Pulmonary Adenocarcinoma Mimicking Pneumonia in a Young Adult.

Lung cancer is the third most common cancer in the United States. Lung adenocarcinoma is a subtype of non-small cell lung cancer. On computed tomography (CT) it can appear as ground glass nodules, consolidative opacity, or solid mass lesions located in the periphery. Because it can appear as a consolidation, it can sometimes be confused with an infectious process such as pneumonia. We present a case of a 27-year-old male initially diagnosed with pneumonia; however, three months later, when he presented to the hospital with worsening pleuritic chest pain, fever, and dyspnea after a bronchoscopy a week before admission, pathology was positive for adenocarcinoma.

An Interesting Case of Prostate Cancer Presenting With Colonic Metastasis.

Prostate cancer is common cancer that grows slowly and tends to metastasize to bones, lungs, and the liver. Most malignancies have established patterns in presentation, localization, and organs where they metastasize. We are presenting a case of a 60-year-old man who presented with abdominal pain and, on further investigation, was found to have polyps in the colon, a flat rectal mass with eccentric thickening of the rectum, a moderately enlarged prostate, and multiple liver masses suggestive of metastasis. It was initially thought to be colorectal cancer with metastasis but was eventually diagnosed as a stage IV prostate adenocarcinoma with metastases to the liver and rectum. It is very unusual for prostate cancer to present with distal metastasis to the liver and rectum, as in this case.

Initial Pain Assessment and Management in Pediatric Burn Patients Presenting to a Major Trauma Center in Saudi Arabia.

BACKGROUND: Pediatric burn injury is a traumatic experience for affected children and their families. Burn pain is frequently undertreated and may adversely affect patient experience and outcomes. The aim of this study was to investigate the current practice of initial pediatric burn pain assessment and management at a major trauma center in Riyadh, Kingdom of Saudi Arabia. METHODS: We conducted a retrospective cohort study that included children 14 years and younger who visited King Saud Medical City in the Kingdom of Saudi Arabia with a presenting complaint of burn injury from January 01, 2017 to August 30, 2018. Variables were reported using descriptive statistics as appropriate. RESULTS: The 309 patients who were analyzed were classified into 3 age groups ranging from 0 to younger than 3 years (61%), 3 to 7 years (24%), and older than 7 years (15%). They included 145 (47%) female and 164 (53%) male patients. Pain levels of 182 patients (59%) were documented using an age-appropriate tool. In 75 children (24%), pain levels were documented using an alternate tool, and the tool used was not defined for 44 children (14%). Pain assessment was not documented for 8 children. Of those with an age-appropriate tool, the median initial pain score was 4 (interquartile range [IQR], 2-4). Analgesia was recorded to have been administered to 139 patients (45%), within a median time of 50 minutes (IQR, 17-154 minutes) to first analgesia. Among patients who had appropriate assessment of pain, 92 (50.3%) received analgesia compared with 52 (41.3%) who did not have appropriate assessment (P = 0.12). Among patients who had appropriate pain assessment, time to analgesia was 42 minutes (IQR, 15-132 minutes) compared with 53 minutes (IQR, 17-189 minutes) among patients who did not have appropriate assessment (P = 0.48). DISCUSSION: Most pediatric patients presenting with burns had pain assessment, but a substantial proportion of children were not managed using recommended age-specific tools. The use of age-specific tools was not necessarily associated with delivery of analgesia. For pediatric burns, prompt delivery of analgesia should be prioritized with pain assessment using age-appropriate tools being recommended, but optional.

A Rare Case of Horseshoe Kidney With Multiple Atrial Myxomas Presenting as Cerebrovascular Accident.

Myxomas are benign tumors of mesenchymal origin, containing a few pluripotent cells in the myxomatous stroma. They usually present at 30-40 years of age and are more common in females than males. These tumors mostly arise in the atria and protrude into the atrial lumen. They cause constitutional symptoms like fever and weight loss and obstructive symptoms related to outflow obstruction in the heart. Some tumors are more fragile and cause embolism and may present as stroke. Mostly sporadic but familial cases and myxomas associated with Carney syndrome (CNC) tend to be multiple. Here, we report a case of a 40-year-old female with a stroke due to embolization from multiple myxomas. She had no family history of myxoma and had no skin findings or other tumors associated with CNC. She also had an atrophied horseshoe kidney with renal failure. The association of a horseshoe kidney with myxoma is rarely reported. In an extensive literature search, we could only find only one other case. Atrial myxomas were detected while investigating the cause of stroke. Our patient gradually improved and was advised surgical removal of the myxomas, which is the treatment of choice.

Dexmedetomidine-Induced Fever in a 66-Year-Old Male With Pneumonia and Pleural Effusion.

Drug-induced fever is a significant adverse effect as many commonly used medications can cause this. The incidence of drug fever is even higher in critical care settings because multiple medications are being administered simultaneously. This poses a serious problem in critical care settings as any new fever in these settings also implies any new infection or worsening of preexisting conditions. This may lead to a detailed investigation for the cause of fever, which can be time-consuming, invasive, costly, and may also increase the duration of stay along with an associated increase in morbidity and mortality. We want to highlight an adverse drug event through a documented case of Dexmedetomidine-induced fever in a critical care patient with multiple pathologies.

ARNSHL gene identification: past, present and future.

Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common hereditary deafness. It is genetically highly heterogeneous and about 89 gene loci and 76 gene's mutations have been implicated in the etiology of ARNSHL. Molecular basis of ARNSHL remains unresolved in 60% of cases and gene mutations are unknown for 23 of 89 reported loci. Techniques used to identify reported ARNSHL gene mutations can be divided into position-dependent and position-independent approaches. The localization of the loci has been facilitated by homozygosity mapping or linkage studies using STR or SNP genotyping in large consanguineous families. First few genes identified for hearing loss exhibited such wide diversity of function and expression patterns that candidate gene approach was not a viable option. The mapping of the disorder to a chromosomal location has been followed by Sanger sequencing of all genes in the target region or confining of the massively parallel sequencing data analyses to the linkage region. Sometimes genes located in the linkage interval were prioritized because there was a reported orthologs with mutations causing hearing loss in mouse or when mutations in the gene caused a related disorder. Position-independent approaches involving use of mouse subtractive cochlear libraries, forward genetic screening, and position-independent analyses of massively parallel sequencing data have helped identify 17 of 68 reported ARNSHL gene mutations. A thorough study of the strategies used in the identification of reported ARNSHL genes and of their relative success can help increase the success rate of future studies.

A Rare Case of Acute Calculous Cholecystitis With Gallbladder Hydrops.

Gallbladder hydrops or mucocele is usually due to the obstruction of the gallbladder by a gallstone. It is usually characterized by an increase in gallbladder volume, which remains clinically silent and is often incidentally diagnosed during exploratory laparotomy or laparoscopy. We report a rare case of acute calculous cholecystitis with gallbladder hydrops (measuring 17 cm in maximum dimension) due to the obstruction of the cystic duct by a gallstone in a 67-year-old female. We highlight the importance of early magnetic resonance imaging (MRI) in patients with right upper quadrant (RUQ) pain to rule out gallbladder hydrops especially in those with a history of gallstones.

Variants of human CLDN9 cause mild to profound hearing loss.

Hereditary deafness is clinically and genetically heterogeneous. We investigated deafness segregating as a recessive trait in two families. Audiological examinations revealed an asymmetric mild to profound hearing loss with childhood or adolescent onset. Exome sequencing of probands identified a homozygous c.475G>A;p.(Glu159Lys) variant of CLDN9 (NM_020982.4) in one family and a homozygous c.370_372dupATC;p.(Ile124dup) CLDN9 variant in an affected individual of a second family. Claudin 9 (CLDN9) is an integral membrane protein and constituent of epithelial bicellular tight junctions (TJs) that form semipermeable, paracellular barriers between inner ear perilymphatic and endolymphatic compartments. Computational structural modeling predicts that substitution of a lysine for glutamic acid p.(Glu159Lys) alters one of two cis-interactions between CLDN9 protomers. The p.(Ile124dup) variant is predicted to locally misfold CLDN9 and mCherry tagged p.(Ile124dup) CLDN9 is not targeted to the HeLa cell membrane. In situ hybridization shows that mouse Cldn9 expression increases from embryonic to postnatal development and persists in adult inner ears coinciding with prominent CLDN9 immunoreactivity in TJs of epithelia outlining the scala media. Together with the Cldn9 deaf mouse and a homozygous frameshift of CLDN9 previously associated with deafness, the two bi-allelic variants of CLDN9 described here point to CLDN9 as a bona fide human deafness gene.

Antimicrobial susceptibility patterns among community and health care acquired carbapenem resistant Enterobacteriaceae, in a tertiary care hospital of Lahore.

OBJECTIVE: To compare the disk susceptibility pattern of healthcare acquired carbapenem-resistant enterobacteraceae with that of community-acquired isolates and their associated clinical presentations. METHODS: The cross-sectional study was conducted at the Department of Microbiology, Combined Military Hospital, and the Institute of Dentistry, Lahore, Pakistan, from November 2017 to July 2018. Patients with positive carbapenem-resistant enterobacteraceae cultures from clinical specimens were included. All the isolates were identified through conventional methods and standard biochemical tests. Antibiotic susceptibility testing was performed by Kirby Bauer Disk Diffusion method on Muller Hinton Agar plates. Data was analysed using SPSS 23. RESULTS: Of the 123 isolates identified, 97(79%) were healthcare acquired and 26(21%) were community-acquired. Statistically significant susceptibility patterns (p<0.001) of community acquired isolates were observed against cefoperazone-sulbactum and amikacin, while a low significance was observed with gentamycin (p<0.05). Significant results were obtained in case of colistin against both the groups (p<0.001). CONCLUSIONS: There was low antimicrobial resistance in community acquired carbapenem-resistant enterobacteraceae isolates.

Post-traumatic stress disorder and association with low birth weight in displaced population following conflict in Malakand division, Pakistan: a case control study.

BACKGROUND: The northern part of the province of Khyber Pakhtunkhwa in Pakistan experienced armed conflict since September 2007 till the autumn of 2011. Conflict involved widespread insurgency activity and military intervention including in 2009 internally displacing the 2.5 million people of the valley of Swat to live in camps, with relatives, or in rented accommodation across the region for approximately 4 months. It was during this period the current study was conducted to determine whether Post-Traumatic Stress Disorder in pregnant women was independently associated with Low Birth Weight (LBW) in an area affected by conflict and militancy. METHODS: A case control study was conducted in tertiary care hospitals of district Peshawar, Khyber Pakhtunkhwa. Two hundred twenty-five cases (neonates with birth weight <  2.5 kg) and 225 controls (neonates with birth weight of > 2.5 kg) were enrolled within 24 h of delivery. Post-Traumatic Stress Disorder was assessed through the MINI Neuropsychiatric Interview 5.0, a validated questionnaire along with the birth weight of the newborn. Maternal anthropometry, anemia and other sociodemographic details were also obtained during data collection. Data was analyzed using statistical package (STATA version 14). Logistic regression analysis of the association between LBW and all variables collected with a p-value of < 0.25 on uni-variate analysis were entered. RESULTS: A total of 450 newborn and mother pairs participated in the study with 225 cases and 225 controls. On univariate analysis factors significantly associated with LBW include: less than 5 years of paternal schooling and PTSD. On logistic regression, PTSD was independently associated with low birth weight in the presence of other factors like maternal/paternal schooling, gravida, history of preterm, BMI of the mother and maternal anemia. CONCLUSION: PTSD was found to be independently associated with LBW. In light of the current findings and other similar literature, intervention programs should be considered for pregnant women exposed to traumatic events.

TRIOBP-5 sculpts stereocilia rootlets and stiffens supporting cells enabling hearing.

TRIOBP remodels the cytoskeleton by forming unusually dense F-actin bundles and is implicated in human cancer, schizophrenia, and deafness. Mutations ablating human and mouse TRIOBP-4 and TRIOBP-5 isoforms are associated with profound deafness, as inner ear mechanosensory hair cells degenerate after stereocilia rootlets fail to develop. However, the mechanisms regulating formation of stereocilia rootlets by each TRIOBP isoform remain unknown. Using 3 new Triobp mouse models, we report that TRIOBP-5 is essential for thickening bundles of F-actin in rootlets, establishing their mature dimensions and for stiffening supporting cells of the auditory sensory epithelium. The coiled-coil domains of this isoform are required for reinforcement and maintenance of stereocilia rootlets. A loss of TRIOBP-5 in mouse results in dysmorphic rootlets that are abnormally thin in the cuticular plate but have increased widths and lengths within stereocilia cores, and causes progressive deafness recapitulating the human phenotype. Our study extends the current understanding of TRIOBP isoform-specific functions necessary for life-long hearing, with implications for insight into other TRIOBPopathies.

Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss.

Consanguineous Pakistani pedigrees segregating deafness have contributed decisively to the discovery of 31 of the 68 genes associated with nonsyndromic autosomal recessive hearing loss (HL) worldwide. In this study, we utilized genome-wide genotyping, Sanger and exome sequencing to identify 163 DNA variants in 41 previously reported HL genes segregating in 321 Pakistani families. Of these, 70 (42.9%) variants identified in 29 genes are novel. As expected from genetic studies of disorders segregating in consanguineous families, the majority of affected individuals (94.4%) are homozygous for HL-associated variants, with the other variants being compound heterozygotes. The five most common HL genes in the Pakistani population are SLC26A4, MYO7A, GJB2, CIB2 and HGF, respectively. Our study provides a profile of the genetic etiology of HL in Pakistani families, which will allow for the development of more efficient genetic diagnostic tools, aid in accurate genetic counseling, and guide application of future gene-based therapies. These findings are also valuable in interpreting pathogenicity of variants that are potentially associated with HL in individuals of all ancestries. The Pakistani population, and its infrastructure for studying human genetics, will continue to be valuable to gene discovery for HL and other inherited disorders.

CDC14A phosphatase is essential for hearing and male fertility in mouse and human.

The Cell Division-Cycle-14 gene encodes a dual-specificity phosphatase necessary in yeast for exit from mitosis. Numerous disparate roles of vertebrate Cell Division-Cycle-14 (CDC14A) have been proposed largely based on studies of cultured cancer cells in vitro. The in vivo functions of vertebrate CDC14A are largely unknown. We generated and analyzed mutations of zebrafish and mouse CDC14A, developed a computational structural model of human CDC14A protein and report four novel truncating and three missense alleles of CDC14A in human families segregating progressive, moderate-to-profound deafness. In five of these families segregating pathogenic variants of CDC14A, deaf males are infertile, while deaf females are fertile. Several recessive mutations of mouse Cdc14a, including a CRISPR/Cas9-edited phosphatase-dead p.C278S substitution, result in substantial perinatal lethality, but survivors recapitulate the human phenotype of deafness and male infertility. CDC14A protein localizes to inner ear hair cell kinocilia, basal bodies and sound-transducing stereocilia. Auditory hair cells of postnatal Cdc14a mutants develop normally, but subsequently degenerate causing deafness. Kinocilia of germ-line mutants of mouse and zebrafish have normal lengths, which does not recapitulate the published cdc14aa knockdown morphant phenotype of short kinocilia. In mutant male mice, degeneration of seminiferous tubules and spermiation defects result in low sperm count, and abnormal sperm motility and morphology. These findings for the first time define a new monogenic syndrome of deafness and male infertility revealing an absolute requirement in vivo of vertebrate CDC14A phosphatase activity for hearing and male fertility.

Public Private Partnership And Utilization Of Maternal And Child Health Services In District Abbottabad, Pakistan.

BACKGROUND: Public Private Partnership has been experimented as an approach in Pakistan in 2005 and in eighteen districts of Khyber Pakhtunkhwa including Abbottabad in 2011, to improve delivery of maternal and child health services. This study was conducted to assess the utilization of maternal and child health services before and after implementation of Public Private Partnership in district Abbottabad. METHODS: A cross sectional study was conducted in district Abbottabad from July to December 2014. Study included all the 53 basic health units, outsourced to People's Primary Healthcare Initiative in 2011. Data related to selected maternal and child health services indicators (family planning services, antenatal and post-natal care, safe delivery, tetanus toxoid vaccination of pregnant women and child immunization), before and after the introduction of Public Private Partnership, was collected. Significance tests (t-test) was applied and p-value <0.05 was taken as significant. RESULTS: Marked improvement was observed in vaccination of target children (127%) and women (42%), respectively. Similarly, utilization of family planning services, antenatal and postnatal care increased by 60%, 9% and 38%, respectively. Public Private Partnership had significant effect on postnatal visits (p<0.001), family planning services (p<0.001), women vaccinated with tetanus toxoid (p<0.001) and children vaccinated in Expanded Program of Immunization (p=0.003). CONCLUSIONS: Public Private Partnership improved the utilization of maternal and child health services, particularly family planning services and maternal & child immunization. The partnership may be scaled up and extended, for an improved coverage of maternal and child health services.

Genetic causes of moderate to severe hearing loss point to modifiers.

The genetic underpinnings of recessively inherited moderate to severe sensorineural hearing loss are not well understood, despite its higher prevalence in comparison to profound deafness. We recruited 92 consanguineous families segregating stable or progressive, recessively inherited moderate or severe hearing loss. We utilized homozygosity mapping, Sanger sequencing, targeted capture of known deafness genes with massively parallel sequencing and whole exome sequencing to identify the molecular basis of hearing loss in these families. Variants of the known deafness genes were found in 69% of the participating families with the SLC26A4, GJB2, MYO15A, TMC1, TMPRSS3, OTOF, MYO7A and CLDN14 genes together accounting for hearing loss in 54% of the families. We identified 20 reported and 21 novel variants in 21 known deafness genes; 16 of the 20 reported variants, previously associated with stable, profound deafness were associated with moderate to severe or progressive hearing loss in our families. These data point to a prominent role for genetic background, environmental factors or both as modifiers of human hearing loss severity.

Mutational Spectrum of MYO15A and the Molecular Mechanisms of DFNB3 Human Deafness.

Deafness in humans is a common neurosensory disorder and is genetically heterogeneous. Across diverse ethnic groups, mutations of MYO15A at the DFNB3 locus appear to be the third or fourth most common cause of autosomal-recessive, nonsyndromic deafness. In 49 of the 67 exons of MYO15A, there are currently 192 recessive mutations identified, including 14 novel mutations reported here. These mutations are distributed uniformly across MYO15A with one enigmatic exception; the alternatively spliced giant exon 2, encoding 1,233 residues, has 17 truncating mutations but no convincing deafness-causing missense mutations. MYO15A encodes three distinct isoform classes, one of which is 395 kDa (3,530 residues), the largest member of the myosin superfamily of molecular motors. Studies of Myo15 mouse models that recapitulate DFNB3 revealed two different pathogenic mechanisms of hearing loss. In the inner ear, myosin 15 is necessary both for the development and the long-term maintenance of stereocilia, mechanosensory sound-transducing organelles that extend from the apical surface of hair cells. The goal of this Mutation Update is to provide a comprehensive review of mutations and functions of MYO15A.

Recessive mutations of TMC1 associated with moderate to severe hearing loss.

TMC1 encodes a protein required for the normal function of mechanically activated channels that enable sensory transduction in auditory and vestibular hair cells. TMC1 protein is localized at the tips of the hair cell stereocilia, the site of conventional mechanotransduction. In many populations, loss-of-function recessive mutations of TMC1 are associated with profound deafness across all frequencies tested. In six families reported here, variable moderate-to-severe or moderate-to-profound hearing loss co-segregated with STR (short tandem repeats) markers at the TMC1 locus DFNB7/11. Massively parallel and Sanger sequencing of genomic DNA revealed each family co-segregating hearing loss with a homozygous TMC1 mutation: two reported mutations (p.R34X and p.R389Q) and three novel mutations (p.S596R, p.N199I, and c.1404 + 1G > T). TMC1 cDNA sequence from affected subjects homozygous for the donor splice site transversion c.1404 + 1G > T revealed skipping of exon 16, deleting 60 amino acids from the TMC1 protein. Since the mutations in our study cause less than profound hearing loss, we speculate that there is hypo-functional TMC1 mechanotransduction channel activity and that other even less damaging variants of TMC1 may be associated with more common mild-to-severe sensorineural hearing loss.

A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss.

BACKGROUND: Hearing loss is a heterogeneous neurosensory disorder. Mutations of 56 genes are reported to cause recessively inherited non-syndromic deafness. OBJECTIVE: We sought to identify the genetic lesion causing hearing loss segregating in a large consanguineous Pakistani family. METHODS AND RESULTS: Mutations of GJB2 and all other genes reported to underlie recessive deafness were ruled out as the cause of the phenotype in the affected members of the participating family. Homozygosity mapping with a dense array of one million SNP markers allowed us to map the gene for recessively inherited severe hearing loss to chromosome 7q31.2, defining a new deafness locus designated DFNB97 (maximum logarithm of the odds score of 4.8). Whole-exome sequencing revealed a novel missense mutation c.2521T>G (p.F841V) in MET (mesenchymal epithelial transition factor), which encodes the receptor for hepatocyte growth factor. The mutation cosegregated with the hearing loss phenotype in the family and was absent from 800 chromosomes of ethnically matched control individuals as well as from 136 602 chromosomes in public databases of nucleotide variants. Analyses by multiple prediction programmes indicated that p.F841V likely damages MET function. CONCLUSIONS: We identified a missense mutation of MET, encoding the hepatocyte growth factor receptor, as a likely cause of hearing loss in humans.

Mutations of GJB2 encoding connexin 26 contribute to non-syndromic moderate and severe hearing loss in Pakistan.

Mutations of GJB2 which encode connexin 26, contribute to 6-7 % of profound deafness in Pakistan. We investigated the involvement of GJB2 mutations in a cohort of 84 pedigrees and 86 sporadic individuals with moderate or severe hearing loss. Individuals in eight consanguineous families and four sporadic cases (9.52 and 4.65 %, respectively) were homozygous or compound heterozygous for p.W24X or p.W77X mutations in GJB2. These two variants are also among the most common mutations known to cause profound deafness in South Asia. The association of identical mutations with both profound and less severe phenotype of hearing loss suggests that alleles of other genes modify the phenotype due to these GJB2 nonsense mutations. Our study demonstrates that GJB2 mutations are an important contributor to aetiology of moderate to severe hearing loss in Pakistan.

A frameshift mutation in GRXCR2 causes recessively inherited hearing loss.

More than 360 million humans are affected with some degree of hearing loss, either early or later in life. A genetic cause for the disorder is present in a majority of the cases. We mapped a locus (DFNB101) for hearing loss in humans to chromosome 5q in a consanguineous Pakistani family. Exome sequencing revealed an insertion mutation in GRXCR2 as the cause of moderate-to-severe and likely progressive hearing loss in the affected individuals of the family. The frameshift mutation is predicted to affect a conserved, cysteine-rich region of GRXCR2, and to result in an abnormal extension of the C-terminus. Functional studies by cell transfections demonstrated that the mutant protein is unstable and mislocalized relative to wild-type GRXCR2, consistent with a loss-of-function mutation. Targeted disruption of Grxcr2 is concurrently reported to cause hearing loss in mice. The structural abnormalities in this animal model suggest a role for GRXCR2 in the development of stereocilia bundles, specialized structures on the apical surface of sensory cells in the cochlea that are critical for sound detection. Our results indicate that GRXCR2 should be considered in differential genetic diagnosis for individuals with early onset, moderate-to-severe and progressive hearing loss.