Medico-legal dispute resolution: Experience of a tertiary-care hospital in Singapore.

INTRODUCTION: The resource burden of healthcare disputes and medico-legal claims has been rising. A dispute resolution system operating at the hospital level could ameliorate this disturbing trend. METHODS: This is a retrospective observational study on patient complaints and medico-legal cases received by the dispute resolution unit of an acute tertiary hospital from 2011 to 2015. We described the characteristics and analysed the resolution methodology and outcomes of all closed medico-legal cases. RESULTS: Patient complaints significantly increased at a compound annual growth rate (CAGR) of 4.2% (p<0.01), while medico-legal cases and ex-gratia payments for case settlements decreased at CAGRs of 4.8% (p<0.05) and 15.9% (p = 0.19), respectively. Out of 237 closed medico-legal cases, 88.6% were resolved without legal action, of which 78.1% were closed without any ex-gratia payments or waivers. Of the 11.4% of medico-legal cases that involved legal action, 66.7% were settled without ex-gratia payments or waivers. The primary resolution modes were the Patient Relations Service (PRS)'s engagement of the complainants and facilitation of written replies. No cases were brought to court. Cases were more likely resolved without legal action when there was engagement by the PRS (p = 0.009). These cases incurred a lower median settlement value than those with legal action. CONCLUSION: Our hospital-based dispute resolution system which addressed patients' core dissatisfactions and providers' perspectives, through a process of early engagement, open disclosure, and fair negotiations, was able to promote claims resolution before legal action was taken. This early dispute resolution strategy contained costs and maintained provider-patient relationships and complements system-level mediation and arbitration to reduce medico-legal litigation.

New thin-film adhesive for sealing full-thickness corneal incisions in rabbits.

PURPOSE: To compare the repair of penetrating corneal incisions in an in vivo rabbit model using a laser-activated thin-film adhesive, sutures, or self-seal. SETTING: The University of Sydney, Camperdown, Australia. DESIGN: Animal studies. METHODS: Under an operating microscope, 2.0 mm penetrating incisions were created in 162 right eyes. Incisions in one group were repaired with the adhesive, the second group received a single 10-0 nylon suture, and the third group was left to self-seal. Rabbits were killed humanely at predetermined timepoints over 2 weeks, and wound healing was assessed using burst pressure and immunohistological studies. A modified McDonald-Shadduck scoring was used to assess eyes. RESULTS: The mean burst pressure of the adhesive group was significantly higher than the sutured or self-sealed groups at all timepoints within the first 72 hours. At 0 hour, the burst pressure was 98.0 (±17.0) mm Hg, 30.6 (±2.1) mm Hg, and 3.8 (±0.6) mm Hg (P < .00001) for adhesive-treated (n = 5), sutured (n = 5), and self-sealed wounds (n = 5), respectively. These increased to 229.0 (±53.7) mm Hg, 12.4 (±2.9) mm Hg, and 27.3 (±4.0) mm Hg (P = .0011) at 72 hours. The modified McDonald-Shadduck score was significantly higher for eyes repaired using the adhesive than those sutured or left to self-seal for the first 72 hours. On histology and immunofluorescence, adhesive treatment demonstrated better wound approximation and higher myofibroblastic activation than the other groups. CONCLUSIONS: The adhesive was efficacious in sealing penetrating corneal incisions and tolerated higher burst pressures than sutures or self-seal. The adhesive was biocompatible in rabbits, and incisions demonstrated a rapid gain in wound strength that sustained over the study period.

Laser-Activated Corneal Adhesive: Retinal Safety in Rabbit Model.

Purpose: The purpose of this study was to investigate whether laser irradiation, used to activate an adhesive for sealing penetrating corneal incisions, causes any ophthalmoscopically or histologically visible retinal changes. Methods: Baseline fundus assessment was conducted prior to laser irradiation of eyes of pigmented Dutch Belted rabbits. Treatment group was 18 eyes with the corneal adhesive activated in situ by a near infrared laser (125 mW for 45 seconds). The positive control group was 18 eyes, each irradiated for 60 seconds at 375, 500, 625, and 750 mW at different retinal locations. Unexposed regions of the retina were used as negative internal control. Ophthalmoscopic assessment was conducted immediately after laser exposure and prior to euthanasia. Retinas were histologically assessed at 0, 3, 72, and 168 hours after treatment. Results: No ophthalmoscopically or histologically visible retinal changes were observed in the treatment group immediately, nor up to 168 hours after laser irradiation. In the positive control group, the incidences of ophthalmoscopically visible retinal lesions increased with irradiation power: 5.6% at 375 mW, 16.7% at 500 mW, 44.4% at 625 mW, and 50% at 750 mW. Histologically, retinal damage was observed as coagulative necrosis to all layers of the neural retina, including the retinal pigment epithelium. Conclusions: The laser irradiation process used in the corneal adhesive technology did not cause any ophthalmoscopically or histologically visible retinal changes in the in vivo pigmented rabbit model. Prolonged exposure with this laser and at higher power can cause coagulative necrosis to the retina. Translational Relevance: The corneal adhesive can be applied in humans without causing laser retinal damage.

Multiplexable fluorescence lifetime imaging (FLIM) probes for Abl and Src-family kinases.

Many commonly employed strategies to map kinase activities in live cells require expression of genetically encoded proteins (e.g. FRET sensors). In this work, we describe the development and preliminary application of a set of cell-penetrating, fluorophore labelled peptide substrates for fluorescence lifetime imaging (FLIM) of Abl and Src-family kinase activities. These probes do not rely on FRET pairs or genetically-encoded protein expression. We further demonstrate probe multiplexing and pixel-by-pixel quantification to estimate the relative proportion of modified probe, suggesting that this strategy will be useful for detailed mapping of single cell and subcellular dynamics of multiple kinases concurrently in live cells.

Corneal Sealants in Clinical Use: A Systematic Review.

AIM: To review the use of clinical corneal sealants for the closure of full thickness corneal wounds. METHODS: A systematic review was conducted across CENTRAL, Medline, PubMed, Embase, Scopus, mRCT and ICTRP for the keywords of 'cornea', 'full-thickness wound', 'sealant' and their synonyms. Only evidence level 2 of higher as graded by Oxford Centre of Evidence-based Medicine were included for this review. RESULTS: Seven studies were included; three randomized controlled trials investigated ReSure® sealant, 2 OcuSeal®, 1 human fibrin glue vs cyanoacrylate and 1 human fibrin glue as an adjunct to sutures vs sutures alone in penetrating keratoplasty. ReSure® was superior to suture for sealing leaking corneal incisions after cataract surgery despite provocation. ReSure® sealant has not been tested on complex full thickness corneal wounds, perforated ulcers or penetrating keratoplasty. OcuSeal® was also able to seal full thickness cornea wound post-cataract surgery to prevent ingress of Trypan blue dye. Human fibrin glue and cyanoacrylate were similarly effective in treating corneal perforations <3 mm of mixed etiologies. CONCLUSION: There are limited high-level evidence for corneal sealants. The currently available sealants with human data are ReSure®, OcuSeal®, human fibrin glue and cyanoacrylates. While ReSure® and OcuSeal® are effective post-cataract surgery, there are no data for perforations from other etiologies. Post-approval data from ReSure® registry report good tolerability and no apparent safety concerns.

The unusual di-domain structure of Dunaliella salina glycerol-3-phosphate dehydrogenase enables direct conversion of dihydroxyacetone phosphate to glycerol.

Dunaliella has been extensively studied due to its intriguing adaptation to high salinity. Its di-domain glycerol-3-phosphate dehydrogenase (GPDH) isoform is likely to underlie the rapid production of the osmoprotectant glycerol. Here, we report the structure of the chimeric Dunaliella salina GPDH (DsGPDH) protein featuring a phosphoserine phosphatase-like domain fused to the canonical glycerol-3-phosphate (G3P) dehydrogenase domain. Biochemical assays confirm that DsGPDH can convert dihydroxyacetone phosphate (DHAP) directly to glycerol, whereas a separate phosphatase protein is required for this conversion process in most organisms. The structure of DsGPDH in complex with its substrate DHAP and co-factor nicotinamide adenine dinucleotide (NAD) allows the identification of the residues that form the active sites. Furthermore, the structure reveals an intriguing homotetramer form that likely contributes to the rapid biosynthesis of glycerol.

Disseminated nontuberculous mycobacterial infection with multifocal retinitis and vasculitis in an immunocompromised patient with anti-IFN-É£ autoantibodies.

BACKGROUND: Nontuberculous mycobacteria (NTM) are found ubiquitously in the environment. Since exposure to NTM is universal, infection likely represents underlying host susceptibility factors. Anti-IFN-É£ autoantibodies have been described previously in patients with NTM. Up to 88 % of patients with disseminated NTM or other opportunistic infections have high-titer anti-IFN-É£ autoantibodies, compared with 2 % of patients with TB and healthy controls. FINDINGS: We report a unique presentation of a patient with anti-IFN-É£ autoantibodies with disseminated NTM infection who presents with panuveitis with multifocal retinitis and vasculitis. Treatment with systemic anti tubercular therapy resulted in complete clinical resolution with good visual recovery. CONCLUSIONS: Patients with anti-IFN-É£ autoantibodies present with a novel syndrome that links autoimmunity and immunodeficiency. This case emphasizes the importance of testing for anti-IFN-É£ autoantibodies in patients with disseminated mycobacterial infection.

Structure of BipA in GTP form bound to the ratcheted ribosome.

BPI-inducible protein A (BipA) is a member of the family of ribosome-dependent translational GTPase (trGTPase) factors along with elongation factors G and 4 (EF-G and EF4). Despite being highly conserved in bacteria and playing a critical role in coordinating cellular responses to environmental changes, its structures (isolated and ribosome bound) remain elusive. Here, we present the crystal structures of apo form and GTP analog, GDP, and guanosine-3',5'-bisdiphosphate (ppGpp)-bound BipA. In addition to having a distinctive domain arrangement, the C-terminal domain of BipA has a unique fold. Furthermore, we report the cryo-electron microscopy structure of BipA bound to the ribosome in its active GTP form and elucidate the unique structural attributes of BipA interactions with the ribosome and A-site tRNA in the light of its possible function in regulating translation.

A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N6-methyladenosine demethylase FTO.

The AlkB family of nucleic acid demethylases are of intense biological and medical interest because of their roles in nucleic acid repair and epigenetic modification. However their functional and molecular mechanisms are unclear, hence, there is strong interest in developing selective inhibitors for them. Here we report the identification of key residues within the nucleotide-binding sites of the AlkB subfamilies that likely determine their substrate specificity. We further provide proof of principle that a strategy exploiting these inherent structural differences can enable selective and potent inhibition of the AlkB subfamilies. This is demonstrated by the first report of a subfamily-selective and cell-active FTO inhibitor 12. The distinct selectivity of 12 for FTO against other AlkB subfamilies and 2OG oxygenases shall be of considerable interest with regards to its potential use as a functional probe. The strategy outlined here is likely applicable to other AlkB subfamilies, and, more widely, to other 2OG oxygenases.

Cationic gold(I) heteroleptic complexes bearing a pyrazole-derived N-heterocyclic carbene: syntheses, characterizations, and cytotoxic activities.

A series of cationic gold(I) heteroleptic complexes bearing the pyrazole-derived N-heterocyclic carbene (NHC) FPyr (1,2,3,4,6,7,8,9-octahydropyridazino[1,2-a]indazolin-11-ylidene), and either a 1,3-disubstituted benzimidazole-derived NHC of the type RR'-bimy (3: R = R' = CHPh2; 4: R = CHPh2, R' = (i)Pr; 5: R = R' = CH2Ph; 6: R = R' = (i)Bu; 7: R = R' = n-Pr; 8: R = R' = Et; 9: R = R' = 2-propenyl) or a non-NHC co-ligand L (10: L = PPh3; 11: L = P(OPh)3; 12: L = DMAP) (DMAP = 4-dimethylaminopyridine) have been synthesized from [AuCl(FPyr)] (1). Complexes 3-12 have been characterized using multinuclei NMR spectroscopies, ESI mass spectrometry, and elemental analysis. X-ray diffraction analyses have been performed on complexes 5, 6, and 9-11. To the best of our knowledge, 11 represents the first gold-NHC complex to bear the P(OPh)3 ligand. The cytotoxic activities of complexes 3-12 have been studied in vitro with the NCI-H1666 non-small cell lung cancer cell line.

Antisense reduction of NADP-malic enzyme in Flaveria bidentis reduces flow of CO2 through the C4 cycle.

An antisense construct targeting the C(4) isoform of NADP-malic enzyme (ME), the primary enzyme decarboxylating malate in bundle sheath cells to supply CO(2) to Rubisco, was used to transform the dicot Flaveria bidentis. Transgenic plants (α-NADP-ME) exhibited a 34% to 75% reduction in NADP-ME activity relative to the wild type with no visible growth phenotype. We characterized the effect of reducing NADP-ME on photosynthesis by measuring in vitro photosynthetic enzyme activity, gas exchange, and real-time carbon isotope discrimination (Δ). In α-NADP-ME plants with less than 40% of wild-type NADP-ME activity, CO(2) assimilation rates at high intercellular CO(2) were significantly reduced, whereas the in vitro activities of both phosphoenolpyruvate carboxylase and Rubisco were increased. Δ measured concurrently with gas exchange in these plants showed a lower Δ and thus a lower calculated leakiness of CO(2) (the ratio of CO(2) leak rate from the bundle sheath to the rate of CO(2) supply). Comparative measurements on antisense Rubisco small subunit F. bidentis plants showed the opposite effect of increased Δ and leakiness. We use these measurements to estimate the C(4) cycle rate, bundle sheath leak rate, and bundle sheath CO(2) concentration. The comparison of α-NADP-ME and antisense Rubisco small subunit demonstrates that the coordination of the C(3) and C(4) cycles that exist during environmental perturbations by light and CO(2) can be disrupted through transgenic manipulations. Furthermore, our results suggest that the efficiency of the C(4) pathway could potentially be improved through a reduction in C(4) cycle activity or increased C(3) cycle activity.

Adverse drug reaction: rosuvastatin as a cause for ischaemic colitis in a 64-year-old woman.

Rosuvastatin (Crestor, AstraZeneca) is a commonly used drug for managing hypercholesterolaemia. It is a very safe medication with mostly acceptable side effects. Rare but serious side effects are not well known. A 64-year-old woman presented with bloody diarrhoea after starting rosuvastatin for hypercholesterolaemia. Stool microscopy and culture ruled out infective causes. Abdominal CT scan revealed normal calibre celiac axis and superior mesenteric artery. Colonoscopic biopsy revealed ischaemic colitis as the final histological diagnosis. The patient is in complete remission after ceasing the medication. Rosuvastatin causing ischaemic colitis should be considered a rare but serious adverse drug reaction.

A game-theoretic model of interactions between Hibiscus latent Singapore virus and tobacco mosaic virus.

Mixed virus infections in plants are common in nature and their interactions affecting host plants would depend mainly on plant species, virus strains, the order of infection and initial amount of inoculum. Hence, the prediction of outcome of virus competition in plants is not easy. In this study, we applied evolutionary game theory to model the interactions between Hibiscus latent Singapore virus (HLSV) and Tobacco mosaic virus (TMV) in Nicotiana benthamiana under co-infection in a plant host. The accumulation of viral RNA was quantified using qPCR at 1, 2 and 8 days post infection (dpi), and two different methods were employed to predict the dominating virus. TMV was predicted to dominate the game in the long run and this prediction was confirmed by both qRT-PCR at 8 dpi and the death of co-infected plants after 15 dpi. In addition, we validated our model by using data reported in the literature. Ten out of fourteen reported co-infection outcomes agreed with our predictions. Explanations were given for the four interactions that did not agree with our model. Hence, it serves as a valuable tool in making long term predictions using short term data obtained in virus co-infections.

Impact of data source and time reference of functional status on hospital mortality prediction.

BACKGROUND: The study objective was to compare physical function documented in the medical records with interview data, and also to evaluate hospital mortality predictions using pre-admission and on-admission functional status derived from these two data sources. METHODS: A prospective cohort study of 1402 subjects aged 65 years and older to the general medicine department of an acute care hospital was conducted. Patient-reported pre-admission and on-admission functional status for impairment in any of the five activities of daily living (ADLs) items (feeding, dressing, grooming, toileting and bathing), transferring and walking, were compared with those extracted from the medical records. For the purpose of mortality prediction, pre-admission and on-admission impairment in transferring from the two data sources were included in separate multivariable logistic regression models. We used a variable selection method that combines bootstrap resampling with stepwise backward elimination. RESULTS: For all ADL categories, the agreement between the data sources was good for pre-admission functional status (k: 0.53-0.75) but poor for on-admission status (k: 0.18-0.31). On-admission impairment was higher in the medical records than at interview for all basic ADLs. Using interview data as the gold standard, although sensitivity for pre- and on-admission ADLs was high (59-93%), specificity for on-admission status was poor (30-37%). The pre-admission models using interview data predicted mortality better than the model using medical records (c-statistic: 0.83 versus 0.82). Similar results were found for models incorporating on-admission functional status (c-statistic: 0.84 versus 0.81). However, the differences between the four models were not statistically significant. CONCLUSION: Medical records can be a good source for pre-admission functional status but on-admission functional impairment was over-reported in the medical records. The discriminatory power of the hospital mortality prediction model was significantly improved with the incorporation of functional status information but it was not significantly affected by their time reference or source of data.

ROS1 as a 'druggable' receptor tyrosine kinase: lessons learned from inhibiting the ALK pathway.

ROS1 is one of 58 receptor tyrosine kinases, and one of two orphan receptor tyrosine kinases where its ligand is unknown. ROS1 is evolutionarily related to ALK. ROS1 rearrangement was discovered in glioblastoma in 1987, in non-small-cell lung cancer (NSCLC) in 2007, and in cholangiocarcinoma in 2011. While the clinicopathologic characteristics of ROS1-rearranged glioblastoma and cholangiocarcinoma patients remain to be defined, the clinicopathologic characteristics of ROS1-rearranged NSCLC patients have recently been described. Although ROS1 shares only 49% amino acid sequence homology with ALK in the kinase domains, several ALK inhibitors have demonstrated in vitro inhibitory activity against ROS1. With the recent US approval of crizotinib, a multi-targeted ALK/MET kinase inhibitor, for the treatment of ALK-rearranged NSCLC, attention has turned to ROS1-rearranged tumors, especially NSCLC. The next few years should witness a rapid pace of clinical research in ROS1-rearranged tumors utilizing available ALK inhibitors.

Utility of short-term evaluation of presbyopic contact lens performance.

OBJECTIVES: To establish if evaluations of multifocal contact lens performance conducted at dispensing are representative of behavior after a moderate adaptation period. METHODS: Eighty-eight presbyopic subjects, across four clinical sites, wore each of four multifocal soft contact lenses (ACUVUE BIFOCAL, Focus Progressives, Proclear Multifocal, and SofLens Multifocal) for 4 days of daily wear. Comprehensive performance assessments were conducted at dispensing and after 4 days wear and included the following objective metrics: LogMAR acuity (contrast, 90% and 10%; illumination, 250 and 10 cd/m; distance, 6 m, 100 cm, and 40 cm), stereopsis (RANDOT), reading critical print size and maximum speed and range of clear vision at near. Subjective assessments were made, with 100-point numerical rating scales, of comfort, ghosting (distance, near), visual quality (distance, intermediate, and near), and the appearance of haloes. At two sites, subjects (n = 39) also rated visual fluctuation (distance, intermediate, and near), facial recognition, and overall satisfaction. RESULTS: Among the objective variables, significant differences (paired t test, P<0.05) between dispensing and 4 days were found only for range of clear vision at near (2.9 +/- 2.0 cm; mean difference +/- standard deviation) and high contrast near acuity in low illumination (-0.013 +/- 0.011 LogMAR). With the exception of insertion comfort, all subjective variables showed significant decrements over the same period. Overall satisfaction declined by an average of 10.9 +/- 5.1 points. CONCLUSIONS: Early assessment is relatively unrepresentative of performance later on during multifocal contact lens wear. Acuity based measures of vision remain substantially unchanged over the medium term, apparently because these metrics are insensitive indicators of performance compared with subjective alternatives.

Decreasing the plasma triglyceride level in hypertriglyceridemia-induced pancreatitis in pregnancy: a case report.

We report a case of hypertriglyceridemia-induced pancreatitis in pregnancy in which continuous intravenous heparin was used effectively and safely to lower the plasma triglyceride level within 24 hours.