Revisiting international human rights treaties: comparing Asian and Western efforts to improve human rights.

This paper presents a review of existing literature to understand the effects and effectiveness of human rights treaties in the Asia Pacific region, particularly in Southeast Asian countries, in contrast to Western nations. The review argues that factors at the international/treaty level and factors at the domestic state level increase the difficulty of implementing effective international treaties on human rights. At the international level, the treaties and organizations to which states belong suffer some weakness as discussed in international relations theories, while seven factors are particularly important for promoting effectiveness of international human rights treaties at the domestic level: political capacity, economic development, national human rights institutes, regional human rights courts, regional intergovernmental organizations, strength of civil society, and political stability. Although the number of international human rights agreements signed and ratified by Asia Pacific states is increasing following the trends of Western states, less research focuses on the implementation and effects of these institutions. Asia Pacific nations face vastly different conditions than Western nations, such as more complicated security environments, larger cultural and religious differences, and less development and democratic values in some cases. Due to these differences, it is important to consider other potential variables that influence efficacy of treaty instruments for non-Western nations. What are the differences between implementation of human rights treaties in Western and Asian nations? How do they affect the efficacy of international agreements on individual human rights?

Engineering two species of yeast as cell factories for 2'-fucosyllactose.

Oligosaccharides present in human breast milk have been linked to beneficial effects on infant health. Inclusion of these human milk oligosaccharides (HMOs) in infant formula can recapitulate these health benefits. As a result, there is substantial commercial interest in a cost-effective source of HMOs as infant formula ingredients. Here we demonstrate that the yeast species Saccharomyces cerevisiae and Yarrowia lipolytica both can be engineered to produce 2'-fucosyllactose (2'FL), which is the most abundant oligosaccharide in human breast milk, at high titer and productivity. Both yeast species were modified to enable uptake of lactose and synthesis of GDP-fucose - the two precursors of 2'FL - by installing a lactose transporter and enzymes that convert GDP-mannose to GDP-fucose. Production of 2'FL was then enabled by expression of α-1,2-fucosyltransferases from various organisms. By screening candidate transporters from a variety of sources, we identified transporters capable of exporting 2'FL from yeast, which is a key consideration for any biocatalyst for 2'FL production. In particular, we identified CDT2 from Neurospora crassa as a promising target for further engineering to improve 2'FL efflux. Finally, we demonstrated production of 2'FL in fermenters at rates and titers that indicate the potential of engineered S. cerevisiae and Y. lipolytica strains for commercial 2'FL production.

Neuroimaging Rates for Closed Head Trauma in a Community Hospital.

OBJECTIVES: We aimed to characterize the utility of neuroimaging for head trauma in a suburban community hospital and determine whether imaging practices conform to most recent pediatric guidelines. METHODS: The electronic medical record was surveyed for computed tomographic and magnetic resonance imaging head scans on patients aged 1 to 18 years who were evaluated for trauma. The query included the following: date, sex, type of scan (computed tomography or magnetic resonance imaging), age, patient location, reason for scan, Glasgow Coma Scale (GCS) score (if entered), result, and text from physician's notes. RESULTS: A total of 2679 patients were identified. Within this cohort was a maximum of 29 surgical patients, of whom 8 required a surgical procedure but not neurosurgery among the 592 patients who had a GCS score of 14-15 entered, 2 were confirmed/possible neurosurgical patients, giving a neurosurgical rate of 0.34%. When the GCS 3-13 patient group was analyzed, the relative risk of requiring neurosurgery climbed to 52. Using an established algorithm for pediatric head trauma imaging would have reduced the number of scanned patients to 533. The individual cost of identifying the 29 surgical patients in our population exceeded $31,000. CONCLUSIONS: Our rate of serious lesions in GCS 14-15 patients was identical to a larger prospective study in urban teaching hospitals. Using their previously described algorithm might have reduced the number of patients scanned by more than 70% and saved close to $750,000 for the study period.

Development of dietary soluble fibres by enzymatic synthesis and assessment of their digestibility in in vitro, animal and randomised clinical trial models.

The aim was to develop novel fibres by enzymatic synthesis, to determine their total dietary fibre by AOAC method 2009.01 and to estimate their potential digestibility and assess their digestibility in vivo using glycaemic and insulinaemic responses as markers in mice and randomised clinical trial models. We found that fibre candidates to which α-(1,2) branching was added were resistant to digestion in the mouse model, depending on the amount of branching. These results show that in vivo models are needed to reliably assess the digestibility of α-glycosidic-linked oligomeric dietary fibre candidates, possibly due to absence of brush border α-glucosidase activity in the current in vitro assessment. α-(1,3)-linked and α-(1,6)-linked glucose oligomers were completely digested in humans and mice. In conclusion, it is possible to develop dietary soluble fibres by enzymatic synthesis. Adding α-(1,2) branching increases their resistance to digestion in vivo and can thus improve their suitability as potential fibre candidates. Clinical Trial Registry: ClinicalTrials.gov, NCT02701270.

Brivaracetam augments short-term depression and slows vesicle recycling.

OBJECTIVE: Brivaracetam (BRV) decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle glycoprotein 2A (SV2A) with a higher affinity than the antiepileptic drug levetiracetam (LEV). Experiments were performed to determine if BRV acted similarly to LEV to induce or augment short-term depression (STD) under high-frequency neuronal stimulation and slow synaptic vesicle recycling. METHODS: Electrophysiologic field excitatory postsynaptic potential (fEPSP) recordings were made from CA1 synapses in rat hippocampal slices loaded with BRV or LEV during intrinsic activity or with BRV actively loaded during hypertonic stimulation. STD was examined in response to 5 or 40 Hz stimulus trains. Presynaptic release of FM1-43 was visualized using two-photon microscopy to assess drug effects upon synaptic vesicle mobilization. RESULTS: When hippocampal slices were incubated in 0.1-30 µm BRV or 30 µm-1 mm LEV for 3 h, the relative CA1 field EPSPs decreased over the course of a high-frequency train of stimuli more than for control slices. This STD was frequency- and concentration-dependent, with BRV being 100-fold more potent than LEV. The extent of STD depended on the length of the incubation time for both drugs. Pretreatment with LEV occluded the effects of BRV. Repeated hypertonic sucrose treatments and train stimulation successfully unloaded BRV from recycling vesicles and reversed BRVs effects on STD, as previously reported for LEV. At their maximal concentrations, BRV slowed FM1-43 release to a greater extent than in slices loaded with LEV during prolonged stimulation. SIGNIFICANCE: BRV, similar to LEV, entered into recycling synaptic vesicles and produced a frequency-dependent decrement of synaptic transmission at 100-fold lower concentrations than LEV. In addition, BRV slowed synaptic vesicle mobilization more effectively than LEV, suggesting that these drugs may modify multiple functions of the synaptic vesicle protein SV2A to curb synaptic transmission and limit epileptic activity.

Seletracetam enhances short term depression in vitro.

Seletracetam (SEL), an analog of the antiepileptic drug levetiracetam (LEV), decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle protein SV2A with a higher affinity than LEV. Experiments were performed to determine if SEL, like LEV, reduces the later EPSPs in long trains of stimuli in a manner dependent upon access to the interior of synaptic vesicles and SV2A binding. When hippocampal slices were incubated in 3-30µM SEL for 3h, but not 30 min, the relative amplitude of the CA1 field excitatory synaptic potentials decreased over the course of a train of high frequency stimuli more than for control slices. This short term depression was frequency and dose dependent and largely disappeared when the spontaneous activity during the loading period was removed by cutting the Schaffer collaterals. The SEL effect was also observed in slices loaded during prolonged stimulation at 1Hz, but not 10Hz. Hippocampal slices loaded with both SEL and FM1-43 to visualize synaptic boutons released the FM1-43 in response to prolonged stimulation much more slowly than control slices during prolonged stimulation. Like LEV, SEL produced a frequency-dependent decrement of synaptic transmission that was dependent upon the drug entering recycling synaptic vesicles and compatible with SV2A binding. Previous observations of SV2A binding affinity correlated with the current effect of SEL and the previously reported effect of LEV on synaptic transmission validate SV2A as an extremely attractive target for future antiepileptic drug development.

Temperatures achieved in human and canine neocortex during intraoperative passive or active focal cooling.

Focal cortical cooling inhibits seizures and prevents acquired epileptogenesis in rodents. To investigate the potential clinical utility of this treatment modality, we examined the thermal characteristics of canine and human brain undergoing active and passive surface cooling in intraoperative settings. Four patients with intractable epilepsy were treated in a standard manner. Before the resection of a neocortical epileptogenic focus, multiple intraoperative studies of active (custom-made cooled irrigation-perfused grid) and passive (stainless steel probe) cooling were performed. We also actively cooled the neocortices of two dogs with perfused grids implanted for 2 hours. Focal surface cooling of the human brain causes predictable depth-dependent cooling of the underlying brain tissue. Cooling of 0.6-2°C was achieved both actively and passively to a depth of 10-15 mm from the cortical surface. The perfused grid permitted comparable and persistent cooling of canine neocortex when the craniotomy was closed. Thus, the human cortex can easily be cooled with the use of simple devices such as a cooling grid or a small passive probe. These techniques provide pilot data for the design of a permanently implantable device to control intractable epilepsy.

Determination of kinetics and the crystal structure of a novel type 2 isopentenyl diphosphate: dimethylallyl diphosphate isomerase from Streptococcus pneumoniae.

Isopentenyl diphosphate isomerase (IDI) is a key enzyme in the isoprenoid biosynthetic pathway and is required for all organisms that synthesize isoprenoid metabolites from mevalonate. Type 1 IDI (IDI-1) is a metalloprotein that is found in eukaryotes, whereas the type 2 isoform (IDI-2) is a flavoenzyme found in bacteria that is completely absent from human. IDI-2 from the pathogenic bacterium Streptococcus pneumoniae was recombinantly expressed in Escherichia coli. Steady-state kinetic studies of the enzyme indicated that FMNH2 (KM =0.3 µM) bound before isopentenyl diphosphate (KM =40 µM) in an ordered binding mechanism. An X-ray crystal structure at 1.4 Å resolution was obtained for the holoenzyme in the closed conformation with a reduced flavin cofactor and two sulfate ions in the active site. These results helped to further approach the enzymatic mechanism of IDI-2 and, thus, open new possibilities for the rational design of antibacterial compounds against sequence-similar and structure-related pathogens such as Enterococcus faecalis or Staphylococcus aureus.

AFib treatment: general population.

When primary care physicians are presented with a patient with atrial fibrillation (AFib), there are two concerns. (online video available at: http://education.amjmed.com/video.php?event_id=445&stage_id=5&vcs=1). One is the choice of strategy to treat the AFib, ie, whether to use rate control or a rhythm control strategy (to keep patients in sinus rhythm). The second concern is preventing the principal risk associated with AFib: stroke and systemic embolism. The focus of this review is stroke prevention, concentrating on risk assessment and traditional versus the new oral anticoagulation agents. For the past several decades, oral anticoagulation therapy has meant warfarin, which has the benefit of >50 years of clinical experience: it is inexpensive, it has generic availability, and it has a wide range of clinical use indications beyond merely stroke prophylaxis in patients with AFib. On the other hand, only about half of the patients who should be receiving warfarin are prescribed it (and even fewer older patients are prescribed it), and only 30% of patients maintain time in therapeutic range (TTR) for serum warfarin levels at or above INR 2-3. According to a recent survey, almost a quarter of physicians employ rhythm control to treat AFib, and many of these believe that rhythm control decreases stroke and mortality risk sufficiently that anticoagulation therapy is not necessary. In addition, many physicians believe that when AFib is paroxysmal as opposed to permanent, then risk of stroke is low enough that long-term anticoagulation is not necessary. As discussed in this review, however, neither of these beliefs is true. Regarding bleeding risk, the same survey found that physicians perceive the risks of anticoagulation to be far greater than the benefits. Again, the evidence reveals that the patients at highest risk of bleeding are also at highest risk of stroke, and the benefits of preventing stroke with anticoagulation therapy almost always outweigh the risk of bleeding. This is discussed in the context of the new NOACs (discussed in the next review), including addressing what physicians should do if patients move from warfarin to one of the NOACs or vice versa. A final challenge for physicians treating patients with AFib has been the often mistaken belief that patients are at a low-risk status, and this review concludes with an overview of the use of the CHADS2 versus the CHA2DS2-VASc risk scoring systems, including why CHA2DS2-VASc provides a better assessment of which patients are or are not at low risk.

Development and validation of a continuous measure of patient condition using the Electronic Medical Record.

Patient condition is a key element in communication between clinicians. However, there is no generally accepted definition of patient condition that is independent of diagnosis and that spans acuity levels. We report the development and validation of a continuous measure of general patient condition that is independent of diagnosis, and that can be used for medical-surgical as well as critical care patients. A survey of Electronic Medical Record data identified common, frequently collected non-static candidate variables as the basis for a general, continuously updated patient condition score. We used a new methodology to estimate in-hospital risk associated with each of these variables. A risk function for each candidate input was computed by comparing the final pre-discharge measurements with 1-year post-discharge mortality. Step-wise logistic regression of the variables against 1-year mortality was used to determine the importance of each variable. The final set of selected variables consisted of 26 clinical measurements from four categories: nursing assessments, vital signs, laboratory results and cardiac rhythms. We then constructed a heuristic model quantifying patient condition (overall risk) by summing the single-variable risks. The model's validity was assessed against outcomes from 170,000 medical-surgical and critical care patients, using data from three US hospitals. Outcome validation across hospitals yields an area under the receiver operating characteristic curve(AUC) of ≥0.92 when separating hospice/deceased from all other discharge categories, an AUC of ≥0.93 when predicting 24-h mortality and an AUC of 0.62 when predicting 30-day readmissions. Correspondence with outcomes reflective of patient condition across the acuity spectrum indicates utility in both medical-surgical units and critical care units. The model output, which we call the Rothman Index, may provide clinicians with a longitudinal view of patient condition to help address known challenges in caregiver communication, continuity of care, and earlier detection of acuity trends.

Risks of mortality associated with common laboratory tests: a novel, simple and meaningful way to set decision limits from data available in the Electronic Medical Record.

BACKGROUND: Laboratory tests provide objective measurements of physiologic functions, but are usually evaluated by demographic reference-intervals (RI), instead of risk-based decision-limits (DL). We show that hospital electronic medical record (EMR) data can be utilized to associate all-cause mortality risks with analyte test values, thereby providing more information than RIs and defining new DLs. METHODS: Our cohort was 39,964 patients admitted for any reason and discharged alive, during two 1-year periods, at Sarasota Memorial Hospital, Florida, USA. We studied five routinely-performed in-hospital laboratory tests: serum creatinine, blood urea nitrogen, serum sodium, serum potassium, and serum chloride. By associating a mortality odds ratio with small intervals of values for each analyte, we calculated relative risk of all-cause mortality as a function of test values. RESULTS: We found mortality risks below the population average within these proposed DLs: potassium 3.4-4.3 mmol/L; sodium 136-142 mmol/L; chloride 100-108 mmol/L; creatinine 0.6-1.1 mg/dL; blood urea nitrogen (BUN) 5-20 mg/dL. The DLs correspond roughly to the usually-quoted RIs, with a notable narrowing for electrolytes. Potassium and sodium have reduced upper limits, avoiding a "high-normal" area where the odds ratio rises 2 to 3 times the population average. CONCLUSIONS: Any clinical laboratory test can be transformed into a mortality odds ratio function, associating mortality risk with each value of the analyte. This provides a DL determined by mortality risk, instead of RI assumptions about distribution in a "healthy" population. The odds ratio function also provides important risk information for analyte values outside the interval.

Placing clinical variables on a common linear scale of empirically based risk as a step towards construction of a general patient acuity score from the electronic health record: a modelling study.

OBJECTIVE: To explore the hypothesis that placing clinical variables of differing metrics on a common linear scale of all-cause postdischarge mortality provides risk functions that are directly correlated with in-hospital mortality risk. DESIGN: Modelling study. SETTING: An 805-bed community hospital in the southeastern USA. PARTICIPANTS: 42302 inpatients admitted for any reason, excluding obstetrics, paediatric and psychiatric patients. OUTCOME MEASURES: All-cause in-hospital and postdischarge mortalities, and associated correlations. RESULTS: Pearson correlation coefficients comparing in-hospital risks with postdischarge risks for creatinine, heart rate and a set of 12 nursing assessments are 0.920, 0.922 and 0.892, respectively. Correlation between postdischarge risk heart rate and the Modified Early Warning System (MEWS) component for heart rate is 0.855. The minimal excess risk values for creatinine and heart rate roughly correspond to the normal reference ranges. We also provide the risks for values outside that range, independent of expert opinion or a regression model. By summing risk functions, a first-approximation patient risk score is created, which correctly ranks 6 discharge categories by average mortality with p<0.001 for differences in category means, and Tukey's Honestly Significant Difference Test confirmed that the means were all different at the 95% confidence level. CONCLUSIONS: Quantitative or categorical clinical variables can be transformed into risk functions that correlate well with in-hospital risk. This methodology provides an empirical way to assess inpatient risk from data available in the Electronic Health Record. With just the variables in this paper, we achieve a risk score that correlates with discharge disposition. This is the first step towards creation of a universal measure of patient condition that reflects a generally applicable set of health-related risks. More importantly, we believe that our approach opens the door to a way of exploring and resolving many issues in patient assessment.

Mild passive focal cooling prevents epileptic seizures after head injury in rats.

OBJECTIVE: Post-traumatic epilepsy is prevalent, often difficult to manage, and currently cannot be prevented. Although cooling is broadly neuroprotective, cooling-induced prevention of chronic spontaneous recurrent seizures has never been demonstrated. We examined the effect of mild passive focal cooling of the perilesional neocortex on the development of neocortical epileptic seizures after head injury in the rat. METHODS: Rostral parasagittal fluid percussion injury in rats reliably induces a perilesional, neocortical epileptic focus within weeks after injury. Epileptic seizures were assessed by 5-electrode video-electrocorticography (ECoG) 2 to 16 weeks postinjury. Focal cooling was induced with ECoG headsets engineered for calibrated passive heat dissipation. Pathophysiology was assessed by glial fibrillary acidic protein immunostaining, cortical sclerosis, gene expression of inflammatory cytokines interleukin (IL)-1α and IL-1ß, and ECoG spectral analysis. All animals were formally randomized to treatment groups, and data were analyzed blind. RESULTS: Cooling by 0.5 to 2°C inhibited the onset of epileptic seizures in a dose-dependent fashion. The treatment induced no additional pathology or inflammation, and normalized the power spectrum of stage N2 sleep. Cooling by 2°C for 5.5 weeks beginning 3 days after injury virtually abolished ictal activity. This effect persisted through the end of the study, >10 weeks after cessation of cooling. Rare remaining seizures were shorter than in controls. INTERPRETATION: These findings demonstrate potent and persistent prevention and modification of epileptic seizures after head injury with a cooling protocol that is neuroprotective, compatible with the care of head injury patients, and conveniently implemented. The required cooling can be delivered passively without Peltier cells or electrical power.

Clinical implications and validity of nursing assessments: a longitudinal measure of patient condition from analysis of the Electronic Medical Record.

OBJECTIVES: This study investigates risk of mortality associated with nurses' assessments of patients by physiological system. We hypothesise that nursing assessments of in-patients performed at entry correlate with in-hospital mortality, and those performed just before discharge correlate with postdischarge mortality. DESIGN: Cohort study of in-hospital and postdischarge mortality of patients over two 1-year periods. SETTING: An 805-bed community hospital in Sarasota, Florida, USA. SUBJECTS: 42 302 inpatients admitted for any reason, excluding obstetrics, paediatric and psychiatric patients. OUTCOME MEASURES: All-cause mortalities and mortality OR. RESULTS: Patients whose entry nursing assessments, other than pain, did not meet minimum standards had significantly higher in-hospital mortality than patients meeting minimums; and final nursing assessments before discharge had large OR for postdischarge mortality. In-hospital mortality OR were found to be: food, 7.0; neurological, 9.4; musculoskeletal, 6.9; safety, 5.6; psychosocial, 6.7; respiratory, 8.1; skin, 5.2; genitourinary, 3.0; gastrointestinal, 2.3; peripheral-vascular, 3.9; cardiac, 2.8; and pain, 1.1. CI at 95% are within ±20% of these values, with p<0.001 (except for pain). Similar results applied to postdischarge mortality. All results were comparable across the two 1-year periods, with 0.85 intraclass correlation coefficient. CONCLUSIONS: Nursing assessments are strongly correlated with in-hospital and postdischarge mortality. No multivariate analysis has yet been performed, and will be the subject of a future study, thus there may be confounding factors. Nonetheless, we conclude that these assessments are clinically meaningful and valid. Nursing assessment data, which are currently unused, may allow physicians to improve patient care. The mortality OR and the dynamic nature of nursing assessments suggest that nursing assessments are sensitive indicators of a patient's condition. While these conclusions must remain qualified, pending future multivariate analyses, nursing assessment data ought to be incorporated in risk-related health research, and changes in record-keeping software are needed to make this information more accessible.

Impact of epilepsy surgery on seizure control and quality of life: a 26-year follow-up study.

PURPOSE: The short-term efficacy and safety of epilepsy surgery relative to medical therapy has been established, but it remains underutilized. There is a lack of data regarding the long-term seizure-control rates and quality of life outcomes after epilepsy surgery. This study represents the longest follow-up study to date, with a mean follow-up duration of 26 years. METHODS: We studied the seizure and health-related quality of life outcomes of patients who underwent epilepsy surgery by Dr. Sidney Goldring from 1967 to 1990. Retrospective clinical chart reviews gathered perioperative data and surveys obtained follow-up data. Seizure outcome was evaluated using the Engel classification system. KEY FINDINGS: Of 361 patients, 117 (32.4%) completed follow-up interviews. Fifty-six patients (48%) were Engel class I. Mean overall Quality of Life in Epilepsy (QOLIE-31) questionnaire score for the cohort was 68.2 ± 16. Eighty percent of patients reported their overall quality of life now as being better than before surgery. Seizure freedom was associated with better quality of life. We did not observe a statistically significant association between postoperative complications and long-term outcome. Patients who underwent temporal lobe resection achieved better seizure outcomes than those who underwent other types of procedures. Astatic seizures and bilateral surgery were associated with a worse Engel class outcome. SIGNIFICANCE: Our study demonstrates that the beneficial effects of epilepsy surgery are sustained over decades, and that these beneficial effects are correlated with an improved quality of life. The confirmation of its durability makes us optimistic that the outcomes from modern epilepsy surgery will be even better and that our present enthusiasm for this treatment modality is not misplaced.

Levetiracetam has an activity-dependent effect on inhibitory transmission.

PURPOSE: Previous work has shown that levetiracetam (LEV) binds the vesicular protein SV2A and reduces excitatory neurotransmitter release during trains of high-frequency activity, most likely by accessing its binding site through vesicular endocytosis into excitatory synaptic terminals. Because there are differences in excitatory and inhibitory transmitter release mechanisms, and there are suggestions that neurons differ in their SV2A expression, we were curious whether LEV also reduces inhibitory transmission. METHODS: We used patch-clamp recording from CA1 neurons in rat brain slices to quantify the effects of LEV on inhibitory postsynaptic currents (IPSCs). We were able to elicit pure IPSCs by stimulating inhibitory terminals close to neuronal soma and blocking excitatory postsynaptic currents with specific antagonists. KEY FINDINGS: We found that LEV reduces inhibitory currents in a frequency-dependent manner, with the largest relative effect on the later IPSCs in the highest frequency trains. However, in contrast to excitatory postsynaptic currents (EPSCs), LEV reduced IPSC trains after a briefer, 30 min incubation. When spontaneous activity during incubation was blocked with antagonists of excitatory transmission, LEV no longer reduced IPSCs. If slices were returned to LEV-free artificial cerebrospinal fluid (ACSF) after LEV incubation, but prior to recording, the IPSC reduction failed to appear. However, if synaptic activity was limited by treating with excitatory transmitter antagonists, after the initial LEV exposure, LEV still diminished trains of IPSC. The concentration required to diminish IPSC trains was lower than for EPSCs. SIGNIFICANCE: LEV exerts a qualitatively similar, frequency-dependent effect on both IPSCs and EPSCs. The much shorter latency for IPSC reduction is consistent with the greater levels of spontaneous inhibition in brain slices, supporting the hypothesis that vesicular uptake is necessary for the entry of LEVs into terminals. The vesicular entry of LEV resembles the cell entry pathways for tetanus and botulinum neurotoxins, but is unique for small, neuroactive drugs. Although the reduction of IPSC trains by LEV initially seems counterintuitive for an antiepileptic drug, there are multiple reasons that disruption of γ-aminobutyric acid (GABA) release could ultimately attenuate pathologic discharges.