Immune Checkpoint Inhibitor-Induced Adrenalitis and Primary Adrenal Insufficiency: Systematic Review and Optimal Management

ObjectiveImmune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 or programmed death 1 and its ligand (programmed death ligand 1) have been approved for the treatment of a variety of cancers. However, ICI therapy is associated with a risk of immune-related adverse events. In this study, we reviewed reported cases of adrenalitis and primary adrenal insufficiency (PAI)—rare but lethal endocrine immune-related adverse events—in patients who underwent ICI therapy.MethodsWe searched multiple databases (PubMed, Web of Science, Cochrane, and Scopus) up to February 2020 for case reports on adrenalitis and PAI caused by ICIs.ResultsWe identified 15 case reports on ICI-induced adrenalitis and PAI and reviewed their clinical presentation, characteristics, immunologic and imaging features, and treatment. We also developed a screening strategy for PAI in patients treated with ICIs.ConclusionGiven the morbidity and mortality associated with acute adrenal crisis, physicians—especially endocrinologists and oncologists—should be aware of this particular risk. PAI caused by autoimmune adrenalitis predominantly occurs in patients treated with programmed death 1 inhibitor monotherapy. PAI often coexists with other endocrinopathies and requires mineralocorticoid as well as glucocorticoid replacement. Even after withdrawal of ICIs, PAI can persist and requires lifelong replacement therapy.     

Testosterone Levels and Androgen Receptor Gene Polymorphism Predict Specific Symptoms of Depression in Young Men

BackgroundTestosterone (T) has been hypothesized to modulate the expression of depressive symptoms in men; however, support for this proposition is mixed.ObjectiveTo investigate bioavailable T, measured from saliva, and androgen receptor gene (AR) polymorphism (the number of glutamine [CAG] repeats in exon 1 of AR) and their relation to discrete symptoms of depression in 150 men aged 17 to 27 years who varied in mood status from depressed to nondepressed.MethodsParticipants completed the Center for Epidemiologic Studies Depression Scale and the Patient Health Questionnaire-9. Principal components analysis of the scales identified 5 factors: Negative Affect, Social/Evaluative, Cognitive, Sleep, and Appetite.ResultsAcross the sample as a whole, higher ratings on sleep symptoms of depression were predicted by lower T concentrations and shorter CAG lengths. The association between T, CAG length, and sleep symptoms was confirmed among the subgroup of men who reported moderate to severe depression. In this subgroup, CAG repeats and T concentrations also emerged as significant predictors of negative affect scores, with the number of CAG repeats making the primary contribution.ConclusionsThese findings suggest that androgens may influence specific symptoms of depression in men.     

Interpersonal stress and style as predictors of biofeedback/relaxation training outcome: Preliminary findings

Although the data base describing clinical outcome following biofeedback/relaxation training is accumulating, there have been relatively few attempts to predict short-term outcome, and even fewer for long-term outcome. Significant short-term outcome predictors have been identified, and they often allude to the level of psychological distress as a major factor affecting outcome. To investigate further the role of psychological variables in outcome prediction, this project presents preliminary findings that demonstrate the relationship involving interpersonal psychological stress, interpersonal style of behavior, and outcome. With a very heterogenous group of patients (N=39), measures of interpersonal style of behavior were used to discriminate correctly 80% of cases by outcome at the 3-month postadmission evaluation. With a more homogeneous group having somatic disorders alone (headache, Raynaud's, etc.), the accuracy of prediction at 3 months was 90%. No measures were capable of predicting long-term outcome with accuracies even moderately greater than chance. The results indicate that style of interpersonal behavior (e.g., managerial, dependent) and, to a lesser extent, interpersonal stress is predictive of short-term outcome following biofeedback/relaxation training. Individuals who tend to like responsibility and who are more executive and independent generally benefited more than doubtful, obedient, and depressed individuals. While the resulting prediction rates were only slightly more accurate than MMPI D and Pt subscales alone, the procedures provide additional information regarding the personality characteristics of successful and unsuccessful biofeedback clients, and may also provide the clinician with information regarding treatment choice if biofeedback is provided as an adjunct to psychotherapy.     

Interpersonal stress and style as predictors of biofeedback/relaxation training outcome: preliminary findings

Although the data base describing clinical outcome following biofeedback/relaxation training is accumulating, there have been relatively few attempts to predict short-term outcome, and even fewer for long-term outcome. Significant short-term outcome predictors have been identified, and they often allude to the level of psychological distress as a major factor affecting outcome. To investigate further the role of psychological variables in outcome prediction, this project presents preliminary findings that demonstrate the relationship involving interpersonal psychological stress, interpersonal style of behavior, and outcome. With a very heterogeneous group of patients (N = 39), measures of interpersonal style of behavior were used to discriminate correctly 80% of cases by outcome at the 3-month postadmission evaluation. With a more homogeneous group having somatic disorders alone (headache, Raynaud's, etc.), the accuracy of prediction at 3 months was 90%. No measures were capable of predicting long-term outcome with accuracies even moderately greater than chance. The results indicate that style of interpersonal behavior (e.g., managerial, dependent) and, to a lesser extent, interpersonal stress is predictive of short-term outcome following biofeedback/relaxation training. Individuals who tend to like responsibility and who are more executive and independent generally benefited more than doubtful, obedient, and depressed individuals. While the resulting prediction rates were only slightly more accurate than MMPI D and Pt subscales alone, the procedures provide additional information regarding the personality characteristics of successful and unsuccessful biofeedback clients, and may also provide the clinician with information regarding treatment choice if biofeedback is provided as an adjunct to psychotherapy.     

Comparing Bona Fide Psychotherapies of Depression in Adults with Two Meta-Analytical Approaches

Objective

Despite numerous investigations, the question whether all bona fide treatments of depression are equally efficacious in adults has not been sufficiently answered.

Method

We applied two different meta-analytical techniques (conventional meta-analysis and mixed treatment comparisons). Overall, 53 studies with 3,965 patients, which directly compared two or more bona fide psychotherapies in a randomized trial, were included. Meta-analyses were conducted regarding five different types of outcome measures. Additionally, the influence of possible moderators was examined.

Results

Direct comparisons of cognitive behavior therapy, behavior activation therapy, psychodynamic therapy, interpersonal therapy, and supportive therapies versus all other respective treatments indicated that at the end of treatment all treatments but supportive therapies were equally efficacious whereas there was some evidence that supportive therapies were somewhat less efficacious than all other treatments according to patient self-ratings and clinical significance. At follow-up no significant differences were present. Age, gender, comorbid mental disorders, and length of therapy session were found to moderate efficacy. Cognitive behavior therapy was superior in studies where therapy sessions lasted 90 minutes or longer, behavior activation therapy was more efficacious when therapy sessions lasted less than 90 minutes. Mixed treatment comparisons indicated no statistically significant differences in treatment efficacy but some interesting trends.

Conclusions

This study suggests that there might be differential effects of bona fide psychotherapies which should be examined in detail.     

Comparison of Prognostic Genomic Predictors in Colorectal Cancer

Background

Although several prognostic genomic predictors have been identified from independent studies, it remains unclear whether these predictors are actually concordant with respect to their predictions for individual patients and which predictor performs best. We compared five prognostic genomic predictors, the V7RHS, the ColoGuideEx, the Meta163, the OncoDX, and the MDA114, in terms of predicting disease-free survival in two independent cohorts of patients with colorectal cancer.

Study Design

Using original classification algorithms, we tested the predictions of five genomic predictors for disease-free survival in two cohorts of patients with colorectal cancer (n = 229 and n = 168) and evaluated concordance of predictors in predicting outcomes for individual patients.

Results

We found that only two predictors, OncoDX and MDA114, demonstrated robust performance in identifying patients with poor prognosis in 2 independent cohorts. These two predictors also had modest but significant concordance of predicted outcome (r>0.3, P<0.001 in both cohorts).

Conclusions

Further validation of developed genomic predictors is necessary. Despite the limited number of genes shared by OncoDX and MDA114, individual-patient outcomes predicted by these two predictors were significantly concordant.     

Predictors of normotension on withdrawal of antihypertensive drugs in elderly patients: prospective study in second Australian national blood pressure study cohort

ObjectivesTo identify simple long term predictors of maintenance of normotension after withdrawal of antihypertensive drugs in elderly patients in general practice.DesignProspective cohort study.Setting169 general practices in Victoria, Australia.Participants503 patients aged 65-84 with treated hypertension who were withdrawn from all antihypertensive drugs and remained drug free and normotensive for an initial two week period; all were followed for a further 12 months.ResultsThe likelihood of remaining normotensive at 12 months was greater among younger patients (65-74 years), patients with lower “on-treatment” systolic blood pressure, patients on single agent treatment, and patients with a greater waist:hip ratio. The likelihood of return to hypertension was greatest for patients with higher “on-treatment” systolic blood pressure.ConclusionsAge, blood pressure control, and the number of antihypertensive drugs are important factors in the clinical decision to withdraw drug treatment. Because of consistent rates of return to antihypertensive treatment, all patients from whom such treatment is withdrawn should be monitored indefinitely to detect a recurrence of hypertension.

What is already known on this topic

Systematic reviews have identified predictors of success of withdrawal of antihypertensive medicationThe reviewed studies have mainly been in a hospital or specialist clinic setting, and their recommendations may not be practical in general practice

What this paper adds

This study has identified simple predictors of success that are readily available to general practitionersOn-treatment systolic blood pressure, the number of blood pressure lowering drugs, and the age of the patient are reliable indicators of who may successfully stop taking their drugsGeneral practitioner practitioners should not be dissuaded from offering drug withdrawal to patients with greater waist:hip ratios     

The Role of Quality Health Services and Discussion about Birth Spacing in Postpartum Contraceptive Use in Sindh,Pakistan: A Multilevel Analysis

IntroductionRapid population growth, stagnant contraceptive prevalence, and high unmet need for family planning present significant challenges for meeting Pakistan’s national and international development goals. Although health behaviors are shaped by multiple social and environmental factors, research on contraceptive uptake in Pakistan has focused on individual and household determinants, and little attention has been given to community characteristics that may affect access to services and reproductive behavior.MethodsIndividual and community determinants of contraceptive use were identified using multivariable multilevel logistic regression to analyze data from a 2014 cross-sectional survey of 6,200 mothers in 503 communities in Sindh, Pakistan.ResultsOnly 27% of women who had given birth in the two years before the study reported using contraceptives. After adjusting for individual and community characteristics, there was no difference in the odds of contraceptive use between urban and rural women. Women who had delivered at a health facility had 1.4 times higher odds of contraceptive use than women who delivered at home. Those who received information about birth spacing from a doctor or relatives/friends had 1.81 and 1.38 times higher odds of contraceptive use, respectively, than those who did not. Living in a community where a higher proportion of women received quality antenatal care and where discussion of birth spacing was more common was significantly associated with contraceptive use. Community-wide poverty lowered contraceptive use.ConclusionsQuality of care at the community level has strong effects on contraceptive use, independent of the characteristics of individual households or women. These findings suggest that powerful gains in contraceptive use may be realized by improving the quality of antenatal care in Pakistan. Community health workers should focus on generating discussion of birth spacing in the community. Outreach efforts should target communities where the demand for contraception appears to be depressed due to high levels of poverty.     

The cortisol response to anticipated intergroup interactions predicts self-reported prejudice

Objectives

While prejudice has often been shown to be rooted in experiences of threat, the biological underpinnings of this threat–prejudice association have received less research attention. The present experiment aims to test whether activations of the hypothalamus-pituitary-adrenal (HPA) axis, due to anticipated interactions with out-group members, predict self-reported prejudice. Moreover, we explore potential moderators of this relationship (i.e., interpersonal similarity; subtle vs. blatant prejudice).

Methodology/Principal findings

Participants anticipated an interaction with an out-group member who was similar or dissimilar to the self. To index HPA activation, cortisol responses to this event were measured. Then, subtle and blatant prejudices were measured via questionnaires. Findings indicated that only when people anticipated an interaction with an out-group member who was dissimilar to the self, their cortisol response to this event significantly predicted subtle (r = .50) and blatant (r = .53) prejudice.

Conclusions

These findings indicate that prejudicial attitudes are linked to HPA-axis activity. Furthermore, when intergroup interactions are interpreted to be about individuals (and not so much about groups), experienced threat (or its biological substrate) is less likely to relate to prejudice. This conclusion is discussed in terms of recent insights from social neuroscience.     

A combination of cellular biomarkers predicts failure to respond to rituximab in rheumatoid arthritis: a 24-week observational study

BackgroundAlthough B cell depletion with rituximab (RTX) is an effective treatment strategy in rheumatoid arthritis (RA), one third of patients do not achieve remission or low disease activity (LDA). Thus, identifying patients who will benefit from RTX is highly desirable. In the present study we investigated whether lymphocyte subsets other than B cells are predictors of a clinical response to RTX treatment.MethodsPatients with RA who were receiving RTX for the first time were included in an observatory registry. Clinical assessments, complete blood count and flow cytometry of lymphocyte subsets were obtained at baseline and at week 24 after RTX. Complete data were available for 44 patients. Logistic regression and receiver operating characteristic curve analyses were computed to analyze the predictive value of lymphocyte subsets for European League Against Rheumatism (EULAR) response and LDA (defined as disease activity score in 28 joints (DAS28) ≤3.2) at week 24.ResultsEULAR responders had lower total lymphocyte counts (LC), T cells and CD4 + T cells at baseline. Although these parameters were independent predictors of EULAR response they failed in determining who would reach LDA. In contrast, LC >2910/μl or plasmablast frequency >2.85 % at baseline predicted a significantly higher DAS28 at week 24 after RTX and identified patients not achieving LDA at week 24 with sensitivity of 93.3 % and specificity of 44.8 %.ConclusionsA combination of LC and plasmablast frequency identifies patients with RA who will not benefit from RTX with high probability.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-016-1091-1) contains supplementary material, which is available to authorized users.     

Morningness-eveningness scores predict outcomes differentially for depressed patients attending morning vs. afternoon day treatment streams

ABSTRACT

At the Center for Addiction and Mental Health (CAMH) Integrated Day Treatment (IDT) program, each patient attends either a morning stream or an afternoon stream, but not both. We examined whether subjective chronotype, or the time of day an individual prefers to be most active and alert, predicted treatment outcomes differentially in depressed patients attending the morning vs. afternoon IDT streams. The Horne-Östberg Morningness-Eveningness Questionnaire (MEQ) was administered before IDT treatment to 203 consecutive patients experiencing a major depressive episode. Multiple regression was used to predict change in depression and quality of life scores based on treatment stream (morning or afternoon), baseline MEQ scores and the treatment stream by MEQ interaction. The treatment stream by MEQ interaction was a highly significant predictor of both depression and quality of life change scores. Post-hoc analyses based on established MEQ categories revealed that definite evening chronotypes had significantly better responses in the morning stream than did morning chronotypes, and significantly worse responses in the afternoon stream relative to moderate evening or neutral chronotypes. There were insufficient morning chronotypes in the afternoon stream to assess clinical responses for this subgroup. In the morning stream only, there was a significant positive correlation between the change in MEQ scores after four weeks of IDT treatment (i.e. a shift to greater morningness) and the decrease in depression scores (r = .36, p = .003), consistent with a therapeutic phase advance in circadian rhythms. In sum, these preliminary data suggest that definite evening chronotypes may have the greatest relative benefit from attending the morning vs. afternoon IDT stream. As patients currently select which IDT stream they will attend, future work based on randomized treatment assignment and using passive actigraphy to assess circadian phase is currently planned to extend these preliminary findings.     

The symptom‐specific efficacy of antidepressant medication vs. cognitive behavioral therapy in the treatment of depression: results from an individual patient data meta‐analysis

A recent individual patient data meta‐analysis showed that antidepressant medication is slightly more efficacious than cognitive behavioral therapy (CBT) in reducing overall depression severity in patients with a DSM‐defined depressive disorder. We used an update of that dataset, based on seventeen randomized clinical trials, to examine the comparative efficacy of antidepressant medication vs. CBT in more detail by focusing on individual depressive symptoms as assessed with the 17‐item Hamilton Rating Scale for Depression. Five symptoms (i.e., “depressed mood” , “feelings of guilt” , “suicidal thoughts” , “psychic anxiety” and “general somatic symptoms”) showed larger improvements in the medication compared to the CBT condition (effect sizes ranging from .13 to .16), whereas no differences were found for the twelve other symptoms. In addition, network estimation techniques revealed that all effects, except that on “depressed mood” , were direct and could not be explained by any of the other direct or indirect treatment effects. Exploratory analyses showed that information about the symptom‐specific efficacy could help in identifying those patients who, based on their pre‐treatment symptomatology, are likely to benefit more from antidepressant medication than from CBT (effect size of .30) versus those for whom both treatments are likely to be equally efficacious. Overall, our symptom‐oriented approach results in a more thorough evaluation of the efficacy of antidepressant medication over CBT and shows potential in “precision psychiatry” .     

Cross sectional study of reporting of epileptic seizures to general practitioners

ObjectiveComparison of reporting of recent epileptic seizures by patients to a doctor and anonymously.DesignCross sectional study of patients with epilepsy by comparison of paired questionnaires.SettingRural and urban general practices in Norfolk. Participants122 patients aged over 16 years and able to self complete a questionnaire who were recruited by 31 general practitioners when attending for review of their epilepsy.Results18 patients failed to report a seizure in the past year to their general practitioner (uncontrolled epilepsy). 40% (24/60) of people with epilepsy who anonymously reported a seizure in the past year held a driving licence, but only six revealed this to their general practitioner. The unemployment rate was 34%, substantially higher than the 9% in the general population. Measures of anxiety, depression, and stigmatisation were higher in patients with uncontrolled epilepsy.ConclusionsA significant proportion of patients with epilepsy underreport their seizures. Recognition of underreporting is important if patients are to benefit from adequate and appropriate treatment. General practitioners'' ability to treat epilepsy is hampered by their role in regulating the rights of epileptic patients to hold a driving licence or access certain occupations.

Key messages

• People with epilepsy may be reluctant to report seizures to their general practitioners as epilepsy affects their eligibility for a driving licence and access to various employment and leisure activities
• In this study about a sixth of patients anonymously reported seizures in the past year which they had not revealed to their general practitioner
• 40% of patients who anonymously reported a seizure in the past year held a driving licence, but only a quarter of these admitted this to their general practitioner
• People who had had seizures in the past year were significantly more depressed and felt more stigmatised than those who had not had a seizure
• Underreporting of seizures has important consequences for treatment, and doctors need to put more effort into explaining this to patients

     

Can Newer Therapies Delay the Progression of Type 2 Diabetes Mellitus?

ObjectiveTo review the multifactorial and progressive nature of type 2 diabetes mellitus (T2DM), the consequences of its progression, and the potential of traditional and newer therapies to delay the progression of this disease.MethodsThe relevant literature is reviewed, and the mechanisms of action of novel agents for treatment of T2DM are discussed.ResultsThe global prevalence of diabetes has been increasing in recent decades, reaching near-epidemic proportions, and is projected to more than double by 2030. More than 90% of cases of diabetes in most countries consist of T2DM, but many individuals remain undiagnosed or are diagnosed only after their disease has progressed considerably. Inadequate glycemic control in a majority of patients with T2DM is due to the progressive nature of the disease, delay in initiating pharmacotherapy, and failure to intensify treatment more quickly in patients who do not achieve glycemic targets. Traditional oral therapies are usually effective at lowering hyperglycemia initially but do not prevent disease progression; thus, many patients ultimately require insulin. Furthermore, because most antidiabetic therapies are associated with weight gain or risk of hypoglycemia (or both), patients may not adhere to treatment recommendations.ConclusionA new therapeutic approach focuses on the use of the incretin hormone glucagon-like peptide-1. Analogues of this hormone delay the progression of β-cell dysfunction and promote β-cell regeneration in animal models. In clinical trials, they have been shown to improve glycemic control by increasing glucose-stimulated insulin secretion and suppressing glucagon secretion. At high concentrations, they also slow gastric emptying and increase satiety, which often promotes weight loss. Another approach is to inhibit the enzyme dipeptidyl-peptidase 4, which rapidly inactivates glucagon-like peptide- 1 and glucose-dependent insulinotropic polypeptide, thereby increasing endogenous incretin levels. (Endocr Pract. 2008;14:625-638)     

Magnitude and Predictors of Anti-Retroviral Treatment (ART) Failure in Private Health Facilities in Addis Ababa,Ethiopia

BackgroundThe public health approach to antiretroviral treatment management encourages the public private partnership in resource limited countries like Ethiopia. As a result, some private health facilities are accredited to provide antiretroviral treatment free services. Evidence on magnitude and predictors of treatment failure are crucial for timely actions. However, there are few studies in this regard.ObjectiveTo assess the magnitude and predictors of ART failure in private health facilities in Addis Ababa, Ethiopia.MethodsThe study followed retrospective cohort design, with 525 adult antiretroviral treatment clients who started the treatment since October 2009 and have at least six months follow up until December 31, 2013. Kaplan Meier survival analysis and Cox proportional hazard model were used for analysis.ResultsTreatment failure, using the three WHO antiretroviral treatment failure criteria, was 19.8%. The immunologic, clinical, and virologic failures were 15%, 6.3% and 1.3% respectively. The mean and median survival times in months were 41.17 with 95% Confidence Interval (CI) [39.69, 42.64] and 49.00, 95% CI [47.71, 50.29] respectively. The multivariate cox regression analysis showed years since HIV diagnosis (Adjusted Hazard Ratio (AHR)=13.87 with 95% CI [6.65, 28.92]), disclosure (AHR=0.59, 95% CI [0.36, 0.96]), WHO stage at start (AHR=1.84, 95% CI [1.16, 2.93]), weight at baseline (AHR=0.58, 95% CI [0.38, 0.89]), and functionality status at last visit (AHR=2.57, 95% CI [1.59, 4.15]) were independent predictors of treatment failure.ConclusionThe study showed that the treatment failure is high among the study subjects. The predictors for antiretroviral treatment failure were years since HIV diagnosis, weight at start, WHO stage at start, status at last visit and disclosure.RecommendationsFacilities need to monitor antiretroviral treatment clients to avoid disease progression and drug resistance.     

Treatment of Type 2 Diabetes Mellitus With Orally Administered Agents: Advances in Combination Therapy

ObjectiveTo discuss the effects and clinical benefit provided by combining various orally administered antidiabetic drugs (OADs) for the treatment of type 2 diabetes and to examine the advantages of single-tablet combinations with respect to targeting hyperglycemia and adherence.MethodsA review of randomized controlled trials that studied OAD combinations for the treatment of type 2 diabetes was conducted by using search terms in PubMed.ResultsReported data have documented that OAD combination therapies have additional benefits over monotherapy in terms of glycemic efficacy. Results from randomized controlled trials on a range of OAD combinations have demonstrated differences in safety and efficacy. The use of single-tablet OAD combinations has been shown to improve adherence in patients.ConclusionThe development of single-tablet OAD combinations that can address all aspects of glycemia with a favorable tolerability profile has the potential to help patients manage their glycemic control more effectively and to minimize the risk of long-term diabetes-related complications. In addition, single-tablet combinations of agents offer improved convenience for patients as well as potential cost benefits. Thus, they represent an important treatment option for type 2 diabetes. (Endocr Pract. 2009;15:750-762)     

High plant taxonomic beta diversity and functional and phylogenetic convergence between two Neotropical inselbergs

ABSTRACT

Background: Inselbergs (granitic and gneissic rock outcrops) are common elements in the Atlantic Forest and present large taxonomic (TD), functional (FD) and phylogenetic (PD) diversity.

Aims: We investigated how plant diversity changed across ecological and biogeographic scales by comparing TD, FD and PD of communities within and between two inselbergs. We expected converging FD and PD but distinct TD between outcrops, because of similar local environmental conditions in inselbergs and the long-term lineage isolation.

Methods: We calculated TD, PD and FD, and partitioned diversity into α (each inselberg), β (between inselbergs) and γ (whole sample) components. Phylogenetic signal was estimated for all traits. To link environmental predictors to functional traits a redundancy analysis was run. Variation in TD, FD and PD was analysed by general linear models with patch area and the two inselbergs as predictors.

Results: The inselbergs were taxonomically different, but showed convergence in their functional and phylogenetic diversity. The limited retention of phylogenetic signal suggests that different species may converge and respond similarly to environmental variables. Within inselbergs, larger patches displayed higher TD, FD and PD.

Conclusions: Seeking conservation strategies for inselbergs is challenging since, despite their functional and phylogenetic similarity, endemic species make individual rock outcrops unique.