Treatment Strategy With Gene Editing for Late-Onset Retinal Degeneration Caused by a Founder Variant in C1QTNF5.

Purpose: Genome editing is an emerging group of technologies with the potential to ameliorate dominant, monogenic human diseases such as late-onset retinal degeneration (L-ORD). The goal of this study was to identify disease stages and retinal locations optimal for evaluating the efficacy of a future genome editing trial. Methods: Twenty five L-ORD patients (age range, 33-77 years; median age, 59 years) harboring the founder variant S163R in C1QTNF5 were enrolled from three centers in the United Kingdom and United States. Patients were examined with widefield optical coherence tomography (OCT) and chromatic perimetry under dark-adapted and light-adapted conditions to derive phenomaps of retinal disease. Results were analyzed with a model of a shared natural history of a single delayed exponential across all subjects and all retinal locations. Results: Critical age for the initiation of photoreceptor loss ranged from 48 years at the temporal paramacular retina to 74 years at the inferior midperipheral retina. Subretinal deposits (sRET-Ds) became more prevalent as critical age was approached. Subretinal pigment epithelial deposits (sRPE-Ds) were detectable in the youngest patients showing no other structural or functional abnormalities at the retina. The sRPE-D thickness continuously increased, reaching 25 µm in the extrafoveal retina and 19 µm in the fovea at critical age. Loss of light sensitivity preceded shortening of outer segments and loss of photoreceptors by more than a decade. Conclusions: Retinal regions providing an ideal treatment window exist across all severity stages of L-ORD.

A 48-Year-Old Woman With Chronic Cough, Dyspnea, and Bronchiectasis.

CASE PRESENTATION: A 48-year-old woman sought a second opinion for dyspnea and chronic productive cough; she was a never smoker. Mild respiratory symptoms persisted since childhood and had progressively worsened over the previous decade. In addition, an unintentional 30-pound weight loss had occurred over several years. Six years previously, a diagnosis of hypersensitivity pneumonitis was made following right upper lobe wedge resection that revealed chronic bronchiolitis with interstitial pneumonia and non-necrotizing granulomatous inflammation. Subsequent use of prednisone elicited mild intermittent improvement. She had used feather pillows in the past without any other significant exposures. There were no reports of sinus or GI symptoms.

Working adeptly to diagnose and treat adult ADHD.

Rely on DSM-5 criteria and an appropriate rating scale to assess how an individual's inattention, hyperactivity, and impulsivity interfere with functioning in different settings.

Paranoid delusions • ideas of reference • sleep problems • Dx?

► Paranoid delusions ► Ideas of reference ► Sleep problems ► Multiple, vague somatic symptoms.

Cognitive behavioural therapy for the treatment of late life depression: study protocol of a multicentre, randomized, observer-blinded, controlled trial (CBTlate).

BACKGROUND: Late-life depression (LLD) is one of the most prevalent mental disorders in old age. It is associated with various adverse outcomes and frequent use of health care services thereby remaining a serious public health concern. Compared with depression in early adulthood, most treatment options of LLD are less effective. Psychotherapy may be particularly beneficial for LLD due to specific psychological conditions in old age and a low risk of side effects. Although cognitive behavioural therapy (CBT) is highly established and effective in depression in young and mid-life there is only a limited number of small studies on CBT in LLD. An LLD-specific CBT has not yet been compared to an active, but unspecific supportive psychological intervention in a multicentre trial. METHODS: Here we present the design of the CBTlate trial, which is a multicentre, randomized, observer-blinded, active-controlled, parallel group trial. CBTlate aims at including 248 patients with LLD of both genders at 7 sites in Germany. The purpose of the study is to test the hypothesis that a 15-session individually-delivered CBT specific for LLD is of superior efficacy in reducing symptoms of depression in comparison with a supportive unspecific intervention (SUI) of the same quantity. The intervention includes 8 weeks of individual treatment sessions twice per week and a follow-up period of 6 months after randomization. The primary end point is the severity of depression at the end of treatment measured by the self-rated 30-item Geriatric Depression Scale (GDS). Secondary endpoints include depressive symptoms at week 5 and at follow-up (6 months after randomization). Additional secondary endpoints include the change of depressive symptoms assessed with a clinician-rating-scale and a patient reported outcome instrument for major depressive disorder, anxiety symptoms, sleep, cognition, quality of life, and overall health status from baseline to end-of treatment and to end of follow-up. Add-on protocols include MRI and the collection of blood samples. DISCUSSION: This study is the first multicentre trial of a specific CBT intervention for LLD compared to an unspecific supportive psychological intervention administered in a specialist setting. It has important implications for developing and implementing efficient psychotherapeutic strategies for LLD and may be a significant step to broaden treatment options for people suffering from LLD. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03735576, registered on 24 October 2018); DRKS (DRKS00013769, registered on 28 June 2018).

The beneficial effects of Qigong on elderly depression.

Health Qigong, especially the Eight-Section Brocades (or Baduanjin), has been well established as an effective adjunct intervention to alleviate depressive symptoms of older adults. The easy to learn and safe format of health Qigong allows the promotion and employment by health care professionals to improve the physical and psychosocial wellness of older adults. The cultural relevance of Qigong practice enhances its popularity as a health maintenance practice in Chinese community. In general, the antidepressive effects of Qigong are put forward through psychosocial, physiological, and neurobiological mechanisms. More specific, the beneficial effects of Qigong can be further substantiated by findings of several research studies.

[Diagnosis and treatment of paranoid and schizophrenia-like psychosis in elderly patients].

Research supports theories on valid differences between early-onset schizophrenia (EOS), which persists through life, versus late-onset schizophrenia. We differentiate between schizophrenia, late-onset schizophrenia (LOS), very late-onset schizophrenia-like psychosis (VLOSLP) and paranoid psychosis in the elderly. While LOS may resemble EOS, VLOSLP may resemble neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. In this review, a treatment guideline is proposed.

Acquired erythropoietic uroporphyria secondary to myelodysplastic syndrome with chromosome 3 alterations: a case report.

Congenital erythropoietic porphyria is a rare autosomal recessive disease caused by a deficiency of uroporphyrinogen III synthase, owing to mutations in UROS in chromosome 10. Occasionally, patients show a mild, late-onset disease, without germline UROS mutations, associated with haematological malignancies. We report a 65-year-old patient with photosensitivity, overexcretion of porphyrins and thrombocytopenia. Bone marrow analysis gave a diagnosis of myelodysplastic syndrome (MDS) with the presence of a derivative chromosome 3, possibly due to an inversion including 3q21 and 3q26 break points. After allogeneic stem-cell transplantation, complete remission of MDS and uroporphyria was achieved. To our knowledge, this is the first reported case of acquired erythropoietic uroporphyria associated with MDS, with chromosome 3 alterations.

Longitudinal assessment of late-onset neurologic conditions in survivors of childhood central nervous system tumors: a Childhood Cancer Survivor Study report.

Background: Survivors of childhood central nervous system (CNS) tumors experience high rates of treatment-related neurologic sequelae. Whether survivors continue to be at increased risk for new events as they age is unknown. Methods: Adverse neurologic health conditions in 5-year survivors of CNS tumors from the Childhood Cancer Survivor Study (n = 1876) were evaluated longitudinally at a median 23.0 years from diagnosis (range, 5.1-38.9), median age at last evaluation 30.3 years (range, 6.1-56.4). Multivariable regression estimated hazard ratios (HRs) and 95% CIs. Results: From 5 to 30 years post diagnosis, cumulative incidence increased for seizures from 27% to 41%, motor impairment 21% to 35%, and hearing loss 9% to 23%. Risks were elevated compared with siblings (eg, seizures HR: 12.7; 95% CI: 9.6-16.7; motor impairment HR: 7.6; 95% CI: 5.8-9.9; hearing loss HR: 18.4; 95% CI: 13.1-25.9). Regional brain doses of radiation therapy were associated with development of new deficits (eg, frontal ≥50 Gy and motor impairment HR: 2.0; 95% CI: 1.2-3.4). Increased risk for motor impairment was also associated with tumor recurrence (HR: 2.6; 95% CI: 1.8-3.8), development of a meningioma (HR: 2.3; 95% CI: 0.9-5.4), and stroke (HR: 14.9; 95% CI: 10.4-21.4). Seizure risk was doubled by recurrence (HR: 2.3; 95% CI: 1.6-3.2), meningioma (HR: 2.6; 95% CI: 1.1-6.5), and stroke (HR: 2.0; 95% CI: 1.1-3.4). Conclusions: CNS tumor survivors remain at risk for new-onset adverse neurologic events across their lifespans at a rate greater than siblings. Cranial radiation, stroke, tumor recurrence, and development of meningioma were independently associated with late-onset adverse neurologic sequelae.

Frailty and the management of hematologic malignancies.

The majority of blood cancers occur in the elderly. This fact conspires with an aging population in many countries to make rigorous assessment for frailty increasingly important for hematologic oncologists. In this review, we first define frailty and its relevance for patients with hematologic malignancy. Next, we review current data regarding the effect of domains of frailty on outcomes for blood cancers including myelodysplastic syndromes, acute leukemia, non-Hodgkin lymphomas such as chronic lymphocytic leukemia, and multiple myeloma. Finally, after presenting assessment and treatment options for the practicing hematologist, we propose elements of a new research agenda for geriatric hematology: the exchange of age limits for rigorous frailty screening, development of disease-specific measures, and inclusion of functional and patient-reported outcomes alongside survival.

Anemia at older age: etiologies, clinical implications, and management.

Anemia is quite frequently diagnosed in older individuals and is a key indicator of various reactive and clonal conditions. Many underlying diseases, like myelodysplastic syndrome (MDS), develop preferentially in elderly individuals. The prevalence of anemia at older age is increasing, and this is mainly attributable to more frequently applied diagnostics and demographic changes in our societies. The etiology of anemia at older age is complex and ranges from bone marrow failure syndromes to chronic kidney disease, and from nutritional deficiencies to inflammatory processes including inflammaging in immunosenescence. In a smaller number of cases, no clear-cut etiology is identified. These patients are referred to as unexplained anemia or idiopathic cytopenia of unknown significance. In others, somatic mutations in leukocytes are found, but diagnostic criteria for MDS or other hematologic diseases are not fulfilled, a condition termed clonal cytopenia of undetermined significance. Management of anemias at older age depends on (1) the severity of the anemia, (2) underlying condition(s), and (3) patient-related factors, including comorbidities. Even a mild anemia may substantially affect physical and cognitive capacities and quality of life. An underestimated aspect is that because of age-related changes, organ function such as erythropoietin production in the kidney may become suboptimal. Management and treatment of anemia in older patients often require a multidisciplinary approach and detailed investigations of organ function. In this article, we review current concepts around anemias at older age, with special emphasis on etiologies, clinical implications, and innovative concepts in the management of these patients.

Predictors of treatment outcome in depression in later life: A systematic review and meta-analysis.

BACKGROUND: Predictor analyses of late-life depression can be used to identify variables associated with outcomes of treatments, and hence ways of tailoring specific treatments to patients. The aim of this review was to systematically identify, review and meta-analyse predictors of outcomes of any type of treatment for late-life depression. METHODS: Pubmed, Embase, CINAHL, Web of Science and PsycINFO were searched for studies published up to December 2016. Primary and secondary studies reported treatment predictors from randomised controlled trials of any treatment for patients with major depressive disorder aged over 60 were included. Treatment outcomes included response, remission and change in depression score. RESULTS: Sixty-seven studies met the inclusion criteria. Of 65 identified statistically significant predictors, only 7 were reported in at least 3 studies. Of these, 5 were included in meta-analyses, and only 3 were statistically significant. Most studies were rated as being of moderate to strong quality and satisfied key quality criteria for predictor analyses. LIMITATIONS: The searches were limited to randomised controlled trials and most of the included studies were secondary analyses. CONCLUSIONS: Baseline depression severity, co-morbid anxiety, executive dysfunction, current episode duration, early improvement, physical illnesses and age were reported as statistically significant predictors of treatment outcomes. Only the first three were significant in meta-analyses. Subgroup analyses showed differences in predictor effect between biological and psychosocial treatment. However, high heterogeneity and small study numbers suggest a cautious interpretation of results. These predictors were associated with various mechanisms including brain pathophysiology, perceived social support and proposed distinct types of depressive disorder. Further investigation of the clinical utility of these predictors is suggested.

Multi-Institutional Survey of Medical Treatment for Late-Onset Hypogonadism in Japan.

The adequate criteria for late-onset hypogonadism (LOH) diagnosis, including serum testosterone levels, type (total or free testosterone) and duration of androgen replacement therapy, and evaluations of treatment effectiveness remain controversial. To evaluate the current status of medical treatment for LOH in Japan, the first nationwide survey were performed. A total of 35 questionnaires answered by urologists in high-volume facilities were analyzed. The median numbers of patients with hypogonadism-related symptoms per month were 10. Aging Male Symptom Score, International Index of Erectile Function, and International Prostate Symptom Score questionnaires were widely used for questionnaires. The diagnostic criteria for LOH varied. Among the patients who presented with hypogonadism-related symptoms, the mean proportion of patients undergoing treatment for LOH was 62.3%. In Japan, LOH was treated not only with testosterone enanthate injections or testosterone ointment but also with Kampo medicine. In many facilities, LOH treatment effectiveness was assessed after a 3-month period. Efficacy was assessed in different ways. Treatment effectiveness rate ranged from 30% to 80%. The duration of LOH treatment was not fixed and was established individually by both the patient and treating physician. This study showed that the real clinical practices for LOH are very diverse, and a general consensus is needed.

Physical Exercise for Late-Life Depression: Effects on Heart Rate Variability.

OBJECTIVES: Late-life major depression is associated with increased cardiovascular risk and impaired autonomic control of the heart, as evident from reduced heart rate variability (HRV). Moreover, antidepressant drug therapy also might be associated with further reductions of HRV. In the SEEDS study, we investigated whether sertraline associated with physical exercise protocols led to improvements of HRV, compared with antidepressant drug therapy alone. DESIGN: Single-blind randomized controlled trial. SETTING: Psychiatric consultation-liaison program for primary care. PARTICIPANTS: Patients aged 65-85 years with major depression, recruited from primary care. INTERVENTIONS: Sertraline plus structured, tailored group physical exercise (S + EX) versus sertraline alone (S) for 24 weeks. MEASUREMENTS: HRV indices (RR, percentage of NN intervals greater than 50 msec [pNN50], square root of the mean squared differences of successive NN intervals [RMSSD], standard deviation of heart rate [SDHR], standard deviation of the NN interval [SDNN], high-frequency band [HF], low-frequency band [LF], and their ratio [LF/HF]) were measured at baseline, week 12, and week 24. Psychiatric and medical assessments. RESULTS: Participants displayed significant improvements of most HRV indices over time, irrespective of the group assignment (pNN50, RMSSD, SDHR, SDNN, HF, LF, and LF/HF). Moreover, patients in the S + EX group displayed greater increases of different HRV indices(RR, pNN50, RMSSD, SDHR, SDNN, HF, and LF) compared with those in the S group. CONCLUSIONS: The combination of structured physical exercise and sertraline might exert positive effects on the autonomic control of the heart among older patients with major depression.

[Late-onset depression : Pathophysiology, diagnostics and treatment]. / Altersdepression : Pathophysiologie, Diagnostik und Therapie.

Late-onset depression (LOD) is defined as depression manifesting for the first time in later life. Up to now, there has been no exact definition of the lower age limit for LOD. Psychopathological symptoms of LOD do not fundamentally differ from depression in other phases of life; however, cognitive deficits are typically more pronounced. The LOD is associated with an increased risk of developing dementia. Imaging studies show reduction in gray matter volume and white matter lesions caused by vascular diseases. The occurrence of depression with vascular lesions of the brain is also referred to as "vascular depression". The diagnostic procedure includes a detailed medical history and the observation of psychopathological changes, physical examination, laboratory tests, electroencephalograph (EEG), electrocardiograph (ECG) and magnetic resonance imaging (MRI) of the head and neuropsychological tests to measure cognitive deficits. Psychotherapy is an effective treatment option. Selective serotonin reuptake inhibitors are the first-line pharmacological therapy.

Cannabis and Neuropsychiatry, 2: The Longitudinal Risk of Psychosis as an Adverse Outcome.

Psychosis is one of the most serious among the adverse effects associated with cannabis use. The association between cannabis use and psychosis has been variously explored in a series of recent meta-analyses. The results of these meta-analyses show that persons who develop psychosis experience onset of psychosis about 2-3 years earlier if they are cannabis users; this effect is not observed with alcohol or other substance use. Higher levels of cannabis use are associated with greater risk of psychosis. Current cannabis abuse or dependence (but not past use or lower levels of current use) increases the risk of transition into psychosis in persons at ultrahigh risk of psychosis. About a third of patients with first-episode psychosis are cannabis users, and, at follow-up, about half of these users are found to continue their cannabis use. Continued cannabis use (in those who are treated after developing psychosis) is associated with higher risk of relapse into psychosis, and discontinuation of cannabis use reduces the risk of relapse to that in cannabis nonusers. Finally, persons with psychosis who continue to use cannabis have more severe positive symptoms and poorer levels of functioning. Because experimental studies in humans show that cannabinoids and cannabis can induce psychotic symptoms, it is reasonable to assume that the epidemiologic data indicate a causal effect of cannabis in anticipating, triggering, or exacerbating psychosis in vulnerable individuals and in worsening the course and outcome of the illness in those who continue to use the substance. Given the public health implications of these findings, the trend to legalize medical marijuana must be viewed with concern, and efforts are necessary to educate patients and the public about the serious mental and physical health risks associated with cannabis use and abuse.

Inspiratory Muscle Training in Late-Onset Pompe Disease: The Effects on Pulmonary Function Tests, Quality of Life, and Sleep Quality.

INTRODUCTION: Late-onset Pompe disease (LOPD) is characterized by progressive skeletal and respiratory muscle weakness. Little is known about the effect of inspiratory muscle training (IMT) on pulmonary function in subjects with LOPD. The aim of the present study was to investigate the effect of an 8-week IMT program on pulmonary function tests, quality of life, and sleep quality in eight patients with LOPD who were receiving enzyme replacement therapy (ERT). METHODS: Before and after the IMT program, spirometric measurements in sitting and supine positions, and measurements of maximum inspiratory and expiratory pressures, peak cough flow, quality of life (assessed using the Nottingham Health Profile), and sleep quality (assessed using the Pittsburgh sleep quality index) were performed. RESULTS: A significant increase in maximum inspiratory pressure (cmH2O and % predicted) (median [interquartile range]: 30.0 cmH2O [21.5-48] versus 39 cmH2O [31.2-56.5] and 38.3 % [28.1-48.4] versus 50.5 % [37.7-54.9]) was observed after training (p = 0.01). There were no significant changes in the other pulmonary function measurements. With the exception of the social isolation subscore (p = 0.02), quality of life subscores did not change after IMT (p > 0.05). Sleep quality subscores and total scores were similar before and after IMT. CONCLUSION: These results suggest that IMT has a positive effect on maximum inspiratory pressure in subjects with LOPD who are under ERT.

A Telephone-Based Program to Provide Symptom Monitoring Alone vs Symptom Monitoring Plus Care Management for Late-Life Depression and Anxiety: A Randomized Clinical Trial.

IMPORTANCE: Mental health (MH) conditions are undertreated in late life. It is important to identify treatment strategies that address variability in treatment content and delivery and take individual-specific symptoms into account, particularly among low-income, community-dwelling older adults. OBJECTIVE: To evaluate program feasibility and MH outcomes among community-dwelling older adults randomized to 1 of 2 treatment arms of varying intensity of evidence-based, collaborative MH care management services (ie, the Supporting Seniors Receiving Treatment and Intervention [SUSTAIN] program) that provide standardized, measurement-based, software-aided MH assessment and symptom monitoring and connection to community resources via telephone. DESIGN, SETTING, AND PARTICIPANTS: Trial participants were 1018 older, community-dwelling, low-income adults prescribed an antidepressant or anxiolytic by a primary care or non-MH professional and experiencing clinically significant MH symptoms at intake. The participant subsample was drawn from a larger parent sample of older adults enrolled in the SUSTAIN program. Individuals were randomized to receive MH symptom monitoring alone (hereafter monitoring alone) or MH symptom monitoring plus care management (hereafter care management) provided by an MH professional. Baseline characteristics were examined, and changes in clinical MH outcomes were evaluated at 3-month and 6-month follow-up. The study dates were August 5, 2010, to May 5, 2014. INTERVENTIONS: Monitoring alone or care management delivered by an MH professional. MAIN OUTCOMES AND MEASURES: Overall MH functioning (primary) and depressive and anxiety symptoms. RESULTS: A total of 509 participants were randomized to the monitoring alone group and 509 to the care management group; 377 and 401 completed ≥2 research assessments in the monitoring alone and case management groups, respectively. Compared with those randomized to monitoring alone, individuals randomized to care management showed greater improvements in the 3 domains of MH functioning (ß [SE], 0.36 [0.12]; 95% CI, 0.12 to 0.60; P = .004), depressive symptoms (ß [SE], -0.20 [0.06]; 95% CI, -0.32 to -0.09; P < .001), and anxiety symptoms (ß [SE], -0.23 [0.05]; 95% CI, -0.33 to -0.14; P < .001) over time. CONCLUSIONS AND RELEVANCE: The SUSTAIN program, which provides assessment, monitoring, care management, and brief therapies for MH symptoms and needs in primary care settings, is feasible and scalable. A more intense level of care (ie, symptom monitoring plus care management) is associated with more favorable individual outcomes for low-income, community-dwelling older adults experiencing clinically significant MH symptoms. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02440594.

Hoarding disorder in older adulthood.

OBJECTIVE: Hoarding disorder (HD) is a chronic condition associated with moderate to severe impairment in health and functioning. HD has been primarily studied in midlife adults, and there is limited research on HD in late life. METHODS: In this review, we summarize research on the presentation and characteristics of HD and hoarding symptoms in older adults, including evidence for associated impairment in daily functioning, physical health, and cognitive function. Finally, we review the evidence available for intervention outcomes for treating HD in older adults. RESULTS: Geriatric HD is characterized by severe functional impairment, medical and psychiatric comorbidities, and cognitive dysfunction. CONCLUSION: There is a lack of randomized controlled trials investigating evidence-based treatments for geriatric HD.