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“What inspired you to become a scientist?” That question was put to nearly 150 notable scientists, engineers, and mathematicians by the Internet magazineSpikedin 2006. The respondents hailed from all corners of the globe, ranged in age from 19 to 93, and represented the full scope of experience from new talent to Nobel laureates (spiked-online.com). While the answers are as diverse as the individuals who provided them, certain patterns emerged. Many, of course, credited superb schoolteachers with igniting the spark that led to a life in STEM. But an almost equal number pointed to non-teacher mentors and informal science

Summer outreach programs usually involve months of hard work to organize, yet the same level of detail is not reflected in the marketing of these programs. The often-misunderstood field of computer science is a good example of a group in need of a good public-relations campaign.

Hereditary spastic paraplegias (HSP) are rare, inherited neurodegenerative or neurodevelopmental disorders that mainly present with lower limb spasticity and muscle weakness due to motor neuron dysfunction. Whole genome sequencing identified bi-allelic truncating variants in AMFR , encoding a RING-H2 finger E3 ubiquitin ligase anchored at the membrane of the endoplasmic reticulum (ER), in two previously genetically unexplained HSP-affected siblings. Subsequently, international collaboration recognized additional HSP-affected individuals with similar bi-allelic truncating AMFR variants, resulting in a cohort of 20 individuals from 8 unrelated, consanguineous families. Variants segregated with a phenotype of mainly pure but also complex HSP consisting of global developmental delay, mild intellectual disability, motor dysfunction, and progressive spasticity. Patient-derived fibroblasts, neural stem cells (NSCs), and in vivo zebrafish modeling were used to investigate pathomechanisms, including initial preclinical therapy assessment. The absence of AMFR disturbs lipid homeostasis, causing lipid droplet accumulation in NSCs and patient-derived fibroblasts which is rescued upon AMFR re-expression. Electron microscopy indicates ER morphology alterations in the absence of AMFR. Similar findings are seen in amfra-/- zebrafish larvae, in addition to altered touch-evoked escape response and defects in motor neuron branching, phenocopying the HSP observed in patients. Interestingly, administration of FDA-approved statins improves touch-evoked escape response and motor neuron branching defects in amfra-/- zebrafish larvae, suggesting potential therapeutic implications. Our genetic and functional studies identify bi-allelic truncating variants in AMFR as a cause of a novel autosomal recessive HSP by altering lipid metabolism, which may potentially be therapeutically modulated using precision medicine with statins.

California sea lions (Zalophus californianus) exposed to anthropogenic noise may experience temporary hearing threshold shift (TTS). The function used in regulations to protect their hearing from such damage in the Pacific Ocean is based on only one datapoint, so more data are needed. To determine their frequency-dependent susceptibility to noise-induced TTS, two California sea lions were exposed for 60 minutes to a continuous one-sixth-octave noise band (NB) centered at 40 kHz as the fatiguing sound, at sound pressure levels of 119 to 143 dB re 1 µPa, resulting in sound exposure levels (SELs) of 155 to 179 dB re 1 µPa2s. TTSs were quantified at the center frequency of the fatiguing sound and up to one octave above that frequency (at 40, 50, 56.5, 63, and 80 kHz). Statistically significant TTS occurred at all hearing test frequencies; higher SELs caused greater TTSs. Significant onset of TTS(1-4 min) occurred after exposure to a minimum SEL of 167 dB re 1 µPa2s—a shift of 5.2 dB at hearing frequency 56.5 kHz. At other hearing frequencies, onset of TTS1-4 occurred at SEL 173 dB re 1 µPa2s. TTSs1-4 ≤ 8 dB recovered within 12 min, and TTSs1-4 of > 8 dB recovered within 60 min. TTSs and hearing recovery patterns were similar in both subjects. Comparison with TTS data for the species’ hearing frequency range (0.6 to 40 kHz) shows that after exposure to fatiguing sound frequencies of 0.6, 1, 4, 8, and 16 kHz, the largest TTS1-4 occurred half an octave above the frequency of each of the fatiguing sounds. After exposure to fatiguing sound frequencies 2, 32, and 40 kHz, the largest TTS occurred at the frequency of the fatiguing sounds. Recovery patterns after exposure to the NB at 40 kHz were similar to those after exposure to NBs at 0.6, 1, 2, 4, 8, 16, and 32 kHz. Over almost the entire hearing range, the shape of the audiogram is a poor predictor of the shape of the TTS-onset function. The low TTS-onset SELs show that the hearing of California sea lions is more vulnerable to injury by anthropogenic sound in the oceans than was previously thought.

Background: Treating rheumatic musculoskeletal diseases (RMDs) during pregnancy and breastfeeding presents significant complexities, mainly due to inconsistencies between the clinical guidance documents and the reference safety information, including the summary of product characteristics (SmPC) and the patient information leaflets (PIL). Objectives: To assess healthcare professionals’ (HCPs) prescribing behaviors, comfort levels, and challenges when advising patients, focusing on discrepancies between clinical guidance documents and SmPC/PIL. Design: Online survey entitled PRAISE (Perception of healthcare providers Regarding Antirheumatics in pregnancy and breastfeeding: advice, Information and patient perSpEctives) and disseminated through HCPs groups and social media. Methods: A cross-sectional survey was conducted among 414 HCPs globally. Respondents were divided into prescribers (n = 336) and non-prescribers (n = 78) based on their self-reported role in prescribing antirheumatic medications to pregnant or breastfeeding patients with RMDs. The survey covered demographics, clinical experience, confidence in prescribing, use of clinical guidelines, and experiences managing conflicting information between guidelines and SmPC/PIL. Results: Prescribers were more likely than non-prescribers to feel comfortable discussing medication safety during pregnancy. Most prescribers found clinical guidance documents useful, with 48% rating them as “very useful” and 38% as “extremely useful.” In case of conflicting information between clinical guidance documents and SmPC/PIL, 58% of HCPs reported that it caused confusion and tension in patient–doctor relationships, and almost 20% of them are “likely” or “very likely” to discontinue ongoing treatment. Clear communication and shared decision-making were the most common strategies used to address patient concerns. Conclusion: HCPs often face significant challenges when advising patients with RMDs on the use of medications during pregnancy and breastfeeding. Conflicting information between clinical guidance documents and SmPC/PIL can disrupt patient–doctor relationship and lead to treatment discontinuation, with potential consequences on maternal disease control. Improved alignment between clinical guidance documents and the SmPC/PIL could enhance patient care and prevent confusion among HCPs and patients. Plain language summary When the patient leaflet and the clinical guidelines say different things on the use of antirheumatic medications during pregnancy and breastfeeding: global health care providers say that conflicting information can cause confusion and tension in the patient-clinician relationship Background: When pregnant or breastfeeding, women with rheumatic musculoskeletal diseases (RMDs) face challenges in managing their condition due to conflicting information about medication safety. Healthcare providers (HCPs) often struggle with discrepancies between clinical guidelines and the safety information provided with medications, such as the Summary of Product Characteristics and Patient Information Leaflets. This discrepancy can lead to difficulties in advising patients about safe medication use during pregnancy and breastfeeding. HCPs might feel uncertain or uncomfortable discussing medication safety, which can affect the patient-doctor relationship and even lead to stopping necessary treatments. The PRAISE study: To understand these challenges better, the PRAISE study conducted an online survey among 414 HCPs worldwide. We aimed to assess how HCPs prescribe medications, their comfort levels in advising patients, and the challenges they face due to conflicting information. Our key findings include: Confidence in prescribing: HCPs who prescribe medications were more comfortable discussing medication safety during pregnancy than those who do not prescribe. Usefulness of guidelines: Most prescribers found clinical guidelines very useful in managing patient care. Conflicting information: Over half of the HCPs reported feeling confused or tense when dealing with conflicting information between guidelines and medication safety documents. This confusion can lead to discontinuing treatments, which might negatively impact disease control. Communication strategies: HCPs often use clear communication and shared decision-making to address patient concerns. In conclusion, PRAISE highlights the need for better alignment between clinical guidelines and medication safety information to improve patient care and reduce confusion. This could help ensure that pregnant and breastfeeding women with RMDs receive the best possible.

Background Previous exposures to flu and subsequent immune responses may impact on 2009/2010 pandemic flu vaccine responses and clinical symptoms upon infection with the 2009 pandemic H1N1 influenza strain. Qualitative and quantitative differences in humoral and cellular immune responses associated with the flu vaccination in 2009/2010 (pandemic H1N1 vaccine) and natural infection have not yet been described in detail. We designed a longitudinal study to examine influenza- (flu-) specific immune responses and the association between pre-existing flu responses, symptoms of influenza-like illness (ILI), impact of pandemic flu infection, and pandemic flu vaccination in a cohort of 2,040 individuals in Sweden in 2009–2010. Methods Cellular flu-specific immune responses were assessed by whole-blood antigen stimulation assay, and humoral responses by a single radial hemolysis test. Results Previous seasonal flu vaccination was associated with significantly lower flu-specific IFN-γ responses (using a whole-blood assay) at study entry. Pandemic flu vaccination induced long-lived T-cell responses (measured by IFN-γ production) to influenza A strains, influenza B strains, and the matrix (M1) antigen. In contrast, individuals with pandemic flu infection (PCR positive) exhibited increased flu-specific T-cell responses shortly after onset of ILI symptoms but the immune response decreased after the flu season (spring 2010). We identified non-pandemic-flu vaccinated participants without ILI symptoms who showed an IFN-γ production profile similar to pandemic-flu infected participants, suggesting exposure without experiencing clinical symptoms. Conclusions Strong and long-lived flu-M1 specific immune responses, defined by IFN-γ production, in individuals after vaccination suggest that M1-responses may contribute to protective cellular immune responses. Silent flu infections appeared to be frequent in 2009/2010. The pandemic flu vaccine induced qualitatively and quantitatively different humoral and cellular immune responses as compared to infection with the 2009 H1N1 pandemic H1N1 influenza strain.

The immune reconstitution inflammatory syndrome (IRIS) in HIV-infected infants and young children is relatively understudied in regions endemic for HIV and TB. We aimed to describe incidence, clinical features and risk factors of pediatric IRIS in Sub-Saharan Africa and India. We conducted an observational multi-centred prospective clinical study from December 2010 to September 2013 in children <72 months of age recruited from public antiretroviral programs. The main diagnostic criterion for IRIS was a new or worsening inflammatory event after initiating antiretroviral therapy (ART). Among 198 participants, median age 1.15 (0.48; 2.21) years, 38 children (18.8%) developed 45 episodes of IRIS. Five participants (13.2%) had two IRIS events and one (2.6%) had 3 events. Main causes of IRIS were BCG (n = 21; 46.7%), tuberculosis (n = 10; 22.2%) and dermatological, (n = 8, 17.8%). Four TB IRIS cases had severe morbidity including 1 fatality. Cytomegalovirus colitis and cryptococcal meningitis IRIS were also severe. BCG IRIS resolved without pharmacological intervention. On multivariate logistic regression, the most important baseline associations with IRIS were high HIV viral load (likelihood ratio [LR] 10.629; p = 0.0011), recruitment at 1 site (Stellenbosch University) (LR 4.01; p = 0.0452) and CD4 depletion (LR 3.4; p = 0.0654). Significantly more non-IRIS infectious and inflammatory events between days 4 and 17 of ART initiation were noted in cases versus controls (35% versus 15.2%: p = 0.0007). IRIS occurs commonly in HIV-infected children initiating ART and occasionally has severe morbidity. The incidence may be underestimated. Predictive, diagnostic and prognostic biomarkers are needed.

Influenza vaccination remains the cornerstone of global, regional and national public health efforts to reduce the impact of both recurrent influenza epidemics and infrequent pandemics. Effective influenza vaccination programmes rely upon the availability of vaccines that are well matched to the latest antigenic variants, and upon timely and equitable access to such vaccines. At the heart of influenza vaccine production lies the vaccine virus selection and development process (Fig. 1) implemented and coordinated by the WHO Global Influenza Surveillance and Response System (GISRS) super(2).