 4 years of follow-up, using the 9 ADL items of the Groningen Activity Restriction Scale. RESULTS: in 86-year-old participants with ADL disability, there were no differences in ADL increase between participants with and without an infection (-0.32 points extra per year; P = 0.230). However, participants without ADL disability at age 86 years (n = 194; 41%) had an accelerated increase in ADL disability of 1.07 point extra per year (P < 0.001). For UTIs, this was 1.25 points per year (P < 0.001) and for LRTIs 0.70 points per year (P = 0.041). In this group, an infection between age 85 and 86 years was associated with a higher risk to develop ADL disability from age 86 onwards [HR: 1.63 (95% CI: 1.04-2.55)]. CONCLUSIONS: among the oldest-old in the general population, clinically diagnosed infections are predictive for the development of ADL disability in persons without ADL disability. No such association was found for persons with ADL disability.

Tissue biomarkers for prostate cancer radiation therapy.

Prostate cancer is the most common cancer and second leading cause of cancer deaths among men in the United States. Most men have localized disease diagnosed following an elevated serum prostate specific antigen test for cancer screening purposes. Standard treatment options consist of surgery or definitive radiation therapy directed by clinical factors that are organized into risk stratification groups. Current clinical risk stratification systems are still insufficient to differentiate lethal from indolent disease. Similarly, a subset of men in poor risk groups need to be identified for more aggressive treatment and enrollment into clinical trials. Furthermore, these clinical tools are very limited in revealing information about the biologic pathways driving these different disease phenotypes and do not offer insights for novel treatments which are needed in men with poor-risk disease. We believe molecular biomarkers may serve to bridge these inadequacies of traditional clinical factors opening the door for personalized treatment approaches that would allow tailoring of treatment options to maximize therapeutic outcome. We review the current state of prognostic and predictive tissue-based molecular biomarkers which can be used to direct localized prostate cancer treatment decisions, specifically those implicated with definitive and salvage radiation therapy.

Predictive factors of urinary tract infections among the oldest old in the general population. A population-based prospective follow-up study.

BACKGROUND: Urinary tract infections (UTI) are common among the oldest old and may lead to a few days of illness, delirium or even to death. We studied the incidence and predictive factors of UTI among the oldest old in the general population. METHODS: The Leiden 85-plus Study is a population-based prospective follow-up study of 86-year-old subjects in Leiden, The Netherlands. Information on the diagnosis of UTI was obtained annually during four years of follow-up from the medical records and interviews of treating physicians. A total of 157 men and 322 women aged 86 years participated in the study. Possible predictive factors were collected at baseline, including history of UTI between the age of 85 and 86 years, aspects of functioning (cognitive impairment (Mini-Mental State Examination (MMSE) < 19), presence of depressive symptoms (Geriatric Depression Scale (GDS) > 4), disability in activities of daily living (ADL)), and co-morbidities. RESULTS: The incidence of UTI from age 86 through 90 years was 11.2 (95% confidence interval (CI) 9.4, 13.1) per 100 person-years at risk. Multivariate analysis showed that history of UTI between the age of 85 and 86 years (hazard ratio (HR) 3.4 (95% CI 2.4, 5.0)), impaired cognitive function (HR 1.9 (95% CI 1.3, 2.9)), disability in daily living (HR 1.7 (95% CI 1.1, 2.5)) and urine incontinence (HR 1.5 (95% CI 1.0, 2.1)) were independent predictors of an increased incidence of UTI from age 86 onwards. CONCLUSIONS: Within the oldest old, a history of UTI between the age of 85 and 86 years, cognitive impairment, ADL disability and urine incontinence are independent predictors of developing UTI. These predictive factors could be used to target preventive measures to the oldest old at high risk of UTI.

Cytomegalovirus infection and responsiveness to influenza vaccination in elderly residents of long-term care facilities.

Ample evidence suggests that infection with cytomegalovirus (CMV) leads to accelerated aging of the immune system and may contribute to poor responsiveness to influenza vaccination in older persons. The objective of this study was to investigate whether CMV infection, acquired earlier in life, affects the response to influenza vaccination in a randomized controlled trial among older persons in long-term care facilities. During the 1997-1998 influenza season, 731 residents (median age 83 [interquartile range 78-88], 75.4% female) in 14 long-term care facilities in the Netherlands were randomly assigned to receive 15 or 30 µg of inactivated influenza vaccine, followed by a 15 µg booster vaccine or a placebo vaccine at day 84. Blood samples were collected at day 0, day 25, day 84 and day 109. Seroresponses to influenza vaccination were measured by hemagglutination-inhibition tests to the A/H3N2 strain at all time points. Subsequently, baseline levels of IgG anti-CMV antibodies were measured using an automated chemiluminescent microparticle immunoassay. Participants with CMV antibody level≥6 AU/mL were considered to harbor CMV infection. At baseline, no differences in pre-vaccination geometric mean antibody titers (GMT) were observed between participants with (n=571, 78.1%) or without CMV infection (n=160, 21.9%). During follow-up, participants with and without CMV infection had similar responses to influenza vaccination as measured with changes in GMT (linear mixed model, adjusted for gender, age, pre-vaccination GMT and vaccination strategy, p=0.46). Analogously, no association was found between CMV infection and a more than 4-fold increase in antibody titer (Generalized Estimating Equations, adjusted OR 1.14 [95%CI 0.80;1.64]) or an antibody titer≥40 (adjusted OR 1.24 [95%CI 0.86;1.80]). In conclusion, CMV infection did not explain poor responsiveness to influenza vaccination in residents of long-term care facilities.