Sleep-disordered breathing in children and adults with intellectual disability: mind the gap!

BACKGROUND: In adults and children with intellectual disability (ID), sleep -disordered breathing (SDB) is thought to be common. However, large epidemiological studies are lacking, and there are few studies on optimal methods of investigation and even fewer randomised, controlled intervention trials of treatment. METHOD: Peer-reviewed publications from various databases were examined in line with search terms relevant to ID and SDB spanning the years 200-2024. RESULTS: Findings suggest that, due to comorbid conditions, children and adults with ID may experience both an increased risk of SDB, as well as lower frequency of diagnosis. SDB can compromise the emotional, physical and mental health of individuals with ID. Appropriate treatment when tolerated leads to an improvement in health and well-being and several studies emphasized the importance of consistent follow-up of people with ID - something that is not universally occurring during childhood, in the transition to adulthood and during adulthood itself. As the most frequently occurring form of ID worldwide, we use Down syndrome as a specific example of how diagnosing and treating SDB can lead to improved outcomes. CONCLUSIONS: This review highlights the importance of identifying SDB in this heterogenous population, recognising the multi-faceted, deleterious consequences of untreated SDB in people with ID, and presents some strategies that can be harnessed to improve diagnosis and management. Until further ID-specific research is available, we urge flexibility in the approach to people with ID and SDB based in guidelines and standard practice developed for the typically developing population.

Nitric oxide mediated kisspeptin regulation of steroidogenesis and gametogenesis in the catfish, Clarias batrachus.

Nitric oxide (NO) is a gaseous molecule that regulates various reproductive functions. It is a well-recognized regulator of GnRH-FSH/LH-sex steroid secretion in vertebrates including fish. Kisspeptin is a recently discovered neuropeptide which also regulates GnRH secretion. Nitrergic and kisspeptin neurons are reported in close physical contact in the mammalian brain suggesting their interactive role in the release of GnRH. The existence of kisspeptin and NOS is also demonstrated in vertebrate gonads, but information on their reciprocal relation in gonads, if any, is obscure. Therefore, attempts were made to evaluate the functional reciprocal relation between nitric oxide and kisspeptin in the catfish gonads, if any, by administering the nitric oxide synthase (NOS) inhibitor, L-NAME {N(G)-nitro-L-arginine methyl ester}, which reduces NO production, and kisspeptin agonist (KP-10) and assessing their impacts on the expressions of kisspeptin1, different NOS isoforms, NO and steroid production in the gonadal tissue. The results revealed that L-NAME suppressed the expression of kiss1 in gonads of the catfish establishing the role of NO in kisspeptin expression. However, KP-10 increased the expression of all the isoforms of NOSs (iNOS, eNOS, nNOS) and concurrently NO and steroids in the ovary and testis. In vitro studies also indicate that kisspeptin stimulates the production of NO and estradiol and testosterone levels in the gonadal explants and medium. Thus, in vivo results clearly suggest a reciprocal interaction between kisspeptin and NO to regulate the gonadal activity of the catfish. The in vitro findings further substantiate our contention regarding the interactive role of kisspeptin and NO in gonadal steroidogenesis.

Assessing bias in the causal role of HPV in oral cancer: A systematic review and meta-analysis.

OBJECTIVE: High-risk human papillomaviruses (HPV) are an established cause of oropharyngeal cancer. Their relationship with oral cancer remains unclear with detection ranging from 0% to 100%. HPV DNA detection or evidence of exposure alone is insufficient to conclude causality. This systematic review assesses the extent of bias in studies of HPV detection in cancers of the oral cavity. METHODS: PubMed, Ovid MEDLINE, EMBASE, and PsycInfo databases were searched for observational studies reporting the effect of HPV in oral cavity specific cancers. RESULTS: All 15 included studies presented HPV DNA detection or serum HPV-antibodies, none included mRNA E6/E7 analysis. Cases with oral cancer had 5.36 times (95% CI 3.29-8.72) higher odds of having HPV detected compared to controls. The odds of HPV detection were higher in cell-based (OR 6.93; 95% CI 0.82-58.55) and tissue samples (OR 5.28; 95% CI 3.41-8.18) than blood-based samples (OR 3.36; 95% CI 1.53-7.40). CONCLUSION: When cancer site is clearly differentiated between oropharynx and oral cavity, 12 studies showed strong association between HPV and oral cancer, but the available estimates lack internal validity due to inconsistent measurements, high confounding, and lack of gold standard testing. There is not high-quality evidence to conclude a causal relationship of HPV with oral cancer.

The workplace culture, mental health and wellbeing of early- and mid-career health academics: a cross-sectional analysis.

There are reports of poor working conditions for early and mid-career academics (EMCAs) in universities, however, empirical data using validated tools are scarce. We conducted an online, cross-sectional survey using validated tools to assess workplace satisfaction, exposure to workplace abuse, and mental health. Participants included employees of medical and health faculties of two of the largest Australian universities, surveyed between October 2020 and January 2021.Overall, 284 participants responded. Many reported job insecurity: half (50.7%) working on contracts with less than one remaining year. Workloads were considerable, with 89.5% of participants working overtime and 54.8% reporting burnout. Workplace abuse in the forms of bullying (46.6%), sexual harassment (25.3%), sexism (49.8%) and racism (22.5%) were commonly reported. Clinically significant symptoms of depression (28.0%), anxiety (21.7%) and suicidal ideation or self-harm (13.6%) were reported; with a higher prevalence among those working more overtime, and those exposed to workplace abuse. Priorities include providing a stable and safe workplace, increasing accountability and transparency in addressing workplace abuse, and supporting professional development.In summary, EMCAs in our study were commonly exposed to precarious employment conditions and workplace abuse. Our findings provide empirical evidence on where universities and funding bodies should direct resources and change organisational risk factors, to improve workplace culture.

Social inequities in early childhood caries in Australia: A population-based study on statewide public dental services data.

BACKGROUND: Social disadvantage leads to dental caries during childhood. AIM: This study investigated whether dental caries occur earlier in children from households experiencing social disadvantage than those not experiencing social disadvantage. DESIGN: The overall risk of, and relative time to, early childhood caries (ECC) according to sociodemographic characteristics in Victoria, Australia, was quantified. Records for 134 463 children in Victoria, Australia, from 2009 to 2019 were analysed. Time ratios (TR) and hazard ratios (HR) of carious lesion(s) in early childhood were estimated. RESULTS: Compared with reference groups, Indigenous children had an adjusted TR of 0.80 (95% CI: 0.78, 0.82), children from households with languages other than English had an adjusted TR of 0.83 (95% CI: 0.82, 0.84), and dependants of concession cardholders had an adjusted TR of 0.81 (95% CI: 0.80, 0.81); therefore, 20%, 17% and 19% reduced times to the first carious lesion, respectively. The estimated HRs were 1.57 (95% CI: 1.49, 1.67) for Indigenous children, 1.46 (95% CI: 1.42, 1.50) for children from households with other languages and 1.57 (CI: 1.53, 1.60) for dependants of concession cardholders. CONCLUSION: Preventive oral health interventions must be targeted early in children from households experiencing social disadvantage to avoid social inequities in ECC.

Effectiveness of school oral health programs in children and adolescents: an umbrella review.

AIM: To evaluate the systematic reviews assessing the effectiveness of any type of school-based oral health programs in children and adolescents. METHODOLOGY: A two-staged search strategy comprising electronic databases and registries based on systematic reviews was employed to evaluate the effectiveness of school-based interventions. The quality assessment of the systematic reviews was carried out using the Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR-2) tool. The Corrected Covered Area was used to evaluate the degree of overlap. RESULTS: Nine reviews were included in this umbrella review. The Critical Covered Area reported moderate overlap (5.70%) among the primary studies. The assessment of risk of bias revealed one study with a high level confidence; one with moderate whereas all other studies with critically low confidence. Inconclusive evidence related to improvements in dental caries and gingival status was reported whereas, plaque status improved in a major proportion of the reviews. Knowledge, attitude, and behavior significantly increased in students receiving educational interventions when compared to those receiving usual care. CONCLUSIONS: The evidence points to the positive impact of these interventions in behavioral changes and clinical outcomes only on a short term basis. There is a need for long-term follow-up studies to substantiate the outcomes of these interventions.

Yield estimation of radionuclides from 6,7Li-induced reactions: A comparative analysis for 97,95Ru.

The article reports the production yields of the medically relevant Ru radionuclides and other co-produced radionuclides from 6,7Li-induced reactions on 93Nb target within the 20-45 MeV energy range. The residues were measured employing the activation technique followed by the offline γ-spectroscopy. Statistical model calculations using EMPIRE3.2.2 code are employed to assess the optimized nuclear model parameters and production mechanisms of the residues. As an outcome, new data from 6Li reaction suggests 9720 MBq/C of thick target yield (TTY) for the production of 95Ru with minimal impurities. While 7Li reaction may be relied upon for producing 97Ru, yielding 813 MBq/C TTY within the studied energy range.

Biomaterial-Based Therapeutic Delivery of Immune Cells.

Immune cell therapy (ICT) is a transformative approach used to treat a wide range of diseases including type 1 diabetes, sickle cell disease, disorders of the hematopoietic system, and certain forms of cancers. Despite excellent clinical successes, the scope of adoptively transferred immune cells is limited because of toxicities like cytokine release syndrome and immune effector cell-associated neurotoxicity in patients. Furthermore, reports suggest that such treatment can impact major organ systems including cardiac, renal, pulmonary, and hepatic systems in the long term. Additionally, adoptively transferred immune cells cannot achieve significant penetration into solid tissues, thus limiting their therapeutic potential. Recent studies suggest that biomaterial-assisted delivery of immune cells can address these challenges by reducing toxicity, improving localization, and maintaining desired phenotypes to eventually regain tissue function. In this review, recent efforts in the field of biomaterial-based immune cell delivery for the treatment of diseases, their pros and cons, and where these approaches stand in terms of clinical treatment are highlighted.

DNA functionalized programmable hybrid biomaterials for targeted multiplexed applications.

With the advent of DNA nanotechnology, DNA-based biomaterials have emerged as a unique class of materials at the center of various biological advances. Owing to DNA's high modification capacity via programmable Watson-Crick base-pairing, DNA structures of desired design with increased complexity have been developed. However, the limited scalability, along with poor mechanical properties, high synthesis costs, and poor stability, reduced the adaptability of DNA-based materials to complex biological applications. DNA-based hybrid biomaterials were designed to overcome these limitations by conjugating DNA with functional materials. Today, DNA-based hybrid materials have attracted significant attention in biological engineering with broad application prospects in biomedicine, clinical diagnosis, and nanodevices. Here, we summarize the recent advances in DNA-based hybrid materials with an in-depth understanding of general molecular design principles, functionalities, and applications. Finally, the challenges and prospects associated with DNA-based hybrid materials are discussed at the end of this review.

Statistical modelling, optimization, and mechanistic exploration of novel ureolytic Enterobacter hormaechei IITISM-SA3 in cadmium immobilization under microbial inclusive and cell-free conditions through microbially induced calcite precipitation.

The study aimed to evaluate the potential of a novel isolated ureolytic Enterobacter hormaechei IITISM-SA3 in cadmium bioremoval through MICP. The optimization and modelling of the biotic and abiotic factors affecting the process of mineralization were also performed. In addition, the underlying mechanism of MICP-driven Cd mineralization under microbial-inclusive and cell-free conditions was revealed and supported through the characterization of the bio-precipitates obtained using various characterization techniques. The results indicated that the isolate could remove 97.18% Cd2+ of 11.4 ppm under optimized conditions of 36.86 h, pH 7.63, and biomass dose of 1.75 ml. Besides, the presence and absence of bacterial cells were found to influence both the morphologies and crystalline structures of precipitates. The precipitates obtained under microbial-inclusive conditions showed typical rhombohedral crystalline structures of the composition comprising CaCO3, CdCO3, and 0.67Ca0.33CdCO3. However, the crystalline nature of the precipitate reduced to a nano-sized granular structure in cell-free media. Unlike the cadmium mineralization process under microbial-inclusive media, where bacterial cells serve as nucleation sites for crystallization, the carbonate precipitation effectively captures Cd2+ through co-precipitation, chemisorption, or alternative mechanisms involving interactions between metal ions and CaCO3 under cell-free conditions. The findings presented suggest that using cell-free culture supernatant enriched with carbonate ions provides an avenue that could be harnessed for sustainable metal remediation.

The effect of informal caring on mental health among adolescents and young adults in Australia: a population-based longitudinal study.

BACKGROUND: Young carers are people aged up to 25 years who provide unpaid care to a relative or a friend living with a long-term condition or a disability. Providing informal care is associated with poor mental health. Longitudinal evidence on this relationship among young people is scarce. To address this gap, we assessed the mental health of people aged 15-25 years when providing informal care compared with when not providing informal care. METHODS: We conducted a population-based longitudinal study using 20 years of data between 2001 and 2020 from the Household Income and Labour Dynamics in Australia (HILDA) survey. We included observations of participants aged 15-25 years with at least two observations across 20 waves of HILDA. Informal care was categorised as 0 h per week, 1-19 h per week, and 20 or more h per week. Mental health was measured using the Mental Health Inventory (MHI-5) from the 36-Item Short Form Survey (SF-36). Multivariate linear fixed-effects regression models were fitted to assess within-person changes in mental health when providing different levels of informal care. FINDINGS: Of 44 663 people with 410 658 observations who participated in HILDA waves 1 to 20, 32 726 were excluded with 351 445 observations. 11 937 young people (with 59 213 observations) were deemed eligible for this study and, of these, 8996 participants with 43 231 observations were included in the complete case analytical sample. When caring for 1-19 h per week, young carers had an MHI-5 score of -1·98 points (95% CI -3·06 to -0·89) compared with when caring for 0 h per week. Mental health was worse when caring for 20 or more h per week, with participants displaying an MHI-5 score of -3·47 points (95% CI -6·02 to -0·92) compared with when caring for 0 h per week. Our findings were consistent across sensitivity tests. INTERPRETATION: Our findings suggest potential mental health effects of informal care in young people, particularly when providing an intense amount of caregiving. Reducing young caring loads could be a possible avenue for intervention. FUNDING: Melbourne Disability Institute Scholarship, University of Melbourne Research Training Program Scholarship, Australian Research Council Discovery Early Career Researcher Award, National Health and Medical Research Council of Australia funded Centre of Research Excellence in Disability and Health.

Making the case for a new typology of dental care systems.

BACKGROUND AND RATIONALE: Dental care systems have the potential to influence population oral health and patterns of socioeconomic inequalities. Therefore, understanding the impact of the ways in which countries fund, provide, and organize their dental care services is key in the analysis of determinants of oral health. In this commentary we offer a synopsis of recent typologies of healthcare systems, based on a rapid review, and highlight that none of them fit dental care services given the separation of dental care from general healthcare provision in many countries. The paper also summarizes evidence on dental care systems as determinants of population oral health and argues why a new typology of dental care systems is needed. CHALLENGES AND WAYS FORWARD: We argue that a typology must consider institutional arrangements, structures, and processes behind the provision of dental care, and that specific dimensions/variables that inform the typology should result from a process of discussion and consensus. Some methodological considerations for developing typologies are also discussed, including the challenges in the collection and analysis of data followed by an advanced cluster analysis. Despite their limitations, typologies have evolved into an essential tool for comparing the similarities and differences of healthcare systems across countries. Therefore, a dental specific typology for health systems will be useful for researchers, policymakers, and dental professionals to characterize the provision of dentalcare services in different countries. This will also enable examining their potential role as determinants of population oral health and inequalities.

The Rapid Evaluation of Down Syndrome With Quantitative Fluorescence Polymerase Chain Reaction (QF-PCR): A Pilot Study Among the Population in Eastern Uttar Pradesh, India.

Background and objective Down syndrome (DS) is characterized by the presence of an additional chromosome; it is a typical chromosomal disorder causing intellectual disability in individuals. The diagnostic process for DS often involves conventional karyotyping, which can be time-consuming. Trisomy 21 and other chromosomal abnormalities may now be quickly and accurately diagnosed using quantitative fluorescence polymerase chain reaction (QF-PCR). In light of this, this study aimed to investigate chromosomal abnormalities in DS using conventional karyotyping and QF-PCR among the population in eastern Uttar Pradesh, India. Methods Blood samples from 40 individuals with clinically diagnosed DS were collected. Conventional karyotyping involved standard cytogenetic techniques, while QF-PCR utilized DNA extraction and analysis with chromosome-specific short tandem repeat (STR) markers. Results Various distinct physical characteristics were observed in the DS individuals, such as mongoloid slant and low-set ears. Karyotyping and QF-PCR analyses revealed different chromosomal configurations associated with DS trisomy 21, with additional chromosomal abnormalities found in some individuals, including partial monosomy 18 and mosaic trisomy 21. However, in a few cases, neither karyotyping nor QF-PCR revealed any abnormalities. Conclusions The study demonstrated that QF-PCR is a reliable and rapid method for diagnosing DS, providing results within 24 hours. This approach allows for the simultaneous diagnosis of a large number of samples and reduces the time required to obtain results. In the diagnostic procedure for DS, we believe QF-PCR will prove to be a useful tool. Furthermore, therapeutic interventions based on their clinical traits and molecular karyotyping can enhance the quality of life of people with DS.

Spatial immunophenotyping using multiplexed imaging of immune follicles in secondary lymphoid tissues.

Secondary lymphoid organs (SLOs), including tonsils (TS), lymph nodes (LN), and Peyer's Patches, exhibit complementary immune functions. However, little is known about the spatial organization of immune cells and extracellular matrix (ECM) in the SLOs. Traditional imaging is limited to a few markers, confining our understanding of the differences between the SLOs. Herein, imaging mass cytometry addressed this gap by simultaneously profiling 25-plex proteins in SLO tissues at subcellular resolution. The antibody panel targeted immune, stromal, chemokine, epigenetic, and functional markers. For robust cell identification, a computational workflow SpatialVizPheno was developed to spatially phenotype 999,970 cells using two approaches, including manual gating and semi-supervised gating, iterative clustering, and annotation. LN exhibited the highest density of B cells while the intestinal tissues contained the highest proportion of regulatory and follicular helper T cells. SpatialVizPheno identified the most prevalent interaction between follicular dendritic cells and stromal cells (SCs), plasmablasts/plasma cells, and the SCs across the lymphoid tissues. Collagen-enriched regions were associated with the spatial orientation of B cell follicles in both TS and LN tissues, but not in intestinal lymphoid tissues. Such spatial differences of immunophenotypes and ECM in different SLO tissues can be used to quantify the relationship between cellular organization and ultimate immune responses.

Comprehensive Genomics Investigation of Neboviruses Reveals Distinct Codon Usage Patterns and Host Specificity.

Neboviruses (NeVs) from the Caliciviridae family have been linked to enteric diseases in bovines and have been detected worldwide. As viruses rely entirely on the cellular machinery of the host for replication, their ability to thrive in a specific host is greatly impacted by the specific codon usage preferences. Here, we systematically analyzed the codon usage bias in NeVs to explore the genetic and evolutionary patterns. Relative Synonymous Codon Usage and Effective Number of Codon analyses indicated a marginally lower codon usage bias in NeVs, predominantly influenced by the nucleotide compositional constraints. Nonetheless, NeVs showed a higher codon usage bias for codons containing G/C at the third codon position. The neutrality plot analysis revealed natural selection as the primary factor that shaped the codon usage bias in both the VP1 (82%) and VP2 (57%) genes of NeVs. Furthermore, the NeVs showed a highly comparable codon usage pattern to bovines, as reflected through Codon Adaptation Index and Relative Codon Deoptimization Index analyses. Notably, yak NeVs showed considerably different nucleotide compositional constraints and mutational pressure compared to bovine NeVs, which appear to be predominantly host-driven. This study sheds light on the genetic mechanism driving NeVs' adaptability, evolution, and fitness to their host species.

Functionalized nanowires for miRNA-mediated therapeutic programming of naïve T cells.

Cellular programming of naïve T cells can improve the efficacy of adoptive T-cell therapy. However, the current ex vivo engineering of T cells requires the pre-activation of T cells, which causes them to lose their naïve state. In this study, cationic-polymer-functionalized nanowires were used to pre-program the fate of primary naïve CD8+ T cells to achieve a therapeutic response in vivo. This was done by delivering single or multiple microRNAs to primary naïve mouse and human CD8+ T cells without pre-activation. The use of nanowires further allowed for the delivery of large, whole lentiviral particles with potential for long-term integration. The combination of deletion and overexpression of miR-29 and miR-130 impacted the ex vivo T-cell differentiation fate from the naïve state. The programming of CD8+ T cells using nanowire-delivered co-delivery of microRNAs resulted in the modulation of T-cell fitness by altering the T-cell proliferation, phenotypic and transcriptional regulation, and secretion of effector molecules. Moreover, the in vivo adoptive transfer of murine CD8+ T cells programmed through the nanowire-mediated dual delivery of microRNAs provided enhanced immune protection against different types of intracellular pathogen (influenza and Listeria monocytogenes). In vivo analyses demonstrated that the simultaneous alteration of miR-29 and miR-130 levels in naïve CD8+ T cells reduces the persistence of canonical memory T cells whereas increases the population of short-lived effector T cells. Nanowires could potentially be used to modulate CD8+ T-cell differentiation and achieve a therapeutic response in vivo without the need for pre-activation.

T Cells Spatially Regulate B Cell Receptor Signaling in Lymphomas through H3K9me3 Modifications.

Activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is a subtype associated with poor survival outcomes. Despite identifying therapeutic targets through molecular characterization, targeted therapies have limited success. New strategies using immune-competent tissue models are needed to understand how DLBCL cells evade treatment. Here, synthetic hydrogel-based lymphoma organoids are used to demonstrate how signals in the lymphoid tumor microenvironment (Ly-TME) can alter B cell receptor (BCR) signaling and specific histone modifications, tri-methylation of histone 3 at lysine 9 (H3K9me3), dampening the effects of BCR pathway inhibition. Using imaging modalities, T cells increase DNA methyltransferase 3A expression and cytoskeleton formation in proximal ABC-DLBCL cells, regulated by H3K9me3. Expansion microscopy on lymphoma organoids reveals T cells increase the size and quantity of segregated H3K9me3 clusters in ABC-DLBCL cells. Findings suggest the re-organization of higher-order chromatin structures that may contribute to evasion or resistance to therapy via the emergence of novel transcriptional states. Treating ABC-DLBCL cells with a G9α histone methyltransferase inhibitor reverses T cell-mediated modulation of H3K9me3 and overcomes T cell-mediated attenuation of treatment response to BCR pathway inhibition. This study emphasizes the Ly-TME's role in altering DLBCL fate and suggests targeting aberrant signaling and microenvironmental cross-talk that can benefit high-risk patients.

Optimising Patient Outcomes in Tongue Cancer: A Multidisciplinary Approach.

A multidisciplinary approach to the management of tongue cancer is vital for achieving optimal patient outcomes. Nursing and allied health professionals play essential roles within the team. We developed symposia comprising a series of online lectures offering a detailed perspective on the role each discipline and consumer perspective has in the management of patients with tongue cancer. The topics, including epidemiology and prevention, diagnosis, treatment planning, surgery, adjuvant care, and the management of recurrent or metastatic disease, were thoroughly examined. The symposia highlighted the significance of fostering collaboration and continuous learning through a multidisciplinary approach. This initiative should be relevant to healthcare professionals, researchers, and policymakers striving to enhance patient outcomes in tongue cancer care through innovative collaboration.

Clinical, biochemical and outcome profile of dengue fever in hospitalised children in Eastern Uttar Pradesh, India.

Dengue fever is an important cause of acute febrile illness in the postmonsoon season in India. This study was done to record the incidence of dengue in admitted patients with acute febrile illness in a hospital setting. The study also intends to record the clinical, biochemical and outcome profile of paediatric dengue cases admitted in tertiary centres in Eastern Uttar Pradesh, India. It was a prospective case record analysis at a tertiary care research hospital in Eastern Uttar Pradesh. The study recruited fifty-53 children (<18 years) with serology-proven diagnosis of dengue disease. Disease was confirmed by doing Ns1Ag, IgM antibody test by ELISA method. Six hundred children were screened and 53 met the inclusion criteria. The incidence of dengue disease in hospitalised acute febrile illness was 8.8%. There were thirty-one males. The mean age of presentation of the study population was 9.32 ± 5 years with a range of 0.25 - 17 years. Fever (94%), nausea and vomiting (59 %), abdominal pain (55%), persistent vomiting (49%), thrombocytopenia (<100,000 [66%]), and petechiae and purpura (43%) were the important clinical manifestations. Six required intensive care monitoring. There was only one death. Dengue fever is an important cause of acute febrile illness in children. Case fatality rate can be minimised with proper World Health Organisation classification and protocol-based management of cases.