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Not all Extension professionals enter the workplace with knowledge and experience in program development. Some may possess extensive expertise in their subject matter but need additional training in teaching-related competencies for adult or youth audiences. Even educators with extensive skill and experience benefit from thoughtful and intentional program planning and implementation design. This article describes the Program Instructional Profile (PIP), created for Extension professionals to design and outline the program delivery processes. We explain how to use the PIP and provide insight into the benefits and challenges of the uses for program development and implementation purposes.

Out-of-school time (OST) programs serving predominantly racialized minority communities can help reduce racial disparities in STEM as they provide a culturally affirming learning environment that includes supportive staff of similar ethnic identities as the youth. However, staff at OST programs located in underserved communities that serve racially minoritized youth, often have limited academic credentials and have constrained opportunities for social mobility. These staff's contributions to informal science learning have largely been neglected by research. A staff mentoring program was piloted to provide professional development in STEM education for racially minoritized staff also referred to as youth development professionals or specialists, at an OST learning organization located in the Midwestern US, that serves predominantly African American low-income communities. The pilot paired three racially minoritized part-time staff (mentees) with three full-time staff including educators and program leaders (mentors) for year-long mentoring relationships. Qualitative data collection tools were used to examine the impact of the pilot program on participants. Results indicate numerous gains for participants including personal and professional skills. These findings contribute to the broader literature on mentoring and suggest that the mentorship program represents a model for access to STEM educational and professional development for OST staff in racially minoritized underserved communities.

BACKGROUND: The safety, tolerability, and immunogenicity of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% (dual-vial unit of human immunoglobulin 10% and recombinant human hyaluronidase [rHuPH20]) were assessed in children with primary immunodeficiency diseases (PIDs). METHODS: This phase 4, post-authorization, prospective, interventional, multicenter study (NCT03116347) conducted in the European Economic Area, enrolled patients aged 2 to < 18 years with a documented PID diagnosis who had received immunoglobulin therapy for ≥ 3 months before enrollment. New fSCIG 10% starters underwent fSCIG 10% dose ramp-up for ≤ 6 weeks (epoch 1) before receiving fSCIG 10% for ≤ 3 years (epoch 2); patients pretreated with fSCIG 10% entered epoch 2 directly. The primary outcome was the number and rate (per infusion) of all noninfectious treatment-related serious and severe adverse events (AEs). RESULTS: In total, 42 patients were enrolled and dosed (median [range] age: 11.5 [3-17] years; 81% male; 23 new starters; 19 pretreated). Overall, 49 related noninfectious, treatment-emergent AEs (TEAEs) were reported in 15 patients; most were mild in severity (87.8%). No treatment-related serious TEAEs were reported. Two TEAEs (infusion site pain and emotional distress) were reported as severe and treatment-related in a single new fSCIG 10% starter. The rate of local TEAEs was lower in pretreated patients (0.1 event/patient-year) versus new starters (1.3 events/patient-year). No patients tested positive for binding anti-rHuPH20 antibodies (titer of ≥ 1:160). CONCLUSIONS: No safety signals were identified, and the incidence of local AEs declined over the duration of fSCIG 10% treatment. This study supports fSCIG 10% long-term safety in children with PIDs. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT03116347.

Catalytic RNAs (ribozymes) were central to early stages of life on earth. The first ribozymes probably emerged in the presence of prebiotically generated peptides because amino acids can be generated under abiotic conditions, and amino acids can oligomerize into peptides under prebiotically plausible conditions. Here we tested whether the presence of prebiotically plausible peptides could have aided the emergence of ribozymes, by an in vitro selection of self-triphosphorylation ribozymes from random sequence in the presence of ten different octapeptides. These peptides were composed of ten different, prebiotically plausible amino acids, each as mixture of d- and l-stereoisomers. After five rounds of selection and high throughput sequencing analysis, ten ribozymes that appeared most promising for peptide benefits were tested biochemically for possible benefits from each of the ten peptides. The strongest peptide benefit enhanced ribozyme activity by 2.6-fold, similar to the effect from an increase in the pH by one-half unit. Four arbitrarily chosen ribozymes from a previous selection without peptides showed no significant change in their activity in the presence of the ten peptides. Therefore, the used prebiotically plausible peptides - peptides without evolutionarily optimized sequence, without cationic or aromatic side chains - did not provide a strong benefit for the emergence of ribozyme activity. This finding stands in contrast to previously identified polycationic peptides, conjugates between peptides and polyaromatic hydrocarbons, and modern mRNA encoded proteins, all of which can strongly increase ribozyme function. The results are discussed in the context of origins of life.

Facilitated subcutaneous immunoglobulin (fSCIG) 10% is an immunoglobulin replacement therapy that utilizes recombinant human hyaluronidase (rHuPH20) to enhance immunoglobulin dispersion and absorption, allowing for longer treatment intervals similar to intravenous immunoglobulin (up to once monthly). fSCIG 10% is indicated in the USA for treating adults and children aged ≥ 2 years with primary immunodeficiency diseases (PIDs). This prospective, non-interventional, open-label, multicenter, post-authorization safety study (NCT02593188) was conducted in the USA from November 2015 to October 2021 to assess the long-term safety of fSCIG 10% in routine clinical practice. Patients with PIDs aged ≥ 16 years who were prescribed and/or had started fSCIG 10% treatment were enrolled. In total, 253 patients were enrolled and included (full analysis set). Participants received fSCIG 10% treatment for a median (interquartile range) of 10.0 (3.5-11.8) months, with the majority of infusions administered every 4 weeks (54.4% [1197/2201 infusions]) and at home (62.6% [1395/2230 infusions]). Overall, 98.5% of infusions were administered without rate reduction, interruption, or discontinuation due to adverse events (AEs). Treatment-related, non-serious AEs were experienced by 52 patients (20.6%, 284 events). Two patients (0.8%) each experienced one treatment-related serious AE (aseptic meningitis and deep vein thrombosis). Development of antibodies against rHuPH20 was uncommon; 14/196 patients (7.1%) tested positive for binding antibodies (titer ≥ 1:160) with no neutralizing antibodies detected. There was no relationship between anti-rHuPH20 antibody positivity and the occurrence of treatment-related serious or non-serious AEs. Long-term, repeated self-administration of fSCIG 10% was well tolerated in US clinical practice by patients with PIDs.

OBJECTIVE: Multifocal motor neuropathy is a rare chronic immune-mediated neuropathy with impaired grip strength representing a common symptom. While intravenous immunoglobulin G is an effective treatment for the disease, significant variation in treatment response has been observed but not well understood. This analysis characterized dose-exposure-response relationships in multifocal motor neuropathy, using grip strength as a clinical efficacy measure. METHODS: Serum immunoglobulin G trough concentrations and grip strength data for the more affected hand from a Phase 3, randomized, double-blind, placebo-controlled, crossover trial of intravenous immunoglobulin 10% in 44 patients with multifocal motor neuropathy (NCT00666263) were used to develop a population pharmacokinetic-pharmacodynamic model. RESULTS: The model adequately described the observed pharmacokinetic and pharmacodynamic data and relationships between intravenous immunoglobulin 10% dose, serum immunoglobulin G trough levels, grip strength, and inter-patient variabilities in multifocal motor neuropathy. Model-based simulations for various dosing regimens (0.4-2.0 g/kg every 2-4 weeks) indicated that ≥1.6 g/kg/month would achieve clinically meaningful improvements in grip strength (≥4 kg) in ≥70% of patients. More frequent dosing at an equivalent monthly dose led to a more consistent response in grip strength. Furthermore, splitting the dose over multiple days for high doses (>1 g/kg) did not impact grip strength. INTERPRETATION: These findings suggest that the majority of patients with multifocal motor neuropathy would respond rapidly to intravenous immunoglobulin 10% with a range of dosing regimens. Shorter dosing intervals may avoid the diminishing response seen with longer dosing intervals. Dose-splitting provided similar outcomes while offering flexibility and convenience.

PURPOSE: Facilitated subcutaneous immunoglobulin (fSCIG; immune globulin infusion 10% [human] with recombinant human hyaluronidase [rHuPH20]) permits high-volume subcutaneous immunoglobulin (SCIG) infusion, shorter infusion times and reduced dosing frequency relative to conventional SCIG. It is initiated by gradually increasing infusion volumes over time (dose ramp-up) to achieve target dose level (TDL). Whether ramp-up strategies have tolerability or safety advantages over direct initiation at full TDL has not been evaluated clinically. METHODS: This phase 1 open-label study assessed tolerability and safety of fSCIG 10% with accelerated or no ramp-up compared with conventional ramp-up in healthy adults (NCT04578535). Participants were assigned to one of the three ramp-up arms to achieve TDLs of 0.4 or 1.0 g/kg/infusion. The primary endpoint was the proportion of infusions completed without interruption or infusion rate reduction owing to treatment-emergent adverse events (TEAEs). Safety was assessed as a secondary endpoint. RESULTS: Of 51 participants enrolled, 50 (98.0%) tolerated all fSCIG 10% infusions initiated (n = 174). Infusion rate was reduced in one participant owing to headache in the 0.4 g/kg/infusion conventional ramp-up arm. Study discontinuations were higher in the no ramp-up arm (70%) versus the conventional (0%) and accelerated (22%) arms at the 1.0 g/kg/infusion TDL. Safety outcomes did not substantially differ between treatment arms. CONCLUSION: The favorable tolerability and safety profiles of fSCIG 10% in healthy participants support initiating treatment with fSCIG 10% with accelerated ramp-up at TDLs up to 1.0 g/kg. Data support no ramp-up at TDLs close to 0.4 g/kg but additional data are needed for higher doses.

"Cena y Ciencias" (Supper and Science), or CyC, is a STEM outreach program for kindergarten through fifth-grade youth and their families. Monthly, university scientists lead interactive experiments with assistance from university student mentors. CyC is conducted entirely in Spanish. While youth complete activities, a separate parent session is held to explain the activities. The overall program goals are to increase interest in STEM careers and encourage Spanish-speaking youth that a scientist can "look like me." We conducted a descriptive, qualitative case study assessing the program's impact on participants, parents, and mentors. Youth participants and parents reported they liked the activities from CyC. Both youth and parents believe anyone can be a scientist. However, few students identified CyC teachers as scientists without further prompting. Neither youth nor parents connected attending CyC with the youth participant's future career. Mentors developed an appreciation of their bilingual skills as a positive identity within their science profession. Mentors expressed new appreciation for science outreach and future intent to do more outreach. All mentors felt CyC was a welcoming environment. Implications for all STEM outreach targeting young audiences include revisiting the connection between fun science activities and careers, confirming participants make the desired connections.

Aim: To assess the long-term safety of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% in European routine clinical practice.Materials & methods: This prospective, noninterventional, open-label, post-authorization safety study (EUPAS5812) sourced data on adverse events, immunogenicity, treatment regimens and product administration for 106 adult patients prescribed fSCIG 10% across 17 sites in six European countries from July 2014 to February 2020.Results: In total, 1171 treatment-emergent adverse events were reported in 94 patients (88.7%); 25.5% of these events were considered related to fSCIG 10%. Positive binding antibody titers developed in three patients; no neutralizing antibodies to recombinant human hyaluronidase were detected.Conclusion: This real-world study of fSCIG 10% is the longest to date and confirms its long-term safety and tolerability in adults with antibody deficiency diseases.

This phase 3, open-label, multidose study (NCT04346108) evaluated the pharmacokinetics, safety, tolerability, and efficacy of immunoglobulin subcutaneous (human) 20% solution (Ig20Gly) administered weekly and every 2 weeks in Japanese patients with primary immunodeficiency diseases (PIDs). The study was conducted at eight study sites in Japan and enrolled patients aged ≥2 years with PIDs treated using a stable intravenous immunoglobulin dose for ≥3 months prior to the study. Patients received intravenous immunoglobulin every 3 or 4 weeks at pre-study dose (200-600 mg/kg) for 13 weeks (Epoch 1), subcutaneous Ig20Gly (50-200 mg/kg) once weekly for 24 weeks (Epoch 2), and Ig20Gly (100-400 mg/kg) every 2 weeks for 12 weeks (Epoch 3). The primary endpoint was serum total immunoglobulin G (IgG) trough levels during Epochs 2 and 3. Overall, 17 patients were enrolled (median [range] age: 24 [5-69] years; 59% male) and participated in Epochs 1 and 2; seven patients entered Epoch 3. Serum total IgG trough levels were maintained at >8 g/l: geometric means (95% confidence intervals) at the end of Epochs 2 and 3 were 8.56 (8.03-9.12) g/l and 8.39 (7.89-8.91) g/l, respectively. Related treatment-emergent adverse events were all mild in severity; the most common treatment-emergent adverse events (excluding infections) in Epochs 2 and 3 were injection site swelling (24%) and injection site erythema (18%). This is the first trial to demonstrate the efficacy and favourable safety profile of 20% subcutaneous immunoglobulin administered every 2 weeks in adult and paediatric Japanese patients with PIDs.

PURPOSE: Hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 20% will allow reduced infusion volumes and frequency versus existing subcutaneous therapies such as fSCIG 10% and conventional subcutaneous immunoglobulin 20%, respectively. We assessed the tolerability, safety, and immunogenicity of warmed and unwarmed fSCIG 20%. METHODS: This phase 1, single-dose, open-label, three-arm study enrolled healthy adults aged 19-50 years (inclusive) at a single US center (NCT05059977). Post-screening, participants received a single fSCIG 20% dose comprising recombinant human hyaluronidase and varying doses of in-line warmed or unwarmed immunoglobulin G (IgG) during a 4-day treatment period in a sentinel and sequential dosing design (treatment arm 1, warmed IgG 20% 0.4 g/kg; treatment arm 2, warmed IgG 20% 1.0 g/kg; treatment arm 3, unwarmed IgG 20% 1.0 g/kg). Participants were followed for 12 (± 1) weeks post-infusion. The primary endpoint was tolerability (tolerable infusions were not interrupted, stopped, or reduced in rate owing to fSCIG 20%-related treatment-emergent adverse events (TEAEs)). Secondary endpoints included occurrence of TEAEs. RESULTS: Overall, 24 participants were included, 8 per treatment arm (mean age 39.0 years, 54.2% men). All participants tolerated the infusions. All TEAEs were mild (107 events, in all participants), and all participants experienced fSCIG 20%-related (105 events) and local (102 events) TEAEs. Infusion site erythema and infusion site swelling were most frequently reported. No serious TEAEs occurred, and no participants discontinued the study owing to TEAEs. CONCLUSION: fSCIG 20% was well-tolerated with a favorable safety profile in healthy adults. Future studies will evaluate fSCIG 20% in primary immunodeficiency diseases. Trial registration number (ClinicalTrials.gov): NCT05059977 (registered 28 September 2021).

Abstract Background The safety, tolerability, and immunogenicity of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% (dual-vial unit of human immunoglobulin 10% and recombinant human hyaluronidase [rHuPH20]) were assessed in children with primary immunodeficiency diseases (PIDs). Methods This phase 4, post-authorization, prospective, interventional, multicenter study (NCT03116347) conducted in the European Economic Area, enrolled patients aged 2 to < 18 years with a documented PID diagnosis who had received immunoglobulin therapy for ≥ 3 months before enrollment. New fSCIG 10% starters underwent fSCIG 10% dose ramp-up for ≤ 6 weeks (epoch 1) before receiving fSCIG 10% for ≤ 3 years (epoch 2); patients pretreated with fSCIG 10% entered epoch 2 directly. The primary outcome was the number and rate (per infusion) of all noninfectious treatment-related serious and severe adverse events (AEs). Results In total, 42 patients were enrolled and dosed (median [range] age: 11.5 [3–17] years; 81% male; 23 new starters; 19 pretreated). Overall, 49 related noninfectious, treatment-emergent AEs (TEAEs) were reported in 15 patients; most were mild in severity (87.8%). No treatment-related serious TEAEs were reported. Two TEAEs (infusion site pain and emotional distress) were reported as severe and treatment-related in a single new fSCIG 10% starter. The rate of local TEAEs was lower in pretreated patients (0.1 event/patient-year) versus new starters (1.3 events/patient-year). No patients tested positive for binding anti-rHuPH20 antibodies (titer of ≥ 1:160). Conclusions No safety signals were identified, and the incidence of local AEs declined over the duration of fSCIG 10% treatment. This study supports fSCIG 10% long-term safety in children with PIDs. Trial registration number (ClinicalTrials.gov) NCT03116347.

Abstract Background Solving the structure of mRNA transcripts is a major challenge for both research and molecular diagnostic purposes. Current approaches based on short-read RNA sequencing and RT-PCR techniques cannot fully explore the complexity of transcript structure. The emergence of third-generation long-read sequencing addresses this problem by solving this sequence directly. However, genes with low expression levels are difficult to study with the whole transcriptome sequencing approach. To fix this technical limitation, we propose a novel method to capture transcripts of a gene panel using a targeted enrichment approach suitable for Pacific Biosciences and Oxford Nanopore Technologies platforms. Results We designed a set of probes to capture transcripts of a panel of genes involved in hereditary breast and ovarian cancer syndrome. We present SOSTAR (iSofOrmS annoTAtoR), a versatile pipeline to assemble, quantify and annotate isoforms from long read sequencing using a new tool specially designed for this application. The significant enrichment of transcripts by our capture protocol, together with the SOSTAR annotation, allowed the identification of 1,231 unique transcripts within the gene panel from the eight patients sequenced. The structure of these transcripts was annotated with a resolution of one base relative to a reference transcript. All major alternative splicing events of the BRCA1 and BRCA2 genes described in the literature were found. Complex splicing events such as pseudoexons were correctly annotated. SOSTAR enabled the identification of abnormal transcripts in the positive controls. In addition, a case of unexplained inheritance in a family with a history of breast and ovarian cancer was solved by identifying an SVA retrotransposon in intron 13 of the BRCA1 gene. Conclusions We have validated a new protocol for the enrichment of transcripts of interest using probes adapted to the ONT and PacBio platforms. This protocol allows a complete description of the alternative structures of transcripts, the estimation of their expression and the identification of aberrant transcripts in a single experiment. This proof-of-concept opens new possibilities for RNA structure exploration in both research and molecular diagnostics.

Abstract Playing music is a complex task that relies on the combination of musicians’ technical and expressive skills. While the literature has investigated the effects of musical expressivity on the listeners, the way how technical difficulty and emotional expressivity affect musicians during playing has surprisingly received no attention. In an attempt to fill this gap in the literature, we collected behavioral and physiological data from twelve violinists playing 29 pieces that included both technical exercises and excerpts from classical repertoire for violin. After playing each stimulus, participants rated it for emotional expressivity and technical difficulty. During the entire session, cardiac parameters and electrodermal activity were collected, together with the kinematic parameters of the bowing gesture. A set of Linear Mixed-Effect (LME) models suggested that emotional expressivity attributed to music affected the fluidity of bowing (i.e., smoothness), with the excerpts rated as more expressive being performed in a less smooth way. In contrast, LME models revealed no effects of expressivity and technical difficulty on any of the physiological parameters of violinists. Our results offer novel insights into the psychophysiological dynamics that link motor parameters with musical expressivity. These findings could influence educational practices in music and deepen our understanding of aesthetic emotions.

The effects of liquid organic fertilizer (LOF) made from anaerobic digestion on some physiological factors and volatile components of arugula plants that were grown in salty conditions were investigated. The experiment was conducted in three different stages. In the first two stages, seeds were grown in petri dishes and pots for seven days. The third stage involved growing seedlings in pots for 60 days. Salinity inhibited the germination of 7-day arugula seedlings in petri dishes and their emergence in pots. In these stages, LOF pretreatment failed to eliminate stress-induced inhibition. Some physiological parameters were analyzed in 60-day seedlings in the third stage. Salt-induced inhibition showed significant negative effects on all parameters. In contrast to previous stages, LOF (1% and 5%) and NPK had positive effects in all groups at the third stage, eliminating salt stress in all parameters except water content. Contrary to expectations, volatile components showed no significant change but had fluctuating values due to salt stress or fertilizer treatments.

PURPOSE: To assess the pharmacokinetics (PK) of subcutaneous immunoglobulin (SCIG) and hyaluronidase-facilitated SCIG (fSCIG) therapy across body mass index (BMI) and age categories in patients with primary immunodeficiency diseases (PIDD) previously treated with intravenous immunoglobulin (IVIG). METHODS: Using our previously published integrated population PK model based on data from eight clinical trials, simulations were conducted to examine the effects of BMI and age on serum immunoglobulin G (IgG) PK after administration of SCIG 0.15 g/kg weekly or fSCIG 0.6 g/kg every 4 weeks in patients switching from stable IVIG. Patients were assumed to have baseline IgG trough concentrations of 7 g/L (hypothetical protective threshold). RESULTS: Mean steady-state serum IgG trough values (Cmin,ss or trough) increased with BMI and age. Mean Cmin,ss was 18% (SCIG) and 16% (fSCIG) higher in the obese than the healthy BMI group. Pediatric patients aged

Early stages of life likely employed catalytic RNAs (ribozymes) in many functions that are today filled by proteins. However, the earliest life forms must have emerged from heterogenous chemical mixtures, which included amino acids, short peptides, and many other compounds. Here we explored whether the presence of short peptides can help the emergence of catalytic RNAs. To do this, we conducted an in vitro selection for catalytic RNAs from randomized sequence in the presence of ten different peptides with a prebiotically plausible length of eight amino acids. This in vitro selection generated dozens of ribozymes, one of them with ∼900-fold higher activity in the presence of one specific peptide. Unexpectedly, the beneficial peptide had retained its N-terminal Fmoc protection group, and this group was required to benefit ribozyme activity. The same, or higher benefit resulted from peptide conjugates with prebiotically plausible polyaromatic hydrocarbons (PAHs) such as fluorene and naphthalene. This shows that PAH-peptide conjugates can act as potent cofactors to enhance ribozyme activity. The results are discussed in the context of the origin of life.

Abstract Objective Multifocal motor neuropathy is a rare chronic immune‐mediated neuropathy with impaired grip strength representing a common symptom. While intravenous immunoglobulin G is an effective treatment for the disease, significant variation in treatment response has been observed but not well understood. This analysis characterized dose–exposure–response relationships in multifocal motor neuropathy, using grip strength as a clinical efficacy measure. Methods Serum immunoglobulin G trough concentrations and grip strength data for the more affected hand from a Phase 3, randomized, double‐blind, placebo‐controlled, crossover trial of intravenous immunoglobulin 10% in 44 patients with multifocal motor neuropathy (NCT00666263) were used to develop a population pharmacokinetic–pharmacodynamic model. Results The model adequately described the observed pharmacokinetic and pharmacodynamic data and relationships between intravenous immunoglobulin 10% dose, serum immunoglobulin G trough levels, grip strength, and inter‐patient variabilities in multifocal motor neuropathy. Model‐based simulations for various dosing regimens (0.4–2.0 g/kg every 2–4 weeks) indicated that ≥1.6 g/kg/month would achieve clinically meaningful improvements in grip strength (≥4 kg) in ≥70% of patients. More frequent dosing at an equivalent monthly dose led to a more consistent response in grip strength. Furthermore, splitting the dose over multiple days for high doses (>1 g/kg) did not impact grip strength. Interpretation These findings suggest that the majority of patients with multifocal motor neuropathy would respond rapidly to intravenous immunoglobulin 10% with a range of dosing regimens. Shorter dosing intervals may avoid the diminishing response seen with longer dosing intervals. Dose‐splitting provided similar outcomes while offering flexibility and convenience.