Development of a High-Throughput Resequencing Array for the Detection of Pathogenic Mutations in Osteogenesis Imperfecta

Objective

Osteogenesis imperfecta (OI) is a rare inherited skeletal disease, characterized by bone fragility and low bone density. The mutations in this disorder have been widely reported to be on various exonal hotspots of the candidate genes, including COL1A1, COL1A2, CRTAP, LEPRE1, and FKBP10, thus creating a great demand for precise genetic tests. However, large genome sizes make the process daunting and the analyses, inefficient and expensive. Therefore, we aimed at developing a fast, accurate, efficient, and cheaper sequencing platform for OI diagnosis; and to this end, use of an advanced array-based technique was proposed.

Method

A CustomSeq Affymetrix Resequencing Array was established for high-throughput sequencing of five genes simultaneously. Genomic DNA extraction from 13 OI patients and 85 normal controls and amplification using long-range PCR (LR-PCR) were followed by DNA fragmentation and chip hybridization, according to standard Affymetrix protocols. Hybridization signals were determined using GeneChip Sequence Analysis Software (GSEQ). To examine the feasibility, the outcome from new resequencing approach was validated by conventional capillary sequencing method.

Result

Overall call rates using resequencing array was 96–98% and the agreement between microarray and capillary sequencing was 99.99%. 11 out of 13 OI patients with pathogenic mutations were successfully detected by the chip analysis without adjustment, and one mutation could also be identified using manual visual inspection.

Conclusion

A high-throughput resequencing array was developed that detects the disease-associated mutations in OI, providing a potential tool to facilitate large-scale genetic screening for OI patients. Through this method, a novel mutation was also found.     

An Approach to Assessing Patient Safety in Hospitals in Low-Income Countries

Objective

The aim of the study was to assess non-technical aspects of patient safety practices using non-participant observation in different clinical areas.

Design

Qualitative study using non-participant observation and thematic analysis.

Setting

Two eye care units in Uganda.

Participants

Staff members in each hospital.

Main outcome measures

A set of observations of patient safety practices by staff members in clinical areas that were then coded using thematic analysis.

Results

Twenty codes were developed that explained patient safety practices in the hospitals based on the observations. These were grouped into four themes: the team, the environment, patient-centred care and the process. The complexity of patient safety in each hospital was described using narrative reports to support the thematic analysis. Overall both hospitals demonstrated good patient safety practices however areas for improvement were staff-patient communication, the presence and use of protocols and a focus on consistent practice.

Conclusions

This is the first holistic assessment of patient safety practices in a low-income setting. The methods allowed the complexity of patient safety to be understood and explained with areas of concern highlighted. The next step will be to develop a useful and easy to use tool to measure patient safety practices in low-income settings.     

Development and Validation of the Keele Musculoskeletal Patient Reported Outcome Measure (MSK-PROM)

Objective

To develop and validate a patient report outcome measure (PROM) for clinical practice that can monitor health status of patients with a range of musculoskeletal (MSK) disorders.

Methods

Constructs for inclusion in the MSK-PROM were identified from a consensus process involving patients with musculoskeletal conditions, clinicians, purchasers of healthcare services, and primary care researchers. Psychometric properties of the brief tool, including face and construct validity, repeatability and responsiveness were assessed in a sample of patients with musculoskeletal pain consulting physiotherapy services in the United Kingdom (n=425).

Results

The consensus process identified 10 prioritised domains for monitoring musculoskeletal health status: pain intensity, quality of life, physical capacity, interference with social/leisure activities, emotional well-being, severity of most difficult thing, activities and roles, understanding independence, and overall impact. As the EuroQol (EQ-5D-5L) is a widely adopted PROMs tool and covers the first four domains listed, to reduce patient burden to a minimum the MSK-PROM was designed to capture the remaining six prioritised domains which are not measured by the EQ-5D-5L. The tool demonstrated excellent reliability, construct validity, responsiveness and acceptability to patients and clinicians for use in clinical practice.

Conclusion

We have validated a brief patient reported outcome measure (MSK-PROM) for use in clinical practice to measure musculoskeletal health status and monitor outcomes over time using domains that are meaningful to patients and sensitive to change. Further work will establish whether the MSK-PROM is useful in other musculoskeletal healthcare settings.     

Care Needs and Clinical Outcomes of Older People with Dementia: A Population-Based Propensity Score-Matched Cohort Study

Objective

To explore the healthcare resource utilization, psychotropic drug use and mortality of older people with dementia.

Design

A nationwide propensity score-matched cohort study.

Setting

National Health Insurance Research database.

Participants

A total of 32,649 elderly people with dementia and their propensity-score matched controls (n=32,649).

Measurements

Outpatient visits, inpatient care, psychotropic drug use, in-hospital mortality and all-cause mortality at 90 and 365 days.

Results

Compared to the non-dementia group, a higher proportion of patients with dementia used inpatient services (1 year after index date: 20.91% vs. 9.55%), and the dementia group had more outpatient visits (median [standard deviation]: 7.00 [8.87] vs. 3.00 [8.30]). Furthermore, dementia cases with acute admission had the highest psychotropic drug utilization both at baseline and at the post-index dates (difference-in-differences: all <0.001). Dementia was associated with an increased risk of all-cause mortality (90 days, Odds ratio (OR)=1.85 [95%CI 1.67-2.05], p<0.001; 365 days, OR=1.59 [1.50-1.69], p<0.001) and in-hospital mortality (90 days, OR=1.97 [1.71-2.27], p<0.001; 365 days, OR=1.82 [1.61-2.05], p<0.001) compared to matched controls.

Conclusions

When older people with dementia are admitted for acute illnesses, they may increase their use of psychotropic agents and their risk of death, particularly in-hospital mortality.     

Scoring System for Mortality in Patients Diagnosed with and Treated Surgically for Differentiated Thyroid Carcinoma with a 20-Year Follow-Up

Background

Differentiated thyroid carcinoma (DTC) is associated with an increased mortality. Few studies have constructed predictive models of all-cause mortality with a high discriminating power for patients with this disease that would enable us to determine which patients are more likely to die.

Objective

To construct a predictive model of all-cause mortality at 5, 10, 15 and 20 years for patients diagnosed with and treated surgically for DTC for use as a mobile application.

Design

We undertook a retrospective cohort study using data from 1984 to 2013.

Setting

All patients diagnosed with and treated surgically for DTC at a general university hospital covering a population of around 200,000 inhabitants in Spain.

Participants

The study involved 201 patients diagnosed with and treated surgically for DTC (174, papillary; 27, follicular).

Exposures

Age, gender, town, family history, type of surgery, type of cancer, histological subtype, microcarcinoma, multicentricity, TNM staging system, diagnostic stage, permanent post-operative complications, local and regional tumor persistence, distant metastasis, and radioiodine therapy.

Main outcome measure

All-cause mortality.

Methods

A Cox multivariate regression model was constructed to determine which variables at diagnosis were associated with mortality. Using the model a risk table was constructed based on the sum of all points to estimate the likelihood of death. This was then incorporated into a mobile application.

Results

The mean follow-up was 8.8±6.7 years. All-cause mortality was 12.9% (95% confidence interval [CI]: 8.3–17.6%). Predictive variables: older age, local tumor persistence and distant metastasis. The area under the ROC curve was 0.81 (95% CI: 0.72–0.91, p<0.001).

Conclusion

This study provides a practical clinical tool giving a simple and rapid indication (via a mobile application) of which patients with DTC are at risk of dying in 5, 10, 15 or 20 years. Nonetheless, caution should be exercised until validation studies have corroborated our results.     

What Are Physicians' Reasons for Not Referring People with Life-Limiting Illnesses to Specialist Palliative Care Services? A Nationwide Survey

Background

Many people who might benefit from specialist palliative care services are not using them.

Aim

We examined the use of these services and the reasons for not using them in a population in potential need of palliative care.

Methods

We conducted a population-based survey regarding end-of-life care among physicians certifying a large representative sample (n = 6188) of deaths in Flanders, Belgium.

Results

Palliative care services were not used in 79% of cases of people with organ failure, 64% of dementia and 44% of cancer. The most frequently indicated reasons were that 1) existing care already sufficiently addressed palliative and supportive needs (56%), 2) palliative care was not deemed meaningful (26%) and 3) there was insufficient time to initiate palliative care (24%). The reasons differed according to patient characteristics: in people with dementia the consideration of palliative care as not meaningful was more likely to be a reason for not using it; in older people their care needs already being sufficiently addressed was more likely to be a reason. For those patients who were referred the timing of referral varied from a median of six days before death (organ failure) to 16 days (cancer).

Conclusions

Specialist palliative care is not initiated in almost half of the people for whom it could be beneficial, most frequently because physicians deem regular caregivers to be sufficiently skilled in addressing palliative care needs. This would imply that the safeguarding of palliative care skills in this regular ‘general’ care is an essential health policy priority.     

A Cross-Sectional Study of the Psychological Needs of Adults Living with Cystic Fibrosis

Background

Depression and anxiety are prevalent in people with cystic fibrosis (CF), yet psychological services are rarely accessible in CF clinics. This cross-sectional single center study reports on a psychological needs assessment of people with CF.

Methods

We asked adults attending a CF clinic, without integrated psychological services, to complete a psychological needs assessment survey that included items on: a) past access to psychological services (via a CF referral service), b) concerns relevant to discuss with a psychologist, and c) their likelihood of accessing psychological services if available at the CF clinic, and standardized measures of depression (CES-D) and anxiety (GAD-7).

Results

We enrolled 49 participants and 45 (91.8%) completed the survey. Forty percent reported elevated symptoms of depression and 13% had elevated anxiety. A majority of individuals (72.2% and 83.3%, respectively) indicated they would be likely to use psychological services, if available at the clinic. Concerns considered most relevant to discuss with a psychologist were: 1) worries (51.1%), 2) mood (44.4%), 3) life stress (46.6%), 4) adjustment to CF (42.2%), 5) life transitions (42.2%) and 6) quality of life (42.2%).

Conclusions

This study highlights the rationale for screening adults with CF for depression and anxiety, and to facilitate provision of psychological services and preventative mental health interventions as an integral component of multi-disciplinary CF care.     

One-Year Follow-Up of Patients Undergoing Transvenous Extraction of Pacemaker and Defibrillator Leads

Introduction

The number of pacemaker and ICD implantations has increased substantially in the recent years. Therefore, complications are also observed in a greater number. In many cases, transvenous extraction of the previously implanted device (pacemaker or ICD) is the only solution. One may find in the literature information about the efficacy and safety of that procedure, but data concerning the results of long-term follow up are still limited.

Aim

The aim of the study was to assess the one-year mortality in the cohort of patients undergoing transvenous lead extraction procedures in our centre.

Methods

Records of the patients undergoing transvenous lead removal in the Department of Cardiology and Electrotherapy of the Medical University of Gdańsk were analyzed. We collected detailed information about 192 patients that had undergone the procedure from January 2003 until June 2012. Data were collected from medical and surgical records. We analyzed concomitant diseases, indications, and possible complications. Long-term follow-up data were gathered in the follow-up ambulatory records and over-the-phone interviews with patients or families. In several cases, we consulted the database of the Polish National Health Fund.

Results

During the early post-operative period 5 patients died, although none of those deaths was associated with the procedure itself. No other major complications were observed. During one-year follow-up other 5 patients died, which gave the overall one-year survival rate of 92.7%. Heart failure, renal failure and an infective indication showed significant association with increased mortality.

Conclusion

Results of transvenous lead extraction, a relatively safe procedure, should be assessed over time extending beyond the sole perioperative period. Some complications may be delayed in their nature, and may be observed only during the long-term follow up.     

Pregnancy Prevention and Condom Use Practices among HIV-Infected Women on Antiretroviral Therapy Seeking Family Planning in Lilongwe,Malawi

Background

Programs for integration of family planning into HIV care must recognize current practices and desires among clients to appropriately target and tailor interventions. We sought to evaluate fertility intentions, unintended pregnancy, contraceptive and condom use among a cohort of HIV-infected women seeking family planning services within an antiretroviral therapy (ART) clinic.

Methods

200 women completed an interviewer-administered questionnaire during enrollment into a prospective contraceptive study at the Lighthouse Clinic, an HIV/ART clinic in Lilongwe, Malawi, between August and December 2010.

Results

Most women (95%) did not desire future pregnancy. Prior reported unintended pregnancy rates were high (69% unplanned and 61% unhappy with timing of last pregnancy). Condom use was inconsistent, even among couples with discordant HIV status, with lack of use often attributed to partner’s refusal. Higher education, older age, lower parity and having an HIV negative partner were factors associated with consistent condom usage.

Discussion

High rates of unintended pregnancy among these women underscore the need for integ rating family planning, sexually transmitted infection (STI) prevention, and HIV services. Contraceptive access and use, including condoms, must be improved with specific efforts to enlist partner support. Messages regarding the importance of condom usage in conjunction with more effective modern contraceptive methods for both infection and pregnancy prevention must continue to be reinforced over the course of ongoing ART treatment.     

Appropriateness,Reasons and Independent Predictors of Consultations in the Emergency Department (ED) of a Dutch Tertiary Care Center: A Prospective Cohort Study

Objective

Consultations occur frequently in the emergency department (ED) of tertiary care centres and pose a threat for patient safety as they contribute to ED lengths of stay (LOS) and overcrowding. The aim of this study was to investigate reasons and appropriateness of consultations, and the relative impact of specialty and patient characteristics on the probability of a consultation, because this could help to improve efficiency of ED patient care.

Methods

This prospective cohort study included ED patients presenting to a Dutch tertiary care centre in a setting where ED physicians mostly treat self-referred and undifferentiated patients and other specialists treat referred patients. Consultations were defined as appropriate if the reason of consultation corresponded with the final advice, conclusion or policy of the consulted specialty. Multivariable logistic regression analysis was used to assess the relative contribution of specialty and patient characteristics on consultation.

Results

In the 344 (24% (95% CI 22 to 26%)) of the 1434 inclusions another specialty was consulted, resulting in a 55% increase of ED LOS. ED physicians more often consulted another specialty with a corrected odds ratio (OR) of 5.6 (4.0 to 7.8), mostly because consultations were mandatory in case of hospitalization or outpatient follow-up. Limited expertise of ED physicians was the reason for consultation in 7% (5 to 9%). The appropriateness of consultations was 84% (81 to 88%), similar between ED physicians and other specialists (P = 0.949). The patient characteristics age, comorbidity, and triage category and complaint predicted consultation.

Conclusion

In a Dutch tertiary care centre another specialty was consulted in 24% of the patients, mostly for an appropriate reason, and rarely because of lack of expertise. The impact of consultations on ED LOS could be reduced if mandatory consultations are abolished and predictors of a consultation are used to facilitate timely consultation.     

Time Trends in Fast Food Consumption and Its Association with Obesity among Children in China

Objective

Study the trends in Western fast food consumption (FFC) among Chinese school-age children and the association between FFC and obesity using nationwide survey data.

Design

Cross-sectional and longitudinal analyses were conducted to study the trends in FFC and the associations between FFC and weight status (overweight, obesity and body mass index (BMI) z-score).

Setting

Longitudinal data from families were collected in the 2004 and 2009 China Health and Nutrition Survey (covering nine provinces throughout China).

Subjects

The analysis included 2656 Chinese children aged 6 to 18 years (1542 and 1114 children in the 2004 and 2009 survey, respectively).

Results

FFC (reported having consumed Western fast food in the past three months) has increased between 2004 and 2009, from 18.5% to 23.9% in those aged 6–18, and increased more rapidly among those aged 13–17, from 17.9% to 26.3%. The increase was significant in almost all groups by age, sex, family income, and residence. Our cross-sectional and longitudinal analyses did not detect a significant association between FFC and obesity/overweight or BMI z-score (e.g., for BMI z-score, boys: β = 0.02, 95% CI: -0.71, 0.75; girls: β = -0.14, 95% CI: -1.03, 0.75).

Conclusions

FFC has increased in Chinese school-age children, especially in older children, boys, and those from low- and medium-income families, rural areas, and East China, but decreased among those from high-income families during 2004–2009. The data did not show a significant association between FFC and obesity.     

A Bundle of Services Increased Ascertainment of Tuberculosis among HIV-Infected Individuals Enrolled in a HIV Cohort in Rural Sub-Saharan Africa

Objectives

To report on trends of tuberculosis ascertainment among HIV patients in a rural HIV cohort in Tanzania, and assessing the impact of a bundle of services implemented in December 2012, consisting of three components:(i)integration of HIV and tuberculosis services; (ii)GeneXpert for tuberculosis diagnosis; and (iii)electronic data collection.

Design

Retrospective cohort study of patients enrolled in the Kilombero Ulanga Antiretroviral Cohort (KIULARCO), Tanzania.)

Methods

HIV patients without prior history of tuberculosis enrolled in the KIULARCO cohort between 2005 and 2013 were included.Cox proportional hazard models were used to estimate rates and predictors of tuberculosis ascertainment

Results

Of 7114 HIV positive patients enrolled, 5123(72%) had no history of tuberculosis. Of these, 66% were female, median age was 38 years, median baseline CD4+ cell count was 243 cells/µl, and 43% had WHO clinical stage 3 or 4. During follow-up, 421 incident tuberculosis cases were notified with an estimated incidence of 3.6 per 100 person-years(p-y)[95% confidence interval(CI)3.26-3.97]. The incidence rate varied over time and increased significantly from 2.96 to 43.98 cases per 100 p-y after the introduction of the bundle of services in December 2012. Four independent predictors of tuberculosis ascertainment were identified:poor clinical condition at baseline (Hazard Ratio (HR) 3.89, 95% CI 2.87-5.28), WHO clinical stage 3 or 4 (HR 2.48, 95% CI 1.88-3.26), being antiretroviralnaïve (HR 2.97, 95% CI 2.25-3.94), and registration in 2013(HR 6.07, 95% CI 4.39-8.38).

Conclusion

The integration of tuberculosis and HIV services together with comprehensive electronic data collection and use of GeneXpert increased dramatically the ascertainment of tuberculosis in this rural African HIV cohort.     

Electronic Cigarettes Efficacy and Safety at 12 Months: Cohort Study

Objective

To evaluate the safety and efficacy as a tool of smoking cessation of electronic cigarettes (e-cigarettes), directly comparing users of e-cigarettes only, smokers of tobacco cigarettes only, and smokers of both.

Design

Prospective cohort study. Final results are expected in 2019, but given the urgency of data to support policies on electronic smoking, we report the results of the 12-month follow-up.

Data Sources

Direct contact and structured questionnaires by phone or via internet.

Methods

Adults (30–75 years) were included if they were smokers of ≥1 tobacco cigarette/day (tobacco smokers), users of any type of e-cigarettes, inhaling ≥50 puffs weekly (e-smokers), or smokers of both tobacco and e-cigarettes (dual smokers). Carbon monoxide levels were tested in a sample of those declaring tobacco smoking abstinence.

Main Outcome Measures

Sustained smoking abstinence from tobacco smoking at 12 months, reduction in the number of tobacco cigarettes smoked daily.

Data Synthesis

We used linear and logistic regression, with region as cluster unit.

Results

Follow-up data were available for 236 e-smokers, 491 tobacco smokers, and 232 dual smokers (overall response rate 70.8%). All e-smokers were tobacco ex-smokers. At 12 months, 61.9% of the e-smokers were still abstinent from tobacco smoking; 20.6% of the tobacco smokers and 22.0% of the dual smokers achieved tobacco abstinence. Adjusting for potential confounders, tobacco smoking abstinence or cessation remained significantly more likely among e-smokers (adjusted OR 5.19; 95% CI: 3.35–8.02), whereas adding e-cigarettes to tobacco smoking did not enhance the likelihood of quitting tobacco and did not reduce tobacco cigarette consumption. E-smokers showed a minimal but significantly higher increase in self-rated health than other smokers. Non significant differences were found in self-reported serious adverse events (eleven overall).

Conclusions

Adding e-cigarettes to tobacco smoking did not facilitate smoking cessation or reduction. If e-cigarette safety will be confirmed, however, the use of e-cigarettes alone may facilitate quitters remaining so.

Registration Number

NCT01785537.     

Use of Public Oral Health Services by the Adult Population: A Multilevel Analysis

Background

It is important to assess context to explain inequalities in oral health, particularly with regard to the type of service used; thus, this study aimed to identify the social determinants of public dental service use by adults and to assess whether, beyond the level individual, existing inequalities are also expressed in the context in which individuals are embedded.

Methods

A multilevel analysis with three levels of aggregation of variables was performed. The individual variables were derived from the database of the SB Minas Gerais project—a survey of oral health status of the population of Minas Gerais, a state of the Brazilian Southeast region. The variable at the neighborhood level came from the Census of 2010. The variables at the municipal level were obtained from available public databases relating to oral health services. At the municipal level, the Human Development Index (HDI) variable was chosen to represent quality of life in the municipalities.

Results

In the final model, the following individual variables were associated with greater use of public dental services: lower income (PR = 1.98, 95% CI = 1.53; 2.58), higher number of residents at home (PR = 1.37, 95% CI = 1.11; 1.68) and higher number of teeth requiring treatment (PR = 1.49, 95% CI = 1.20; 1.84). With regard to context variables, a poorer infrastructure (PR = 0.62, 95% CI = 0.40; 0.96) leads to a lower use of public services.

Conclusion

The use of public services is associated with family income, how this income is divided in households, the need for treatment presented by the individual and the organization of the existing oral health service infrastructure in the municipality.     

Rehabilitation Utilization following a Work-Related Traumatic Brain Injury: A Sex-Based Examination of Workers’ Compensation Claims in Victoria,Australia

Objectives

To report on and examine differences in the use of four types of rehabilitation services (occupational therapy, physiotherapy, psychology, and speech therapy) by men and women following a work-related traumatic brain injury in Victoria, Australia; and to examine the importance of demographic, need, work-related and geographic factors in explaining these differences.

Methods

A retrospective cohort design was used to analyze 1786 work-related traumatic brain injury workers’ compensation claims lodged between 2004 and 2012 in Victoria, Australia. ZINB regressions were conducted for each type of rehabilitation service to examine the relationship between sex and rehabilitation use. Covariates included demographic, need-related, work-related, and geographic factors.

Results

Out of all claims (63% male, 37% female), 13% used occupational therapy, 23% used physiotherapy, 9% used psychology, and 2% used speech therapy at least once during the first year of service utilization. After controlling for demographic, need-related, work-related, and geographic factors, women were more likely to use physiotherapy compared to men. Men and women were equally likely to use occupational therapy and psychology services. The number of visits in the first year for each type of service did not differ between male and female users.

Conclusions

Our findings support a sex-based approach to studying rehabilitation utilization in work-related populations. Future research is needed to examine other factors associated with rehabilitation utilization and to determine the implications of different rehabilitation utilization patterns on health and return-to-work outcomes.