Publications by authors named "Lauren Donnelly"

14 Publications

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Changes in Attitudes and Knowledge after Trainings in a Clinical Care Pathway for Autism Spectrum Disorder.

J Autism Dev Disord 2020 Nov 17. Epub 2020 Nov 17.

Child Study Center, Department of Child and Adolescent Psychiatry, NYU Langone, New York, NY, 10016, USA.

Caring for individuals with autism spectrum disorder (ASD) can be complicated, especially when challenging behaviors are present. Providers may feel unprepared to work with these individuals because specialized training for medical and social service providers is limited. To increase access to specialized training, we modified an effective half-day ASD-Care Pathway training (Kuriakose et al. 2018) and disseminated it within five different settings. This short, focused training on strategies for preventing and reducing challenging behaviors of patients with ASD resulted in significant improvements in staff perceptions of challenging behaviors, increased comfort in working with the ASD population, and increased staff knowledge for evidence-informed practices. Implications, including the impact of sociodemographic characteristics on pre/post changes, and future directions are discussed.
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http://dx.doi.org/10.1007/s10803-020-04775-yDOI Listing
November 2020

Staff Perceptions and Implementation Fidelity of an Autism Spectrum Disorder Care Pathway on a Child/Adolescent General Psychiatric Inpatient Service.

J Autism Dev Disord 2021 Jan;51(1):158-168

Department of Child and Adolescent Psychiatry, Child Study Center, Hassenfeld Children's Hospital at NYU Langone, One Park Avenue, 7th Floor, New York, NY, 10016, USA.

While youth with autism spectrum disorder (ASD) are psychiatrically hospitalized at high rates, general psychiatric settings are not designed to meet their unique needs. Previous evaluations of an ASD-Care Pathway (ASD-CP) on a general psychiatric unit revealed sustained reductions in crisis interventions (intramuscular medication use, holds/restraints; Cervantes et al. in J Autism Dev Disord 49(8):3173-3180, https://doi.org/10.1007/s10803-019-04029-6 , 2019; Kuriakose et al. in J Autism Dev Disord 48(12):4082-4089, https://doi.org/10.1007/s10803-018-3666-y , 2018). The current study investigated staff perceptions of the ASD-CP (N = 30), and examined rates of ASD-CP implementation fidelity in relation to patient outcomes (N = 28). Staff identified visual communication aids and reward strategies as most helpful. The number of days of reward identification early in the inpatient stay was associated with fewer crisis interventions later in a patient's stay.
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http://dx.doi.org/10.1007/s10803-020-04509-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034489PMC
January 2021

Brief Report: A Job-Based Social Skills Program (JOBSS) for Adults with Autism Spectrum Disorder: A Pilot Randomized Controlled Trial.

J Autism Dev Disord 2020 Dec;50(12):4527-4534

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.

Adults with autism spectrum disorder (ASD) have low employment rates; even those who are employed have low wages and limited hours. This study evaluated the effectiveness of the Job-Based Social Skills (JOBSS) curriculum, a manualized, 15-week, group-delivered intervention for adults with ASD. The intervention aimed to increase social-pragmatic skills necessary to obtain and maintain employment. Twenty-two adults were randomly assigned to either JOBSS intervention or wait-list control groups. Results showed significant improvement in social cognition, as reported by caregivers, among JOBSS group participants compared to wait-list control participants. Forty-five percent of intervention participants gained employment in the six months following participation. This curriculum has potential to improve social skills of adults with ASD, thereby increasing successful employment.
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http://dx.doi.org/10.1007/s10803-020-04482-8DOI Listing
December 2020

Differential effects of 'resurrecting' Csp pseudoproteases during Clostridioides difficile spore germination.

Biochem J 2020 04;477(8):1459-1478

Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, U.S.A.

Clostridioides difficile is a spore-forming bacterial pathogen that is the leading cause of hospital-acquired gastroenteritis. C. difficile infections begin when its spore form germinates in the gut upon sensing bile acids. These germinants induce a proteolytic signaling cascade controlled by three members of the subtilisin-like serine protease family, CspA, CspB, and CspC. Notably, even though CspC and CspA are both pseudoproteases, they are nevertheless required to sense germinants and activate the protease, CspB. Thus, CspC and CspA are part of a growing list of pseudoenzymes that play important roles in regulating cellular processes. However, despite their importance, the structural properties of pseudoenzymes that allow them to function as regulators remain poorly understood. Our recently solved crystal structure of CspC revealed that its pseudoactive site residues align closely with the catalytic triad of CspB, suggesting that it might be possible to 'resurrect' the ancestral protease activity of the CspC and CspA pseudoproteases. Here, we demonstrate that restoring the catalytic triad to these pseudoproteases fails to resurrect their protease activity. We further show that the pseudoactive site substitutions differentially affect the stability and function of the CspC and CspA pseudoproteases: the substitutions destabilized CspC and impaired spore germination without affecting CspA stability or function. Thus, our results surprisingly reveal that the presence of a catalytic triad does not necessarily predict protease activity. Since homologs of C. difficile CspA occasionally carry an intact catalytic triad, our results indicate that bioinformatic predictions of enzyme activity may underestimate pseudoenzymes in rare cases.
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http://dx.doi.org/10.1042/BCJ20190875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200643PMC
April 2020

The CspC pseudoprotease regulates germination of Clostridioides difficile spores in response to multiple environmental signals.

PLoS Genet 2019 07 5;15(7):e1008224. Epub 2019 Jul 5.

Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.

The gastrointestinal pathogen, Clostridioides difficile, initiates infection when its metabolically dormant spore form germinates in the mammalian gut. While most spore-forming bacteria use transmembrane germinant receptors to sense nutrient germinants, C. difficile is thought to use the soluble pseudoprotease, CspC, to detect bile acid germinants. To gain insight into CspC's unique mechanism of action, we solved its crystal structure. Guided by this structure, we identified CspC mutations that confer either hypo- or hyper-sensitivity to bile acid germinant. Surprisingly, hyper-sensitive CspC variants exhibited bile acid-independent germination as well as increased sensitivity to amino acid and/or calcium co-germinants. Since mutations in specific residues altered CspC's responsiveness to these different signals, CspC plays a critical role in regulating C. difficile spore germination in response to multiple environmental signals. Taken together, these studies implicate CspC as being intimately involved in the detection of distinct classes of co-germinants in addition to bile acids and thus raises the possibility that CspC functions as a signaling node rather than a ligand-binding receptor.
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http://dx.doi.org/10.1371/journal.pgen.1008224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636752PMC
July 2019

Sustainability of a Care Pathway for Children and Adolescents with Autism Spectrum Disorder on an Inpatient Psychiatric Service.

J Autism Dev Disord 2019 Aug;49(8):3173-3180

Department of Child and Adolescent Psychiatry, Child Study Center, Hassenfeld Children's Hospital, NYU Langone Health, New York, NY, USA.

Children with autism spectrum disorder (ASD) are frequently hospitalized within general psychiatric settings, which are not usually designed to meet their needs. An initial evaluation of a care pathway developed for youth with ASD receiving services in a general psychiatric inpatient unit (ASD-CP) showed promise in improving outcomes while using few resources (Kuriakose et al. in J Autism Dev Disord 48:4082-4089, 2018). As sustainability of inpatient psychiatric initiatives is imperative but rarely investigated, this study examined the stability of ASD-CP outcomes during an 18-month follow-up period (n = 15) compared to the 18-month initial evaluation (n = 20) and 18-month pre-implementation (n = 17) periods. Decreased use of crisis interventions, including holds/restraints and intramuscular medication use, was sustained in the 18 months after the initial implementation period. Implications and limitations are discussed.
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http://dx.doi.org/10.1007/s10803-019-04029-6DOI Listing
August 2019

A Clostridium difficile-Specific, Gel-Forming Protein Required for Optimal Spore Germination.

mBio 2017 01 17;8(1). Epub 2017 Jan 17.

Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont, USA

Clostridium difficile is a Gram-positive spore-forming obligate anaerobe that is a leading cause of antibiotic-associated diarrhea worldwide. In order for C. difficile to initiate infection, its aerotolerant spore form must germinate in the gut of mammalian hosts. While almost all spore-forming organisms use transmembrane germinant receptors to trigger germination, C. difficile uses the pseudoprotease CspC to sense bile salt germinants. CspC activates the related subtilisin-like protease CspB, which then proteolytically activates the cortex hydrolase SleC. Activated SleC degrades the protective spore cortex layer, a step that is essential for germination to proceed. Since CspC incorporation into spores also depends on CspA, a related pseudoprotease domain, Csp family proteins play a critical role in germination. However, how Csps are incorporated into spores remains unknown. In this study, we demonstrate that incorporation of the CspC, CspB, and CspA germination regulators into spores depends on CD0311 (renamed GerG), a previously uncharacterized hypothetical protein. The reduced levels of Csps in gerG spores correlate with reduced responsiveness to bile salt germinants and increased germination heterogeneity in single-spore germination assays. Interestingly, asparagine-rich repeat sequences in GerG's central region facilitate spontaneous gel formation in vitro even though they are dispensable for GerG-mediated control of germination. Since GerG is found exclusively in C. difficile, our results suggest that exploiting GerG function could represent a promising avenue for developing C. difficile-specific anti-infective therapies.

Importance: The spore-forming bacterium Clostridium difficile is a leading cause of health care-associated infections. While a subset of antibiotics can treat C. difficile infections (CDIs), the primary determinant of CDI disease susceptibility is prior antibiotic exposure, since it reduces the colonization resistance conferred by a diverse microflora. Thus, therapies that minimize perturbations to the gut microbiome should be more effective at reducing CDIs and their recurrence, the main source of disease complications. Given that spore germination is essential for C. difficile to initiate infection and that C. difficile uses a unique pathway to initiate germination, methods that inhibit distinct elements of germination could selectively prevent C. difficile disease recurrence. Here, we identify GerG as a C. difficile-specific protein that controls the incorporation of germinant signaling proteins into spores. Since gerG mutant spores exhibit germination defects and are less responsive to germinant, GerG may represent a promising target for developing therapeutics against CDI.
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http://dx.doi.org/10.1128/mBio.02085-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241399PMC
January 2017

Characterization of Clostridium difficile Spores Lacking Either SpoVAC or Dipicolinic Acid Synthetase.

J Bacteriol 2016 06 13;198(11):1694-1707. Epub 2016 May 13.

Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont, USA

Unlabelled: The spore-forming obligate anaerobe Clostridium difficile is a leading cause of antibiotic-associated diarrhea around the world. In order for C. difficile to cause infection, its metabolically dormant spores must germinate in the gastrointestinal tract. During germination, spores degrade their protective cortex peptidoglycan layers, release dipicolinic acid (DPA), and hydrate their cores. In C. difficile, cortex hydrolysis is necessary for DPA release, whereas in Bacillus subtilis, DPA release is necessary for cortex hydrolysis. Given this difference, we tested whether DPA synthesis and/or release was required for C. difficile spore germination by constructing mutations in either spoVAC or dpaAB, which encode an ion channel predicted to transport DPA into the forespore and the enzyme complex predicted to synthesize DPA, respectively. C. difficile spoVAC and dpaAB mutant spores lacked DPA but could be stably purified and were more hydrated than wild-type spores; in contrast, B. subtilis spoVAC and dpaAB mutant spores were unstable. Although C. difficile spoVAC and dpaAB mutant spores exhibited wild-type germination responses, they were more readily killed by wet heat. Cortex hydrolysis was not affected by this treatment, indicating that wet heat inhibits a stage downstream of this event. Interestingly, C. difficile spoVAC mutant spores were significantly more sensitive to heat treatment than dpaAB mutant spores, indicating that SpoVAC plays additional roles in conferring heat resistance. Taken together, our results demonstrate that SpoVAC and DPA synthetase control C. difficile spore resistance and reveal differential requirements for these proteins among the Firmicutes

Importance: Clostridium difficile is a spore-forming obligate anaerobe that causes ∼500,000 infections per year in the United States. Although spore germination is essential for C. difficile to cause disease, the factors required for this process have been only partially characterized. This study describes the roles of two factors, DpaAB and SpoVAC, which control the synthesis and release of dipicolinic acid (DPA), respectively, from bacterial spores. Previous studies of these proteins in other spore-forming organisms indicated that they are differentially required for spore formation, germination, and resistance. We now show that the proteins are dispensable for C. difficile spore formation and germination but are necessary for heat resistance. Thus, our study further highlights the diverse functions of DpaAB and SpoVAC in spore-forming organisms.
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http://dx.doi.org/10.1128/JB.00986-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959285PMC
June 2016

Identification of a Novel Lipoprotein Regulator of Clostridium difficile Spore Germination.

PLoS Pathog 2015 Oct 23;11(10):e1005239. Epub 2015 Oct 23.

Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont, United States of America.

Clostridium difficile is a Gram-positive spore-forming pathogen and a leading cause of nosocomial diarrhea. C. difficile infections are transmitted when ingested spores germinate in the gastrointestinal tract and transform into vegetative cells. Germination begins when the germinant receptor CspC detects bile salts in the gut. CspC is a subtilisin-like serine pseudoprotease that activates the related CspB serine protease through an unknown mechanism. Activated CspB cleaves the pro-SleC zymogen, which allows the activated SleC cortex hydrolase to degrade the protective cortex layer. While these regulators are essential for C. difficile spores to outgrow and form toxin-secreting vegetative cells, the mechanisms controlling their function have only been partially characterized. In this study, we identify the lipoprotein GerS as a novel regulator of C. difficile spore germination using targeted mutagenesis. A gerS mutant has a severe germination defect and fails to degrade cortex even though it processes SleC at wildtype levels. Using complementation analyses, we demonstrate that GerS secretion, but not lipidation, is necessary for GerS to activate SleC. Importantly, loss of GerS attenuates the virulence of C. difficile in a hamster model of infection. Since GerS appears to be conserved exclusively in related Peptostreptococcaeace family members, our results contribute to a growing body of work indicating that C. difficile has evolved distinct mechanisms for controlling the exit from dormancy relative to B. subtilis and other spore-forming organisms.
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http://dx.doi.org/10.1371/journal.ppat.1005239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619724PMC
October 2015

Regulation of Clostridium difficile Spore Formation by the SpoIIQ and SpoIIIA Proteins.

PLoS Genet 2015 Oct 14;11(10):e1005562. Epub 2015 Oct 14.

Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont, United States of America.

Sporulation is an ancient developmental process that involves the formation of a highly resistant endospore within a larger mother cell. In the model organism Bacillus subtilis, sporulation-specific sigma factors activate compartment-specific transcriptional programs that drive spore morphogenesis. σG activity in the forespore depends on the formation of a secretion complex, known as the "feeding tube," that bridges the mother cell and forespore and maintains forespore integrity. Even though these channel components are conserved in all spore formers, recent studies in the major nosocomial pathogen Clostridium difficile suggested that these components are dispensable for σG activity. In this study, we investigated the requirements of the SpoIIQ and SpoIIIA proteins during C. difficile sporulation. C. difficile spoIIQ, spoIIIA, and spoIIIAH mutants exhibited defects in engulfment, tethering of coat to the forespore, and heat-resistant spore formation, even though they activate σG at wildtype levels. Although the spoIIQ, spoIIIA, and spoIIIAH mutants were defective in engulfment, metabolic labeling studies revealed that they nevertheless actively transformed the peptidoglycan at the leading edge of engulfment. In vitro pull-down assays further demonstrated that C. difficile SpoIIQ directly interacts with SpoIIIAH. Interestingly, mutation of the conserved Walker A ATP binding motif, but not the Walker B ATP hydrolysis motif, disrupted SpoIIIAA function during C. difficile spore formation. This finding contrasts with B. subtilis, which requires both Walker A and B motifs for SpoIIIAA function. Taken together, our findings suggest that inhibiting SpoIIQ, SpoIIIAA, or SpoIIIAH function could prevent the formation of infectious C. difficile spores and thus disease transmission.
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http://dx.doi.org/10.1371/journal.pgen.1005562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605598PMC
October 2015

Do evidence-based group parenting programs for high-risk or maltreating parents include content about psychological maltreatment?: a program review.

Child Welfare 2012 ;91(2):7-37

Fontana Center, New York, Foundling, USA.

Psychological maltreatment (PM) is a wide-spread form of child maltreatment, both in high-risk and maltreating parents, yet there are no intervention programs that target it directly. In this study, the content of parenting programs for high-risk and maltreating parents was assessed to determine whether the program manuals include content on PM. Nine evidence-based group parenting programs for high-risk or maltreating parents (e.g., included in the SAMHSA or a comparable model program registry) were identified. Program manuals were rated for whether they included content on 18 types of psychological maltreatment (PM). Only one type of PM was rated as being included in all nine programs. Not one of the remaining PM types was rated as being included in more than four programs; and many of the PM types were not rated as being included in any program manual. Therefore, existing parenting program manuals do not contain content related to many forms of psychological maltreatment.
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March 2013

Primary healthcare transformation: moving from common sense to common practice.

Healthc Pap 2012 ;12(2):46-50; discussion 66-70

Health Quality Council.

There is no disputing that the key to any high-performing healthcare system is a high-performing primary healthcare system. As health systems around the globe grapple with aging, sicker populations, variable quality of care and unsustainable growth in health expenditures, the overhauling of primary healthcare cannot be put off any longer. Patient centred. Community designed. Team delivered. These are the tenets behind Saskatchewan's recently released framework for achieving a high-performing primary healthcare system. It has much in common with the primary healthcare framework offered by Kates and colleagues; and given its promising genesis, perhaps (finally) what has eluded many health systems so far can be achieved in the province that 50 years ago led the country in healthcare innovation.
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http://dx.doi.org/10.12927/hcpap.2012.22983DOI Listing
September 2012

How well do evidence-based universal parenting programs teach parents about psychological maltreatment?: a program review.

Child Abuse Negl 2011 Oct 19;35(10):855-65. Epub 2011 Oct 19.

Fontana Center for Child Protection, NY 10014, USA.

Objective: Psychological maltreatment (PM) is a widespread form of child maltreatment both in high-risk and maltreating families as well as in the general population of parents, yet there are no intervention programs that target it directly. The current study was designed as the first step in a larger program of research concerning educating parents about PM. In this study we evaluated the content of universal parenting programs to assess whether they include content on PM. Three questions were addressed: (1) Which types, if any, of PM were included in the content of these programs? (2) Which programs, if any, have content about each of the types of PM? (3) What are the implications for the development of PM curricula for parents?

Method: Ten evidence-based, manualized, universal parenting programs identified from SAMHSA or a comparable model program registry were rated on how well their content covered 18 types of psychological maltreatment (PM), as defined by the American Professional Society on the Abuse of Children, APSAC (Bingelli, Hart, & Brassard, 2001; Hart & Brassard, 1995). Each type of PM was coded along several dimensions which resulted in two summary scores: (1) Does the program contain content designed to teach parents what not to do in regards to the 18 psychologically maltreating behaviors and (2) Does the program contain content designed to teach parents what to do instead?

Results: Content related to most PM types were not included in the curricula, especially regarding "what not to do" and not one program was rated as having content related to teaching all 18 types of PM.

Conclusions: Existing parenting programs do not currently cover content for teaching community parents about psychological maltreatment.
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http://dx.doi.org/10.1016/j.chiabu.2011.05.013DOI Listing
October 2011

The Saskatchewan Surgical Care Network--toward timely and appropriate access.

Hosp Q 2003 ;7(1):44-8, 4

Acute and Emergency Services Branch, Saskatchewan Health.

Earlier this year, a paper in Hospital Quarterly, "Creating a Surgical Wait List Management Strategy for Saskatchewan," described the development of a surgical wait list strategy for Saskatchewan. The initial strategy development process uncovered several issues that needed to be addressed including lack of data, inconsistent priorities and frustration on the parts of both providers and patients. This second paper outlines the key points of the recommended surgical wait list strategy and the work to date in its implementation.
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http://dx.doi.org/10.12927/hcq..16613DOI Listing
February 2004