Baseline Gastric Volume in Fasting Diabetic Patients Is Not Higher than That in Nondiabetic Patients: A Cross-sectional Noninferiority Study.

BACKGROUND: The physiology of diabetes mellitus can increase the risk of perioperative aspiration, but there is limited and contradictory evidence on the incidence of "full stomach" in fasting diabetic patients. The aim of this study is to assess the baseline gastric content (using gastric ultrasound) in diabetic and nondiabetic patients scheduled for elective surgery who have followed standard preoperative fasting instructions. METHODS: This was a prospective, noninferiority study of 180 patients (84 diabetic and 96 nondiabetic patients). Bedside ultrasound was used for qualitative and quantitative assessment of the gastric antrum in the supine and right lateral decubitus positions. Fasting gastric volume was estimated based on the cross-sectional area of the gastric antrum and a validated model. The hypothesis was that diabetic patients would not have a higher baseline fasting gastric volume compared to nondiabetic patients, with a noninferiority margin of 0.4 ml/kg. Secondary aims included the comparison of the incidence of full stomach (solid content or more than 1.5 mL/kg of clear fluid), estimation of the 95th percentile of the gastric volume distribution in both groups, and examination of the association between gastric volume, glycemic control, and diabetic comorbidities. RESULTS: The baseline gastric volume was not higher in diabetic patients (0.81 ± 0.61 ml/kg) compared to nondiabetic patients (0.87 ± 0.53 ml/kg) with a mean difference of -0.07 ml/kg (95% CI, -0.24 to 0.10 ml/kg). A total of 13 (15.5%) diabetic and 11 (11.5%) nondiabetic patients presented more than 1.5 ml/kg of gastric volume (95% CI for difference, -7.1 to 15.2%). There was little correlation between the gastric volume and either the time since diagnosis or HbA1C. CONCLUSIONS: The data suggest that the baseline gastric volume in diabetic patients who have followed standard fasting instructions is not higher than that in nondiabetic patients.

Effect of intravenous acetaminophen on postoperative outcomes in hip fracture patients: a systematic review and narrative synthesis.

PURPOSE: Hip fractures are debilitating in older adults because of their impact on quality of life. Opioids are associated with adverse effects in this population, so oral acetaminophen is commonly prescribed to minimize opioid use. Intravenous (iv) acetaminophen has been reported to have superior efficacy and bioavailability than oral acetaminophen. Nevertheless, its effect on postoperative outcomes in emergency hip fractures is unclear. This systematic review assessed the effect of iv acetaminophen on postoperative outcomes in older hip fracture patients. SOURCE: We searched multiple databases from inception to June 2021 for studies on adults > 50 yr of age undergoing emergency hip fracture surgery who received iv acetaminophen (or paracetamol) and that reported postoperative outcomes. Relevant titles, abstracts, and full texts were screened based on the eligibility criteria. The Newcastle-Ottawa scale was used to assess the quality of the selected papers. PRINCIPAL FINDINGS: Of 3,510 initial studies, four met the inclusion criteria. One was a prospective cohort study and three were retrospective cohort studies. All four studies used historical control groups. Three studies reported a significantly lower mean opioid dose with iv acetaminophen than with oral acetaminophen. Three studies also reported a significantly shorter hospital stay. One study each reported a significant decrease in the number of missed physical therapy sessions, the need for one-to-one supervision, and episodes of delirium. CONCLUSION: There is very limited low-level evidence that iv acetaminophen improves preoperative and postoperative analgesia and shortens hospital stay in older hip fracture patients. Nevertheless, our results should be interpreted with caution since there are no prospective randomized trials investigating whether iv acetaminophen improves postoperative outcomes in this patient population. STUDY REGISTRATION: PROSPERO (CRD42021198174); registered 15 August 2021.

RéSUMé: OBJECTIF: Les fractures de la hanche sont débilitantes chez les personnes âgées en raison de leur impact sur leur qualité de vie. Les opioïdes sont associés à des effets indésirables chez cette population, de sorte que l'acétaminophène par voie orale est couramment prescrit pour minimiser la consommation d'opioïdes. L'acétaminophène par voie intraveineuse (IV) a une efficacité et une biodisponibilité supérieures à celles de l'acétaminophène par voie orale. Néanmoins, son effet sur les devenirs postopératoires dans les fractures d'urgence de la hanche n'est pas clair. Cette revue systématique a évalué l'effet de l'acétaminophène IV sur les devenirs postopératoires chez les patients âgés avec une fracture de la hanche. SOURCES: Nous avons effectué des recherches dans plusieurs bases de données de leur création à juin 2021 pour en tirer les études portant sur des adultes > 50 ans bénéficiant d'une chirurgie d'urgence pour une fracture de la hanche et ayant reçu de l'acétaminophène IV (ou paracétamol), et qui rapportait les devenirs postopératoires. Les titres, résumés et textes intégraux pertinents ont été sélectionnés en fonction des critères d'admissibilité. L'échelle de Newcastle-Ottawa a été utilisée pour évaluer la qualité des articles sélectionnés. CONSTATATIONS PRINCIPALES: Sur les 3510 études initiales, quatre ont répondu aux critères d'inclusion. L'une était une étude de cohorte prospective et trois étaient des études de cohorte rétrospectives. Les quatre études ont utilisé des groupes témoins historiques. Trois études ont rapporté une dose moyenne d'opioïdes significativement plus faible avec l'acétaminophène IV qu'avec de l'acétaminophène par voie orale. Trois études ont également rapporté un séjour à l'hôpital significativement plus court. Une diminution significative du nombre de séances de physiothérapie manquées a été rapporté dans une étude, une autre a rapporté une diminution significative de la nécessité de supervision individuelle, et une troisième une réduction des épisodes d'état confusionnel aigu. CONCLUSION: : Il n'existe que très peu de données probantes qui sont de faible qualité et selon lesquelles l'acétaminophène IV améliore l'analgésie préopératoire et postopératoire et réduit la durée de séjour à l'hôpital chez les patients âgés atteints d'une fracture de hanche. Néanmoins, nos résultats doivent être interprétés avec prudence car il n'existe pas d'étude randomisée prospective évaluant si l'acétaminophène IV améliore les issues postopératoires dans cette population de patients. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42021198174); enregistrée le 15 août 2021.

Using the Cyclotide Scaffold for Targeting Biomolecular Interactions in Drug Development.

This review provides an overview of the properties of cyclotides and their potential for developing novel peptide-based therapeutics. The selective disruption of protein-protein interactions remains challenging, as the interacting surfaces are relatively large and flat. However, highly constrained polypeptide-based molecular frameworks with cell-permeability properties, such as the cyclotide scaffold, have shown great promise for targeting those biomolecular interactions. The use of molecular techniques, such as epitope grafting and molecular evolution employing the cyclotide scaffold, has shown to be highly effective for selecting bioactive cyclotides.

Determinants of Discharge Disposition From Acute Care for Survivors of Hypoxic-Ischemic Brain Injury: Results From a Large Population-Based Cohort Data Set.

OBJECTIVE: To identify determinants of discharge disposition from acute care among survivors of hypoxic-ischemic brain injury (HIBI), stratified by sex. DESIGN: Population-based retrospective cohort study using provincial data in Ontario, Canada. The determinants were grouped into predisposing, need, and enabling factors using the Anderson Behavioral Model. SETTING: Acute care. PARTICIPANTS: Survivors of HIBI aged ≥20 years at the time of hospitalization and discharged alive from acute care between April 1, 2002, and March 31, 2017. There were 7492 patients with HIBI, of whom 28% (N=2077) survived their acute care episode. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Discharge disposition from acute care, categorized as complex continuing care (CCC), long-term care (LTC), inpatient rehabilitation (IR), home with support, home without support, and transferred to another acute care. RESULTS: The discharge dispositions for the 2077 survivors were IR 23.4% (n=487), CCC 19.5% (n=404), LTC 6.2% (n=128), home without support 31.2% (n=647), home with support 15.1% (n=314), and other 4.6%. Multinomial multivariable logistic regression analysis using home without support as the reference category revealed that female patients were significantly more likely than male patients to be discharged to LTC/CCC. Those who were older, were frail, and had longer stay in acute care or special care unit (SCU) were more likely to be discharged to LTC/CCC. The only significant determinant for IR was longer stay in acute care. Survivors with cardiac-related injury were less likely to be discharged to LTC/CCC. Income was a significant factor for male patients but not for female patients in the sex-stratified analysis. The following variables were investigated but were not significant determinants in this study: need factors (comorbidity score, prior psychiatric disorders, health care utilization) and enabling factors (income quintile, rural area of residence). CONCLUSIONS: Predisposing (age, sex) and need factors (frailty, acute care days, SCU days, type of injury) were significant determinants of discharge disposition from acute care after HIBI. In spite of a system with universal coverage, sex differences were found, with more female patients being discharged to CCC/LTC rather than IR, controlling for age and other confounders. These findings should be considered in appropriate discharge planning from acute care for survivors of HIBI.

Predictors of in-hospital mortality following hypoxic-ischemic brain injury: a population-based study.

Objective: To identify predictors of in-hospital mortality following Hypoxic-Ischemic Brain Injury (HIBI) using the Anderson Behavioral Model.Design and Setting: Population based retrospective cohort study in Ontario, Canada with data collected between 1 April 2002 and 31 March 2017.Patients: Adult patients aged 20 years and older with HIBI-related acute care admission were identified in the health administrative data. Multivariable cox proportional hazard regression models were used to identify predisposing, need and enabling factors that predict in-hospital mortality.Results: Of the 7492 patients admitted to acute care with HIBI, the in-hospital mortality rate was 71%. The predisposing factors associated with mortality were female sex (HR, 1.16; 95% CI, 1.10-1.23) and older age (65-79 vs. 20-34: HR, 1.17; 95% CI, 1.02-1.35). The need factors associated with mortality were the presence of COPD (HR, 1.10; 95% CI, 1.02-1.17), psychiatric illness (HR, 1.13; 95% CI, 1.05-1.20) injury due to cardiac illness (HR, 1.19; 95% CI, 1.12-1.26) and longer emergency department length of stay. Having spending any time in an alternate level of care and the application of tracheotomy procedures were found to reduce mortality.Conclusions: The acute/critical care centers need to consider these findings to adopt prevention strategies targeting reduced in-hospital mortality.

Change in Function Over Inpatient Rehabilitation After Hypoxic Ischemic Brain Injury: A Population-Wide Cohort Study.

OBJECTIVE: To estimate change in motor, cognitive, and overall functional performance during inpatient rehabilitation (IR) and to identify potential determinants of these outcomes among patients with hypoxic-ischemic brain injury (HIBI). DESIGN: Population-based retrospective cohort study using Ontario's health administrative data. SETTING: Inpatient rehabilitation. PARTICIPANTS: Survivors of HIBI 20 years and older discharged from acute care between fiscal years 2002-2003 and 2010-2011 and admitted to IR within 1 year of acute care discharge (N=159). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Functional status as measured by FIM, total, and scores on motor and cognitive subscales. RESULTS: A higher proportion (77%) of HIBI patients in the study were male and 28% were older than 65 years. We observed material improvements in FIM total, motor, and cognitive scores from across the IR episode. Potential determinants of total FIM gain were living in rural location (ß, 10.4; 95% CI, 0.21-21), having shorter preceding acute care length of stay (15-30 vs >60 days ß, 10.4; 95% CI, 1.4-19.5), and failing to proceed directly to IR following acute care discharge (ß, 8.7; 95% CI, 1.8-15.5). Motor FIM gain had similar identified potential determinants. Identified potential determinants of cognitive FIM gain were shorter (ie, 31-60 vs >60 days) preceding acute care, longer IR and length of stay, and proceeding directly to IR. There were no sex differences in functional gain. CONCLUSIONS: Inpatient rehabilitation is beneficial to HIBI survivors. Timely access to these services may be crucial in achieving optimal outcomes for these patients.

Cost Analysis of a High Support Housing Initiative for Persons with Severe Mental Illness and Long-Term Psychiatric Hospitalization.

OBJECTIVE: The objective of this article was to conduct a cost analysis comparing the costs of a supportive housing intervention to inpatient care for clients with severe mental illness who were designated alternative-level care while inpatient at the Centre for Addiction and Mental Health in Toronto. The intervention, called the High Support Housing Initiative, was implemented in 2013 through a collaboration between 15 agencies in the Toronto area. METHOD: The perspective of this cost analysis was that of the Ontario Ministry of Health and Long-Term Care. We compared the cost of inpatient mental health care to high-support housing. Cost data were derived from a variety of sources, including health administrative data, expenditures reported by housing providers, and document analysis. RESULTS: The High Support Housing Initiative was cost saving relative to inpatient care. The average cost savings per diem were between $140 and $160. This amounts to an annual cost savings of approximately $51,000 to $58,000. When tested through sensitivity analysis, the intervention remained cost saving in most scenarios; however, the result was highly sensitive to health system costs for clients of the High Support Housing Initiative program. CONCLUSIONS: This study suggests the High Support Housing Initiative is potentially cost saving relative to inpatient hospitalization at the Centre for Addiction and Mental Health.

Patterns of methadone maintenance treatment provision in Ontario: Policy success or pendulum excess?

OBJECTIVE: To describe recent trends and patterns in methadone maintenance treatment (MMT) practice regionally and over time in the province of Ontario. DESIGN: Population-based descriptive study using health administrative data between September 1, 2011, and December 31, 2014. SETTING: Ontario. PARTICIPANTS: All active MMT-prescribing physicians and patients receiving MMT in the study period. MAIN OUTCOME MEASURES: Characteristics of MMT-prescribing physicians, including age, sex, specialty type, practice region, and practice volume; characteristics of patients receiving MMT, including age, sex, neighbourhood income, and region of residence. RESULTS: Between September 1, 2011, and December 31, 2014, the number of MMT-prescribing physicians and patients who received MMT increased by 26% and 42%, respectively. In 2014, there was a total of 312 MMT-prescribing physicians and 49 703 patients receiving MMT. In 2014 and on a per capita basis, patients receiving MMT were more prevalent in rural regions; and within rural regions, there were disproportionately large numbers of young female MMT patients residing in low-income neighbourhoods. CONCLUSION: The number of physicians prescribing MMT and patients receiving MMT has increased substantially between 2011 and 2014, with the largest per capita distribution occurring in rural regions and involving young adults. While availability of and access to MMT has improved considerably from before 2000 to levels of high use, these developments are likely influenced by recent trends in the proliferation of prescription opioid misuse across general populations.

The stereochemical effect of SMAP-29 and SMAP-18 on bacterial selectivity, membrane interaction and anti-inflammatory activity.

Sheep myeloid antimicrobial peptide-29 (SMAP-29) is a cathelicidin-related antimicrobial peptide derived from sheep myeloid cells. In order to investigate the effects of L-to-D-amino acid substitution in SMAP-29 on bacterial selectivity, membrane interaction and anti-inflammatory activity, we synthesized its two D-enantiomeric peptides (SMAP-29-E1 and SMAP-29-E2 containing D-Ile and D-allo-Ile, respectively) and two diastereomeric peptides (SMAP-29-D1 and SMAP-29-D2). Additionally, in order to address the effect of L-to-D-amino acid substitution in the N-terminal helical peptide of SMAP-29 (named SMAP-18) on antimicrobial activity, we synthesized its two D-enantiomeric peptides (SMAP-18-E1 and SMAP-18-E2), which are composed of D-amino acids entirely. L-to-D-amino acid substitution in membrane-targeting AMP, SMAP-29 did not affect its antimicrobial activity. However, D-allo-Ile containing-SMAP-29-E2 and SMAP-29-D2 exhibited less hemolytic activity compared to D-Ile containing-SMAP-29-E1 and SMAP-29-D1, respectively. L-to-D-amino acid substitution in intracellular targeting-AMPs, SMAP-18 and buforin-2 improved antimicrobial activity by 2- to eightfold. The improved antimicrobial activity of the D-isomers of SMAP-18 and buforin-2 seems to be due to the stability against proteases inside bacterial cells. Membrane depolarization and dye leakage suggested that the membrane-disruptive mode of SMAP-29-D1 and SMAP-29-D2 is different from that of SMAP-29, SMAP-29-E1, and SMAP-29-E2. L-to-D-amino acid substitution in SMAP-29 improved anti-inflammatory activity in LPS-stimulated RAW 264.7 cells. In summary, we propose here that D-allo-Ile substitution is a more powerful strategy for increasing bacterial selectivity than D-Ile substitution in the design of D-enantiomeric and diastereomeric AMPs. SMAP-29-D1, and SMAP-29-D2 with improved bacterial selectivity and anti-inflammatory activity can serve as promising candidates for the development of anti-inflammatory and antimicrobial agents.

Toward a Theory of Stuttering.

Stuttering affects about 1% of the general population and from 8 to 11% of children. The onset of persistent developmental stuttering (PDS) typically occurs between 2 and 4 years of age. The etiology of stuttering is unknown and a unifying hypothesis is lacking. Clues to the pathogenesis of stuttering include the following observations: PDS is associated with adverse perinatal outcomes and birth-associated trauma; stuttering can recur or develop in adulthood following traumatic events such as brain injury and stroke; PDS is associated with structural and functional abnormalities in the brain associated with speech and language; and stuttering resolves spontaneously in a high percentage of affected children. Evidence marshaled from the literature on stuttering and from related sources suggests the hypothesis that stuttering is a neuro-motor disorder resulting from perinatal or later-onset hypoxic-ischemic injury (HII), and that chronic stuttering and its behavioral correlates are manifestations of recurrent transient ischemic episodes affecting speech-motor pathways. The hypothesis could be tested by comparing children who stutter and nonstutterers (controls) in terms of the occurrence of perinatal trauma, based on birth records, and by determining rates of stuttering in children exposed to HII during the perinatal period. Subject to testing, the hypothesis suggests that interventions to increase brain perfusion directly could be effective both in the treatment of stuttering and its prevention at the time of birth or later trauma.

Bacterial killing mechanism of sheep myeloid antimicrobial peptide-18 (SMAP-18) and its Trp-substituted analog with improved cell selectivity and reduced mammalian cell toxicity.

To develop short antimicrobial peptide with improved cell selectivity and reduced mammalian cell toxicity compared to sheep myeloid antimicrobial peptide-29 (SMAP-29) and elucidate the possible mechanisms responsible for their antimicrobial action, we synthesized a N-terminal 18-residue peptide amide (SMAP-18) from SMAP-29 and its Trp-substituted analog (SMAP-18-W). Due to their reduced hemolytic activity and retained antimicrobial activity, SMAP-18 and SMAP-18-W showed higher cell selectivity than SMAP-29. In addition, SMAP-18 and SMAP-18-W had no cytotoxicity against three different mammalian cells such as RAW 264.7, NIH-3T3 and HeLa cells even at 100 µM. These results suggest that SMAP-18 and SMAP-18-W have potential for future development as novel therapeutic antimicrobial agent. Unlike SMAP-29, SMAP-18 and SMAP-18-W showed relatively weak ability to induce dye leakage from bacterial membrane-mimicking liposomes, N-phenyl-1-napthylamine (NPN) uptake and o-nitrophenyl-ß-galactoside (ONPG) hydrolysis. Similar to SMAP-29, SMAP-18-W led to a significant membrane depolarization (> 80%) against Staphylococcus aureus at 2 × MIC. In contrast, SMAP-18 did not cause any membrane depolarization even at 4 × MIC. In confocal laser scanning microscopy, we observed translocation of SMAP-18 across the membrane in a non-membrane disruptive manner. SMAP-29 and SMAP-18-W were unable to translocate the bacterial membrane. Collectively, we propose here that SMAP-29 and SMAP-18-W kill microorganisms by disrupting/perturbing the lipid bilayer and forming pore/ion channels on bacterial cell membranes, respectively. In contrast, SMAP-18 may kill bacteria via intracellular-targeting mechanism.

Poly-lysine peptidomimetics having potent antimicrobial activity without hemolytic activity.

Diversity of sequence and structure in naturally occurring antimicrobial peptides (AMPs) limits their intensive structure-activity relationship (SAR) study. In contrast, peptidomimetics have several advantages compared to naturally occurring peptide in terms of simple structure, convenient to analog synthesis, rapid elucidation of optimal physiochemical properties and low-cost synthesis. In search of short antimicrobial peptides using peptidomimetics, which provide facile access to identify the key factors involving in the destruction of pathogens through SAR study, a series of simple and short peptidomimetics consisting of multi-Lys residues and lipophilic moiety have been prepared and found to be active against several Gram-negative and Gram-positive bacteria containing methicillin-resistant Staphylococcus aureus (MRSA) without hemolytic activity. Based on the SAR studies, we found that hydrophobicity, +5 charges of multiple Lys residues, hydrocarbon tail lengths and cyclohexyl group were crucial for antimicrobial activity. Furthermore, membrane depolarization, dye leakage, inner membrane permeability and time-killing kinetics revealed that bacterial-killing mechanism of our peptidomimetics is different from the membrane-targeting AMPs (e. g. melittin and SMAP-29) and implied our peptidomimetics might kill bacteria via the intracellular-targeting mechanism as done by buforin-2.

Methodological approaches to population based research of screening procedures in the presence of selection bias and exposure measurement error: colonoscopy and colorectal cancer outcomes in Ontario.

BACKGROUND: The study describes the methodological challenges encountered in an observational study estimating the effectiveness of colonoscopy in reducing colorectal cancer (CRC) incidence and mortality. METHODS: Using Ontario provincial administrative data, we conducted a population-based retrospective cohort study to assess CRC incidence and mortality in a group of average-risk subjects aged 50-74 years who underwent colonoscopy between 1996-2000. We created two study cohorts; unselected and restricted. The unselected cohort consists of subjects aged 50-74 years who were eligible for CRC screening and who had the same primary care physician (PCP) during the period 1996-2000 with at least two years of follow-up. PCPs are general practioners/family physicians who are the main source of health care for Ontarians. The restricted cohort was a nested sample of unselected cohort who were alive and free of CRC as on January 1, 2001 and whose PCPs had at least 10 screen-eligible patients with a colonoscopy referral rate of more than 3%. We compared the outcomes in the two study cohorts; unselected vs. restricted. We then estimated the absolute risk reduction associated with colonoscopy in preventing CRC incidence and mortality in the restricted cohort, using traditional regression analysis, propensity score analysis and instrumental variable analysis. RESULTS: The unselected cohort (N = 1,341,612) showed that colonoscopy was associated with an increase in CRC incidence (1.61% vs. 4.61%) and mortality (0.36% vs. 1.16%), whereas the restricted cohort (N = 1,089,998) showed that colonoscopy was associated with a reduction in CRC incidence (1.36% vs. 0.84%) and mortality (0.23% vs. 0.15%). For CRC incidence, the absolute risk reduction (ARR) associated with colonoscopy use was 0.52% in an unadjusted model, 0.53% in a multivariate logistic regression model, 0.54% in a propensity score-weighted outcome model, 0.56% in propensity score-matched model, and 0.60% using instrumental variable analysis. For CRC mortality, the ARR was 0.08% in the unadjusted model, multivariate logistic regression model and for a propensity score- weighted outcome model, 0.10% using propensity score matched model and 0.17% using the IVA model. CONCLUSIONS: Colonoscopy use reduced the risk of CRC incidence and mortality in the restricted cohort. The study highlights the importance of appropriate selection of study subjects and use of analytic methods for the evaluation of screening methods using observational data.

Non hemolytic short peptidomimetics as a new class of potent and broad-spectrum antimicrobial agents.

Since the bacterial resistance to antibiotics is increasing rapidly, numerous studies have contributed to the design and synthesis of potent synthetic mimics of antimicrobial peptides (AMPs). In an attempt to find the pharmacophore of short antimicrobial peptidomimetics through systematic tuning of hydrophobic and hydrophilic patterns, we have identified a set of short histidine-derived antimicrobial peptides (SAMPs) with potent and broad-spectrum activity. A combination of high antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), without hemolytic activity and proteolytic stability makes these molecules promising candidates for novel antimicrobial therapeutics.

Short KR-12 analogs designed from human cathelicidin LL-37 possessing both antimicrobial and antiendotoxic activities without mammalian cell toxicity.

KR-12 (residues 18-29 of LL-37) was known to be the smallest peptide of human cathelicidin LL-37 possessing antimicrobial activity. In order to optimize α-helical short antimicrobial peptides having both antimicrobial and antiendotoxic activities without mammalian cell toxicity, we designed and synthesized a series of KR-12 analogs. Highest hydrophobic analogs KR-12-a5 and KR-12-a6 displayed greater inhibition of lipopolysaccharide (LPS)-stimulated tumor necrosis factor-α production and higher LPS-binding activity. We have observed that antimicrobial activity is independent of charge, but LPS neutralization requires a balance of hydrophobicity and net positive charge. Among KR-12 analogs, KR-12-a2, KR-12-a3 and KR-12-a4 showed much higher cell specificity for bacteria over erythrocytes and retained antiendotoxic activity, relative to parental LL-37. KR-12-a5 displayed the strongest antiendotoxic activity but almost similar cell specificity as compared with LL-37. Also, these KR-12 analogs (KR-12-a2, KR-12-a3, KR-12-a4 and KR-12-a5) exhibited potent antimicrobial activity (minimal inhibitory concentration: 4 µM) against methicillin-resistant Staphylococcus aureus. Taken together, these KR-12 analogs have the potential for future development as a novel class of antimicrobial and anti-inflammatory therapeutic agents.

Lipidation of a bioactive cyclotide-based CXCR4 antagonist greatly improves its pharmacokinetic profile in vivo.

The CXCR4 chemokine is a key molecular regulator of many biological functions controlling leukocyte functions during inflammation and immunity, and during embryonic development. Overexpression of CXCR4 is also associated with many types of cancer where its activation promotes angiogenesis, tumor growth/survival, and metastasis. In addition, CXCR4 is involved in HIV replication, working as a co-receptor for viral entry, making CXCR4 a very attractive target for developing novel therapeutic agents. Here we report the pharmacokinetic profile in rats of a potent CXCR4 antagonist cyclotide, MCo-CVX-5c, previously developed in our group that displayed a remarkable in vivo resistance to biological degradation in serum. This bioactive cyclotide, however, was rapidly eliminated through renal clearance. Several lipidated versions of cyclotide MCo-CVX-5c showed a significant increase in the half-life when compared to the unlipidated form. The palmitoylated version of cyclotide MCo-CVX-5c displayed similar CXCR4 antagonistic activity as the unlipidated cyclotide, while the cyclotide modified with octadecanedioic (18-oxo-octadecanoic) acid exhibited a remarkable decrease in its ability to antagonize CXCR4. Similar results were also obtained when tested for its ability to inhibit growth in two cancer cell lines and HIV infection in cells. These results show that the half-life of cyclotides can be improved by lipidation although it can also affect their biological activity depending on the lipid employed.

Effect of colonoscopy on colorectal cancer incidence and mortality: an instrumental variable analysis.

BACKGROUND: Using population-based health services information to estimate the effectiveness of colonoscopy on colorectal cancer (CRC) outcomes is prone to selection bias. OBJECTIVE: To determine the effect of colonoscopy on CRC incidence and mortality. DESIGN: Population-based retrospective cohort study. SETTING: Ontario provincial health data information. PATIENTS: This study involved average-risk persons aged 50 to 74 years from 1996 to 2000 who were alive and free of CRC on January 1, 2001. INTERVENTION: Colonoscopy between 1996 and 2000. MAIN OUTCOME MEASUREMENTS: CRC incidence and mortality from 2001 to 2007. RESULTS: The study cohort contained 1,089,998 persons, 7.9% of whom had undergone a colonoscopy between 1996 and 2000. Using primary care physician rate of discretionary colonoscopy as an instrumental variable, the receipt of colonoscopy was associated with a 0.60% (95% confidence interval [CI], 0.31%-0.78%) absolute reduction in the 7-year colorectal cancer incidence and a 0.17% (95% CI, 0.14%-0.21%) absolute reduction in the 5-year risk of death caused by CRC. This corresponds to a 48% relative decrease in CRC incidence (risk ratio [RR] 0.52; 95% CI, 0.34-0.76) and 81% decrease in mortality caused by CRC (RR 0.19, 95% CI, 0.07-0.47). In subgroup analyses, the reduction in the risk of death due to CRC was larger in women than men. The reduction in CRC incidence was larger for complete colonoscopies and for left-sided cancers. LIMITATIONS: Instrumental variable methods estimate only the marginal effect on the population studied. CONCLUSION: Increased use of colonoscopy procedures is associated with a reduction in the incidence and mortality of CRC in the population studied.

Linear bactenecin analogs with cell selectivity and anti-endotoxic activity.

Bactenecin (Bac) is a 12-residue disulfide-linked antimicrobial peptide isolated from the granules of bovine neutrophils. In this study, to develop novel linear Bac analogs with cell selectivity and anti-endotoxic activity, we designed and synthesized a series of linear Bac analogs with amino acid substitution in Cys3,11 and/or Val6,7 of Bac. Among Bac analogs, some analogs (Bac-W, Bac-KW, Bac-L, Bac-KL, Bac-LW, and Bac-KLW) with higher hydrophobicity showed the amalgamated property of cell selectivity and anti-endotoxic activity. Furthermore, Bac-W, Bac-KW, Bac-LW, and Bac-KLW showed serum stability comparable with that of disulfide-bonded Bac. Therefore, these Bac analogs (Bac-W, Bac-KW, Bac-LW, and Bac-KLW) can serve as promising antibiotics for the development of therapeutic agents for treatment against endotoxic shock and bacterial infection. In addition, our results suggest that a little increase in hydrophobicity may be responsible for the decreased cell selectivity of the multiple Arg-containing peptides (Bac-W, Bac-L, and Bac-LW) over the multiple Lys-containing peptides (Bac-KW, Bac-KL, and Bac-KLW).

A nationally representative case-control study of smoking and death in India.

BACKGROUND: The nationwide effects of smoking on mortality in India have not been assessed reliably. METHODS: In a nationally representative sample of 1.1 million homes, we compared the prevalence of smoking among 33,000 deceased women and 41,000 deceased men (case subjects) with the prevalence of smoking among 35,000 living women and 43,000 living men (unmatched control subjects). Mortality risk ratios comparing smokers with nonsmokers were adjusted for age, educational level, and use of alcohol. RESULTS: About 5% of female control subjects and 37% of male control subjects between the ages of 30 and 69 years were smokers. In this age group, smoking was associated with an increased risk of death from any medical cause among both women (risk ratio, 2.0; 99% confidence interval [CI], 1.8 to 2.3) and men (risk ratio, 1.7; 99% CI, 1.6 to 1.8). Daily smoking of even a small amount of tobacco was associated with increased mortality. Excess deaths among smokers, as compared with nonsmokers, were chiefly from tuberculosis among both women (risk ratio, 3.0; 99% CI, 2.4 to 3.9) and men (risk ratio, 2.3; 99% CI, 2.1 to 2.6) and from respiratory, vascular, or neoplastic disease. Smoking was associated with a reduction in median survival of 8 years for women (99% CI, 5 to 11) and 6 years for men (99% CI, 5 to 7). If these associations are mainly causal, smoking in persons between the ages of 30 and 69 years is responsible for about 1 in 20 deaths of women and 1 in 5 deaths of men. In 2010, smoking will cause about 930,000 adult deaths in India; of the dead, about 70% (90,000 women and 580,000 men) will be between the ages of 30 and 69 years. Because of population growth, the absolute number of deaths in this age group is rising by about 3% per year. CONCLUSIONS: Smoking causes a large and growing number of premature deaths in India.

Social disparities in the use of colonoscopy by primary care physicians in Ontario.

BACKGROUND: It is unclear if all persons in Ontario have equal access to colonoscopy. This research was designed to describe long-term trends in the use of colonoscopy by primary care physicians (PCPs) in Ontario, and to determine whether PCP characteristics influence the use of colonoscopy. METHODS: We conducted a population-based retrospective study of PCPs in Ontario between the years 1996-2005. Using administrative data we identified a screen-eligible group of patients aged 50-74 years in Ontario. These patients were linked to the PCP who provided the most continuous care to them during each year. We determined the use of any colonoscopy among these patients. We calculated the rate of colonoscopy for each PCP as the number of patients undergoing colonoscopies per 100 screen eligible patients. Negative binomial regression was used to identify factors associated with the rate of colonoscopy, using generalized estimating equations to account for clustering of patients within PCPs. RESULTS: Between 7,955 and 8,419 PCPs in Ontario per year (median age 43 years) had at least 10 eligible patients in their practices. The use of colonoscopy by PCPs increased sharply in Ontario during the study period, from a median rate of 1.51 [inter quartile range (IQR) 0.57-2.62] per 100 screen eligible patients in 1996 to 4.71 (IQR 2.70-7.53) in 2005. There was substantial variation between PCPs in their use of colonoscopy. PCPs who were Canadian medical graduates and with more years of experience were more likely to use colonoscopy after adjusting for their patient characteristics. PCPs were more likely to use colonoscopy if their patient populations were predominantly women, older, had more illnesses, and if their patients resided in less marginalized neighborhoods (lower unemployment, fewer immigrants, higher income, higher education, and higher English/French fluency). CONCLUSIONS: There is substantial variation in the use of colonoscopy by PCPs, and this variation has increased as the overall use of colonoscopy increased over time. PCPs whose patients were more marginalized were less likely to use colonoscopy, suggesting that there are inequities in access.