Advances in endophenotyping schizophrenia

The search for the genetic architecture of schizophrenia has employed multiple, often converging strategies. One such strategy entails the use of tracing the heritability and neurobiology of endophenotypes. Endophenotypes are quantifiable traits not visible to the eye, which are thought to reflect an intermediate place on the path from genes to disorder. Endophenotype abnormalities in domains such as neurophysiology or neurocognition occur in schizophrenia patients as well as their clinically “unaffected” relatives, and reflect polymorphisms in the DNA of schizophrenia spectrum subjects which create vulnerability to developing schizophrenia. By identifying the single nucleotide polymorphisms (SNPs) associated with endophenotypes in schizophrenia, psychiatric neuroscientists can select new strong inference based molecular targets for the treatment of schizophrenia.     

Sagittal Abdominal Diameter as a Surrogate Marker of Insulin Resistance in an Admixtured Population—Brazilian Metabolic Syndrome Study (BRAMS)

BackgroundSagittal abdominal diameter (SAD) has been proposed as a surrogate marker of insulin resistance (IR). However, the utilization of SAD requires specific validation for each ethnicity. We aimed to investigate the potential use of SAD, compared with classical anthropometrical parameters, as a surrogate marker of IR and to establish the cutoff values of SAD for screening for IR.MethodsA multicenter population survey on metabolic disorders was conducted. A race-admixtured sample of 824 adult women was assessed. The anthropometric parameters included: BMI, waist circumference (WC), waist-to-hip ratio and SAD. IR was determined by a hyperglycemic clamp and the HOMA-IR index.ResultsAfter adjustments for age and total body fat mass, SAD (r = 0.23 and r = -0.70) and BMI (r = 0.20 and r = -0.71) were strongly correlated with the IR measured by the HOMA-IR index and the clamp, respectively (p < 0.001). In the ROC analysis, the optimal cutoff for SAD in women was 21.0 cm. The women with an increased SAD presented 3.2 (CI 95%: 2.1-5.0) more likelihood of having IR, assessed by the HOMA-IR index compared with those with normal SAD (p < 0.001); whereas women with elevated BMI and WC were 2.1 (95% CI: 1.4-3.3) and 2.8 (95% CI: 1.7-4.5) more likely to have IR (p < 0.001), respectively. No statistically significant results were found for waist-to-hip ratio.ConclusionsSAD can be a suitable surrogate marker of IR. Understanding and applying routine and simplified methods is essential because IR is associated with an increased risk of obesity-related diseases even in the presence of normal weight, slight overweight, as well as in obesity. Further prospective analysis will need to verify SAD as a determinant of clinical outcomes, such as type 2 diabetes and cardiovascular events, in the Brazilian population.     

Effects of Statin Therapy on Clinical Outcomes of Survivors of Acute Myocardial Infarction with Severe Systolic Heart Failure

Objective

Large randomized trials have failed to show a beneficial effect of statin treatment in chronic HF. The investigators tried to evaluate the long-term effects of statin therapy in patients with new onset heart failure (HF) following acute myocardial infarction (AMI).

Methods

Between January 2008 and December 2011, a total of 13,616 AMI patients were enrolled in the Korea Acute Myocardial Infarction Registry (KAMIR) which was a prospective, multi-center, nationwide, web-based database of AMI in Korea. From this database, we studied 1,055 patients with AMI who had newly developed severe acute HF [left ventricular ejection fraction ≤ 40%] and were discharged alive. The patients were divided into two groups, a statin group (n = 756) and a no-statin group (n = 299). We investigated the one-year major adverse cardiovascular events (MACEs), including all-cause mortality, MI, and any revascularization of each group. We then performed a propensity-score matched analysis.

Results

In the original cohort, one-year MACEs were similar between the two groups (16.5% vs. 14.7% in the statin or no-statin groups; p = 0.47). Propensity-score matching yielded 256 pairs, and in that population we observed comparable results in terms of MACEs (18.0% vs. 12.5% in the statin or no-statin groups, p = 0.11) and mortality (5.1% vs. 3.5% in the statin or no-statin groups, p = 0.51). Cox-regression analysis revealed that statin therapy was not an independent predictor for occurrence of a MACE [Hazard ratio (HR) 1.11, 95% CI 0.79–1.57, p = 0.54] or all-cause mortality (HR 1.42, 95% CI 0.75–2.70, p = 0.28).

Conclusion

Statin therapy was not associated with a reduction in the long-term occurrence of MACEs or mortality in survivors of AMI with severe acute HF in this retrospective cohort study.     

Angiographic Lesion Complexity Score and In-Hospital Outcomes after Percutaneous Coronary Intervention

Objective

We devised a percutaneous coronary intervention (PCI) scoring system based on angiographic lesion complexity and assessed its association with in-hospital complications.

Background

Although PCI is finding increasing application in patients with coronary artery disease, lesion complexity can lead to in-hospital complications.

Methods

Data from 3692 PCI patients were scored based on lesion complexity, defined by bifurcation, chronic total occlusion, type C, and left main lesion, along with acute thrombus in the presence of ST-segment elevation myocardial infarction (1 point assigned for each variable).

Results

The patients’ mean age was 67.5 +/- 10.8 years; 79.8% were male. About half of the patients (50.3%) presented with an acute coronary syndrome, and 2218 (60.1%) underwent PCI for at least one complex lesion. The patients in the higher-risk score groups were older (p < 0.001) and had present or previous heart failure (p = 0.02 and p = 0.01, respectively). Higher-risk score groups had significantly higher in-hospital event rates for death, heart failure, and cardiogenic shock (from 0 to 4 risk score; 1.7%, 4.5%, 6.3%, 7.1%, 40%, p < 0.001); bleeding with a hemoglobin decrease of >3.0 g/dL (3.1%, 11.0%, 13.1%, 10.3%, 28.6%, p < 0.001); and postoperative myocardial infarction (1.5%, 3.1%, 3.8%, 3.8%, 10%, p = 0.004), respectively. The association with adverse outcomes persisted after adjustment for known clinical predictors (odds ratio 1.72, p < 0.001).

Conclusion

The complexity score was cumulatively associated with in-hospital mortality and complication rate and could be used for event prediction in PCI patients.     

Procalcitonin Identifies Cell Injury,Not Bacterial Infection,in Acute Liver Failure

Background

Because acute liver failure (ALF) patients share many clinical features with severe sepsis and septic shock, identifying bacterial infection clinically in ALF patients is challenging. Procalcitonin (PCT) has proven to be a useful marker in detecting bacterial infection. We sought to determine whether PCT discriminated between presence and absence of infection in patients with ALF.

Method

Retrospective analysis of data and samples of 115 ALF patients from the United States Acute Liver Failure Study Group randomly selected from 1863 patients were classified for disease severity and ALF etiology. Twenty uninfected chronic liver disease (CLD) subjects served as controls.

Results

Procalcitonin concentrations in most samples were elevated, with median values for all ALF groups near or above a 2.0 ng/mL cut-off that generally indicates severe sepsis. While PCT concentrations increased somewhat with apparent liver injury severity, there were no differences in PCT levels between the pre-defined severity groups–non-SIRS and SIRS groups with no documented infections and Severe Sepsis and Septic Shock groups with documented infections, (p = 0.169). PCT values from CLD patients differed from all ALF groups (median CLD PCT value 0.104 ng/mL, (p ≤0.001)). Subjects with acetaminophen (APAP) toxicity, many without evidence of infection, demonstrated median PCT >2.0 ng/mL, regardless of SIRS features, while some culture positive subjects had PCT values <2.0 ng/mL.

Summary/Conclusions

While PCT appears to be a robust assay for detecting bacterial infection in the general population, there was poor discrimination between ALF patients with or without bacterial infection presumably because of the massive inflammation observed. Severe hepatocyte necrosis with inflammation results in elevated PCT levels, rendering this biomarker unreliable in the ALF setting.     

Determinants for Achieving the LDL-C Target of Lipid Control for Secondary Prevention of Cardiovascular Events in Taiwan

Background

Epidemiological and clinical studies have clearly established the link between low-density lipoprotein cholesterol (LDL-C) and atherosclerosis-related cardiovascular consequences. Although it has been a common practice for physicians to prescribe lipid-lowering therapy for patients with dyslipidemia, the achievement rate is still not satisfied in Taiwan. Therefore, the determinants for achieving the LDL-C target needed to be clarified for better healthcare of the patients with dyslipidemia.

Method

This registry-type prospective observational study enrolled the patients with cardiovascular diseases (coronary artery disease (CAD) and cerebrovascular disease (CVD)) from 18 medical centers across Taiwan, and clinically followed them for five years. At every clinical visit, vital signs, clinical endpoints, adverse events, concurrent medications and laboratory specimens were obtained as thoroughly as possible. The lipid profile (total cholesterol, high-density lipoprotein cholesterol, LDL-C, triglyceride), liver enzymes, and creatinine phosphokinase were evaluated at baseline, and every year thereafter. The cross sectional observational data was analyzed for this report.

Result

Among the 3,486 registered patients, 54% had their LDL-C < 100 mg/dL. By univariate analysis, the patients achieving the LDL-C target were associated with older age, more male sex, taller height, lower blood pressure, more under lipid-lowering therapy, more smoking cessation, more history of CAD, DM, physical activity, but less history of CVD. The multivariate analysis showed statin therapy was the most significant independent determinant for achieving the treatment target, followed by age, history of CAD, diabetes, blood pressure, and sex. However, most patients were on regimens of very-low to low equipotent doses of statins.

Conclusion

Although the lipid treatment guideline adherence is improving in recent years, only 54% of the patients with cardiovascular diseases have achieved their LDL-C target in Taiwan, and the most significant determinant for this was statin therapy.     

Hi-Plex targeted sequencing is effective using DNA derived from archival dried blood spots

Many genetic epidemiology resources have collected dried blood spots (predominantly as Guthrie Cards) as an economical and efficient means of archiving sources of DNA, conferring great value to genetic screening methods that are compatible with this medium. We applied Hi-Plex to screen the breast cancer predisposition gene PALB2 in 93 Guthrie Card-derived DNA specimens previously characterized for PALB2 genetic variants via DNA derived from lymphoblastoid cell lines, whole blood, and buffy coat. Of the 93 archival Guthrie Card-derived DNAs, 92 (99%) were processed successfully and sequenced using approximately half of a MiSeq run. From these 92 DNAs, all 59 known variants were detected and no false-positive variant calls were yielded. Fully 98.13% of amplicons (5417/5520) were represented within 15-fold of the median coverage (2786 reads), and 99.98% of amplicons (5519/5520) were represented at a depth of 10 read-pairs or greater. With Hi-Plex, we show for the first time that a High-Plex amplicon-based massively parallel sequencing (MPS) system can be applied effectively to DNA prepared from dried blood spot archival specimens and, as such, can dramatically increase the scopes of both method and resource.     

Effect of older age on treatment decisions and outcomes among patients with traumatic spinal cord injury

Background:

Older people are at increased risk of traumatic spinal cord injury from falls. We evaluated the impact of older age (≥ 70 yr) on treatment decisions and outcomes.

Methods:

We identified patients with traumatic spinal cord injury for whom consent and detailed data were available from among patients recruited (2004–2013) at any of the 31 acute care and rehabilitation hospitals participating in the Rick Hansen Spinal Cord Injury Registry. Patients were assessed by age group (< 70 v. ≥ 70 yr). The primary outcome was the rate of acute surgical treatment. We used bivariate and multivariate regression models to assess patient and injury-related factors associated with receiving surgical treatment and with the timing of surgery after arrival to a participating centre.

Results:

Of the 1440 patients included in our study cohort, 167 (11.6%) were 70 years or older at the time of injury. Older patients were more likely than younger patients to be injured by falling (83.1% v. 37.4%; p < 0.001), to have a cervical injury (78.0% v. 61.6%; p = 0.001), to have less severe injuries on admission (American Spinal Injury Association Impairment Scale grade C or D: 70.5% v. 46.9%; p < 0.001), to have a longer stay in an acute care hospital (median 35 v. 28 d; p < 0.005) and to have a higher in-hospital mortality (4.2% v. 0.6%; p < 0.001). Multivariate analysis did not show that age of 70 years or more at injury was associated with a decreased likelihood of surgical treatment (adjusted odds ratio [OR] 0.48, 95% confidence interval [CI] 0.22–1.07). An unplanned sensitivity analysis with different age thresholds showed that a threshold of 65 years was associated with a decreased chance of surgical treatment (OR 0.39, 95% CI 0.19–0.80). Older patients who underwent surgical treatment had a significantly longer wait time from admission to surgery than younger patients (37 v. 19 h; p < 0.001).

Interpretation:

We found chronological age to be a factor influencing treatment decisions but not at the 70-year age threshold that we had hypothesized. Older patients waited longer for surgery and had a substantially higher in-hospital mortality despite having less severe injuries than younger patients. Further research into the link between treatment delays and outcomes among older patients could inform surgical guideline development.Globally there has been an epidemiologic shift in the age of patients who sustain a traumatic spinal cord injury.^1–3 Although most people who have traumatic spinal cord injuries are 16–30 years old, there has been a progressive increase in the number who are over 70. The average age at injury has increased from 29 to 40 years.⁴ By 2032, patients over 70 are predicted to account for most patients with new traumatic spinal cord injuries.⁵ This change is attributed in part to aging baby boomers. It is unknown whether the management and outcomes of these older patients differ compared with younger patients.Older patients typically have more comorbid conditions, including cardiovascular disease, respiratory disorders, cerebrovascular disease and dementia, which are thought to increase their risk of perioperative adverse events.⁶ The use of anticoagulants for cardiac and cerebrovascular indications can delay timely surgical interventions. Older patients are also at increased risk of postoperative and medication-related adverse events, such as delirium.⁷ As a direct consequence of this perceived risk of perioperative adverse events and ambiguity about the optimal treatment for spinal cord injury in older patients, surgeons may deliberate for some time before making a clear therapeutic decision, they may choose nonoperative treatment,⁸ or they may delay the surgical treatment in an effort to optimize the patient’s condition medically.Given the increasing incidence of traumatic spinal cord injury in older adults, and the potential for differences in treatment among older and younger patients, we evaluated the impact of age on treatment decisions and outcomes among patients with traumatic spinal cord injury. We hypothesized that surgical management would differ at an age threshold of 70 years.