Invited Review - A 5-year update on epigenome-wide association studies of DNA modifications in Alzheimer's disease: progress, practicalities and promise.

In late 2014, the first epigenome-wide association studies of DNA modifications in Alzheimer's disease brain samples were published. Over the last 5 years, further studies have been reported in the field and have highlighted consistent and robust alterations in DNA modifications in AD cortex. However, there are some caveats associated with the majority of studies undertaken to date; for example, they are predominantly restricted to profiling a limited number of loci, are principally focused on DNA methylation, are performed on bulk tissue at the end stage of disease and are restricted to nominating associations rather than demonstrating causal relationships. Consequently, the downstream interpretation of these studies is limited. Owing to recent advances in state-of-the-art cell profiling techniques, long-read genomic technologies and genetic engineering methodologies, identifying cell-type-specific causal epigenetic changes is becoming feasible. This review seeks to provide an overview of the last 5 years of epigenomic studies of DNA modifications in Alzheimer's disease brain samples and propose new avenues for future research.

Social and Financial Outcomes of Living Liver Donation: A Prospective Investigation Within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study 2 (A2ALL-2).

Because results from single-center (mostly kidney) donor studies demonstrate interpersonal relationship and financial strains for some donors, we conducted a liver donor study involving nine centers within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study 2 (A2ALL-2) consortium. Among other initiatives, A2ALL-2 examined the nature of these outcomes following donation. Using validated measures, donors were prospectively surveyed before donation and at 3, 6, 12, and 24 mo after donation. Repeated-measures regression models were used to examine social relationship and financial outcomes over time and to identify relevant predictors. Of 297 eligible donors, 271 (91%) consented and were interviewed at least once. Relationship changes were positive overall across postdonation time points, with nearly one-third reporting improved donor family and spousal or partner relationships and >50% reporting improved recipient relationships. The majority of donors, however, reported cumulative out-of-pocket medical and nonmedical expenses, which were judged burdensome by 44% of donors. Lower income predicted burdensome donation costs. Those who anticipated financial concerns and who held nonprofessional positions before donation were more likely to experience adverse financial outcomes. These data support the need for initiatives to reduce financial burden.

Psychological Outcomes of Living Liver Donors From a Multicenter Prospective Study: Results From the Adult-to-Adult Living Donor Liver Transplantation Cohort Study2 (A2ALL-2).

Although single-center and cross-sectional studies have suggested a modest impact of liver donation on donor psychological well-being, few studies have assessed these outcomes prospectively among a large cohort. We conducted one of the largest, prospective, multicenter studies of psychological outcomes in living liver donors within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study2 (A2ALL-2) consortium. In total, 271 (91%) of 297 eligible donors were interviewed at least once before donation and at 3, 6, 12, and 24 mo after donation using validated measures. We found that living liver donors reported low rates of major depressive (0-3%), alcohol abuse (2-5%), and anxiety syndromes (2-3%) at any given assessment in their first 2 years after donation. Between 4.7% and 9.6% of donors reported impaired mental well-being at various time points. We identified significant predictors for donors' perceptions of being better people and experiencing psychological growth following donation, including age, sex, relationship to recipient, ambivalence and motivation regarding donation, and feeling that donation would make life more worthwhile. Our results highlight the need for close psychosocial monitoring for those donors whose recipients died (n=27); some of those donors experienced guilt and concerns about responsibility. Careful screening and targeted, data-driven follow-up hold promise for optimizing psychological outcomes following this procedure for potentially vulnerable donors.

Complications and Their Resolution in Recipients of Deceased and Living Donor Liver Transplants: Findings From the A2ALL Cohort Study.

The purpose of this study was to explore long-term complications in recipients of deceased donor liver transplant (DDLT) and living donor liver transplant (LDLT) in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). We analyzed 471 DDLTs and 565 LDLTs from 1998 to 2010 that were followed up to 10 years for 36 categories of complications. Probabilities of complications and their resolutions were estimated using the Kaplan-Meier method, and predictors were tested in Cox proportional hazards models. Median follow-up for DDLT and LDLT was 4.19 and 4.80 years, respectively. DDLT recipients were more likely to have hepatocellular carcinoma and higher disease severity, including Model for End-Stage Liver Disease score. Complications occurring with higher probability in LDLT included biliary-related complications and hepatic artery thrombosis. In DDLT, ascites, intra-abdominal bleeding, cardiac complications and pulmonary edema were significantly more probable. Development of chronic kidney disease stage 4 or 5 was less likely in LDLT recipients (hazard ratio [HR] 0.41, p = 0.02). DDLT and LDLT had similar risk of grade 4 complications (HR 0.89, p = 0.60), adjusted for other risk factors. Once a complication occurred, the time to resolution did not differ between LDLT and DDLT. Future efforts should be directed toward reducing the occurrence of complications after liver transplantation.

Examination of the relationship between obesity and suicidal ideation.

OBJECTIVE: The relationship between obesity and suicidal ideation and behavior (suicidality) is not well understood, and conventional suicide risk factors do not adequately explain the associations observed. Thus, the current study aimed to further examine the relationship between body mass index (BMI; kg m(-2)) and suicidal ideation as well as potential mechanisms of this relationship. METHODS: Two hundred seventy-one adults (n=151 undergraduates; n=120 obesity treatment participants) completed self-report questionnaires assessing relevant variables, including suicidal ideation, perceived burdensomeness, thwarted belongingness and current height/weight used to calculate BMI. RESULTS: There was a significant, quadratic relationship between BMI and suicidal ideation (b=0.001, t=2.21, P=0.03, partial r=0.14) and between BMI and perceived burdensomeness (b=0.003, t=2.50, P=0.013, partial r=0.16), such that as BMI increased, these positive associations became more pronounced. Additionally, perceived burdensomeness partially mediated the relationship between BMI and suicidal ideation. CONCLUSIONS: Individuals with a higher BMI demonstrated increased suicidal ideation as well as greater feelings of perceived burdensomeness. These results provide novel information regarding potential mechanisms explaining the obesity-suicidal ideation association.

Why don't women participate? A qualitative study on non-participation in a surgical randomised controlled trial.

INTRODUCTION AND HYPOTHESIS: The objective of the study was to identify reasons why women declined participation in a pilot randomised controlled trial (RCT) comparing tension-free vaginal tape (TVT) under general anaesthetic (GA) with single incision sling (SIS) under local anaesthetic (LA). These data would inform the design of a larger trial to improve patient recruitment. METHODS: This was a qualitative interview study on women eligible to have a TVT for stress urinary incontinence in a tertiary referral hospital in the UK. Women were counselled in a standardised manner. They were informed that the short-term success rates were similar for both operations. Women who declined to take part in the RCT were interviewed using a topic guide. Themes and sub-themes on non-participation were identified by two independent observers using a constant comparison method. RESULTS: Twenty-three non-participants of the RCT were interviewed. Common themes for non-participation were a preference for TVT and request for GA. Sub-themes showed that the TVT was preferred due to its perceived better efficacy as well as a minimal benefit from a SIS and also an unwillingness to take unknown risks. GA was favoured due to fear of local awareness, past negative experiences and embarrassment. Additional tests and follow-up visits were not cited as a reason for non-participation. CONCLUSIONS: The study found that non-participants are not research averse in general but they had strong preferences about specific aspects of treatment. Risk propensity and personality may also influence this behaviour. The study also demonstrates how a qualitative pilot study may improve trial design.

Effects of fluorination on iridium(III) complex phosphorescence: magnetic circular dichroism and relativistic time-dependent density functional theory.

We use a combination of low temperature, high field magnetic circular dichroism, absorption, and emission spectroscopy with relativistic time-dependent density functional calculations to reveal a subtle interplay between the effects of chemical substitution and spin-orbit coupling (SOC) in a family of iridium(III) complexes. Fluorination at the ortho and para positions of the phenyl group of fac-tris(1-methyl-5-phenyl-3-n-propyl-[1,2,4]triazolyl)iridium(III) cause changes that are independent of whether the other position is fluorinated or protonated. This is demonstrated by a simple linear relationship found for a range of measured and calculated properties of these complexes. Further, we show that the phosphorescent radiative rate, k(r), is determined by the degree to which SOC is able to hybridize T(1) to S(3) and that k(r) is proportional to the inverse fourth power of the energy gap between these excitations. We show that fluorination in the para position leads to a much larger increase of the energy gap than fluorination at the ortho position. Theory is used to trace this back to the fact that fluorination at the para position increases the difference in electron density between the phenyl and triazolyl groups, which distorts the complex further from octahedral symmetry, and increases the energy separation between the highest occupied molecular orbital (HOMO) and the HOMO-1. This provides a new design criterion for phosphorescent iridium(III) complexes for organic optoelectronic applications. In contrast, the nonradiative rate is greatly enhanced by fluorination at the ortho position. This may be connected to a significant redistribution of spectral weight. We also show that the lowest energy excitation, 1A, has almost no oscillator strength; therefore, the second lowest excitation, 2E, is the dominant emissive state at room temperature. Nevertheless the mirror image rule between absorption and emission is obeyed, as 2E is responsible for both absorption and emission at all but very low (<10 K) temperatures.

Periurethral abscess following polyacrylamide hydrogel (Bulkamid) for stress urinary incontinence.

Bulkamid is a periurethral bulking agent used to treat stress urinary incontinence (SUI). Manufacturers describe it as nontoxic, nonbiodegradable and biocompatible. Periurethral abscesses are one of the known complications of bulking agents. We present the first reported case of periurethral abscess following Bulkamid injection. The woman had previously had a transobturator tape (TOT) and total vaginal mesh repair. At 6 weeks after injection of the bulking agent, she reported 100 % cure of her SUI. Transperineal ultrasound was used to diagnose and monitor an abscess that developed anterior and lateral to the urethra and separate from the TOT. Magnetic resonance imaging was helpful in delineating the extent of the abscess into the retropubic space but was not able to identify the urethra or the TOT. Surgical drainage of the abscess was performed vaginally, resulting in successful resolution of pain but recurrence of incontinence.

Spatial behaviour of sheep during the neonatal period: Preliminary study on the influence of shelter.

Effective shelter has been demonstrated to reduce neonatal lamb mortality rates during periods of inclement weather. Periods of high wind speed and rainfall have been shown to influence shelter usage; however, it is not yet known how ewe factors such as breed, age and body condition score influence shelter-seeking behaviour. This study, conducted on a working upland farm in the UK, examined impact of artificial shelter on the biological and climatic factors that influence peri-parturient ewe behaviour. Pregnant ewes (n = 147) were randomly allocated between two adjacent fields which were selected for their similarity in size, topography, pasture management, orientation to the prevailing wind and available natural shelter. In one field, three additional artificial shelters were installed to increase the available shelter for ewes, this field was designated the Test field; no additional artificial shelter was provided in the second field which was used as the Control field. Individual ewes were observed every 2 h between 0800 and 1600 for 14 continuous days to monitor their location relative to shelter. Ewe breed (Aberfield and Highlander), age (2-8 years) and body condition score were considered as explanatory variables to explain flock and individual variance in shelter-seeking behaviour and the prevalence of issues which required the intervention of the shepherd, termed 'shepherding problems'. Any ewe observed with dystocia, a dead or poor vigour lamb or who exhibited mismothering behaviour was recorded as a shepherding problem. The prevalence of these shepherding problems which necessitate human intervention represents arguably the most critical limiting factor for the successful management of commercial sheep flocks in outdoor lambing systems. Overall, ewes in the Test field with access to additional artificial shelter experienced fewer shepherding problems than those in the Control field (P < 0.05). A significant breed effect was also observed, with Highlander ewes more likely to seek shelter than Aberfield ewes (P < 0.001), and experiencing significantly fewer shepherding interventions (P < 0.05). These findings demonstrate the substantial and significant benefits to animal welfare and productivity that can be achieved through the provision of shelter in commercial, upland, outdoor lambing systems in the UK.

A 2-year observational study to determine the efficacy of a novel single incision sling procedure (Minitape) for female stress urinary incontinence.

OBJECTIVE: Assessment of the 2 year outcome of the Minitape procedure. DESIGN: A prospective observational study of women undergoing the Minitape procedure for urodynamic stress incontinence. Setting Two tertiary referral urogynaecology units in the north of England. POPULATION: Sixty women between November 2002 and March 2006. METHODS: Women attended a research clinic where they completed a standardised 1 hour pad test and were examined. Women were assessed preoperatively and postoperatively at 6 months, 1 year and 2 years. MAIN OUTCOME MEASURES: Success was determined by a negative 1 hour pad test (gain of <1 g) and no desire for further treatment for stress urinary incontinence. RESULTS: All procedures were completed with local anaesthesia, with no additional sedation in 82% of cases. Intra-operative and immediate postoperative complications were rare. Twelve women (20%) experienced mesh complications, half of which were considered to be serious adverse events requiring exit from the study. At 2 years following Minitape insertion, six women (10%) were defined as cured. CONCLUSIONS: Although feasible to perform, this procedure is associated with a substantially lower cure rate than that published previously for other procedures. Cure rates decline over the 2 year follow-up period, especially during the first 6 months.

Social anxiety and age are associated with neural response to social evaluation during adolescence.

Adolescence is a sensitive period for the development of adaptive social behaviors and social anxiety, possibly due to aspects of brain development. However, research is needed to examine interactions among age, social anxiety, and social dynamics previously shown to influence neural responding. The current functional magnetic resonance imaging (fMRI) study examines brain function in 8-18 year-olds with varying levels of social anxiety. Interactions are examined among age, social anxiety, and two key task factors: valence and predictability of social interactions. Results demonstrate age, social anxiety severity, and each of the two key task-based factors interact to predict neural response in the caudate, middle and superior temporal gyri. In particular, among adolescents less-than 13 years of age, higher social anxiety predicted greater responding to unpredictable negative evaluations. However, in this same age group, the opposite pattern emerged during receipt of unpredictable positive evaluations, with less neural response in more anxious youth. Adolescents aged 13 and older overall showed less robust effects. We discuss these findings in terms of age- and anxiety-related differences in socioemotional processing.

Radiological physics characteristics of the extracted heavy ion beams of the bevatron.

Studies of the depth-ionization properties and the biological effects of heavy ion beams produced at the bevatron have extended work previously done with less energetic beams from other sources. Results indicate that heavy ion beams are suitable for tumor therapy, studies relating to space biology, and fundamental radiobiology.

The effect of physical activity on pelvic organ prolapse.

OBJECTIVE: The objective of this study was to determine whether pelvic organ prolapse increases after physical activity. DESIGN: Prospective observational study. SETTING: St Mary's Hospital, Manchester, UK. SAMPLE: Women undergoing surgery for pelvic organ prolapse. METHODS: Fifty-four women were recruited to the study. Symptoms and POPQ findings were assessed after a period of prescribed activity and overnight bedrest. MAIN OUTCOME MEASURES: Primary outcome was an increase in Pelvic Organ Prolapse Quantification (POPQ) measurements with activity. Secondary outcomes were association of symptoms or quality-of-life scores (Pelvic Floor Distress Inventory [PFDI] and Pelvic Floor Impact Questionnaire [PFIQ]) with an increase in POPQ measurements. RESULTS: There was a significant increase in POPQ stage and five vaginal parameters (Aa, Ba, C, Ap and Bp) with physical activity (P < 0.001). Reported symptoms, higher PFDI and PFIQ scores and higher individual symptom bother scores were not more common in the women with greater pelvic organ descent (measured by the POPQ system) following physical activity. CONCLUSIONS: Greater pelvic organ prolapse was found on POPQ examination following physical activity, but this was not associated with worsening of symptoms and greater impairment of quality of life.

A prospective study of laparoscopic sacrocolpopexy for the management of pelvic organ prolapse.

OBJECTIVE: Assessment of the 2-year outcome of laparoscopic sacrocolpopexy. DESIGN: A prospective observational study of women undergoing laparoscopic sacrocolpopexy for prolapse. SETTING: A tertiary referral unit in the North West of England. POPULATION: A total of 22 women taking part in a prospective longitudinal study of prolapse who had a laparoscopic sacrocolpopexy between September 2002 and January 2005. METHODS: Women attended a research clinic where they completed validated quality-of-life questionnaires and were examined. Women were assessed preoperatively and postoperatively at 6 months, 1 year and 2 years. MAIN OUTCOME MEASURES: Pelvic organ support assessed by Pelvic Organ Prolapse Quantification score. Assessment of the degree and impact of vaginal, urinary and bowel symptoms using validated quality-of-life questionnaires. RESULTS: At a mean follow up of 26.5 months, all 22 women had stage 0 vault support with 21 cured of prolapse symptoms. Stress urinary incontinence resolved in half of women without concomitant continence surgery. Bowel symptoms were uncommon, but of those reporting postoperative bowel symptoms, approximately one-third had no symptoms prior to surgery. No new onset dyspareunia was reported in those women sexually active at 2 years. CONCLUSIONS: Laparoscopic sacrocolpopexy is a safe and effective treatment for vault prolapse, providing excellent vault support in the medium term. The outcome for anterior and posterior support is less predictable, and anatomical outcome correlated poorly with functional outcome.

Lipoic acid significantly restores, in rats, the age-related decline in vasomotion.

BACKGROUND AND PURPOSE: The age-related decline in vasorelaxation is largely due to ceramide-induced induction of phosphatase 2A (PP2A), which limits nitric oxide synthase (eNOS) phosphorylation at stimulatory sites. We hypothesized that ceramide accumulation was from an age-related loss of endothelial glutathione (GSH) and subsequent activation of neutral sphingomyelinase (nSMase), an enzyme whose activity increases when GSH is limited. EXPERIMENTAL APPROACH: Old (30-32 mo) F344xBN rats were given (R)-alpha-lipoic acid (LA), an agent known to induce GSH synthesis. Vasorelaxation was measured in aortic rings; GSH and ceramide levels, activity of nSMase and eNOS phosphorylation (by Western blot) was measured in aortic endothelial cells, isolated from the same aortas. KEY RESULTS: In old animals, endothelium-dependent relaxation in aortic rings was decreased, GSH levels and its redox state in aortic endothelia were over 30% lower and nSMase activity and endothelial ceramide levels were three-fold increased, relative to young (2-4 mo) rats. LA treatment of old animals improved relaxation in aortic rings, reversed the changes in endothelial GSH, in nSMase activities and in ceramide levels. Similar effects on GSH levels and nSMase activity in old rats were also induced by treatment with GSH monoethylester. Activation (by phosphorylation) of eNOS was decreased by about 50% in old rats and this age-related decrease was partially reversed by LA treatment. CONCLUSIONS AND IMPLICATIONS: Decreased endothelial GSH was partly responsible for the age-related loss of vascular endothelial function and LA might be therapeutically evaluated to treat endothelial dysfunction.

Antimicrobial action of N-(n-dodecyl)diethanolamine on Escherichia coli: effects on enzymes and growing cultures.

AIMS: This study investigates the effects of N-(n-dodecyl)diethanolamine (DDA) on enzymes and growing cells of Escherichia coli NCIMB 8277. METHODS AND RESULTS: Enzyme activities in the presence of DDA were determined by measuring substrate-dependent oxygen consumption by whole cells, or of NADH formation or oxidation by cell extracts. Lysis of growing cells was followed by measuring changes in turbidity and cell count. DDA promptly arrested oxygen uptake on pyruvate and acetate, due to cofactor loss rather than to enzyme denaturation, since cell-free glyceraldehyde-3-phosphate and NADH dehydrogenases remained active. Formate and succinate oxidation by membrane-bound enzyme systems independent of cofactors was likewise unaffected. DDA lysed growing cells at rates related to drug concentration, pH, and the previous growth rate. CONCLUSIONS: Loss of cellular enzyme activity following addition of DDA is due to cofactor leakage and not to enzyme denaturation. Whereas nongrowing cells remain intact in the presence of DDA, actively-growing organisms undergo lysis, consistent with autolysin action. SIGNIFICANCE AND IMPACT OF THE STUDY: Cell lysis, not normally observed with membrane-active antimicrobials, also occurs with cetrimide, and may be dependent on the alkyl chain length in these compounds. The action on growing cells parallels that of penicillin and daptomycin, which bears a decanoyl residue that penetrates the cell membrane, causing leakage and membrane depolarization.

Outcomes following autologous hematopoietic stem cell transplant for patients with relapsed Wilms' tumor: a CIBMTR retrospective analysis.

Despite the marked improvement in the overall survival (OS) for patients diagnosed with Wilms' tumor (WT), the outcomes for those who experience relapse have remained disappointing. We describe the outcomes of 253 patients with relapsed WT who received high-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplant (HCT) between 1990 and 2013, and were reported to the Center for International Blood and Marrow Transplantation Research. The 5-year estimates for event-free survival (EFS) and OS were 36% (95% confidence interval (CI); 29-43%) and 45% (95 CI; 38-51%), respectively. Relapse of primary disease was the cause of death in 81% of the population. EFS, OS, relapse and transplant-related mortality showed no significant differences when broken down by disease status at transplant, time from diagnosis to transplant, year of transplant or conditioning regimen. Our data suggest that HDT followed by autologous HCT for relapsed WT is well tolerated and outcomes are similar to those reported in the literature. As attempts to conduct a randomized trial comparing maintenance chemotherapy with consolidation versus HDT followed by stem cell transplant have failed, one should balance the potential benefits with the yet unknown long-term risks. As disease recurrence continues to be the most common cause of death, future research should focus on the development of consolidation therapies for those patients achieving complete response to therapy.

6-Thioguanine-induced growth arrest in 6-mercaptopurine-resistant human leukemia cells.

The thiopurines 6-thioguanine (6TG) and 6-mercaptopurine (6MP) are cytotoxic to proliferating cells by a mechanism involving incorporation into DNA via the purine salvage pathway, and resistance to these agents can be conferred by lack of the salvage pathway enzyme hypoxanthine-guanine phosphoribosyltransferase. However, human and murine hypoxanthine-guanine phosphoribosyltransferase-deficient leukemia cell lines have been shown to respond to 6TG by growth arrest and differentiation by a mechanism apparently not involving incorporation of 6TG into DNA. If so, leukemia cells resistant to 6MP should still respond to 6TG by growth arrest via an undescribed epigenetic mechanism. To test this, polyclonal 6MP-resistant variants were produced from three human leukemia cell lines, HL-60, U937, and CCRF-CEM. Treatment of both sensitive and resistant cells with 6TG induced growth arrest. The effect of 6TG in the 6MP-sensitive HL-60 and U937 cells was associated with significant loss of viability and DNA fragmentation. In contrast, the 6TG-treated 6MP-resistant cells exhibited a slower decline in viability and no DNA fragmentation. To identify the mechanism by which 6TG may induce growth arrest, tRNA was isolated from 6MP-resistant cells cultured for 48 h with 6TG. 6TG was found to be incorporated into tRNAs normally containing queuine in the anticodon wobble position. These studies may provide a basis for the development of new therapeutic regimens for the treatment of leukemia.

Ovarian function after hematopoietic cell transplantation: a descriptive study following the use of GnRH agonists for myeloablative conditioning and observation only for reduced-intensity conditioning.

Gonadal failure is a health and quality-of-life concern in hematopoietic cell transplant (HCT) survivors. While ovarian dysfunction is nearly universal following myeloablative (MA) conditioning, the risk is unclear after reduced-intensity conditioning (RIC). Gonadotropin-releasing hormone agonists decrease ovarian failure rates following conventional chemotherapy, but little is known about its effectiveness with HCT. We investigated the impact of leuprolide on ovarian function after MA conditioning and monitored ovarian function after RIC in this descriptive pilot study. Post-menarchal females <50 years undergoing HCT with adequate baseline ovarian function (follicle-stimulating hormone (FSH) level <40 mIU/mL and normal menstruation) were eligible. Prior to MA conditioning, leuprolide was administered. Those undergoing RIC were observed. FSH was measured at various time points. Seventeen women aged 12-45 years were evaluated (7 in the intervention group and 10 in the observation group). Compared to the historical high rate of ovarian failure after MA conditioning, 3 of 7 evaluable Lupron recipients had ovarian failure at a median of 703 days post transplant. Ovarian failure occurred in 1 of 10 recipients of RIC at a median follow-up of 901 days. In conclusion, leuprolide may protect ovarian function after MA conditioning. Additionally, RIC with cyclophosphamide, fludarabine and low-dose TBI has a low risk of ovarian failure.

Therapeutic step and shoot proton beam spot-scanning with a multi-leaf collimator: a Monte Carlo study.

In step and shoot spot-scanning, a small-diameter proton beam is magnetically swept and varied in energy in order to cover the tumour. Initial estimates of the beam size indicate that additional collimating hardware will be needed for lower energy proton beams in order to achieve a clinically acceptable lateral dose falloff at the edge of the proton beam. In this report, we present dosimetric data from Monte Carlo simulations with a model of a simple multileaf collimator which indicate that such a device may be used to improve the lateral dose falloff. The dosimetric quantities relevant to the clinical usefulness of the device are studied, including lateral penumbra, leaf transmission and scalloping effect. Multileaf collimation is compared with a differential spot-weighting technique of sharpening the lateral dose falloff.