Association of dipeptidyl peptidase-4 inhibitor initiation at glycated haemoglobin <7.5% with reduced major clinical events mediated by low glycated haemoglobin variability.

AIM: Therapeutic inertia, hypoglycaemia and poor treatment persistence can lead to glycaemic fluctuation and poor outcomes in type 2 diabetes (T2D). We compared glycated haemoglobin (HbA1c) variability, insulin initiation, severe hypoglycaemia and clinical events in patients with T2D initiated dipeptidyl peptidase-4 inhibitors (DPP4is) at low versus high HbA1c thresholds. METHODS: Using territory-wide electronic medical records in Hong Kong, we curated a propensity score-matched cohort of patients initiated DPP4i at HbA1c <7.5% versus ≥7.5% in 2007-2019. We expressed the HbA1c variability score (HVS) as a proportion of HbA1c varied by ≥0.5% compared with preceding values. We used the Cox model to compare the risks of insulin initiation and clinical outcomes, adjusted for time-varying variables between the two groups. Mediation analysis estimated the effects of HbA1c variability on outcomes. RESULTS: Among 6874 insulin-naïve patients who initiated DPP4i, 88.7% were treated with metformin and 79.6% with sulphonylureas at baseline (54.9% men; mean age 65.2 ± 11.4 years). After a median follow-up of 4.6 years, compared with the high-threshold plus high-HVS group (≥50%), the low-threshold plus low-HVS (<50%) group had reduced hazard ratios (95% confidence interval) of insulin initiation (0.35, 0.31-0.40), severe hypoglycaemia (0.38, 0.34-0.44), major adverse cardiovascular endpoints (0.76, 0.66-0.88), heart failure (0.42, 0.36-0.49), end-stage kidney disease (0.65, 0.36-0.49) and mortality (0.45, 0.35-0.57). Reduced HbA1c variability explained 31.1%-81.2% of the effect size of DPP4i initiation at HbA1c <7.5% versus ≥7.5% on outcomes. CONCLUSIONS: In Chinese patients with T2D, avoiding therapeutic inertia with intensified glycaemic control at HbA1c <7.5% using drugs with low risk of hypoglycaemia and good tolerability, such as DPP4i, delayed insulin treatment, reduced HbA1c variability and improved clinical events.

Factors influencing risk perception during Public Health Emergencies of International Concern (PHEIC): a scoping review.

The unknownness and dread potential of a risk event shapes its perceived risk. A public health emergency of international concern (PHEIC) declaration by the World Health Organisation (WHO) is a signal for such an event. Understanding perceived risk then shapes risk-avoiding behaviours, important for health prevention. The review aims to consolidate the determinants of risk perception during a PHEIC, underscoring the need for grounding in context and theory. Studies published from 2010 until end-2020, searching PubMed, PsycINFO, MedlinePlus, PubPsych, and CINAHL, were included. Studies with only biological conceptualisations of risk, or no association to risk perception, were excluded. A total of 65 studies were included. Quality of the cross-sectional studies was assessed using Newcastle Ottawa Scale (NOS), yielding an average of 5.4 stars (out of 10). Factors were classified into three broad categories - individual, contextual, and media. Individual risk factors include emotions; beliefs, trust, and perceptions; immutable physical traits (sex, age, ethnicity); mutable traits (education, income, etc.); and knowledge, with no definitive correlation to risk perception. Contextual traits include pandemic experience, time, and location, with only time negatively correlated to risk perception. Media traits include exposure, attention, and framing of media, with no clear association to risk perception. One limitation is excluding a portion of COVID-19 studies due to censoring. Still, this lack of consensus highlights the need to better conceptualise "risk perception". Specifying the context and timing is also important since jurisdictions experience different outbreaks depending on outbreak histories. Using theories to ground risk perception research assists with these tasks.

Associations of comorbid depression with cardiovascular-renal events and all-cause mortality accounting for patient reported outcomes in individuals with type 2 diabetes: a 6-year prospective analysis of the Hong Kong Diabetes Register.

Background: Psychosocial status and patient reported outcomes (PRO) [depression and health-related quality-of-life (HRQoL)] are major health determinants. We investigated the association between depression and clinical outcomes in Chinese patients with type 2 diabetes (T2D), adjusted for PRO. Methods: Using prospective data from Hong Kong Diabetes Register (2013-2019), we estimated the hazard-ratio (HR, 95%CI) of depression (validated Patient Health Questionnaire 9 (PHQ-9) score≥7) with incident cardiovascular disease (CVD), ischemic heart disease (IHD), chronic kidney disease (CKD: eGFR<60 ml/min/1.73m2) and all-cause mortality in 4525 Chinese patients with T2D adjusted for patient characteristics, renal function, medications, self-care and HRQoL domains (mobility, self-care, usual activities, pain/discomfort, anxiety/depression measured by EQ-5D-3L) in linear-regression models. Results: In this cohort without prior events [mean ± SD age:55.7 ± 10.6, 43.7% women, median (IQR) disease duration of 7.0 (2.0-13.0) years, HbA1c, 7.2% (6.6%-8.20%), 26.4% insulin-treated], 537(11.9%) patients had depressive symptoms and 1923 (42.5%) patients had some problems with HRQoL at baseline. After 5.6(IQR: 4.4-6.2) years, 141 patients (3.1%) died, 533(11.8%) developed CKD and 164(3.6%) developed CVD. In a fully-adjusted model (model 4) including self-care and HRQoL, the aHR of depression was 1.99 (95% confidence interval CI):1.25-3.18) for CVD, 2.29 (1.25-4.21) for IHD. Depression was associated with all-cause mortality in models 1-3 adjusted for demographics, clinical characteristics and self-care, but was attenuated after adjusting for HRQoL (model 4- 1.54; 95%CI: 0.91-2.60), though HR still indicated same direction with important magnitude. Patients who reported having regular exercise (3-4 times per week) had reduced aHR of CKD [0.61 (0.41-0.89)]. Item 4 of PHQ-9 (feeling tired, little energy) was independently associated with all-cause mortality with aHR of 1.66 (1.30-2.12). Conclusion: Depression exhibits significant association with CVD, IHD, and all-cause mortality in patients with diabetes, adjusting for their HRQoL and health behaviors. Despite the association between depression and all-cause mortality attenuated after adjusting for HRQoL, the effect size remains substantial. The feeling of tiredness or having little energy, as assessed by item Q4 of the PHQ-9 questionnaire, was found to be significantly associated with an increased risk of all-cause mortality after covariate adjustments. Our findings emphasize the importance of incorporating psychiatric evaluations into holistic diabetes management.

How do organizational culture and leadership style affect nurse presenteeism and productivity?: A cross sectional study of Hong Kong acute public hospitals.

BACKGROUND: Presenteeism is defined as a type of work behavior in which employees are physically present at work when ill, often with reduced performance. While organizational culture and leadership style are known to impact the organizational behavior of hospital staff, as indicated by increased burnout and decreased work engagement, their impact on nurse presenteeism and productivity has not been explored. Moreover, nursing studies often neglect the importance of using multi-level analysis, adopting aggregated unit-level scores to account for collective perceptions to evaluate culture and leadership. OBJECTIVE: This study aims to evaluate the impact of unit-level organizational culture and leadership style on individual-level nurse presenteeism and productivity in acute care hospitals using multilevel analysis. DESIGN: Cross-sectional study. SETTING(S): Three major acute care public hospitals in Hong Kong, where public hospitals provide over 90 % of inpatient services. PARTICIPANTS: All full-time nurses (N = 4657) in the three study hospitals were invited to participate in this study. A total of 2339 nurses responded to the survey for a 65 % response rate. METHODS: Organizational culture and leadership style are characterized using the competing values framework and a two-factor leadership style typology, respectively. Multilevel hierarchical linear modeling was applied with unit-level clustering in each hospital. RESULTS: Hierarchical culture was the dominant culture (M = 3.64, SD = 0.74) in our nurse sample. None of the unit-level organizational culture and leadership styles were associated with nurse presenteeism, however, rational organizational culture at the unit-level was significantly associated with increased productivity (regression coefficient: 0.17, 95 % CI: 0.04-0.31). CONCLUSIONS: This study provides hospital managers with improved understanding of the differential impact of unit-level organizational culture and leadership style on nurse presenteeism and productivity. Unit-level leadership style did not have a direct impact on nurse presenteeism and productivity in this study, while the externally focused rational organizational culture increased nurse productivity. Further research is needed to understand the impacts of modifiable work factors and nurse psychosocial emotions on presenteeism and productivity.

Temporal associations of diabetes-related complications with health-related quality of life decrements in Chinese patients with type 2 diabetes: A prospective study among 19 322 adults-Joint Asia Diabetes Evaluation (JADE) register (2007-2018).

BACKGROUND: Patients with type 2 diabetes (T2D) are at high risk of developing multiple complications, affecting their health-related quality of life (HRQoL). Existing studies only considered impact of complication on HRQoL in the year of occurrence but not its residual impacts in subsequent years. We investigated temporal impacts of diabetes-related complications on HRQoL in a 12-year prospective cohort of ambulatory Chinese patients with T2D enrolled in the clinic-based Joint Asia Diabetes Evaluation (JADE) Register. METHODS: HRQoL utility measures were derived from EuroQol five-dimensional three-level questionnaire (EQ-5D-3L) questionnaires completed by 19 322 patients with T2D in Hong Kong (2007-2018). Temporal EQ-5D utility decrements associated with subtypes of cardiovascular-renal events were estimated using generalized linear regression model after stepwise selection of covariates with p < .01 as cutoff. RESULTS: In this cohort (mean ± SD age:61.2 ± 11.5 years, 55.3% men, median [interquartile range] duration of diabetes:10.1 [3.0-15.0] years, glycated hemoglobin [HbA1C ] 7.5 ± 1.5%), EQ-5D utility was 0.860 ± 0.163. The largest HRQoL decrements were observed in year of occurrence of hemorrhagic stroke (-0.230), followed by ischemic stroke (-0.165), peripheral vascular disease (-0.117), lower extremity amputation (-0.093), chronic kidney disease (CKD) G5 without renal replacement therapy (RRT) (-0.079), congestive heart failure (CHF) (-0.061), and CKD G3-G4 without RRT (-0.042). Residual impacts on HRQoL persisted for 2 years after occurrence of CHF or ischemic stroke and 1 year after hemorrhagic stroke or CKD G3-G4 without RRT. CONCLUSION: This is the first comprehensive report on temporal associations of HRQoL decrements with subtypes of diabetes-related complications in ambulatory Asian patients with T2D. These data will improve the accuracy of cost-effectiveness analysis of diabetes interventions at an individual level in an Asian setting.

Impact of New Cardiovascular Events on Quality of Life and Hospital Costs in People With Cardiovascular Disease in the United Kingdom and United States.

BACKGROUND: Despite optimized risk factor control, people with prior cardiovascular disease remain at high cardiovascular disease risk. We assess the immediate- and longer-term impacts of new vascular and nonvascular events on quality of life (QoL) and hospital costs among participants in the REVEAL (Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification) trial in secondary prevention. METHODS AND RESULTS: Data on demographic and clinical characteristics, health-related quality of life (QoL: EuroQoL 5-Dimension-5-Level), adverse events, and hospital admissions during the 4-year follow-up of the 21 820 participants recruited in Europe and North America informed assessments of the impacts of new adverse events on QoL and hospital costs from the UK and US health systems' perspectives using generalized linear regression models. Reductions in QoL were estimated in the years of event occurrence for nonhemorrhagic stroke (-0.067 [United Kingdom], -0.069 [US]), heart failure admission (-0.072 [United Kingdom], -0.103 [US]), incident cancer (-0.064 [United Kingdom], -0.068 [US]), and noncoronary revascularization (-0.071 [United Kingdom], -0.061 [US]), as well as in subsequent years following these events. Myocardial infarction and coronary revascularization (CRV) procedures were not found to affect QoL. All adverse events were associated with additional hospital costs in the years of events and in subsequent years, with the highest additional costs in the years of noncoronary revascularization (£5830 [United Kingdom], $14 133 [US Medicare]), of myocardial infarction with urgent CRV procedure (£5614, $24722), and of urgent/nonurgent CRV procedure without myocardial infarction (£4674/£4651 and $15 251/$17 539). CONCLUSIONS: Stroke, heart failure, and noncoronary revascularization procedures substantially reduce QoL, and all cardiovascular disease events increase hospital costs. These estimates are useful in informing cost-effectiveness of interventions to reduce cardiovascular disease risk in secondary prevention. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01252953; https://www.Isrctn.com. Unique identifier: ISRCTN48678192; https://www.clinicaltrialsregister.eu. Unique identifier: 2010-023467-18.

The Physical and Psychosocial Outcomes of a Psychosocial Home-Based end-of-Life Care Intervention in Hong Kong.

OBJECTIVE: Living the final days of life being cared for at home is a preference expressed by many. The data on the effectiveness of home-based end-of-life care (EoLC) intervention to improve the holistic conditions of terminally ill patients are scanty. This study sought to evaluate a psychosocial home-based EoLC intervention for terminally ill patients in Hong Kong. METHODS: A prospective cohort study was conducted, applying the Integrated Palliative Care Outcome Scale (IPOS) at 3 timepoints (service intake, 1-month, and 3-months after enrollment). A total of 485 eligible, consenting terminally ill people (mean age = 75.48, SD = 11.39) were enrolled, with 40.21% (n = 195) providing data at all 3 timepoints for this study. RESULTS: Decreasing symptom severity scores were observed for all IPOS psychosocial symptoms, and most physical symptoms, over the 3 timepoints. Improvements in depression and practical concerns had the highest omnibus time effects (F > 31.92, P < .01) and T0 to T2 paired comparison effects (Cohen's d > 0.54, P < .01). Physical symptoms of weakness/lack of energy, poor mobility, and poor appetite also showed significant improvements at T1 and T2 (Cohen's d: 0.22-0.46, P < .05). Bivariate regression analyses showed that improvements in anxiety, depression, and family anxiety were associated with improvements in physical symptoms of pain, shortness of breath, weakness/lack of energy, nausea, poor appetite, and poor mobility. Patients' demographic and clinical characteristics were not associated with changes in symptoms. CONCLUSIONS: The psychosocial home-based EoLC intervention effectively improved the psychosocial and physical status of terminally ill patients, irrespective of their clinical characteristics or demographics.

Does Seasonal Influenza Related Hospital Occupancy Surge Impact Hospital Staff Sickness Presenteeism and Productivity Costs?

Background-The workload of public hospital staff is heightened during seasonal influenza surges in hospitals serving densely populated cities. Such work environments may subject staff to increased risk of sickness presenteeism. Presenteeism is detrimental to nurses' health and may lead to downstream productivity loss, resulting in financial costs for hospital organizations. Aims-This study aims to quantify how seasonal influenza hospital occupancy surge impacts nurses' sickness presenteeism and related productivity costs in high-intensity inpatient metropolitan hospitals. Methods-Full-time nurses in three Hong Kong acute-care hospitals were surveyed. Generalized estimating equations (GEE) was applied to account for clustering in small number of hospitals. Results-A total of 71.3% of nurses reported two or more presenteeism events last year. A 6.8% increase in hospital inpatient occupancy rate was associated with an increase of 19% (1.19, 95% CI: 1.06-1.34) in nurse presenteeism. Presenteeism productivity loss costs between nurses working healthy (USD1983) and worked sick (USD 2008) were not significantly different, while sick leave costs were highest (USD 2703). Conclusion-Presenteeism prevalence is high amongst acute-care hospital nurses and workload increase during influenza flu surge significantly heightened nurse sickness presenteeism. Annual presenteeism productivity loss costs in this study of USD 24,096 were one of the highest reported worldwide. Productivity loss was also considerably high regardless of nurses' health states, pointing towards other potential risk factors at play. When scheduling nurses to tackle flu surge, managers may want to consider impaired productivity due to staff presenteeism. Further longitudinal research is essential in identifying management modifiable risk factors that impact nurse presenteeism and impairing downstream productivity loss.

Working while sick: validation of the multidimensional presenteeism exposures and productivity survey for nurses (MPEPS-N).

BACKGROUND: Presenteeism is the employee behaviour of physically attending work with reduced performance due to illness or for other reasons. Nurses are four times more likely to exhibit presenteeism compared to other occupations, threatening patient safety through increased patient falls, medication errors and staff-to-patient disease transmission. There is a paucity of standardized instruments that quantify the association between presenteeism with its exposures and related productivity. This study aims to validate an instrument that comprehensively measures presenteeism workplace and personal exposures specifically for Asian nurses. METHODS: Questionnaire domain items were selected based on the JD-R framework and a previously conducted systematic review of pre-existing validated scales measuring work attendance exposures used in previous healthcare studies. The preliminary questionnaire consisted of two outcomes (presenteeism frequency, productivity) and five exposure domains: work resources, work demands, work stress, work engagement, personal traits and health. Content validation and back translation (English-Cantonese Chinese-English) were carried out. Responses from full-time nurses working in two acute care hospitals (Preliminary questionnaire at Hospital 1: N = 295 and main round questionnaire at Hospital 2: N = 1146) were included in the validation study to ensure an adequate sample size of ten cases per indicator variable for CFA analysis. A random sample of 80 nurses from Hospital 1 were selected for test-retest reliability 4 weeks post the initial survey. Internal consistency, convergent and discriminant validity tests were also tested. RESULTS: Satisfactory internal consistency (Cronbach's alpha > 0.7), test-retest reliability (ICC > 0.4); and construct validity - convergent and discriminant validity was achieved. Confirmatory factor analysis yielded satisfactory fitness indices (CFI and TLI > 0.95, RMSEA < 0.08). Presenteeism and productivity significantly associated with all work resources, work engagement and work stress constructs in Hospital 2. CONCLUSION: A reliable Multidimensional Presenteeism Exposures and Productivity Survey (MPEPS-N) has been validated in two distinct hospital environments. The instrument helps to identify and quantify organizational or individual exposures that significantly associate with presenteeism and its related productivity, thus allowing hospital managers to set evidence-based intervention targets for wellness programs and formulate human resource policies in reducing presenteeism-related productivity loss.

Validation of the nurse leadership and organizational culture (N-LOC) questionnaire.

BACKGROUND: Leadership style and organizational culture have often been studied independently in nursing research despite abundant evidence that the two factors both influence employee outcomes. Moreover, diverse theoretical typology and measuring instruments challenges generalizability of findings. Employees from different cultural, geographical, occupational settings were also reported to have varying interpretation on organizational culture and leadership style underlying constructs. This study aims to validate the Nursing Leadership and Organizational Culture (N-LOC) questionnaire, based on the two commonly used theoretical frameworks: Multifactor Leadership Theory and Competing Values Framework, on its applicability in an Asian hospital setting. METHODS: All full-time nurses from two distinctive Asian hospitals (H1: n = 295 and H2: n = 1146) were invited to participate in this questionnaire study. Exploratory factor analysis (EFA) was carried out when confirmatory factor analysis (CFA) fit indices were not satisfactory after model refinement to explore the actual underlying construct in sampled population. Part-time and outsourced nurses were excluded. 93 nurses from H1 were randomly selected for test-retest reliability 4 weeks post initial survey. Scale internal consistency, convergent and discriminant validity were also assessed. RESULTS: CFA results indicated that the proposed CVF organizational culture 4-factor structure was applicable to our sample but not the MLQ leadership 3-factor/9-factor structure. EFA revealed a 2-factor leadership style construct for our sample, named Confucius transformational and Laissez-Faire passive leadership. Transformational leadership traits already embedded in Confucius cultural values (self-sacrifice, stresses collective mission, instills pride) did not apply, the new Confucius transformational construct which resembles LMX theory paternalistic leadership style is deemed more suitable in an Asian context. A final 14-item 2-factor leadership and 13-item 4-factor organizational culture construct was yielded with satisfactory fit indices (CFI, TLI > 0.95, RMSEA < 0.08), internal consistency (Cronbach's alpha > 0.7), test-retest reliability (ICC > 0.4) and convergent and discriminant validity. CONCLUSION: A reliable N-LOC organizational culture and leadership questionnaire (N-LOC) has been validated in an Asian nurse context. Study results demonstrated the importance of scale validation in cross-cultural adaptation, as underlying scale constructs may change with specific cultural and contextual factors. Future studies are encouraged to test the adaptation of this scale in other cultural and occupational settings.

Presenteeism exposures and outcomes amongst hospital doctors and nurses: a systematic review.

BACKGROUND: Presenteeism is a behavior in which an employee is physically present at work with reduced performance due to illness or other reasons. Hospital doctors and nurses are more inclined to exhibit presenteeism than other professional groups, resulting in diminished staff health, reduced team productivity and potentially higher indirect presenteeism-related medical costs than absenteeism. Robust presenteeism intervention programs and productivity costing studies are available in the manufacturing and business sectors but not the healthcare sector. This systematic review aims to 1) identify instruments measuring presenteeism and its exposures and outcomes; 2) appraise the related workplace theoretical frameworks; and 3) evaluate the association between presenteeism, its exposures and outcomes, and the financial costs of presenteeism as well as interventions designed to alleviate presenteeism amongst hospital doctors and nurses. METHODS: A systematic search was carried out in ten electronic databases from 1998 to 2017 and screened by two reviewers. Quality assessment was carried out using the Critical Appraisal Skills Program (CASP) tool. Publications meeting predefined assessment criteria were selected for data extraction. RESULTS: A total of 275 unique English publications were identified, 38 were selected for quality assessment, and 24 were retained for data extraction. Seventeen publications reported on presenteeism exposures and outcomes, four on financial costing, one on intervention program and two on economic evaluations. Eight (39%) utilized a theoretical framework, where the Job-Demands Resources (JD-R) framework was the most commonly used model. Most assessed work stressors and resources were positively and negatively associated with presenteeism respectively. Contradictory and limited comparability on findings across studies may be attributed to variability of selected scales for measuring both presenteeism and its exposures/outcomes constructs. CONCLUSION: The heterogeneity of published research and limited quality of measurement tools yielded no conclusive evidence on the association of presenteeism with hypothesized exposures, economic costs, or interventions amongst hospital healthcare workers. This review will aid researchers in developing a standardized multi-dimensional presenteeism exposures and productivity instrument to facilitate future cohort studies in search of potential cost-effective work-place intervention targets to reduce healthcare worker presenteeism and maintain a sustainable workforce.

A validation study of public health knowledge, skills, social responsibility and applied learning.

OBJECTIVES: To design and validate a questionnaire to measure medical students' Public Health (PH) knowledge, skills, social responsibility and applied learning as indicated in the four domains recommended by the Association of Schools & Programmes of Public Health (ASPPH). METHODS: A cross-sectional study was conducted to develop an evaluation tool for PH undergraduate education through item generation, reduction, refinement and validation. The 74 preliminary items derived from the existing literature were reduced to 55 items based on expert panel review which included those with expertise in PH, psychometrics and medical education, as well as medical students. Psychometric properties of the preliminary questionnaire were assessed as follows: frequency of endorsement for item variance; principal component analysis (PCA) with varimax rotation for item reduction and factor estimation; Cronbach's Alpha, item-total correlation and test-retest validity for internal consistency and reliability. RESULTS: PCA yielded five factors: PH Learning Experience (6 items); PH Risk Assessment and Communication (5 items); Future Use of Evidence in Practice (6 items); Recognition of PH as a Scientific Discipline (4 items); and PH Skills Development (3 items), explaining 72.05% variance. Internal consistency and reliability tests were satisfactory (Cronbach's Alpha ranged from 0.87 to 0.90; item-total correlation > 0.59). Lower paired test-retest correlations reflected instability in a social science environment. CONCLUSIONS: An evaluation tool for community-centred PH education has been developed and validated. The tool measures PH knowledge, skills, social responsibilities and applied learning as recommended by the internationally recognised Association of Schools & Programmes of Public Health (ASPPH).

Glycine insertion at protease cleavage site of SNAP25 resists cleavage but enhances affinity for botulinum neurotoxin serotype A.

The light chain of botulinum neurotoxin A (BoNT/A-LC) is a Zn-dependent protease that specifically cleaves SNAP25 of the SNARE complex, thereby impairing vesicle fusion and neurotransmitter release at neuromuscular junctions. The C-terminus of SNAP25 (residues 141-206) retains full activity for BoNT/A-LC-catalyzed cleavage at P1-P1' (Gln197-Arg198). Using the structure of a complex between the C-terminus of SNAP25 and BoNT/A-LC as a model to design SNAP25-derived pseudosubstrate inhibitors (SNAPIs) that prevent presentation of the scissile bond to the active site, we introduced multiple His residues to replace Ala-Asn-Gln-Arg (residues 195-198) at the substrate cleavage site, with the intent to identify possible side-chain interactions with the active site Zn. We also introduced multiple Gly residues between the P1-P1' residues to explore the spatial tolerance within the active-site cleft. Using a FRET substrate YsCsY, we compared a series of SNAPIs for inhibition of BoNT/A-LC. Among the SNAPIs tested, several known cleavage-resistant, single-point mutants of SNAP25 were poor inhibitors, with most of the mutants losing binding affinity. Replacement with His at the active site did not improve inhibition over wildtype substrate. In contrast, Gly-insertion mutants were not only resistant to cleavage, but also surprisingly showed enhanced affinity for BoNT/A-LC. Two of the Gly-insertion mutants exhibited 10-fold lower IC50 values than the wildtype 66-mer SNAP25 peptide. Our findings illustrate a scenario, where the induced fit between enzyme and bound pseudosubstrate fails to produce the strain and distortion required for catalysis to proceed.