Commentary: an industry perspective on the importance of incorporating participant voice before, during, and after clinical trials.

It is increasingly recognized that involving patients and the public in the design of clinical trials can lead to better recruitment, retention, and satisfaction. A recent scoping review determined that between 1985 and 2018, just 23 articles meeting quality criteria obtained feedback from clinical trial participants after a trial had been completed. In a timespan that presumably included thousands of trials across hundreds of indications, the paucity of the literature seems surprising, if not outright disappointing. By contrast, practitioners in the life sciences industry are increasingly incorporating patient research into their trial design process before, during, and after trial completion. Examples of approaches used include recruitment of "look alike" participant samples through online communities, surveys, and the use of smartphone apps to directly record participants' spoken reactions to trial materials like recruitment materials, site visit schedules, or informed consent materials. However, commercial organizations tend not to publish their findings, leading to a potential two-tier experience for trial participants depending on whether the trial they participate in will be industry-funded or government-funded. This seems problematic on a number of levels. Increasing regulatory, funder, and publisher interest in improving the inclusivity of clinical trial participants may act as a timely lever to spur patient-centered coproduction of trials. Until continuous feedback processes are the mandated, funded, and published norm, participating in a clinical trial will be more arduous than it needs to be.

What role can decentralized trial designs play to improve rare disease studies?

People affected by rare diseases want to be involved in research and the search for new treatments. Randomized controlled trials remain the best way of finding new interventions, but many elements of traditional study design are not best suited for rare diseases. Barriers to patients and families include the use of specialist hospital sites for recruitment, requiring frequent site-based study visits for data collection, and a high burden of tests and outcome measures in research. While decentralized clinical trial (DCT) designs have been developed in some rare disease trials, changes necessitated by the COVID-19 pandemic present an opportunity for them to become a standard approach. DCT approaches have been shown to be more resilient to changes in enrolment and attrition during COVID-19 than traditional designs and offer benefits in terms of patient burden, convenience, inclusion, and data quality. Digital tools such as wearable devices and electronic clinical outcome assessments may also provide more convenient and environmentally valid measures of how a condition affects the life of an individual in their regular environment (e.g. mobility around the home versus a hospital corridor). Digital solutions have greater ability to support language localization, accessibility, and may lead to increase access to global rare disease trials. In parallel, challenges exist, such as the technical support, the digital divide, ensuring high quality data, and delivering safe trials.

Women's experiences of menopause in an online MS cohort: A case series.

BACKGROUND: Many women with multiple sclerosis (MS) are postmenopausal. Previously reported findings from an online MS cohort suggested that earlier, surgical menopause may be associated with higher patient-reported MS severity scores. OBJECTIVE: To explore experiences of menopause in a series of MS women responding to a reproductive survey from an online research platform, PatientsLikeMe (PLM). METHODS: The free-text responses from a detailed reproductive history survey deployed to PLM members were analyzed using grounded theory approach. RESULTS: Of the 208 free text responses, 127 responses related to menopause. Five themes emerged: (1) perimenopausal onset of MS symptoms, (2) overlap of MS and menopausal symptoms, (3) MS exacerbations and pseudo-exacerbations triggered by hot flashes, (4) escalation of disease course after menopause, including increasing fatigue, cognitive disturbance, and other symptoms; and (5) effect of HRT on MS symptoms. Some women reported no effects of menopause or HRT. CONCLUSION: Given an aging population and a median age of individuals currently living with MS very close to menopausal age in many cohorts, there is a pressing need to understand the impact of menopause on MS course. Qualitative responses in this study illustrated several specific themes that require quantitative testing in clinic-based cohorts.

Patients report worse MS symptoms after menopause: findings from an online cohort.

BACKGROUND: Many women with multiple sclerosis (MS) are postmenopausal, yet the impact of menopause on MS symptoms is unknown. OBJECTIVE: To investigate patient-reported impact of menopause in a large online research platform, PatientsLikeMe (PLM). METHODS: A detailed reproductive history survey was deployed to PLM members, and responses were linked to PLM׳s prospectively collected patient-reported severity score (MS Rating Scale, MSRS). The MSRS has previously shown good correlation with physician-derived EDSS scores. RESULTS: Of the 513 respondents, 55% were postmenopausal; 54% of these reported induced menopause. Median age at natural menopause was 51. Surgical menopause occurred at an earlier age (p<0.001) and was associated with more hormone replacement therapy use (p=0.02) than natural menopause. Postmenopausal status, surgical menopause, and earlier age at menopause were all associated with worse MSRS scores (p≤0.01) in regressions adjusting for age, disease type and duration. CONCLUSION: Postmenopausal patients in this study reported worse MS disease severity. Further, this study highlights a utility for online research platforms, which allow for rapid generation of hypotheses that then require validation in clinical settings.

Concordance between site of onset and limb dominance in amyotrophic lateral sclerosis.

BACKGROUND: Focality of onset of amyotrophic lateral sclerosis (ALS) is not understood. Attempts to implicate physical exercise in the aetiology of ALS have provided inconsistent results. If physical use of a limb were important in defining the site of onset, then handedness might be expected to influence the side of upper limb-onset disease and footedness likewise in lower limb-onset ALS. METHODS: ALS patients registered with an internet-based support site were invited to complete an online questionnaire concerning site of onset of symptoms and their dominant hand and foot. A binomial test of proportions was used to investigate the null hypothesis that handedness and footedness do not influence side of onset in upper and lower limb-onset ALS, respectively. RESULTS: 343 ALS patients with limb-onset disease were studied. For upper limb-onset patients, there was concordance for side of onset and handedness (64%; p<0.0006). For lower limb-onset patients, concordance for side of onset and footedness was absent. The frequency of left handedness was commensurate with that found in the general population. INTERPRETATION: These results are potentially consistent with the hypothesis that exercise influences pathogenesis in ALS since routine physical demands on the upper limb are heavily influenced by limb dominance, whereas in the lower limbs the commonest function is standing or locomotion, which uses both legs equally. However, there may also be an inherent cortical vulnerability underlying upper limb-onset laterality, possibly influenced by changes in neuronal connectivity and cortical excitability in relation to handedness and reflected by the "split hand" phenomenon consistently observed in ALS.

Prevalence of depression in amyotrophic lateral sclerosis and other motor disorders.

BACKGROUND: Research suggests the prevalence of severe depression in ALS is <20%. In contrast, studies have reported that severe depression affects 40-50% of patients with other neurodegenerative motor conditions (e.g. multiple sclerosis, Parkinson's disease and Huntington's disease). The comparison with such disorders has generated a clinical impression that patients with ALS have surprisingly low rates of depression. However, comparisons with such disorders do not take into account the markedly different pathological, physical and behavioural profiles associated with these disorders. To assess further the extent to which ALS is associated with a low prevalence of depression, we compared the prevalence of depression in patients with ALS to that in patients with neuromuscular disorders with more comparable disease profiles. METHODS: The Beck Depression Inventory-II (BDI-II), the Major Depression Inventory (MDI), the Hospital Anxiety and Depression Scale (HADS) and the ALS Functional Rating Scale-Revised were sent to 212 patients from a tertiary referral Motor Nerve Clinic in London, UK. RESULTS: Data were obtained from 51 people with ALS and 39 with other neuromuscular disorders. The non-ALS group included patients diagnosed with disorders that are characterized by motor neurone dysfunction and/or a decline in everyday function. Analyses revealed no between-group differences on severity and prevalence rates of depression according to the BDI-II, HADS Depression Subscale and MDI. CONCLUSIONS: Our findings do not support the impression that patients with ALS have lower rates of depression than patients with other varied neuromuscular disorders.

Measuring function in advanced ALS: validation of ALSFRS-EX extension items.

BACKGROUND: With the aid of assistive technology, some patients with amyotrophic lateral sclerosis (ALS) are able to live for several years past the lowest measurable level of function on the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R), a widely used end-point in ALS assessment. There is a research need to monitor patient function at the end of life, particularly in the face of severe impairment or 'locked in syndrome'. METHODS: We used an online community for people with ALS (PALS) (PatientsLikeMe) to construct and pilot a number of new items to add to the ALSFRS-R scale to improve its sensitivity at lower levels of physical function in patients with advanced ALS. RESULTS: Ten new scale items were generated by a survey of PALS with advanced disease. These were added to the existing ALSFRS-R and data were received from 326 PALS at baseline with 169 PALS (52%) completing a 1-week test-retest and 218 PALS (67%) completing a 3-month retest [corrected]. CONCLUSIONS: Three new items were selected which conformed to the existing factor structure of the ALFRS-R. These relate to the ability to use fingers to manipulate devices, ability to show emotional expression in the face, and ability to get around inside the home. Real-world validation is the next step to assess the utility of the ALFRS-EX.

SOD1 and cognitive dysfunction in familial amyotrophic lateral sclerosis.

BACKGROUND: Sporadic Amyotrophic Lateral Sclerosis (sALS) is associated with frontotemporal dementia (ALS-FTD) or milder deficits of cognitive (predominantly executive) dysfunction (ALSCi) in some patients. Some forms of familial ALS (FALS) have a family history of FTD, ALS-FTD, or both, but there have been few reports of ALS-FTD in FALS patients with mutations of the gene superoxide dismutase-1 (SOD1 FALS). The aim of this study was to test the hypothesis that ALSCi may be found in non-SOD1 FALS, but that SOD1 FALS patients would show little or no evidence of cognitive change. METHODS: A neuropsychological test battery was administered to 41 SALS patients, 35 control participants, 7 FALS patients with a SOD1 mutation (SOD1 FALS) and 10 FALS patients without a SOD1 mutation (non-SOD1 FALS). RESULTS: Relative to control participants, non-SOD1 FALS patients had impaired performance on written verbal fluency and confrontation naming, and reported higher levels of executive behavioural problems. These deficits were absent in SOD1 FALS patients. SALS patients performed poorer than controls only on the Graded Naming Test. All ALS groups had higher levels of behavioural apathy and emotional lability than were found in control participants. Cognitive domains of memory, receptive language, and visuospatial perception were spared. Groups were matched for age, gender, premorbid full-scale IQ, anxiety and depression. DISCUSSION: Individuals with SOD1 gene mutations are less likely to have significant cognitive changes compared to non-SOD1 FALS patients. Cognitive abnormalities in ALS are heterogeneous and may reflect underlying genetic variations rather than a simple spectrum of extra-motor involvement.

ALS patients request more information about cognitive symptoms.

BACKGROUND AND PURPOSE: Once thought to impact only voluntary motor function, ALS/Motor neuron disease (MND) is now seen as a multi-system disorder in which a minority of patients experience mild cognitive dysfunction or frontotemporal dementia. Despite clinical guidelines advocating supplying complete information to patients, educational materials on ALS often state that the mind is unaffected. We sought to establish how much patients and caregivers understand about ALS, what they have been told to expect by their physician, and if they would have appreciated more complete information. METHODS: A two-part survey was administered online. An 'ALS quiz' gauged participants' knowledge of physical and psychological aspects of ALS. A second questionnaire assessed which symptoms patients had discussed with their clinician and explored patients' desire to receive information on psychological effects. RESULTS: A total of 247 ALS patients and 87 caregivers participated. Participants knew less about psychological symptoms than physical ones (72% correct responses versus 82%; paired t((333)) = -5.04, P < 0.001). Patients commonly reported being told by their doctor about physical symptoms such as problems walking (85%) or stiffness/cramps (74%) but not psychological issues like emotional lability (46%) or cognitive change (11%). The majority of patients (62%) and carers (71%) indicated a desire to be informed that cognitive change or dementia might occur. CONCLUSION: ALS is a multi-system disorder. However, despite a desire for more information from patients and their carers, healthcare professionals continue to primarily address only the physical consequences of the disease.

Prevalence of depression in a 12-month consecutive sample of patients with ALS.

There is an impression both in clinical practice and in research literature that patients with amyotrophic lateral sclerosis (ALS) possess 'heroic stoicism with a low frequency of depression'. Reliance on specific interview methods may have contributed to differing estimates of mood disorder in people with ALS. The objective of the current study was to compare prevalence rates of depression and anxiety in ALS using different assessment tools. The Beck Depression Inventory (BDI), The Hospital Anxiety and Depression Scale (HADS) and the Spielberger State-Trait Anxiety Inventory (STAI) were sent to a 12-month consecutive sample of 190 patients with ALS attending a tertiary referral clinic in the UK. Data were collected from 104 patients with ALS. Using BDI scores, 44% were categorized as not depressed, 37% were mild-moderately depressed, 13% were moderately-severely depressed, and 6% were severely depressed. In contrast, the HADS depression subscale identified 75% as not depressed, 13% were in the borderline range, and 13% were categorized as meeting 'caseness' for depression. Twenty-five percent of the patients were using antidepressant medication. The estimated prevalence of mood disorder amongst patients with ALS may vary significantly depending on the measure used.

Contact area inside the distal radioulnar joint: effect of axial loading and position of the forearm.

BACKGROUND: A biomechanical study was performed to define the normal profiles of contact area inside the distal radioulnar joint and how these profiles change as a result of damage to the distal radioulnar ligaments. METHODS: Twelve cadaver arms were used and a custom-made jig was designed to allow axial loading of the hand. Tekscan sensor film was used to measure the contact area inside the joint. Measurements were taken with different loads and in different positions of the forearm. The same measurements were taken after dividing either the volar or dorsal distal radioulnar ligament. Finally the measurements were repeated after reconstruction of the divided ligament. FINDINGS: The contact area increases with axial loading of the hand and is greater in supination than pronation. Division of a single distal radioulnar ligament increases the contact area inside the distal radioulnar joint (123% of normal) and reconstruction of the divided distal radioulnar ligament restores the contact patterns towards the normal values (113% of normal). INTERPRETATION: The results show that axial loading of the hand and position of the forearm has a significant effect on the contact area inside the distal radioulnar joint. The study also shows that injury of the distal radioulnar ligament disturbs the normal profiles of contact.

Outcome in the real-world of coronary high-risk intervention with drug-eluting stents (ORCHID) -- a single-center study comparing Cypher sirolimus-eluting with Taxus paclitaxel-eluting stents.

OBJECTIVE: We present real world experience from a single center registry comparing the 6-month outcome of percutaneous coronary intervention (PCI) in unselected high-risk individuals using either sirolimus-eluting (SES) or paclitaxel-eluting stents (PES). METHODS/RESULTS: We compared clinical outcome at 6 months follow-up in two cohorts of 156 consecutive patients (total n = 312) who underwent SES (June 2002-February 2003) and PES (march 2003-July 2003) implantation. The primary endpoint was a composite of major adverse cardiac events (MACE). Baseline clinical characteristics were well matched. The 6-month target vessel revascularization (TVR) rates were 1.9% (SES) and 2.6% (PES) and MACE rates were similar in the two groups (SES 4.5% vs. PES 3.2%, P = NS). In the PES group, intervention for multivessel disease, bifurcation lesions and in small vessels was more common, and for in-stent restenosis less common, reflecting the impact of drug eluting stents on indications for PCI. The incidence of sub-acute stent thrombosis, related to inadequate antiplatelet therapy in 3 of the 6 cases, was 0.95% with no difference between the two groups. CONCLUSION: This study confirms the safety and efficacy of SES and PES in unselected high risk patients undergoing PCI. Clinical outcomes of both stents are equivalent at 6 months with low rates of MACE and TVR. These data provide important complementary information to forthcoming randomized studies.

The load-bearing characteristics of the forearm: pattern of axial and bending force transmitted through ulna and radius.

A biomechanical study was performed on 12 cadaveric arms to define the normal profiles of force transmission through the ulna and radius and demonstrate the effect on these of simulated injury of the distal radioulnar joint (DRUJ). Strain gauges were used to measure the axial and bending forces transmitted through each bone. Axial force transmitted through the ulna is, broadly, reciprocal to that seen in the radius, with the greatest force seen in supination. In all 12 arms, axial loading of the hand created an anterior bending force (to create a posterior convexity) in the distal radius. Axial loading of the hand created an anterior bending force in the distal ulna for half the specimens and a posterior bending force in the remaining half. Division and division with reconstruction of either the volar or the dorsal distal radioulnar ligament (DRUL) had no significant effect on force transmission through the ulna and radius, while excision of the ulnar head significantly disrupted the profiles of the axial and bending forces.

Changes in memory for emotional material in amyotrophic lateral sclerosis (ALS).

The current study sought to examine the performance of non-demented ALS patients on neuropsychological tests involving emotional perception and memory. Nineteen non-demented patients with ALS were compared with 20 healthy controls on assessments of facial expression recognition, social judgement ratings of faces and recognition memory for emotional words. Patients and controls were well matched to exclude a range of potentially confounding variables. The patients and controls demonstrated significant differences on only one test of cognitive functioning. The ALS group demonstrated a failure to show the normative pattern of enhanced recognition memory for emotional words compared to neutral words and produced higher scores than controls on recognition memory for neutral words. These findings suggest that patients with ALS show a different pattern of cognitive performance with respect to memory for emotional material when compared to healthy adults.

T594M and G442V polymorphisms of the sodium channel beta subunit and hypertension in a black population.

Polymorphisms of the epithelial sodium channel may raise blood pressure by increasing renal sodium reabsorption. This study examines frequency distributions and associations with hypertension of the T594M and of the G442V polymorphisms of the beta subunit of the epithelial sodium channel in a population-based sample. We studied a stratified random sample of 459 subjects (279 women), aged 40-59 years, of black African origin from general practices' lists within a defined area of South London. All were first generation immigrants. The polymorphic variants were detected using single strand conformational polymorphism technique (SSCP). The prevalence of hypertension (BP > or =160 and/or 95 mm Hg or on drug therapy) was 43%; of these, 76% were on drug therapy. The main analysis was carried out by three ordered blood pressure categories (I to III) according to increasing blood pressure and presence or absence of drug therapy. The frequency of the 594M variant (heterozygotes and homozygotes) was 4.6%; the frequency of the 442V variant was higher (27.0%). The frequency of the 594M variant increased with increasing blood pressure category (P = 0.05) and was more common in hypertensives than normotensives. By contrast the frequency of the 442V variant did not vary across increasing blood pressure categories (P = 0.62). No gender difference was observed. Adjustment for age, sex and body mass index did not alter these findings. These results suggest that the 594M variant may contribute to high blood pressure in black people of African origin whereas the G442V polymorphism is unlikely to influence blood pressure in this population.