Nationwide, Multioperator Self-Exclusion and Psychiatric Comorbidity in Patients with Gambling Disorder: A Retrospective Chart Review Study from a Regional Treatment Unit.

Gambling disorder is an addictive disorder that has been shown to have a detrimental effect on an individual's health, social, and financial situations. Voluntary self-exclusion is one way for patients to reduce harm in gambling disorder, but breaching one's self-exclusion appears to be common. In January 2019, Sweden launched a nationwide, multioperator self-exclusion instrument called Spelpaus (literally "game break"). Spelpaus is unique to Sweden, and there is limited research on the use of this type of nationwide, multioperator self-exclusion services, also in relation to gambling disorder and mental health. There is a reason to follow the clinical picture of treatment seeking for gambling disorder over time, and this study aims to explore clinical characteristics of patients seeking clinical gambling disorder treatment, including sex distribution and mental health comorbidity, as well as the use of Spelpaus amongst patients with gambling disorder and how frequently users gambled despite ongoing self-exclusion, in relation to sex and psychiatric comorbidities. A retrospective chart study was carried out on patients presenting to a regional gambling disorder treatment unit. Information regarding self-exclusions using Spelpaus, gambling despite self-exclusion, and the method of gambling despite self-exclusion as well as psychiatric comorbidities were extracted from medical records. Females were markedly more likely to report overall psychiatric comorbidities (48% vs. 25% among males, p < 0.001), affective, neurotic/anxiety-related (p < 0.001), and behavioral/emotional (p = 0.028) diagnoses and more likely to have two or more diagnoses excluding gambling disorder (p = 0.001). From 120 patients from whom information regarding self-exclusion was present, 114 (95%) had chosen to self-exclude. From the 114 self-excluders, 67 reported to have gambled despite self-exclusion, with unregistered websites being the most common method. Self-exclusion was not significantly related to sex (p = 0.146) or to psychiatric comorbidities (p = 0.178). In conclusion, psychiatric comorbidity was particularly common in female gambling disorder patients and gambling despite self-exclusion was common. Gambling regulations should be improved to help self-excluders avoid being able to gamble on unlicensed gambling operators. Further research should focus on sex differences and the association with psychiatric comorbidities.

Effective Altruism as an Ethical Lens on Research Priorities.

Effective altruism is an ethical framework for identifying the greatest potential benefits from investments. Here, we apply effective altruism concepts to maximize research benefits through identification of priority stakeholders, pathosystems, and research questions and technologies. Priority stakeholders for research benefits may include smallholder farmers who have not yet attained the minimal standards set out by the United Nations Sustainable Development Goals; these farmers would often have the most to gain from better crop disease management, if their management problems are tractable. In wildlands, prioritization has been based on the risk of extirpating keystone species, protecting ecosystem services, and preserving wild resources of importance to vulnerable people. Pathosystems may be prioritized based on yield and quality loss, and also factors such as whether other researchers would be unlikely to replace the research efforts if efforts were withdrawn, such as in the case of orphan crops and orphan pathosystems. Research products that help build sustainable and resilient systems can be particularly beneficial. The "value of information" from research can be evaluated in epidemic networks and landscapes, to identify priority locations for both benefits to individuals and to constrain regional epidemics. As decision-making becomes more consolidated and more networked in digital agricultural systems, the range of ethical considerations expands. Low-likelihood but high-damage scenarios such as generalist doomsday pathogens may be research priorities because of the extreme potential cost. Regional microbiomes constitute a commons, and avoiding the "tragedy of the microbiome commons" may depend on shifting research products from "common pool goods" to "public goods" or other categories. We provide suggestions for how individual researchers and funders may make altruism-driven research more effective.[Formula: see text] Copyright © 2020 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Hinge Region in DNA Packaging Terminase pUL15 of Herpes Simplex Virus: A Potential Allosteric Target for Antiviral Drugs.

Approximately 80% of adults are infected with a member of the herpesviridae family. Herpesviruses establish life-long latent infections within neurons, which may reactivate into lytic infections due to stress or immune suppression. There are nine human herpesviruses (HHV) posing health concerns from benign conditions to life threatening encephalitis, including cancers associated with viral infections. The current treatment options for most HHV conditions mainly include several nucleoside and nucleotide analogs targeting viral DNA polymerase. Although these drugs help manage infections, their common mechanism of action may lead to the development of drug resistance, which is particularly devastating in immunocompromised patients. Therefore, new classes of drugs directed against novel targets in HHVs are necessary to alleviate this issue. We analyzed the conservation rates of all proteins in herpes simplex virus 1 (HHV-1), a representative of the HHV family and one of the most common viruses infecting the human population. Furthermore, we generated a full-length structure model of the most conserved HHV-1 protein, the DNA packaging terminase pUL15. A series of computational analyses were performed on the model to identify ATP and DNA binding sites and characterize the dynamics of the protein. Our study indicates that proteins involved in HHV-1 DNA packaging and cleavage are amongst the most conserved gene products of HHVs. Since the packaging protein pUL15 is the most conserved among all HHV-1 gene products, the virus will have a lower chance of developing resistance to small molecules targeting pUL15. A subsequent analysis of the structure of pUL15 revealed distinct ATP and DNA binding domains and the elastic network model identifies a functionally important hinge region between the two domains of pUL15. The atomic information on the active and allosteric sites in the ATP- and DNA-bound model of pUL15 presented in this study can inform the structure-based drug discovery of a new class of drugs to treat a wide range of HHVs.

Adhesion-mediated cytoskeletal remodeling is controlled by the direct scaffolding of Src from FAK complexes to lipid rafts by SSeCKS/AKAP12.

Metastatic cell migration and invasion are regulated by altered adhesion-mediated signaling to the actin-based cytoskeleton via activated Src-FAK complexes. Src-suppressed C-kinase substrate (SSeCKS, the rodent orthologue of human Gravin/AKAP12), whose expression is downregulated by oncogenic Src and in many human cancers, antagonizes oncogenic Src pathways including those driving neovascularization at metastatic sites, metastatic cell motility and invasiveness. This is likely manifested through its function as a scaffolder of F-actin and signaling proteins such as cyclins, calmodulin, protein kinase C and A. Here we show that in contrast to its ability to inhibit haptotaxis, SSeCKS increased prostate cancer cell adhesion to fibronectin and type I collagen in a FAK-dependent manner, correlating with a relative increase in FAK(poY397) levels. In contrast, SSeCKS suppressed adhesion-induced Src activation (Src(poY416)) and phosphorylation of FAK at Y925, a known Src substrate site. SSeCKS also induced increased cell spreading, cell flattening, integrin ß1 clustering and formation of mature focal adhesion plaques. An in silico analysis identified a Src-binding domain on SSeCKS(aa 153-166) that is homologous to the Src-binding domain of caveolin-1, and this region is required for SSeCKS-Src interaction, for SSeCKS-enhanced Src activity and sequestration to lipid rafts and for SSeCKS-enhanced adhesion of MAT-LyLu and CWR22Rv1 prostate cancer cells. Our data suggest a model in which SSeCKS suppresses oncogenic motility by sequestering Src to caveolin-rich lipid rafts, thereby disengaging Src from FAK-associated adhesion and signaling complexes.

Laparoscopic cholecystectomy in cirrhotic patients.

BACKGROUND: Due to unacceptable increases in intra- and postoperative complications and associated morbidity, cirrhosis of the liver is often considered to be a contraindication for laparoscopic cholecystectomy (LC). However, recent advances have now made it increasingly possible for experienced surgeons to perform LC on this high-risk population. The aim of this study was to evaluate the impact of the coagulopathy associated with cirrhosis on the performance and results of LC. We hypothesized that the factors leading to hemorrhage, rather than Child's classification, would drive operating time and resource utilization. METHODS: Between 1 July 1996 and 30 June 2003, 1,285 cholecystectomies were performed. Thirty one of these patients had evidence of cirrhosis at the time of operation. The 31 patients were divided into high, (low platelets, prolonged International Normalized Ratio) (n = 18), intermediate, (abnormal liver function tests, normal clotting) (n = 5), and low, (normal platelets, normal clotting, and normal liver function tests) (n = 8) surgical risk categories for further analysis. Based on the Child-Turcotte-Pugh (CTP) classification of cirrhosis, there were three grade C and 28 grade A or grade B patients. RESULTS: There were 24 LC, three of which were started laparoscopically and then converted to open, and four open cholecystectomies. Operating room time ranged from 79 to 450 min, with the extent of coagulopathy correlating with the length of time needed to achieve satisfactory hemostasis. Median length of stay postoperatively in the high-risk group was 2 days (range, 0-20). Nine of the cholecystectomies were performed on an outpatient basis. One patient received a liver transplantation 5 months post-LC. There were no operative deaths, bile duct injuries, or returns to the operating room for bleeding. Blood product usage correlated with preexisting coagulopathy. CONCLUSIONS: Currently, the classification of cirrhotic patients is normally done using the CTP score. However, preoperative platelet levels and INR more accurately predict the difficulty of cholecystectomy than CTP score, because intraoperative hemorrhage is the primary concern in these patients. This study demonstrates that preoperative degree of coagulopathy, and not Child's class, should guide the surgeon's approach and expectations when LC is performed in a cirrhotic patient.

Laparoscopic cholecystectomy after the learning curve: what should we expect?

BACKGROUND: The introduction of laparoscopic cholecystectomy (LC) in the late 1980s was accompanied an increase in common bile duct (CBD) injuries. This retrospective analysis of 2,005 cholecystectomies performed at a single institution investigates the factors that have contributed to a record of zero CBD injuries in 1,674 consecutive LC. METHODS: The medical records of 1,285 consecutive patients operated on from 7 July 1996 to 6 June 2003 were obtained. We also examined the peer review records of an additional 720 LC performed between 1 January 1990 and 7 July 1996. RESULTS: There were no CBD injuries among 1,674 consecutive LC patients spanning the period since 1990. Of the 954 patients who underwent LC since 1996, six had a cystic duct leak and five had a duct of Luschka leak. Intraoperative cholangiography (IOC) was performed in 20.2% of cases (n = 193/954). Seventy of 157 patients who underwent cholangiography alone demonstrated one or more stones in the CBD (44.6%). In 40 patients (58.0%), endoscopic retrograde cholangio pancreatography (ERCP) was uniformly successful in clearing intraoperatively identified stones. In36.2% of cases, the stones were removed via laparoscopic CBD exploration (CBDE) (n = 25). In 5.8% of positive cases, the stones were removed via open CBDE (n = 4). Among 761 patients who did not undergo IOC, seven patients (0.92%) returned to the hospital for retained stones. Three of these patients had elevated liver function tests (LFT) preoperatively (1.3%) and four had normal LFT (1.1%). CONCLUSIONS: Injuries of the CBD can be avoided by performing an extensive dissection of the triangle of Calot and by developing a critical view of the operative field to ensure the patient's safety during LC. If all LFT are normal and IOC is not performed, the occurrence of clinically significant stones postoperatively is minimal; in this group, only four patients had retained stones. Thus, in the face of normal LFT, routine IOC is unnecessary for a low CBD injury rate, and a return to the hospital for retained bile duct stones is rarely required, regardless of the number of times ductal stones are found on routine cholangiography. This implies that the significance of the stones discovered at IOC is questionable in most cases, thereby providing an argument against routine cholangiography. Most discovered CBD stones can be treated by ERCP, thus obviating the need for the T-tube drainage associated with CBDE. The 21st century finds LC to be a mature and safe surgical procedure.

Using computerized data to identify adverse drug events in outpatients.

OBJECTIVE: To evaluate the use of a computer program to identify adverse drug events (ADEs) in the ambulatory setting and to evaluate the relative contribution of four computer search methods for identifying ADEs, including diagnosis codes, allergy rules, computer event monitoring rules, and text searching. DESIGN: Retrospective analysis of one year of data from an electronic medical record, including records for 23,064 patients with a primary care physician, of whom 15,665 actually came for care. MEASUREMENT: Presence of an ADE; sensitivity and specificity of computer searches for ADE. RESULTS: The computer program identified 25,056 incidents, which were associated with an estimated 864 (95 percent confidence interval [CI], 750-978) ADES. Thus, the ADE rate was 5.5 (CI, 5.2-5.9) per 100 patients coming for care. Furthermore, in 79 (CI, 68-89) ADEs, the patient required hospitalization, resulting in an estimated rate of 3.4 (CI, 2.7-4.3) admissions per 1,000 patients. The sensitivity of the search methods for identifying ADEs was estimated to be 58 (CI, 18-98) percent, and the estimated specificity was 88 (CI, 87-88) percent. The positive predictive value was 7.5 (CI, 6.5-8.5) percent, and the negative predictive value was 99.2 (CI, 95.5-99.98) percent. Compared with age and gender-matched controls with no positive screen, patients with ADEs had twice as many outpatient visits and were taking nearly three times as many drugs. Antihypertensives, ACE-inhibitors, antibiotics, and diuretics were associated with 56 (CI, 47-65) percent of ADES. Among ADEs, 23 (CI, 16-32) percent were life-threatening or serious, and 38 (CI, 29-47) percent were judged preventable. CONCLUSION: Computerized search programs can detect ADEs, and free-text searches were especially useful. Adverse drug events were frequent, and admissions were not rare, although most hospitals today do not identify them. Thus, such detection programs demonstrate "value-added" for the electronic record and may be useful for directing and assessing the impact of quality improvement efforts.

Abdominal cross-sectional imaging for inpatients with abnormal liver function test results: yield and usefulness.

BACKGROUND: Abdominal cross-sectional imaging is often performed to evaluate abnormal liver function test (LFT) results in hospitalized patients. However, few data are available regarding the yield and usefulness of imaging inpatients for the indication of abnormal LFT results, the process of requesting abdominal imaging studies, or the response to their findings. METHODS: We retrospectively reviewed abdominal imaging scans that were obtained during a 27-month period. We matched the imaging studies done with the indication of abnormal LFT results; all scans were requested using computerized physician order entry. Reports were coded for interpretation and associated process step results. To determine the usefulness of the imaging studies, a random sample of patient charts with positively coded imaging studies were reviewed. Imaging examinations were considered useful if they provided new diagnostic information and/or changed subsequent patient care. RESULTS: Of 6494 abdominal imaging studies, 856 were performed for the indication of abnormal LFT results and matched to both image reports and laboratory results. Report coding judged 37% of interpretations as clinically significant, including 27% with "positive" (abnormal results and explain the abnormal LFT results) examinations. Among the positive examinations, the most common diagnoses were biliary obstruction (25%), cholecystitis (21%), malignancy (20%), and cirrhosis (14%). Positively coded reports provided new clinical information in 63% of these studies and changed patient care in 42% of cases. Process measures assessed provision of additional information to and from radiologists (69% and 8%, respectively) and the frequency with which the findings of current abdominal imaging studies were compared with those of prior studies (59%). CONCLUSION: Abdominal cross-sectional imaging studies performed on inpatients with abnormal LFT results had a high diagnostic yield and frequently changed patient care.

Metallic fragments on mammography after intraoperative deployment of radiopaque clips.

OBJECTIVE: Our objective was to report the occurrence and determine the frequency of metallic fragments in the breast after placement of surgical clips that are used to delineate the margins of the biopsy cavity. CONCLUSION: Metallic fragments are commonly present in patients who have surgical clips placed during breast biopsy for both benign and malignant disease. Awareness of this phenomenon may prevent the misidentification of these fragments as microcalcifications and thus avert unnecessary concern or biopsy.

Preventable medical injuries in older patients.

Injuries associated with hospitalization are more common in older (>/=65 years) than in younger patients (<65 years), and they may be more severe and more often preventable. The increasing age of the population magnifies the importance of this problem. In this review, we first consider medical injuries in general and then review the literature for 6 categories: adverse drug events, falls, nosocomial infections, pressure sores, delirium, and surgical and perioperative complications. For each of these categories, older patients appear to be at higher risk, ranging from a 2.2-fold increase for perioperative complications to a 10-fold increase for falling, based on Harvard Medical Practice Study rates. The main cause of these increased risks appears to be the diminished physiological reserve of elderly patients; however, age alone is a less important predictor of adverse events than comorbidities and functional status. Furthermore, many of these complications appear to be preventable, although the proportion preventable varies by type of complication. While some prevention strategies are specifically beneficial in older patients, many apply to all age groups. Geriatric care units and consultation systems have improved outcomes in some instances, although the data are mixed. The success of intervention varies by type of complications. For medications, various interventions have been successful, and fall prevention programs have been demonstrated to be effective in the nursing home and home.

Comparison of the frequency of behavioral disinhibition on alprazolam, clonazepam, or no benzodiazepine in hospitalized psychiatric patients.

Several case reports have suggested that treatment with the benzodiazepine alprazolam can result in behavioral disinhibition. To address this question, the authors reviewed the medical records (blinded to all pharmacologic treatments the patients received) of 323 psychiatric inpatients treated with alprazolam (108 patients), clonazepam (111 patients), or no benzodiazepine (104 patients) between January 1989 and June 1990. During benzodiazepine treatment, there were no significant differences among the three groups on the following measures: (1) acts of self-injury (alprazolam, 1.9%; clonazepam, 1.8%; no benzodiazepine, 2.9%); (2) assaults on staff or other patients (alprazolam, 0%; clonazepam, 0.9%; no benzodiazepine, 1.0%); (3) need for seclusion or restraints (alprazolam, 3.7%; clonazepam, 6.3%; no benzodiazepine, 4.8%); (4) increased need for observation by hospital staff (alprazolam, 8.3%; clonazepam, 7.2%; no benzodiazepine, 6.7%); and (5) decrease in patient privileges (alprazolam, 11.1%; clonazepam, 12.6%; no benzodiazepine, 11.5%). The results indicate that in an inpatient psychiatric population, the frequency of behavioral disturbances with alprazolam, clonazepam, or no benzodiazepine does not differ. This suggests that alprazolam does not possess unique disinhibitory activity. Second, these data suggest that disinhibition may not be an important clinical problem associated with benzodiazepine use. The design of the study does not allow one to establish a relationship between the prescription of the benzodiazepine and worsening behaviors, and the findings need to be interpreted conservatively because it was a retrospective review of a heterogeneous population. However, it is noteworthy that the incidence of adverse events was low even in this high-risk population, and because the patients were in the hospital and under constant observation, the objective assessment of so-called paradoxical reactions was undertaken in a controlled setting.

A clinical trial of retroviral-mediated transfer of a rev-responsive element decoy gene into CD34(+) cells from the bone marrow of human immunodeficiency virus-1-infected children.

Genetic modification of hematopoietic stem cells with genes that inhibit replication of human immunodeficiency virus-1 (HIV-1) could lead to development of T lymphocytes and monocytic cells resistant to HIV-1 infection after transplantation. We performed a clinical trial to evaluate the safety and feasibility of this procedure, using bone marrow from four HIV-1-infected pediatric subjects (ages 8 to 17 years). We obtained bone marrow, isolated CD34(+) cells, performed in vitro transduction with a retroviral vector carrying a rev-responsive element (RRE) decoy gene, and reinfused the cells into these subjects with no evidence of adverse effects. The levels of gene-containing leukocytes in peripheral blood samples in the 1 year after gene transfer/cell infusion have been extremely low. These observations support the potential of performing gene therapy for HIV-1 using hematopoietic cells, but emphasize the need for improved gene transfer techniques.

Unipolar sensing in contemporary pacemakers: using myopotential testing to define optimal sensitivity settings.

Bipolar lead use has increased due to oversensing concerns with older unipolar systems. Data on contemporary unipolar devices with improved hardware design and greater programming flexibility is lacking. Using a randomized crossover design, unipolar and bipolar sensing characteristics of 22 atrial and 16 ventricular leads were compared in 34 patients who had pulse generators of programmable polarity. Unipolar and bipolar intracardiac electrogram amplitudes, pacing and sensing thresholds at rest were similar. Provocative maneuvers were used to assess for myopotential inhibition. At atrial sensitivities of 0.625-1.50 mV, myopotential inhibition occurred in 11 (50%) atrial leads in the unipolar mode compared to 1 (5%) in the bipolar mode (p < 0.001). At sensitivities of > 1.50 mV myopotential inhibition occurred in only 1 ventricular (unipolar) lead. An optimal sensitivity setting for each polarity was derived using clinic test results and assessed by ambulatory ECG (AECG). At these optimal settings, oversensing occurred in 1 (6%) atrial and 1 (8%) ventricular unipolar lead during AECG monitoring, whereas oversensing was not seen in any leads programmed to the bipolar mode. Undersensing occurred in 5 (29%) atrial unipolar versus 1 (6%) bipolar lead (p = 0.08). Undersensing was not observed in any of the ventricular leads. Myopotential inhibition may be frequently provoked by provocative maneuvers at higher sensitivity settings in atrial unipolar leads. The frequency of oversensing can be significantly reduced by defining an optimal sensitivity setting using simple isometric maneuvers. Given present day concerns over bipolar lead longevity, increased utilization of unipolar ventricular leads should be considered.

What alternatives has minimally invasive surgery provided the surgeon?

When a new technology bursts on the horizon and reenergizes a field that has seemed to be flagging, as minimally invasive surgery has done for the field of general surgery, many enthusiasts rapidly embrace the discipline. Questions should arise, however, as to what novelty has really been introduced, where it should fit in our treatment of patients, and, when the dust settles, what alternatives truly have been provided to the advantage of our patients. This article provides information and data about some of these procedures, while trying to address these issues and answer some questions that new technology raises.

Changes in pacing lead impedance over time predict lead failure.

It has been suggested that a decrease in lead impedance may predict pacing lead failure, but there is limited prospective data about the relation of changes in lead impedance over time to lead performance. We monitored changes in lead impedance through implantable pulse generators with real-time telemetry data capability in 105 patients with Medtronic 4012 leads (n = 38) and Medtronic 4004 leads (n = 67). Pacing lead failure was documented by serial ambulatory electrocardiographic monitoring or intensified pacemaker clinic surveillance. A significant decrease in lead impedance was observed in patients with Medtronic 4012 and Medtronic 4004 leads with documented lead failure, whereas lead impedance remained stable over time in patients without documented lead failure. The sensitivity and specificity of a lead impedance decrease of > or =15% to predict lead failure were 69% and 70%, respectively. The sensitivity and specificity of a lead impedance decrease of > or =30% to predict lead failure were 36% and 90%, respectively. The positive and negative predictive values for a lead impedance decrease of > or =15% were 54% and 81%, respectively, and for a lead impedance decrease of > or = 30% were 65% and 73%, respectively. Thus, small decreases in lead impedance may identify failing leads. Serial measurement of pacing lead impedance over time is a useful tool to monitor pacing lead performance.

Factors determining outcome for breast-conserving irradiation with margin-directed dose escalation to the tumor bed.

PURPOSE: A prospectively applied treatment policy for breast-conserving therapy used margin assessment as the exclusive guide to the intensity of therapy directed at the tumor-bearing quadrant. METHODS AND MATERIALS: From 1982-1994, there were 509 treated Stage I and II breast carcinomas with a median follow-up of 72 months. For operational purposes, tumor excision margins were prospectively defined as: > 5 mm, 2.1-5 mm, > 0 < or = 2 mm, and positive. If a margin was assessed as < or = 2 mm or indeterminate, and it was deemed cosmetically feasible, a reexcision of the tumor bed would be performed. All patients received whole breast irradiation to 50-50.4 Gy. The following scheme for tumor bed boost irradiation as a function of final margin status (FMS) was observed: (a) Minimal risk = no tumor found on reexcision, no boost performed; (b) low risk = FMS > 5 mm, boost of 10 Gy; intermediate risk = FMS 2.1-5 mm, boost to 14 Gy; high risk = FMS < or = 2 mm or positive, boost to 20 Gy. Cases were analyzed for local failure (LF) with respect to histology (invasive ductal (IDC), IDC with associated DCIS (IDC/DCIS), invasive lobular (ILC)), age, tumor size, total excision volume, reexcision, total dose, tamoxifen therapy, and chemotherapy. RESULTS: There were 19 breast recurrences for a Kaplan-Meier local failure rate for all cases at 5 and 10 years of 2.7% and 7.1%, respectively. Local failure in the first 4 years of follow-up was rare, with a mean annual incidence rate of 0.25% that rose to a mean of 1.1% in subsequent years. Univariate results of Cox proportional hazards regression survival models found positive FMS (p = 0.02), IDC/DCIS (p = 0.04) and age (0.0006) as significantly associated with local failure. In a multivariable model of FMS and IDC/DCIS, FMS retained significance (p = 0.01) but IDC/DCIS was borderline (p = 0.06). When FMS and age were included in a multivariable model, there was a significant interaction (p = 0.01) between the two variables. There was a significant increase in the relative risk of LF for age < or = 45 years (range 11.1-17.4), irrespective of FMS category. Although excellent overall control rates were achieved for patients > 45 years, for younger patients LF rates appeared to remain proportional to the relative closeness of the FMS, despite rigorous dose escalation. CONCLUSIONS: Graded tumor-bed dose escalation in response to FMS results in an exceptionally low risk of "early" local recurrence within the first 5 years of follow-up. However, this strategy is unable to completely overcome the longer term adverse influence of young age and positive FMS.