Pain Medication and Pain Intensity Following Hip Fractures-Analyses Based on the ProFem Cohort Study.

PURPOSE: Pain is a common symptom following proximal femoral fractures (PFF), however, information on its treatment in terms of agents and type of use (scheduled vs. pro re nata [PRN]) is scarce. The main objective of this study was to examine pain medication regimens according to pain intensity following PFF. Furthermore, we explored the utilization of medication plans. METHODS: The "ProFem"-study on healthcare provision, functional ability, and quality of life after PFF is a German population-based prospective cohort study based on statutory health insurance data and individually linked survey data from different time points including information on the currently used medication. This present analysis refers to the participants' baseline interviews (about 3 months following PFF) conducted from 2018 to 2019 in the participants' private surroundings. RESULTS: The study population comprised 444 participants (mean age: 81.2 years, 71.0% female). Half of them reported high intensity pain, and the mean value for the EuroQol visual analogue scale was 50.8. Most commonly used analgesics were metamizole and tilidine/naloxone. Among participants with high intensity pain, 21.9% received only PRN pain medication and 17.2% no pain medication at all. Overall, 61.5% of participants presented any (printed) medication plan and only 25.2% a "federal standardized medication plan" (BMP). CONCLUSION: As a substantial number of patients reports high intensity pain about 3 months following a PFF, the large proportion of those receiving no or only PRN pain medication raises questions regarding the appropriateness of the therapy. The overall low utilization of the BMP indicates potential for improvement.

Preserving visual acuity: a compelling 12-year case study of controlling neovascular age-related macular degeneration.

INTRODUCTION: In neovascular age-related macular degeneration (nAMD) trials, anti-VEGF injection frequency decreases after the first year, while outcomes remain primarily related to the number of injections. To the best of our knowledge, there are no reports of maintaining the best corrected visual acuity (BCVA) for more than 7 years in extension studies. OBJECTIVE: To report a 12-year follow-up of a real-world case of nAMD where BCVA was preserved from declining. CASE DESCRIPTION: A 67-year-old Caucasian female presented to our department in June 2010 due to decreased vision in her left eye (LE) within the preceding months. Examination showed a BCVA of 85 letters (L) in the right eye (RE) and 35 L in the LE. Fundus examination showed drusen in the macula of both eyes. Macular edema, loss of the macular lutein pigment, macular hypo/hyperpigmentation were observed in the LE. A diagnosis of Type 2 choroidal neovascular membrane (CNV) in the LE was established and within two months a Type 1 CNV developed in the RE. She undergone 9 injections of bevacizumab (six) and ranibizumab (three) within the first year of treatment in the LE and seven injections of ranibizumab within the first year in the RE. RESULTS: The LE had a mean of 5.2 injections per year, and the RE had a mean of 7.5 injections per year, from 2010 to 2022. RE's BCVA dropped by 8L (85L to 77L) and central retinal thickness (CRT) increased by 16 µm (276 µm to 292 µm) while LE's BCVA increased by 28L (35L to 63L) and CRT decreased by 369 µm (680 µm to 311 µm), at the twelfth year. CONCLUSIONS: Although the final visual outcome depends on baseline BCVA and lesion type or size, the number of injections is paramount in preserving BCVA and achieving favorable functional outcomes in nAMD, even after 12 years of treatment.

Effect of Pro Re Nata Regimen with Anti-VEGF on Type 3 Macular Neovascularization: Long-Term Outcomes.

INTRODUCTION: The purpose of this study was to investigate long-term outcomes of intravitreal injections (IVI) of antivascular endothelial growth factor (VEGF) in neovascular age-related macular degeneration (nAMD) with type 3 macular neovascularization (MNV). METHODS: This retrospective study included 19 eyes of 17 patients with nAMD and type 3 MNV treated with anti-VEGF IVI with a loading dose and a PRN regimen. Best corrected visual acuity (BCVA), central macular thickness (CMT), presence of macular intraretinal fluid (IRF) and subretinal fluid (SRF), flow area (FA), subfoveal choroidal thickness (CT), and macular atrophy (MA) were assessed at baseline (T0) and during follow-up (T1, post-loading phase; T2, 1 year; T3, 2 years; T4 >2 years). The correlations between MA at the last follow-up and standard deviation (SD) values of CMT and CT during follow-up were assessed. The influence of the number of injections on the change in MA over time was also analyzed. MA differences at T4 were assessed for pseudodrusen presence. RESULTS: BCVA improved significantly during follow-up (p = 0.013) particularly increasing from baseline to post-loading phase and then did not modify significantly thereafter. CMT significantly reduced from T0 to T1 and remained stable during follow-up (p = <0.001). MNV flow area showed a trend toward an increase in the post-loading phase that was not statistically significant (p = 0.082) and CT decreased significantly during follow-up (p < 0.001). MA changed significantly during follow-up (p < 0.001) with a significant increase from T0 to T3 and from T0 to T4 (p < 0.010). A Cochran-Armitage test for trend showed a significant reduction (p = 0.001) of macular IRF and SRF during follow-up. MA at T4 showed a significant positive correlation with SD (standard deviation) values of CMT (p = 0.040) and CT (p = 0.020). Indeed, the number of injections did not influence the change over time of MA (p = 0.709). MA at T4 was not statistically significantly different between patients with pseudodrusen at baseline (p = 0.497). CONCLUSIONS: Intravitreal anti-VEGF injections with PRN regimen in MNV type 3 showed functional and anatomical benefits. Variations of retinal thickness and choroidal thickness during treatment were related to MA modification over time.

Pro re nata anti-VEGF treatment in pachychoroid neovasculopathy compared with age-related macular degeneration based on optical coherence tomography.

PURPOSE: To compare anti-vascular endothelial growth factor (anti-VEGF) treatment in pachychoroid neovasculopathy (PNV) and age related macular degeneration (AMD). METHODS: Cases having pro re nata (PRN) anti-VEGF treatment for choroidal neovascularization were reviewed and grouped as PNV and AMD. Groups were compared according to central foveal thickness (CFT), best corrected visual acuity (BCVA), and total injection over 12 months. The correlation of beginning choroidal thickness, CFT, and BCVA with final BCVA was analyzed. RESULTS: Forty-seven PNV and 65 AMD cases were reviewed. Both the PNV group (p = 0.0001) and the AMD group (p = 0.003) had a significant improvement in BCVA and a significant decrease in CFT (p = 0.0001). However, BCVA was better at the 3-, 6-, and 12-month follow-up in PNV (p = 0.003, 0.002, 0.02). No significant CFT difference was observed between groups. The total number of injections was 5.7 ± 1.7 for PNV and 5.2 ± 1.5 for AMD (p = 0.09). Beginning BCVA was positively correlated with final BCVA in both groups. CONCLUSION: The PRN treatment regimen was effective for PNV and AMD in terms of visual and anatomical outcomes. Visual response was better in PNV with PRN treatment with the same number of injections.

Association between time to treatment and outcome in branch retinal vein occlusion.

PURPOSE: To investigate the association between the time from onset to initial treatment and changes in visual acuity or the number of treatments in patients with branch retinal vein occlusion (BVO). DESIGN: Retrospective. METHODS: Thirty-nine eyes of 39 consecutive patients with untreated acute-phase BVO who visited the University of Tokyo Hospital and were followed up for at least one year were included. The patients were initially treated with anti-vascular endothelial growth factor (VEGF) therapy and additional pro re nata therapy within six months of onset. The patients were classified according to the time from disease onset to the first treatment (group A: 28 days or less, group B: over 28 days). RESULTS: The mean (SD) age was 73 ± 8 years, and 19 patients were male. The mean (SD) time to the first treatment was 31.6 ± 17.9 days. The mean (SD) logMAR visual acuity at first treatment was 0.37 ± 0.30. After 12 months of treatment, the mean (SD) logMAR change was - 0.15 ± 0.23, and the mean number (SD) of treatments was 3.1 ± 1.7. No significant association was observed between the timing of treatment initiation and changes in logMAR visual acuity. Patients in group A and central macular thickness at the initial visit were independently associated with the greater number of treatments at one year (p = 0.03 and p = 0.01, respectively). CONCLUSIONS: At one year, the time between onset and the start of anti-VEGF therapy for BVO was not associated with subsequent visual acuity changes. Meanwhile, it may have significant association with the number of treatments.

Use of a Novel Standardized Administration Protocol Reduces Agitation Pro Re Nata (PRN) Medication Requirements: The Birmingham Agitation Management (BAM) Initiative.

BACKGROUND: Agitation management is a principal challenge on inpatient psychiatric units. Overreliance on common prescribing strategies of pro re nata (PRN) medication administration is problematic, given the tendencies to have overlapping or unclear indications. OBJECTIVE: Piloted project to determine whether a standardized protocol for agitation intervention may reduce PRN medication administration. METHODS: The Birmingham Agitation Management (BAM) interdisciplinary team uniquely connected the Brøset Violence Checklist (BVC) for assessment of agitation severity to a standardized PRN medication order set. Nurses on the piloted unit were trained on how to score the BVC and administer medications. Patients were assessed by the BVC every 4 hours and, based on their score, would receive no medication, low-dose benzodiazepine, high-dose benzodiazepine, or high-dose benzodiazepine plus antipsychotic. The primary end point compared the number of PRNs administered after novel protocol implementation with a retrospective cohort. Secondary measures included analysis of medication-related effects, seclusion, and physical restraint rates. RESULTS: 377 patients were included in the final analyses (184 pre-BAM, 193 BAM intervention group). No significant differences were seen in patient characteristics between groups. The total number of PRNs administered decreased by 42.5%, with both the mean and median number of administrations decreasing significantly (95% confidence interval [CI] = [1.68-5.75]; P < 0.001). A trend was noted between the number of PRNs administered and seclusion rates, but did not reach statistical significance (95% CI = [-7.28 to 60.31]; P = 0.124). CONCLUSIONS: In seemingly the first initiative of its kind, we found that a standardized agitation management protocol can help decrease the total number of PRN administrations for agitation without worsening of restraint rates and may possibly reduce the risk of adverse effects. These results require validation in specific, larger populations.

The Effects of Treatment Regimen on the Initial Management of Macular Neovascularization Subtypes in Age-Related Macular Degeneration.

INTRODUCTION: The aim of this study was to evaluate the effect of initial treatment regimen individualization (pro re nata or treat-and-extend [TAE]), according to macular neovascularization (MNV) subtype, on the functional and anatomical response in neovascular age-related macular degeneration (nAMD). The secondary objective was to compare the treatment burden between each MNV subtype. METHODS: Consecutive treatment-naïve nAMD patients were retrospectively included. MNV subtype was graded by 2 independent blinded investigators on multimodal imaging. Functional and anatomical outcomes were analysed according to treatment regimen and MNV subtypes. RESULTS: A total of 281 eyes from 243 patients were included in the study. According to the treatment regimen, there was no significant difference in best-corrected visual acuity gain within the first 2 years of treatment for type 1 (p = 0.106) and type 3 MNV (p = 0.704). Conversely, there was a significant difference in favour of TAE regimen for type 2 (p = 0.017) and type 4 MNV (p = 0.047). Type 1 MNV had a higher proportion of visits with subretinal fluid (p = 0.0007) but not with intraretinal fluid (p = 0.22). The mean interval between the last 2 injections was significantly shorter for type 1 MNV (p = 0.0045). CONCLUSION: The individualization of the initial treatment protocol according to MNV subtype can improve the functional outcome and may decrease the treatment burden.

Is there any association between the frequency of wet age-related macular degeneration recurrences and the seasons of the year?

PURPOSE: To investigate whether a seasonal distribution of the frequency of exudative age-related macular degeneration (wet AMD) recurrences exists. METHODS: In total, 129 eyes with 171 recurrences in patients suffering from wet AMD were included in the study. All the patients had been treated with intravitreal anti-VEGF injections according to Pro Re Nata treatment regimen. Recurrence was defined as the re-detection of sub-retinal fluid, intraretinal fluid, and/or sub-macular hemorrhage in optical coherence tomography scans, after at least two consecutive monthly examinations with a "dry" macula. The year was divided in three 4-month periods (zone A: June-September, zone B: October-January, and zone C: February-May) based on the weather conditions prevailing in each period. Mean temperature and hours of sunlight exposure were the main weather markers recorded. RESULTS: Eighty-two recurrences (48%) occurred during the period June-September, 50 (29.2%) during the period October-January, and 39 (22.8%) during the period February-May (Chi-square = 17.5, p < 0.001). Among the groups, neither patients' age (78 ± 8 years A, 76 ± 7 years B, and 79 ± 8 years C, p = 0.15) nor gender status (40% men A, 36% men B, and 51% men C, p = 0.35) differed significantly. Mean temperature was 27.6 ± 1.8 °C, 15.1 ± 4.6 °C, and 16.5 ± 4.4 °C in zones A, B, and C, respectively. Hours (h) of sunlight exposure (average hours/month) were 344 ± 34 h, 188 ± 42 h, and 223 ± 57 h in zones A, B, and C. CONCLUSION: We demonstrated that the frequency of wet AMD recurrences is significantly elevated during the warmer months, possibly due to the higher levels of UV radiation and mean temperature. Further research is necessary to validate our findings.

N-alpha-acetylation of Huntingtin protein increases its propensity to aggregate.

Huntington's disease (HD) is a neurodegenerative disorder caused by a poly-CAG expansion in the first exon of the HTT gene, resulting in an extended poly-glutamine tract in the N-terminal domain of the Huntingtin (Htt) protein product. Proteolytic fragments of the poly-glutamine-containing N-terminal domain form intranuclear aggregates that are correlated with HD. Post-translational modification of Htt has been shown to alter its function and aggregation properties. However, the effect of N-terminal Htt acetylation has not yet been considered. Here, we developed a bacterial system to produce unmodified or N-terminally acetylated and aggregation-inducible Htt protein. We used this system together with biochemical, biophysical, and imaging studies to confirm that the Htt N-terminus is an in vitro substrate for the NatA N-terminal acetyltransferase and show that N-terminal acetylation promotes aggregation. These studies represent the first link between N-terminal acetylation and the promotion of a neurodegenerative disease and implicates NatA-mediated Htt acetylation as a new potential therapeutic target in HD.

To investigate treat and extend versus pro re nata regimen in neovascular age-related macular degeneration: results from the IDEM study.

PURPOSE: The purpose of this study is to report the 24-month outcomes of a pro re nata (PRN) compared with a treat and extend (T&E) regimen in patients previously treated for neovascular age-related macular degeneration (nAMD). METHODS: This was a 2-year prospective, single-center study. Previously treated patients for nAMD were randomized into two regimen groups: T&E and PRN groups. Main outcome measured was change in best corrected visual acuity (BCVA) from baseline to month 24. Secondary outcomes encompassed anatomical features such as central retinal thickness (CRT), number of intravitreal injections (IVI), and visits required. RESULTS: A total of 124 eyes received the T&E (n = 61) or PRN (n = 63) regimen. At month 24, the mean BCVA change was -4.4 early treatment diabetic retinopathy study (ETDRS) letters (T&E) and -3.4 ETDRS letters (PRN), with a difference of +1.1 ETDRS letters (95% CI [-2.25]; p = 0.006). The mean change in CRT was -10.6 µm (T&E) and -7.9 µm (PRN), with a difference of +2.6 µm (95% CI [+19.2]; p = 0.004). The T&E group had received a mean of +4.6 more injections (95% CI [-7.06; -2.12]; p < 0.001) at month 24. CONCLUSION: There was statistically proven non-inferiority between the PRN and T&E regimens in terms of visual and anatomical outcomes at 24 months, with significantly more IVI administered in the T&E regimen.

The characteristics of discharge prescriptions including pro re nata psychotropic medications for patients with schizophrenia and major depressive disorder from the survey of the "Effectiveness of guidelines for dissemination and education in psychiatric treatment (EGUIDE)" project.

BACKGROUND: Several guidelines recommend monotherapy in pharmacotherapy for schizophrenia and major depressive disorder. The content of regular prescriptions has been reported in several studies, but not enough research has been conducted on the content of pharmacotherapy, including pro re nata (PRN) medications. The purpose of this study was to evaluate the content of pharmacotherapy, including PRN medications, and to clarify the relationship with regular prescriptions. METHODS: We used data from the "Effectiveness of Guidelines for Dissemination And Education in psychiatric treatment" (EGUIDE) project to investigate the presence or absence of PRN psychotropic medications at discharge for each drug category. We compared the PRN psychotropic prescription ratio at discharge by diagnosis for each drug category. The antipsychotic monotherapy ratio and no prescription ratio of other psychotropics for schizophrenia at discharge and the antidepressant monotherapy ratio and no prescription ratio of other psychotropics for major depressive disorder at discharge were calculated for each regular prescription, including PRN psychotropic medications, as quality indicators (QIs). Spearman's rank correlation test was performed for QI values of regular prescriptions and the QI ratio between regular prescriptions and prescriptions including PRN medications for each diagnosis. RESULTS: The PRN psychotropic prescription ratio at discharge was 28.7% for schizophrenia and 30.4% for major depressive disorder, with no significant differences by diagnosis. The prescription ratios of PRN antipsychotic medications and PRN antiparkinsonian medications were significantly higher for schizophrenia. The prescription ratios of PRN anxiolytic and hypnotic and PRN antidepressant medications were significantly higher for patients with major depressive disorder. For both schizophrenia and major depressive disorder, the QI was lower for discharge prescriptions, including PRN medications, than for regular prescriptions. QI values for regular prescriptions and the QI ratio were positively correlated. CONCLUSIONS: Considering PRN psychotropic medications, the monotherapy ratio and no prescription ratio of other psychotropics at discharge decreased in pharmacotherapy for schizophrenia and major depressive disorder. A higher ratio of monotherapy and no prescription of other psychotropics on regular prescriptions may result in less concomitant use of PRN psychotropic medications. Further studies are needed to optimize PRN psychotropic prescriptions.

UBA domain protein SUF1 interacts with NatA-complex subunit NAA15 to regulate thermotolerance in Arabidopsis.

During recovery from heat stress, plants clear away the heat-stress-induced misfolded proteins through the ubiquitin-proteasome system (UPS). In the UPS, the recognition of substrate proteins by E3 ligase can be regulated by the N-terminal acetyltransferase A (NatA) complex. Here, we determined that Arabidopsis STRESS-RELATED UBIQUITIN-ASSOCIATED-DOMAIN PROTEIN FACTOR 1 (SUF1) interacts with the NatA complex core subunit NAA15 and positively regulates NAA15. The suf1 and naa15 mutants are sensitive to heat stress; the NatA substrate N SNC1 is stabilized in suf1 mutant plants during heat stress recovery. Therefore, SUF1 and its interactor NAA15 play important roles in basal thermotolerance in Arabidopsis.

Progress of Diabetic Macular Edema after Loading Injection of Anti-Vascular Endothelial Growth Factor Agents in Real-World Cases.

Background and Objectives: To evaluate the recurrence of diabetic macular edema (DME) after loading an injection of anti-VEGF agents by a pro re nata (PRN) protocol using central retinal thickness (CRT) as a re-injection criterion. Materials and Methods: This is a retrospective, observational single-center study. DME patients with a central retinal thickness (CRT) over 350 µm received a PRN injection of anti-VEGF agents following one to three consecutive monthly loading injections (bevacizumab, ranibizumab, and aflibercept) for 6 months from January 2012 to June 2019. Results: We enrolled a total of 72 eyes for loading injections and the mean CRT improved from 434.04 ± 139.4 µm (before treatment) to 362.9 ± 125.0 µm after the loading injection. One week after injection, 36 eyes (50%) obtained a CRT of ≤350 µm. Fourteen eyes (19.4%) remained with a CRT of ≤350 µm for 6 months without additional injections. A total of 22 eyes (30.6%) had a CRT of >350 µm at 6 months. Fifteen eyes did not receive additional injections because of visual improvement. Conclusions: About 20% of DME patients can be maintained at a CRT of ≤350 µm for 6 months with only a loading injection. However, there is a tendency to delay additional injections for patients with recurrences using PRN protocol.

Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

Confirmation of Ogden syndrome as an X-linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature.

Ogden syndrome is a rare lethal X-linked recessive disorder caused by a recurrent missense variant (Ser37Pro) in the NAA10 gene, encoding the catalytic subunit of the N-terminal acetyltransferase A complex (NatA). So far eight boys of two different families have been described in the literature, all presenting the distinctive and recognizable phenotype, which includes mostly postnatal growth retardation, global severe developmental delay, characteristic craniofacial features, and structural cardiac anomalies and/or arrhythmias. Here, we report the ninth case of Ogden syndrome with an independent recurrence of the Ser37Pro variant. We were able to follow the clinical course of the affected boy and delineate the evolving phenotype from his birth until his unfortunate death at 7 months. We could confirm the associated phenotype as well as the natural history of this severe disease. By describing new presenting features, we are further expanding the clinical spectrum associated with Ogden syndrome and review other phenotypes associated with NAA10 variants.

Charting the N-Terminal Acetylome: A Comprehensive Map of Human NatA Substrates.

N-terminal acetylation (Nt-acetylation) catalyzed by conserved N-terminal acetyltransferases or NATs embodies a modification with one of the highest stoichiometries reported for eukaryotic protein modifications to date. Comprising the catalytic N-alpha acetyltransferase (NAA) subunit NAA10 plus the ribosome anchoring regulatory subunit NAA15, NatA represents the major acetyltransferase complex with up to 50% of all mammalian proteins representing potential substrates. Largely in consequence of the essential nature of NatA and its high enzymatic activity, its experimentally confirmed mammalian substrate repertoire remained poorly charted. In this study, human NatA knockdown conditions achieving near complete depletion of NAA10 and NAA15 expression resulted in lowered Nt-acetylation of over 25% out of all putative NatA targets identified, representing an up to 10-fold increase in the reported number of substrate N-termini affected upon human NatA perturbation. Besides pointing to less efficient NatA substrates being prime targets, several putative NatE substrates were shown to be affected upon human NatA knockdown. Intriguingly, next to a lowered expression of ribosomal proteins and proteins constituting the eukaryotic 48S preinitiation complex, steady-state levels of protein N-termini additionally point to NatA Nt-acetylation deficiency directly impacting protein stability of knockdown affected targets.

Severe syndromic ID and skewed X-inactivation in a girl with NAA10 dysfunction and a novel heterozygous de novo NAA10 p.(His16Pro) variant - a case report.

BACKGROUND: NAA10 is the catalytic subunit of the major N-terminal acetyltransferase complex NatA which acetylates almost half the human proteome. Over the past decade, many NAA10 missense variants have been reported as causative of genetic disease in humans. Individuals harboring NAA10 variants often display variable degrees of intellectual disability (ID), developmental delay, and cardiac anomalies. Initially, carrier females appeared to be oligo- or asymptomatic with X-inactivation pattern skewed towards the wild type allele. However, recently it has been shown that NAA10 variants can cause syndromic or non-syndromic intellectual disability in females as well. The impact of specific NAA10 variants and the X-inactivation pattern on the individual phenotype in females remains to be elucidated. CASE PRESENTATION: Here we present a novel de novo NAA10 (NM_003491.3) c.[47A > C];[=] (p.[His16Pro];[=]) variant identified in a young female. The 10-year-old girl has severely delayed motor and language development, disturbed behavior with hyperactivity and restlessness, moderate dilatation of the ventricular system and extracerebral CSF spaces. Her blood leukocyte X-inactivation pattern was skewed (95/5) towards the maternally inherited X-chromosome. Our functional study indicates that NAA10 p.(H16P) impairs NatA complex formation and NatA catalytic activity, while monomeric NAA10 catalytic activity appears to be intact. Furthermore, cycloheximide experiments show that the NAA10 H16P variant does not affect the cellular stability of NAA10. DISCUSSION AND CONCLUSIONS: We demonstrate that NAA10 p.(His16Pro) causes a severe form of syndromic ID in a girl most likely through impaired NatA-mediated Nt-acetylation of cellular proteins. X-inactivation analyses showed a skewed X-inactivation pattern in DNA from blood of the patient with the maternally inherited allele being preferentially methylated/inactivated.

A Trinity regimen with aflibercept for treatment-naïve neovascular age-related macular degeneration: 2-year outcomes.

PURPOSE: To evaluate the advantages of the Trinity regimen for treatment-naïve neovascular age-related macular degeneration (nAMD). METHODS: Thirty-one treatment-naïve nAMD eyes were treated using the Trinity regimen with an intravitreal aflibercept injection (IVA) and evaluated after 24 months. Three treatment methods, pro re nata (PRN), treat and extend (TAE), and fixed regimen were changed depending on recurrence frequency. After the initial treatment, PRN or TAE (started for 4 or 8 weeks) was selected as per the recurrence interval. Subsequently, the recurrence interval became constant, transitioning from a TAE to fixed regimen. When the recurrence frequency became irregular, the treatment regimen was changed to TAE. RESULTS: After the initial treatment, 15 eyes (48.4%) were allocated to the PRN group, 12 (38.7%) to the TAE 8-week group, and 4 (12.9%) to the TAE 4-week group. Mean logMAR significantly improved in all cases, 0.53 ± 0.40 at baseline to 0.36 ± 0.34 at 24 months (p < 0.01), in the PRN group (0.63 ± 0.46 to 0.42 ± 0.43, p < 0.01), and the TAE 8-week group (0.44 ± 0.29 to 0.27 ± 0.19, p < 0.05). LogMAR in the TAE 4-week group was maintained. The mean number of injections for all and in the PRN, TAE 8-week, and TAE 4-week groups were 9.7, 5.3, 13.1, and 15.8, respectively, with the PRN group being significantly less (p < 0.01). CONCLUSION: The Trinity regimen delivered the benefits of the PRN, TAE, and FIXED regimens while minimizing injections during the early treatment phase without visual loss. TRIAL REGISTRATION: This trial was registered with the University Hospital Medical Information Network (UMIN ID: 000038335).

Anatomical and functional responses in eyes with diabetic macular edema treated with "1 + PRN" ranibizumab: one-year outcomes in population of mainland China.

BACKGROUND: To evaluate the anatomical and functional responses in eyes with diabetic macular edema (DME) treated with ranibizumab under "1 + pro re nata (PRN)" regimen. METHODS: This prospective interventional case series included 69 eyes of 69 patients with DME treated with intravitreal injections of 0.5 mg ranibizumab followed by repeated injections as needed. Best-corrected visual acuity (BCVA), central foveal thickness (CFT), subfoveal choroidal thickness (SFCT), and predictive factors for final visual outcomes were assessed. RESULTS: Logarithm of minimal angle of resolution (logMAR) BCVA improved from 0.64 ± 0.23 at baseline to 0.56 ± 0.27, 0.53 ± 0.26, 0.47 ± 0.25, 0.44 ± 0.32, 0.47 ± 0.26 and 0.46 ± 0.26 at time-point of months 1, 2, 3, 6, 9, and 12, respectively (P < 0.05 for any follow-up time-point except month 1). CFT decreased from 478.23 ± 172.31 µm at baseline to 349.74 ± 82.21 µm, 313.52 ± 69.62 µm, 292.59 ± 61.07 µm, 284.67 ± 69.85 µm, 268.33 ± 43.03 µm, and 270.39 ± 49.27 µm at above time-points, respectively (P < 0.05). The number of injections was 6.83 times over 12 months' follow-up under "1 + PRN" regimen. Multivariate analysis showed that the factors including age, BCVA at baseline, disruption of ellipsoid zone, posterior vitreous detachment (PVD), and vitreomacular traction (VMT) were correlated with the final BCVA. CONCLUSIONS: Intravitreal injections of ranibizumab under "1 + PRN" regimen is a not only effective but also safe way to improve visual acuity of DME patients. And older age, lower baseline BCVA, VMT, and disruption of ellipsoid zone are predictors for final poor BCVA while PVD is a positive predictive factor for good final BCVA. TRIAL REGISTRATION: The trial was registered retrospectively in ClinicalTrials.gov on 2 June 2019 (NCT03973138).

'To give or not to give medication, that is the question.' Healthcare personnel's perceptions of factors affecting pro re nata medication in sheltered housing for older adults - a focus-group interview study.

BACKGROUND: Residents living in sheltered housing depend on help from healthcare personnel (HCP) with medication management, regarding regular long-term and pro re nata (PRN) medication. The HCP assess the need for PRN medication prior to administration to the residents. The purpose of this study was to describe HCP's perceptions of factors affecting PRN medication management in sheltered housing for older adults. METHOD: This was a qualitative study with five focus-group interviews with 22 HCP working in sheltered housing for older adults. The HCP were heterogenous regarding scholarly education and experiences, working in four different municipalities in mid-Norway, representing urban, sub-urban and rural districts. The analysis was inductive, based on qualitative, manifest, content analysis. The main outcome was HCP perceptions of the factors affecting PRN medication management in sheltered housing. RESULTS: Four main factors affecting the PRN medication management were identified in the data and were related to either: 1) the medication; 2) the resident; 3) the HCP; or 4) the organisation. These categories included 14 subcategories. Overall, the HCP described the management of PRN medication as a complex process, where the above factors all have impact on the residents' health and safety. CONCLUSION: HCP working in sheltered housing describe that PRN medication management is affected by numerous human factors, that consequently may affect patient outcomes and safety. HCP involved in PRN medication management should be aware of factors that affect their decision-making, and safe management requires a professional practice built on medicines competence, practical skills and experience.