Kingsbrook Jewish Medical Center

Nineteen isolates of carbapenem-resistant Klebsiella species were recovered from 7 hospitals in New York City. Most K. pneumoniae belonged to a single ribotype. Nucleotide sequencing identified KPC-2, a carbapenem-hydrolyzing beta -lactamase. In 3 strains, TEM-30, an inhibitor-resistant beta -lactamase, was detected. Carbapenem-resistant Klebsiella species possessing KPC-2 are endemic in New York City. This study documents the identification of an inhibitor-resistant TEM beta -lactamase in the United States.

Parkinson disease is caused by neuronal loss in the substantia nigra which manifests by abnormality of movement, muscle tone, and postural stability. Several genes have been implicated in the pathogenesis of Parkinson disease, but the underlying molecular basis is still unknown for ,70% of the patients. Using homozygosity mapping and whole exome sequencing we identified a deleterious mutation in DNAJC6 in two patients with juvenile Parkinsonism. The mutation was associated with abnormal transcripts and marked reduced DNAJC6 mRNA level. DNAJC6 encodes the HSP40 Auxilin, a protein which is selectively expressed in neurons and confers specificity to the ATPase activity of its partner Hcs70 in clathrin uncoating. In Auxilin null mice it was previously shown that the abnormally increased retention of assembled clathrin on vesicles and in empty cages leads to impaired synaptic vesicle recycling and perturbed clathrin mediated endocytosis. Endocytosis function, studied by transferring uptake, was normal in fibroblasts from our patients, likely because of the presence of another J-domain containing partner which co-chaperones Hsc70-mediated uncoating activity in non-neuronal cells. The present report underscores the importance of the endocytic/lysosomal pathway in the pathogenesis of Parkinson disease and other forms of Parkinsonism.

A solitary tumor which by light microscopy was classified as a neurofibroma was found by electron microscopic study to be composed of parallel, elongate cells with collagen rich intervening matrix. The cells showed thin, polar cytoplasmic processes which extended long distances, frequent junctional complexes between cell processes, numerous surface vesicles, and either no or fragmented and variable basement membrane. Perineurial cells from small peripheral nerves of skin were demonstrated to have similar morphologic characteristics as the tumor cells. The present study, together with previous ultrastructural findings, indicate that benign peripheral nerve sheath tumors should be placed in at least three categories: Schwannoma, neurofibroma and perineurioma.

PURPOSE: Guidelines for writing patient case reports, with a focus on medication-related reports, are provided. SUMMARY: The format of a patient case report encompasses the following five sections: an abstract, an introduction and objective that contain a literature review, a description of the case report, a discussion that includes a detailed explanation of the literature review, a summary of the case, and a conclusion. The abstract of a patient case report should succinctly include the four sections of the main text of the report. The introduction section should provide the subject, purpose, and merit of the case report. It must explain why the case report is novel or merits review, and it should include a comprehensive literature review that corroborates the author's claims. The case presentation section should describe the case in chronological order and in enough detail for the reader to establish his or her own conclusions about the case's validity. The discussion section is the most important section of the case report. It ought to evaluate the patient case for accuracy, validity, and uniqueness; compare and contrast the case report with the published literature; derive new knowledge; summarize the essential features of the report; and draw recommendations. The conclusion section should be brief and provide a conclusion with evidence-based recommendations and applicability to practice. CONCLUSION: Patient case reports are valuable resources of new and unusual information that may lead to vital research.

We investigated upper-body (ie, trunk) angular kinematics (motions) during gait, stair climbing and descending, and rising from a chair in two reference frames--relative to the pelvis and to room coordinates. Bilateral kinematic data were collected from 11 healthy subjects (6 female, 5 male), who were 27 to 88 years of age (mean = 58.9, SD = 17.9). During stair climbing, maximum trunk flexion relative to the room was at least double that during stair descending and gait. Arising from a chair required the most trunk flexion/extension range of motion (ROM) but the least abduction/adduction and medial/lateral (internal/external) rotation. Trunk ROM during gait was small (mean less than or equal to 12 degrees) and consistent with previous literature. Trunk range of motion relative to the room during stair climbing and descending was greater than trunk ROM during gait in all planes. The pelvis and trunk rotate in the transverse plane in greater synchrony during stair descending (mean = 8.1 degrees, SD = 5.6 degrees) than during gait (mean = 12.0 degrees, SD = 4.2 degrees). For all activities, trunk frontal and sagittal ROM relative to the pelvis was greater than that relative to the room coordinates. This finding suggests that trunk/pelvis coordination may be used to reduce potentially destabilizing anti-gravity trunk motions during daily activities. We conclude that upper-body kinematics relative to both pelvis and gravity during daily activities are important to locomotor control and should be considered in future studies of patients with locomotor disabilities.

In 4 infants with a new lethal autonomic sensory neuropathy with clinical features similar to familial dysautonomia as well as contractures, we identified a deleterious mutation in the DST gene, using homozygosity mapping followed by exome sequencing. DST encodes dystonin, a cytoskeleton linker protein, and the mutation results in an unstable transcript. Interestingly, dystonin is significantly more abundant in cells of familial dysautonomia patients with IKBKAP (I-κ-B kinase complex-associated protein) mutation compared to fibroblasts of controls, suggesting that upregulation of dystonin is responsible for the milder course in familial dysautonomia. Homozygosity mapping followed by exome sequencing is a successful approach to identify mutated genes in rare monogenic disorders.

STUDY OBJECTIVES: To date, conflicting observations have been made regarding ethnic differences in sleep patterns. Plausibly, differing sampling strategies and disparity in the cohorts investigated might help explain discrepant findings. To our knowledge population-based studies investigating ethnic differences in sleep complaints have not addressed within-group ethnic heterogeneity, although within-group health disparities have been documented. DESIGN: Volunteers (n =1118) in this study were community-residing older European Americans and African Americans residing in Brooklyn, New York, which were recruited by a stratified, cluster sampling technique. Trained interviewers of the same race as the respondents gathered data during face-to-face interviews conducted either in the respondent's home or another location of their choice. Data included demographic and health risk factors, physical health, social support, and emotional experience. Relationships of demographic and health risk factors to sleep disturbances were examined in multiple linear regression analyses. Within-group differences in sleep complaints were also explored. SETTING: N/A. PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Of the factors showing significant associations with sleep disturbance, European American ethnicity was the most significant predictor (r2 = 0.20). Worse sleep and greater reliance on sleep medicine were observed among European Americans. Caribbean Americans reported less sleep complaints than did U.S.-born African Americans, and immigrant European Americans reported greater complaints than did US-born European Americans. CONCLUSIONS: As expected several health risk factors were predictive of sleep disturbance among urban community-dwelling older adults, but ethnicity was the most significant predictor. The present data suggest both between-group and within-group ethnic differences in sleep complaints. Understanding of demographic and cultural differences between African Americans and European Americans may be critical in interpreting subjective health-related data.

OBJECTIVE: To determine if the spread of Clostridium difficile-associated diarrhea is related to the use of electronic thermometers in an acute hospital and a chronic healthcare facility. DESIGN: After finding that a significant percentage (20.8%) of electronic rectal thermometer handles were contaminated with C difficile, all electronic thermometers were replaced with disposables. A before/after trial was conducted to determine if the change to disposable thermometers would reduce the incidence of C difficile-associated diarrhea. SETTING: The study took place in a 343-bed acute hospital and a 538-bed skilled nursing facility. PATIENTS: All patients who underwent routine microbiological evaluation for nosocomially acquired diarrhea over a 1-year period were included in the study. Nosocomial diarrhea was defined as 3 or more loose stools per day for 2 consecutive days and/or abdominal findings such as pain, distension, and ileus occurring 3 or more days after admission. RESULTS: During the 6-month postintervention period, the incidence of C difficile-associated diarrhea was reduced from 2.71/1,000 patient days to 1.76/1,000 patient days in the acute hospital and from 0.41/1,000 patient days to 0.11/1,000 patient days in the skilled nursing facility. The protective effect of the intervention was statistically significant for both facilities. CONCLUSIONS: Replacement of electronic thermometers with single-use disposables significantly reduced the incidence of C difficile-associated diarrhea in both acute care and skilled nursing care facilities. Data suggest that the rectal route may be important in the transmission of C difficile in these settings.

The SH2B adaptor protein 3 (SH2B3) gene encodes a negative regulator of cytokine signaling with a critical role in the homeostasis of hematopoietic stem cells and lymphoid progenitors. Here, we report the identification of germline homozygous SH2B3 mutations in 2 siblings affected with developmental delay and autoimmunity, one in whom B-precursor acute lymphoblastic leukemia (ALL) developed. Mechanistically, loss of SH2B3 increases Janus kinase-signal transducer and activator of transcription signaling, promotes lymphoid cell proliferation, and accelerates leukemia development in a mouse model of NOTCH1-induced ALL. Moreover, extended mutation analysis showed homozygous somatic mutations in SH2B3 in 2 of 167 ALLs analyzed. Overall, these results demonstrate a Knudson tumor suppressor role for SH2B3 in the pathogenesis of ALL and highlight a possible link between genetic predisposition factors in the pathogenesis of autoimmunity and leukemogenesis.

A carbapenem-resistant isolate of Escherichia coli was identified that possessed a 23-kb plasmid encoding Klebsiella pneumoniae carbapenemase type 2 (KPC-2). A subsequent surveillance study involving hospitals in Brooklyn, New York, revealed that, among 1417 E. coli isolates, 7 isolates (from 3 hospitals) possessed bla(KPC-2). E. coli possessing KPC-2 is emerging in our region, and improved methods for detection are urgently needed.

Abstract Subacromial decompression is one of the most commonly performed shoulder procedures. Debridement of the subacromial soft tissues is a critical part of the procedure. However, the extent of soft tissue debridement is not well defined. The purpose of this study was to identify neural elements within the soft tissues composing the subacromial space. Using special immunohistochemical stains and electron microscopy, neural elements were identified within the subacromial bursa, rotator cuff tendon, biceps tendon and tendon sheat, and transverse humeral ligament. There was a significantly richer supply of free nerve fibers in the bursa compared with the other tissues. The nociceptive information relayed by these fibers may be responsible for the pain associated with impingement syndrome.

ABSTRACT: A random sampling of 160 patients in a chronic disease facility showed that 36 patients (22.5 percent) had chronic hyponatremia. Their mean age was 72 years (range, 42–94 years); 75 percent of the patients were more than 65 years old. Women comprised 57 percent of the group. The mean serum sodium level was 120 mEq/L (range, 109–135 mEq/L). The mean serum osmolarity was 270 mOsm/L (range, 251–294 mOsm/L). Of the 36 patients, 9 were asymptomatic. Symptoms were associated with underlying disorders rather than with hyponatremia, although in 9 patients the hyponatremia appeared to have intensified existing symptoms. The most common cause of hyponatremia (in 41.6 percent of 20 overhydrated patients) was inappropriate secretion of antidiuretic hormone ( IADH syndrome). Factors accounting for the high incidence of IADH were the age of the patient and the nature of the underlying disorders, particularly diseases associated with aging. Simple measures were used to manage the hyponatremia, e.g., water restriction for patients who were overhydrated; replacement of sodium chloride for patients who were losing salt excessively and had a low sodium intake; and control of hyperglycemia in the pseudohyponatremic patients with hyperglycemia. No treatment was required for pseudohyponatremia associated with hyperlipidemia. When hyponatremia was due to drug‐induced ADH excess, the involved drug was discontinued. Emphasis on management of the patients' primary disorders also ameliorated the hyponatremic state.

OBJECTIVE: To provide ICU clinicians with evidence-based guidance on safe medication use practices for the critically ill. DATA SOURCES: PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, Scopus, and ISI Web of Science for relevant material to December 2015. STUDY SELECTION: Based on three key components: 1) environment and patients, 2) the medication use process, and 3) the patient safety surveillance system. The committee collectively developed Population, Intervention, Comparator, Outcome questions and quality of evidence statements pertaining to medication errors and adverse drug events addressing the key components. A total of 34 Population, Intervention, Comparator, Outcome questions, five quality of evidence statements, and one commentary on disclosure was developed. DATA EXTRACTION: Subcommittee members were assigned selected Population, Intervention, Comparator, Outcome questions or quality of evidence statements. Subcommittee members completed their Grading of Recommendations Assessment, Development, and Evaluation of the question with his/her quality of evidence assessment and proposed strength of recommendation, then the draft was reviewed by the relevant subcommittee. The subcommittee collectively reviewed the evidence profiles for each question they developed. After the draft was discussed and approved by the entire committee, then the document was circulated among all members for voting on the quality of evidence and strength of recommendation. DATA SYNTHESIS: The committee followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation system to determine quality of evidence and strength of recommendations. CONCLUSIONS: This guideline evaluates the ICU environment as a risk for medication-related events and the environmental changes that are possible to improve safe medication use. Prevention strategies for medication-related events are reviewed by medication use process node (prescribing, distribution, administration, monitoring). Detailed considerations to an active surveillance system that includes reporting, identification, and evaluation are discussed. Also, highlighted is the need for future research for safe medication practices that is specific to critically ill patients.

Hearing loss is the most prevalent sensory perception deficit in humans, affecting 1/500 newborns, can be syndromic or nonsyndromic and is genetically heterogeneous. Nearly 80% of inherited nonsyndromic bilateral sensorineural hearing loss (NBSNHI) is autosomal recessive. Although many causal genes have been identified, most are minor contributors, except for GJB2, which accounts for nearly 50% of all recessive cases of severe to profound congenital NBSNHI in some populations. More than 60% of children with a NBSNHI do not have an identifiable genetic cause. To identify genetic contributors, we genotyped 659 GJB2 mutation negative pediatric probands with NBSNHI and assayed for copy number variants (CNVs). After identifying 8 mild-moderate NBSNHI probands with a Chr15q15.3 deletion encompassing the Stereocilin (STRC) gene amongst this cohort, sequencing of STRC was undertaken in these probands as well as 50 probands and 14 siblings with mild-moderate NBSNHI and 40 probands with moderately severe-profound NBSNHI who were GJB2 mutation negative. The existence of a STRC pseudogene that is 99.6% homologous to the STRC coding region has made the sequencing interpretation complicated. We identified 7/50 probands in the mild-moderate cohort to have biallelic alterations in STRC, not including the 8 previously identified deletions. We also identified 2/40 probands to have biallelic alterations in the moderately severe-profound NBSNHI cohort, notably no large deletions in combination with another variant were found in this cohort. The data suggest that STRC may be a common contributor to NBSNHI among GJB2 mutation negative probands, especially in those with mild to moderate hearing impairment.

<div><p>As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at <a href="https://ibd.broadinstitute.org" target="_blank">https://ibd.broadinstitute.org</a>, also available in gnomAD at <a href="http://gnomad.broadinstitute.org" target="_blank">http://gnomad.broadinstitute.org</a>). We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 148 AJ enriched protein-altering alleles that overlap with "pathogenic" ClinVar alleles (table available at <a href="https://github.com/macarthur-lab/clinvar/blob/master/output/clinvar.tsv" target="_blank">https://github.com/macarthur-lab/clinvar/blob/master/output/clinvar.tsv</a>), including those that account for 10–100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases, especially recessive conditions, including Gaucher disease (<i>GBA</i>, p.Asn409Ser, 8-fold enrichment); Canavan disease (<i>ASPA</i>, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (<i>HEXA</i>, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohn's disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically attempt to evaluate whether strong acting rare alleles, particularly protein-truncating or otherwise large effect-size alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohn's disease in AJ, and find that ten rare genetic risk factors in <i>NOD2</i> and <i>LRRK2</i> are enriched in AJ (p < 0.005), including several novel contributing alleles, show evidence of association to CD. Independently, we find that genomewide common variant risk defined by GWAS shows a strong difference between AJ and non-AJ European control population samples (0.97 s.d. higher, p<10<sup>−16</sup>). Taken together, the results suggest coordinated selection in AJ population for higher CD risk alleles in general. The results and approach illustrate the value of exome sequencing data in case-control studies along with reference data sets like ExAC (sites VCF available via FTP at <a href="http://ftp.broadinstitute.org/pub/ExAC_release/release0.3/" target="_blank">ftp.broadinstitute.org/pub/ExAC_release/release0.3/</a>) to pinpoint genetic variation that contributes to variable disease predisposition across populations.</p></div>

BACKGROUND: Human congenital non-syndromic hydrocephalus is a vastly heterogeneous condition. A subgroup of cases are not secondary to a specific cause (eg, a neural tube defect), and within this subgroup, autosomal recessive inheritance has been described. One homozygous mutation in the DAPLE (Dvl-associating protein with a high frequency of leucine residues) protein-encoding gene CCDC88C (coiled-coil domain containing 88C) has recently been reported in a single family. The role of this gene has not been validated in another family, and no other autosomal recessive gene has been reported. METHODS: We used homozygosity mapping and whole exome sequencing in two families with primary, non-syndromic congenital hydrocephalus from two different ethnic backgrounds. RESULTS: In each family, we identified a novel homozygous mutation of CCDC88C. One mutation produced a premature stop codon at position 312 of the protein, while the second mutation induced a frameshift in the last exon, producing a stop codon that truncated the extreme C-terminus of DAPLE, including the 2026-2028 Gly-Cys-Val motif known to bind the post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein (zo-1) (PDZ) domain of Dishevelled. CONCLUSIONS: Our data validate CCDC88C as causing autosomal recessive, primary non-syndromic congenital hydrocephalus, suggesting this gene may be an important cause of congenital hydrocephalus, and underscore the important role of the C-terminal PDZ domain-binding motif in the DAPLE protein.

Bacterial contamination with pan-resistant Acinetobacter and Klebsiella, multidrug-resistant Pseudomonas, and methicillin-resistant Staphylococcus aureus (MRSA) was noted on the surfaces of dispensers of hand soap with 2% chlorhexidine. Gram-negative isolates could multiply in the presence of 1% chlorhexidine. In contrast, MRSA was inhibited in vitro by chlorhexidine at concentrations as low as 0.0019%.

The absence of circadian zeitgebers in the social environment causes circadian misalignment, which is often associated with sleep disturbances. Circadian misalignment, defined as a mismatch between the sleep-wake cycle and the timing of the circadian system, can occur either because of inadequate exposure to the light-dark cycle, the most important synchronizer of the circadian system, or reduction in light transmission resulting from ophthalmic diseases (e.g., senile miosis, cataract, diabetic retinopathy, macular degeneration, retinitis pigmentosa, and glaucoma). We propose that glaucoma may be the primary ocular disease that directly compromises photic input to the circadian time-keeping system because of inherent ganglion cell death. Glaucomatous damage to the ganglion cell layer might be particularly harmful to melanopsin. According to histologic and circadian data, a subset of intrinsically photoresponsive retinal ganglion cells, expressing melanopsin and cryptochromes, entrain the endogenous circadian system via transduction of photic input to the thalamus, projecting either to the suprachiasmatic nucleus or the lateral geniculate nucleus. Glaucoma provides a unique opportunity to explore whether in fact light transmission to the circadian system is compromised as a result of ganglion cell loss.

BACKGROUND: L-serine plays an essential role in neuronal development and function. Although a non-essential amino acid, L-serine must be synthesised within the brain because of its poor permeability by the blood-brain barrier. Within the brain, its synthesis is confined to astrocytes, and its shuttle to neuronal cells is performed by a dedicated neutral amino acid transporter, ASCT1. METHODS AND RESULTS: Using exome analysis we identified the recessive mutations, p.E256K, p.L315fs, and p.R457W, in SLC1A4, the gene encoding ASCT1, in patients with developmental delay, microcephaly and hypomyelination; seizure disorder was variably present. When expressed in a heterologous system, the mutations did not affect the protein level at the plasma membrane but abolished or markedly reduced L-serine transport for p.R457W and p.E256K mutations, respectively. Interestingly, p.E256K mutation displayed a lower L-serine and alanine affinity but the same substrate selectivity as wild-type ASCT1. CONCLUSIONS: The clinical phenotype of ASCT1 deficiency is reminiscent of defects in L-serine biosynthesis. The data underscore that ASCT1 is essential in brain serine transport. The SLC1A4 p.E256K mutation has a carrier frequency of 0.7% in the Ashkenazi-Jewish population and should be added to the carrier screening panel in this community.

OBJECTIVE: To contain a nosocomial outbreak of vancomycin-resistant Enterococcus (VRE). DESIGN: Intervention study, with comparison of incidence rates before and after intervention to assess whether changes in incidence followed the intervention and were greater than expected based on trends observed before the intervention. SETTING: A 343-bed acute-care hospital serving a predominantly elderly population referred from nursing homes, as well as patients admitted from the community. METHODS: Interventions strategies were tested on three high-risk nursing stations. These included enhanced environmental sanitation; intensive staff retraining in Universal Precautions, body substance isolation, and proper use of gloves; and the use of tympanic thermometers to avoid possible rectal or oral VRE transmission during temperature taking. RESULTS: Nosocomial VRE infections were reduced by 48% 9 months after switching to tympanic thermometers; incidence of Clostridium difficile infections also was reduced. As a result, tympanic thermometers were introduced facilitywide; additional observation for 20 months showed a risk reduction of 60% for VRE and 40% for C difficile. CONCLUSION: Cross-transmission of VRE and C difficile during temperature taking may result in bowel colonization, placing the patient at increased risk for infection. This risk may be reduced by the use of tympanic thermometers.