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To discuss the recommended best practices for germline variant calling, we will consider trio sequencing for inherited disorders, which is a common scenario for clinical genetic testing. A trio analysis pipeline typically begins with the analysis-ready BAM files for the proband and both parents (Fig. 1b). For optimal results, all three samples should be sequenced under identical protocols (capture kit, instrument, and reagent kit) and processed with identical alignment and pre-processing steps. This is particularly important for copy number variant calling and SV calling, which rely on uniform sequencing depth and library insert size, respectively.
Numerous variant callers have been published for this purpose; a list of the most cited callers can be found in Table 2. Widely used somatic mutation callers, such as MuTect2 , Strelka2 , and VarScan2 , consider aligned data from the tumor and normal simultaneously. Several groups have attempted to directly compare the performance of mutation callers for different applications [111,112,113], finding that each has strengths and weaknesses. Because no somatic caller has emerged which offers superior performance in all scenarios, an ensemble approach that combines the results of two or more complementary callers may offer the best balance of sensitivity and specificity [73, 114].
We argue that TBI, and especially mild TBI, is not a contraindication for antidepressant therapy. Proactive detection and treatment of psychiatric problems following TBI of any severity has the potential to improve not only mental health outcomes [14, 15] but also cognition [16,17,18], somatic symptoms [19, 20], and daily functioning [2, 4, 21]. We recognize that a systematic review of randomized placebo-controlled trials is the highest level of evidence, but caution clinicians against changing their practice on the basis of the Kreitzer et al.  study. Clinicians who continue to prescribe will be compliant with practice guidelines [7, 8] and the best available evidence [6, 9, 10]. Selective serotonin reuptake inhibitors (e.g., sertraline or citalopram) are generally recommended as first-line [7, 18, 22, 23]. Efficacy and tolerability of selective serotonin-epinephrine reuptake inhibitors are less well-established , but expert consensus guidelines endorse their use . Tricyclic antidepressants are thought to have a less favorable benefit-risk profile, with lowering of the seizure threshold in patients with moderate-severe TBI being a potential concern [8, 23, 24].
Similar to current discussions around prescribing guidelines , deprescribing protocols are important as a summary of the best available evidence and an outline of the different deprescribing steps. We argue that additional resources are needed to help clinicians and patients determine if deprescribing is appropriate given their context, and determine how medications can be carefully ceased or doses reduced to achieve the best health goals and outcomes desired by the patient. To achieve our aim, we have developed a conceptual framework in the form of a deprescribing rainbow (Fig. 1), outlining the clinical, psychological, social, financial and physical determinants that should be considered in conjunction with clinical deprescribing guidelines and together with the patient when deciding to undertake an episode of deprescribing to ensure the process has the best chance of success (Table 1). This framework incorporates principles of patient-centered communication and decision-making for people with multimorbidity and the concept of Minimally Disruptive Medicine [16, 28,29,30,31,32]. The rainbow analogy highlights the heterogeneity of the older population and how patient-centered deprescribing needs to acknowledge this diversity and individuality . A rainbow, which has been previously used as a model to conceptulise health , also symbolizes that deprescribing should be recognized as a positive intervention aimed at improving outcomes important to the patient, and that the relationship between these factors is fluent and may change over time. We illustrate the potential application of the deprescribing rainbow to a hypothetical patient case to highlight the importance of the five deprescribing determinants, as described below. The hypothetical case was initially developed from the clinical experience of authors AT, JJ, AM; it was then discussed informally with healthcare professionals who have responsibility for prescribing medication to older people to ensure the case was realistic and relevant to clinical practice; finally, and importantly, the case was discussed and refined with a patient and carer group, and also with co-author JC, who is a health consumer representative for this work, to ensure it was relevant and meaningful to patients and other healthcare users.
Hopewell S, Keene DJ, Heine P, et al. Progressive exercise compared with best practice advice, with or without corticosteroid injection, for rotator cuff disorders: the GRASP factorial RCT. Health Technol Assess (in press). 2b1af7f3a8