Roche (Ireland)

This multiauthor review article aims to bring readers up to date with some of the current trends in the field of process analytical technology (PAT) by summarizing each aspect of the subject (sensor development, PAT based process monitoring and control methods) and presenting applications both in industrial laboratories and in manufacture e.g. at GSK, AstraZeneca and Roche. Furthermore, the paper discusses the PAT paradigm from the regulatory science perspective. Given the multidisciplinary nature of PAT, such an endeavour would be almost impossible for a single author, so the concept of a multiauthor review was born. Each section of the multiauthor review has been written by a single expert or group of experts with the aim to report on its own research results. This paper also serves as a comprehensive source of information on PAT topics for the novice reader.

Importance: Faricimab neutralizes angiopoietin-2 and vascular endothelial growth factor A via both simultaneous and independent binding. Objective: To evaluate extended dosing with faricimab, the first bispecific antibody designed for intraocular use, in patients with neovascular age-related macular degeneration. Design, Setting, and Participants: This phase 2 randomized clinical trial was a 52-week multicenter, active comparator-controlled, parallel-group study. Study participants were enrolled in 25 sites in the US from January and March 2017 with treatment-naive choroidal neovascularization secondary to neovascular age-related macular degeneration and best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter score of 73 (approximate Snellen equivalent, 20/40) to 24 (approximate Snellen equivalent, 20/320). Analysis began January 2017 and ended March 2018. Interventions: Participants were randomized 1:2:2 to receive intravitreal ranibizumab, 0.5 mg, every 4 weeks or faricimab, 6.0 mg, every 12 or 16 weeks. Participants in the faricimab arms initially received 4 monthly injections of faricimab. No rescue injections were allowed. Participants randomized to dosing every 16 weeks were assessed for disease activity at week 24 using prespecified criteria. Those with no active disease continued dosing every 16 weeks through trial end; participants with disease activity continued received dosing every 12 weeks. Main Outcomes and Measures: Mean change in BCVA from baseline at week 40. Results: Of 76 participants enrolled (mean [SD] age, 78.5 [8.5] years; age range, 56-94 years; 41 women [58%]; 69 white [97%]), 16 (21.0%) were randomized to ranibizumab every 4 weeks, 29 (38.2%) to faricimab every 12 weeks, and 31 (40.8%) to faricimab every 16 weeks. At week 24, 12 weeks after their last initiation injection, 65% (36 of 55) of all faricimab-treated participants had no disease activity. At week 40, adjusted mean BCVA gains from baseline (Early Treatment Diabetic Retinopathy Study letters) were +11.4 (80% CI, 7.8-15.0), +9.3 (80% CI, 6.4-12.3), and +12.5 (80% CI, 9.9-15.1) for the ranibizumab every 4 weeks, faricimab every 12 weeks, and faricimab every 16 weeks arms, respectively. Participants received a mean (SD) total of 12.9 (0.25), 6.7 (0.91), and 6.2 (0.93) injections, for the ranibizumab every 4 weeks, faricimab every 12 weeks, and faricimab every 16 weeks arms, respectively, through week 52. The secondary BCVA and anatomical imaging end points supported the primary end point and were comparable with ranibizumab every 4 weeks. No new or unexpected safety signals were identified. Conclusions and Relevance: At week 52, faricimab dosing every 16 weeks and every 12 weeks resulted in maintenance of initial vision and anatomic improvements comparable with monthly ranibizumab. These results suggest a role for simultaneous neutralization of angiopoietin-2 and vascular endothelial growth factor A in providing sustained efficacy through extended durability, warranting further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT03038880.

ADVERTISEMENT RETURN TO ISSUEPREVReviewSulfamic Acid and Its N- and O-Substituted DerivativesWilliam Spillane* and Jean-Baptiste MalaubierView Author Information School of Chemistry, National University of Ireland, Galway, University Road, Galway, Ireland Manufacturing Science and Technology, Roche Ireland Limited, Clarecastle, Co. Clare, Ireland*E-mail: [email protected]. Phone: +353 91492475.Cite this: Chem. Rev. 2014, 114, 4, 2507–2586Publication Date (Web):December 17, 2013Publication History Received29 April 2013Published online17 December 2013Published inissue 26 February 2014https://pubs.acs.org/doi/10.1021/cr400230chttps://doi.org/10.1021/cr400230creview-articleACS PublicationsCopyright © 2013 American Chemical SocietyRequest reuse permissionsArticle Views7765Altmetric-Citations92LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Anions,Catalysts,Inhibitors,Organic compounds,Reaction products Get e-Alerts

PurposeTo describe the design and rationale of the phase 3 TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) trials that aimed to assess efficacy, safety, and durability of faricimab, the first bispecific antibody for intraocular use, which independently binds and neutralizes both angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A) versus aflibercept in patients with neovascular age-related macular degeneration (nAMD).DesignIdentical, global, double-masked, randomized, controlled, phase 3 clinical trials.ParticipantsAdults with treatment-naïve nAMD.MethodsThese trials were designed to evaluate patients randomized to receive faricimab 6.0 mg up to every 16 weeks after 4 initial every-4-week doses or aflibercept 2.0 mg every 8 weeks after 3 initial every-4-week doses. The initial doses in the faricimab arm were followed by individualized fixed treatment intervals up to week 60, based on disease activity assessment at weeks 20 and 24, guided by central subfield thickness, best-corrected visual acuity (BCVA), and investigator assessment. The primary efficacy end point was BCVA change from baseline averaged over weeks 40, 44, and 48. Secondary end points included the proportion of patients receiving every-8-week, every-12-week, and every-16-week faricimab and anatomic outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. From week 60, faricimab-treated patients followed a personalized treatment interval (PTI), a novel protocol-driven treat-and-extend regimen with interval adjustment from every 8 weeks to every 16 weeks based on individualized treatment response measured by anatomic criteria, functional criteria, and investigator assessment of patients’ disease activity.Main Outcome MeasuresRationale for trial design and PTI approach.ResultsThe TENAYA and LUCERNE trials were the first registrational trials in nAMD to test fixed dosing regimens up to every 16 weeks based on patients' disease activity in year 1 and incorporate a PTI paradigm during year 2. The PTI approach was designed to tailor treatment intervals to individual patient needs, to reflect clinical practice treatment practice, and to reduce treatment burden.ConclusionsThe innovative trial design rationale for the TENAYA and LUCERNE trials included maximizing the benefits of angiopoietin-2 blockade through dosing up to every 16 weeks and PTI regimens based on patients' disease activity while fulfilling health authority requirements for potential registrational efforts. To describe the design and rationale of the phase 3 TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) trials that aimed to assess efficacy, safety, and durability of faricimab, the first bispecific antibody for intraocular use, which independently binds and neutralizes both angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A) versus aflibercept in patients with neovascular age-related macular degeneration (nAMD). Identical, global, double-masked, randomized, controlled, phase 3 clinical trials. Adults with treatment-naïve nAMD. These trials were designed to evaluate patients randomized to receive faricimab 6.0 mg up to every 16 weeks after 4 initial every-4-week doses or aflibercept 2.0 mg every 8 weeks after 3 initial every-4-week doses. The initial doses in the faricimab arm were followed by individualized fixed treatment intervals up to week 60, based on disease activity assessment at weeks 20 and 24, guided by central subfield thickness, best-corrected visual acuity (BCVA), and investigator assessment. The primary efficacy end point was BCVA change from baseline averaged over weeks 40, 44, and 48. Secondary end points included the proportion of patients receiving every-8-week, every-12-week, and every-16-week faricimab and anatomic outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. From week 60, faricimab-treated patients followed a personalized treatment interval (PTI), a novel protocol-driven treat-and-extend regimen with interval adjustment from every 8 weeks to every 16 weeks based on individualized treatment response measured by anatomic criteria, functional criteria, and investigator assessment of patients’ disease activity. Rationale for trial design and PTI approach. The TENAYA and LUCERNE trials were the first registrational trials in nAMD to test fixed dosing regimens up to every 16 weeks based on patients' disease activity in year 1 and incorporate a PTI paradigm during year 2. The PTI approach was designed to tailor treatment intervals to individual patient needs, to reflect clinical practice treatment practice, and to reduce treatment burden. The innovative trial design rationale for the TENAYA and LUCERNE trials included maximizing the benefits of angiopoietin-2 blockade through dosing up to every 16 weeks and PTI regimens based on patients' disease activity while fulfilling health authority requirements for potential registrational efforts.

PurposeFaricimab is a novel anti–angiopoietin-2 and anti–vascular endothelial growth factor (VEGF) bispecific antibody with high affinities and specificities for both VEGF and angiopoietin-2. It is postulated that targeting angiogenic factors and inflammatory pathways in addition to the VEGF pathway will increase treatment durability and improve outcomes. The phase 3 YOSEMITE (ClinicalTrials.gov identifier, NCT03622580) and RHINE (ClinicalTrials.gov identifier, NCT03622593) trials are designed to assess efficacy, safety, and durability of faricimab compared with aflibercept in patients with diabetic macular edema (DME). The trials evaluate a personalized treatment interval (PTI) approach to address heterogeneity in treatment response among patients with DME.DesignTwo identically designed, global, double-masked, randomized, controlled phase 3 trials (YOSEMITE and RHINE).ParticipantsAdults with center-involving DME secondary to type 1 or 2 diabetes mellitus.MethodsThese studies were designed to evaluate 3 treatment groups: faricimab 6.0 mg dosed either at fixed dosing every 8 weeks after initial treatment with 6 intravitreal doses at 4-week intervals, or faricimab 6.0 mg dosed according to PTI after initial treatment with 4 every-4-week doses, compared with aflibercept 2.0 mg dosed every 8 weeks after 5 initial every-4-week doses. The primary end point of the studies was change from baseline in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Secondary end points included anatomic, durability, and patient-reported outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. The PTI is a protocol-defined flexible regimen based on the treat-and-extend concept, which allowed up to every-16-week adjustable dosing based on objective and standardized criteria. The PTI design aimed to maximize therapeutic results while minimizing treatment burden.Main Outcome MeasuresWe describe the rationale for the study design and the novel PTI (up to every-16-week adjustable dosing) approach for treatment with faricimab.ResultsYOSEMITE and RHINE enrolled 940 and 951 patients, respectively. Results from each study will be reported separately.ConclusionsYOSEMITE and RHINE were the first registrational trials in retinal disease to incorporate an objective PTI regimen, allowing for up to every-16-week adjustable dosing with a dual angiopoietin-2 and VEGF-A inhibitor, faricimab 6.0 mg, for treatment of DME. Faricimab is a novel anti–angiopoietin-2 and anti–vascular endothelial growth factor (VEGF) bispecific antibody with high affinities and specificities for both VEGF and angiopoietin-2. It is postulated that targeting angiogenic factors and inflammatory pathways in addition to the VEGF pathway will increase treatment durability and improve outcomes. The phase 3 YOSEMITE (ClinicalTrials.gov identifier, NCT03622580) and RHINE (ClinicalTrials.gov identifier, NCT03622593) trials are designed to assess efficacy, safety, and durability of faricimab compared with aflibercept in patients with diabetic macular edema (DME). The trials evaluate a personalized treatment interval (PTI) approach to address heterogeneity in treatment response among patients with DME. Two identically designed, global, double-masked, randomized, controlled phase 3 trials (YOSEMITE and RHINE). Adults with center-involving DME secondary to type 1 or 2 diabetes mellitus. These studies were designed to evaluate 3 treatment groups: faricimab 6.0 mg dosed either at fixed dosing every 8 weeks after initial treatment with 6 intravitreal doses at 4-week intervals, or faricimab 6.0 mg dosed according to PTI after initial treatment with 4 every-4-week doses, compared with aflibercept 2.0 mg dosed every 8 weeks after 5 initial every-4-week doses. The primary end point of the studies was change from baseline in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Secondary end points included anatomic, durability, and patient-reported outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. The PTI is a protocol-defined flexible regimen based on the treat-and-extend concept, which allowed up to every-16-week adjustable dosing based on objective and standardized criteria. The PTI design aimed to maximize therapeutic results while minimizing treatment burden. We describe the rationale for the study design and the novel PTI (up to every-16-week adjustable dosing) approach for treatment with faricimab. YOSEMITE and RHINE enrolled 940 and 951 patients, respectively. Results from each study will be reported separately. YOSEMITE and RHINE were the first registrational trials in retinal disease to incorporate an objective PTI regimen, allowing for up to every-16-week adjustable dosing with a dual angiopoietin-2 and VEGF-A inhibitor, faricimab 6.0 mg, for treatment of DME.

) and IF irradiation (30/40 Gy). The primary endpoint was progression-free survival (PFS) 2 years from treatment start. Secondary endpoints were overall survival (OS), complete response rates, toxicity, quality of life, and minimal residual disease (MRD) response with protocol defined visits up to month 30. For the primary endpoint, PFS at 2 years was 85% for the intention-to-treat set. Long-term data were captured in selected sites and evaluated as post hoc analysis in the per protocol (PP) set: PFS and OS were 78% and 96% at 5 years with a median follow-up of 66 or 78 months, respectively. There were 17/76 recurrences in the PP set, of which 14 were outside the radiation volume only. MRD analyses revealed a clonal marker in 36% of patients at diagnosis. All but 1 marker positive patients experienced a molecular treatment response. There were 13 serious adverse events (4 related to the therapy) during the first 30 months. IF radiotherapy combined with Rituximab is well tolerated and highly efficient with low rates of recurrence in the first years in early-stage FL. The efficacy is comparable with more aggressive therapy approaches without compromising the quality of life and maintains for an extended follow-up of more than 5 years.

PurposeDual inhibition of angiopoietin-2 and VEGF-A with faricimab (Vabysmo) offers excellent visual acuity gains with strong durability in patients with diabetic macular edema (ME) and neovascular age-related macular degeneration. The phase III BALATON/COMINO (NCT04740905/NCT04740931) trials will investigate the efficacy, safety, and durability of faricimab in patients with ME due to retinal vein occlusion (RVO).DesignTwo identically designed global, randomized, double-masked, active comparator–controlled studies.ParticipantsAnti-VEGF treatment-naive patients with branch, central, or hemiretinal RVO.MethodsPatients were randomized to 6 monthly injections of faricimab 6.0 mg or aflibercept 2.0 mg. From weeks 24 to 72, all patients received faricimab 6.0 mg administered in up to 16-week intervals using an automated treatment algorithm to generate a treat-and-extend–based personalized treatment interval dosing regimen. Personalized treatment interval adjustments were based on changes in central subfield thickness (CST) and best-corrected visual acuity (BCVA).Main Outcome MeasuresPrimary end point was noninferiority of faricimab versus aflibercept in mean change from baseline in BCVA (week 24; noninferiority margin: 4 letters). Secondary end points (weeks 0–24) were mean change from baseline in BCVA, CST, and National Eye Institute Visual Function Questionnaire 25 composite score; proportion of patients gaining or avoiding loss of ≥ 15/≥ 10/≥ 5/> 0 letters. Secondary end points (weeks 24–72) were treatment durability (week 68); continuation of weeks 0 to 24 end points. Ocular/nonocular adverse events will be assessed.ResultsIn total, 1282 patients across 22 countries were enrolled (BALATON, 553 patients, 149 centers; COMINO, 729 patients, 193 centers).ConclusionsUsing a novel automated interval algorithm, BALATON/COMINO will evaluate the efficacy and safety of faricimab for ME secondary to RVO and provide key insights into how to personalize treatment.Financial Disclosure(s)Proprietary or commercial disclosure may be found after the references. Dual inhibition of angiopoietin-2 and VEGF-A with faricimab (Vabysmo) offers excellent visual acuity gains with strong durability in patients with diabetic macular edema (ME) and neovascular age-related macular degeneration. The phase III BALATON/COMINO (NCT04740905/NCT04740931) trials will investigate the efficacy, safety, and durability of faricimab in patients with ME due to retinal vein occlusion (RVO). Two identically designed global, randomized, double-masked, active comparator–controlled studies. Anti-VEGF treatment-naive patients with branch, central, or hemiretinal RVO. Patients were randomized to 6 monthly injections of faricimab 6.0 mg or aflibercept 2.0 mg. From weeks 24 to 72, all patients received faricimab 6.0 mg administered in up to 16-week intervals using an automated treatment algorithm to generate a treat-and-extend–based personalized treatment interval dosing regimen. Personalized treatment interval adjustments were based on changes in central subfield thickness (CST) and best-corrected visual acuity (BCVA). Primary end point was noninferiority of faricimab versus aflibercept in mean change from baseline in BCVA (week 24; noninferiority margin: 4 letters). Secondary end points (weeks 0–24) were mean change from baseline in BCVA, CST, and National Eye Institute Visual Function Questionnaire 25 composite score; proportion of patients gaining or avoiding loss of ≥ 15/≥ 10/≥ 5/> 0 letters. Secondary end points (weeks 24–72) were treatment durability (week 68); continuation of weeks 0 to 24 end points. Ocular/nonocular adverse events will be assessed. In total, 1282 patients across 22 countries were enrolled (BALATON, 553 patients, 149 centers; COMINO, 729 patients, 193 centers). Using a novel automated interval algorithm, BALATON/COMINO will evaluate the efficacy and safety of faricimab for ME secondary to RVO and provide key insights into how to personalize treatment.

BACKGROUND: Repeated rehearsal is one method by which verbal material may be transferred from short- to long-term memory. We hypothesised that extended engagement of memory structures through prolonged rehearsal would result in enhanced efficacy of recall and also of brain structures implicated in new learning. Twenty-four normal participants aged 55-70 (mean = 60.1) engaged in six weeks of rote learning, during which they learned 500 words per week every week (prose, poetry etc.). An extensive battery of memory tests was administered on three occasions, each six weeks apart. In addition, proton magnetic resonance spectroscopy (1H-MRS) was used to measure metabolite levels in seven voxels of interest (VOIs) (including hippocampus) before and after learning. RESULTS: Results indicate a facilitation of new learning that was evident six weeks after rote learning ceased. This facilitation occurred for verbal/episodic material only, and was mirrored by a metabolic change in left posterior hippocampus, specifically an increase in NAA/(Cr+Cho) ratio. CONCLUSION: Results suggest that repeated activation of memory structures facilitates anamnesis and may promote neuronal plasticity in the ageing brain, and that compliance is a key factor in such facilitation as the effect was confined to those who engaged fully with the training.

The use of lateral mass screws for posterior cervical fixation has become widespread. It allows for stable fixation in the absence of the posterior elements and confers immediate stability. Lateral mass fixation has been shown to impart equal or greater biomechanical stability when compared to posterior interosseous wiring or anterior plating. The utilization of intraoperative fluoroscopy to guide screw placement has been recommended previously and is considered routine practice in many centers. This prospective study shows that lateral mass screws can be safely positioned without intraoperative fluoroscopy. The procedure is both safe and effective, provided that the operator has a thorough understanding of lateral mass anatomy coupled with careful adherence to the established guidelines for screw positioning. Exposure to radiation is reduced and time taken for operation can be shortened.

Internet of Things (IoT) does not stop integrating an important number of components and objects that are characterised by their complexity and heterogeneity. Such constraints make the existing routing protocols unsuitable for IoT communications in a smart cities environment. To accomplish all the expected tasks and satisfy the user services, it is important to guarantee a quality of communication that answers to the requirements of smart cities applications in terms of data and processing. This study addresses the problem of the performance degradation of IoT communications in smart cities and proposes a new routing algorithm to improve them. The proposed algorithm is called SSRA (smart and self‐organised routing algorithm), which can select the best route for the packets. SSRA allows a self‐organising routing process according to a new situation of the network and devices parameters recently detected. When using SSRA, the communication records an improvement in performance in terms of packet delivery rate, throughput, end‐to‐end delay and overhead packets. SSRA extends also the devices lifetime by allowing fair and efficient energy consumption.

BACKGROUND: Orthopedic surgeons routinely prescribe opioids to manage post-operative pain. In the face of an opioid epidemic, a one-size-fits-all approach to pain management is no longer appropriate. Patient-centred prescribing practices should be used by surgeons; however, little is known about what influences patient attitudes toward postoperative pain and its management to inform such practices. We sought to explore patient attitudes toward postsurgical pain management, including opioids. METHODS: We conducted qualitative, semistructured interviews of 11 opioid-naive patients (age 16-46 yr) who were scheduled to undergo arthroscopic knee surgery. Transcripts were analyzed thematically using a framework analysis that involved familiarization, developing a thematic framework, indexing, charting and mapping, and interpretation. RESULTS: Participant attitudes toward postoperative pain and opioids were influenced by perceived tolerance to pain based on personal experience, perceived predisposition to addiction based on personal assumptions regarding addictive personality traits and risk factors, and perceptions of opioid use shaped by external influences, including family, friends and the media's depiction of the opioid epidemic. Every patient expressed that preoperative counselling and education regarding postoperative pain management would be beneficial in improving their knowledge base, easing anxieties and clarifying misunderstandings. CONCLUSION: Surgeons can address the patient-reported factors identified in this study to help optimize a patient's perioperative experience without relying solely on prescribed analgesia. By improving accessibility to education and promoting safe, patient-centred prescribing practices, we may reduce reliance on opioids in orthopedic surgery.

AIMS: When relying on clinical assessment alone, an estimated 22% of acute heart failure (AHF) patients are missed, so clinical guidelines recommend the use of N-terminal pro-B-type natriuretic peptide (NT-proBNP) for AHF diagnosis. Since publication of these guidelines, there has been poor uptake of NT-proBNP testing in part due to concerns over excessive false positive referrals resulting from the low specificity of a single 'rule-out' threshold of <300 pg/mL. Low specificity can be mitigated by the addition of age-specific 'rule-in' NT-proBNP thresholds. METHODS AND RESULTS: A theoretical hybrid decision tree/semi-Markov model was developed, combining global trial and audit data to evaluate the cost-effectiveness of NT-proBNP testing using age-specific rule-in/rule-out (RI/RO) thresholds, compared with NT-proBNP RO only and with clinical decision alone (CDA). Cost-effectiveness was measured as the incremental cost per quality-adjusted life year (QALY) gained and incremental net health benefit. In the base case, using UK-specific inputs, NT-proBNP RI/RO was associated with both greater QALYs and lower costs than CDA. At a willingness-to-pay threshold of £20 000/QALY, NT-proBNP RO was also cost-effective compared with CDA [incremental cost-effectiveness ratio (ICER) of £8322/QALY], but not cost-effective vs. RI/RO (ICER of £64 518/QALY). Overall, NT-proBNP RI/RO was the most cost-effective strategy. Sensitivity and scenario analyses were undertaken; the conclusions were not impacted by plausible variations in parameters, and similar conclusions were obtained for the Netherlands and Spain. CONCLUSIONS: An NT-proBNP strategy that combines an RO threshold with age-specific RI thresholds provides a cost-effective alternative to the currently recommended NT-proBNP RO only strategy, achieving greater diagnostic specificity with minimal reduction in sensitivity and thus reducing unnecessary echocardiograms and hospital admissions.

Assessment is a key component of the occupational therapy intervention process. Standardized assessments provide objectivity to this process. It is important that, in addition, these assessments reflect the client-centred philosophy of the profession. This article addresses key issues regarding the use of standardized assessments, and reports on the results of a study investigating the assessment practices of a group of Irish occupational therapists. The purpose of this article is to identify the attributes of standardized assessments and to question their place within the practice of occupational therapy. Occupational therapy philosophy stresses the importance of a client-centred approach to intervention, where the client's problems, needs and priorities are determined by the client or by the therapist in collaboration with the client or care giver. Many of the current standardized tests lack this client-centred approach. This article looks at current assessment practices among a group of Irish occupational therapists and suggests some future directions worth considering to optimize the use of standardized assessments.

PURPOSE. To examine the visual status of a cohort of older adults on an orthopedic unit to determine their level of available vision to complete everyday activities in the hospital setting. METHOD. A convenience sample of 50 people was recruited. A visual history was obtained, and participants' glasses were inspected. Distance acuity, reading acuity, and contrast sensitivity were assessed using standardized screening charts. RESULTS. Of participants, 26% did not have their glasses with them until prompted, and 85% had glasses in poor condition. When tested wearing their habitual correction, 6% had low vision, 2% were blind, 41% had reading acuities worse than 20/25, and 28% had contrast sensitivity deficits. CONCLUSION. Visual impairment is prevalent in older adults, yet visual function is not routinely screened in hospitals. Occupational therapists should routinely inquire about patients' visual status, inspect their glasses, and encourage regular eye examinations. Failure to address vision could lead to inaccurate evaluation results.

Methylmagnesium chloride (MeMgCl) is a key reagent in research and industry typically as a nucleophile. In this article we develop the use of MeMgCl as a non‐nucleophilic base in conjunction with catalytic amounts of an amine mediator. Specifically, we use the base to deprotonate α to a variety of nitriles in alkylation reactions, applying it to the synthesis of a wide variety of tertiary and quaternary nitriles, including examples where we successively and successfully added three different substituents on the carbon α to the nitrile. This method is generally applicable, high yielding and much greener than existing methods, and it has considerable advantages for industrial application.

PURPOSE: For many low- and middle-income countries (LMICs), breast cancer (BC) screening based on mammography is not a viable option. Clinical breast examination (CBE) may represent a pragmatic and cost-effective alternative. This paper examines the cost-effectiveness of CBE screening programme among a patient group for whom its cost-effectiveness is likely to be least evident (HER2-positive patients) and discuss the wider implications for BC screening in LMICs. METHODS: A Markov model was used to examine clinical and economic outcomes over a life-time horizon from the patient, public payer, and healthcare sector perspective. HER2-positive patients entered the model at either disease-free survival or metastatic BC state. The downstaging effect of CBE determined the starting probabilities in the no-screening and screening scenarios. The model used a monthly cycle length, with half-cycle correction. Costs and outcomes were discounted at 1.5% annually. RESULTS: Compared with no-screening, the cost-effectiveness ratio (ICER) per quality-adjusted life-year gained for the CBE screening programme was $1801, $2381, and $4179 from three mentioned perspectives, respectively. The finding of cost-effectiveness remained robust to a range of sensitivity analyses. The parameters to which ICERs are most sensitive are average age of cohorts, reduction in proportion of metastatic patients at diagnosis, cost of CBE, and BC detection rate of the programme. CONCLUSION: For HER2-positive patients and compared with no-screening, CBE screening programme in Vietnam is cost-effective from all investigated perspectives. CBE is a 'good value' intervention and should be considered for implementation throughout Vietnam as well as in LMICs where mammography is not feasible.

BACKGROUND: Globally, healthcare systems are experiencing a workforce crisis which has been exacerbated by the COVID19 pandemic. Numerous reports have documented the deterioration of healthcare professional wellbeing with burnout being called the new pandemic. Rehabilitation Medicine Physicians are among the most likely specialties to experience burnout. There is a strong association between staff and patient experience and global and national policies and strategies have recognized the importance of ensuring staff wellbeing in healthcare organisations. Although there have been many publications on interventions focusing on wellbeing, these have been directed mainly at personal rather than organisational factors. Maslow's hierarchy of needs, an integrated hierarchy of human needs, has been utilised as a framework to assess wellbeing in doctors but not heretofore in Rehabilitation Medicine. This study aimed to explore Rehabilitation Medicine Physician wellbeing in a complex specialist rehabilitation setting. METHODS: Qualitative deductive content analysis (an approach to reanalyzing existing data in a new context) was the approach used. Maslow's hierarchy of needs was used as the categorization matrix. Qualitative data from three different data sources were systematically analysed. RESULTS: Using Maslow's five needs (psychological, safety, social, esteem, and self-actualisation needs), the analysis demonstrated that Rehabilitation Medicine Consultants' needs were not being met at any of the five levels. The data revealed what constitutes relative deprivation and organisational injustice. CONCLUSIONS: In order to enable the flourishing of the Rehabilitation Medicine Consultants, the organisation needs to focus on satisfying not just basic needs but creating the conditions for them to function at the highest level. The adapted Maslow framework provides a scaffolding for interventions to support such flourishing.

Dalcetrapib (1), a cholesterol ester transfer protein inhibitor, was a clinical candidate at Roche until 2012. By this time, manufacturing processes capable of efficiently delivering kilotonne annual volumes of Dalcetrapib had been developed and demonstrated at the commercial scale. This paper describes the development of synthetic routes for the manufacture of key intermediate 1-(2-ethylbutyl)-cyclohexanecarboxylic acid (2) and selection of the preferred process. The selected process involves novel methods for the α-alkylation of a nitrile using methylmagnesium chloride as a non-nucleophilic base and for the hydrolysis of a highly sterically hindered nitrile using sodium hydroxide in methanol/water at 200 °C. The performance of the process at plant scale is reported. Safety considerations and the chemistry behind the formation of side-products are discussed. Continuous-flow processes with potential operational benefits were demonstrated at laboratory scale for both the alkylation and the nitrile hydrolysis steps. A possible second-generation process for the manufacture of acid 2 is also described, which involves a novel reductive alkylation of benzoic acid.

PURPOSE: To evaluate the efficacy, durability and safety of intravitreal faricimab versus aflibercept over 48 weeks in patients with neovascular age-related macular degeneration (nAMD) from the LUCERNE China subpopulation. DESIGN: LUCERNE (NCT03823300) was a phase 3 global, double-masked, active comparator-controlled trial. The China subpopulation comprised patients from mainland China, Taiwan and Hong Kong. METHODS: Treatment-naïve patients aged ≥50 years with nAMD were randomized 1:1 to receive faricimab 6.0 mg up to every 16 weeks (Q16W) based on prespecified disease criteria after four initial Q4W doses or aflibercept 2.0 mg Q8W after three initial Q4W doses. The primary endpoint was mean change from baseline in best-corrected visual acuity (BCVA) averaged over weeks 40 to 48. Anatomical, durability and safety outcomes were also evaluated. RESULTS: The China subpopulation comprised 119 patients (faricimab: n = 59, aflibercept: n = 60). At weeks 40 to 48, adjusted mean (95% confidence interval [CI]) BCVA letter gains from baseline were +9.7 (7.4 to 12.0) and +9.8 (7.5 to 12.1) with faricimab and aflibercept, respectively. Central subfield thickness was reduced from baseline by weeks 40 to 48 in both arms, with an adjusted mean (95% CI) change of -145.4 µm (-156.2 to -134.6) and -156.5 µm (-167.3 to -145.7) for faricimab and aflibercept, respectively. By week 48, 87.3% of the patients were on extended ≥Q12W faricimab dosing. Faricimab was well tolerated with no new safety signals. CONCLUSIONS: Faricimab up to Q16W showed durable efficacy in the LUCERNE China subpopulation, consistent with global findings. Faricimab may reduce treatment burden for patients with nAMD in China, without compromising efficacy.

A56 Treatment of B-cell non-Hodgkin lymphoma (NHL) with the CD20 antibody rituximab in combination with chemotherapy is standard clinical practice. Two different types of CD20 MAb differing significantly in their mode of binding and biological activities have been described: type I antibodies, as rituximab, are potent in complement mediated cytotoxicity, whereas type II antibodies, as tositumomab, initiate target cell death with concomitant phosphatidylserine exposure. GA101 is a humanized and optimized type II CD20 IgG1 antibody that mediates superior caspase-independent cell death induction and enhanced ADCC in comparison to other CD20 antibodies. GA101 was humanized by grafting CDR sequences from the murine antibody B-ly1 on framework regions with fully human germline sequences. During humanization different elbow hinge sequences in the variable region were studied for their capability to induce phosphatidylserine exposure. GA101 binds CD20 as type II antibody with nanomolar affinity. Furthermore, the Fc region-carbohydrates were glycoengineered using GlycoMAb technology leading to bisected, afucosylated carbohydrates. Its glycoengineered Fc region bound with ca. 50-fold higher affinity to human FcgammaRIII receptors compared to a standard, non-glycoengineered antibody. Increased FcgammaRIII binding led to a 5-50-fold increase in ADCC against CD20-expressing NHL cell lines. The selection of a specific elbow hinge sequence within the antibody variable framework region resulted in an enhanced cell death-inducing activity of GA101 upon CD20 binding on target cells. In direct comparison to other CD20 antibodies GA101 showed enhanced cell death induction in both a panel of NHL cell lines and ex vivo in samples from patients with a variety of B-cell leukemias. Furthermore, in B-cell depletion assays with whole blood from healthy donors, an assay combining ADCC-, CDC- and cell death-mediated mechanisms of action, GA101 was significantly more potent and efficacious than other CD20 antibodies including rituximab and Fc-variants of rituximab that have increased ADCC. Most importantly, the in vitro superiority of GA101 translated into superior efficacy in NHL xenograft models. In NHL xenograft models of different histological origin, including aggressive diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), treatment with GA101 resulted in complete tumor remission and long-term survival compared to tumor stasis, at best, for rituximab. Compared to existing CD20 antibodies GA101 thus represents a novel, third generation antibody with significantly enhanced efficacy in a variety of preclinical models. GA101 constitutes the first type II CD20 antibody successfully engineered for increased ADCC. Based on these data, GA101 is a promising therapeutic antibody candidate for the treatment of B-cell malignancies.