text:
export { pipeUpdaters, filterUpdater, createUpdater } from './old'

import dotProp from 'dot-prop-immutable'
import compose from 'compose-function'

let warning = {}

/**
 * **Syntax**
 * ```javascript
 * match(predicateUpdater, leftUpdater)
 * ```
 *
 * ```javascript
 * match(predicateUpdater, leftUpdater, rightUpdater)
 * ```
 *
 * ```javascript
 * match(predicateUpdater)(leftUpdater)
 * ```
 *
 * ```javascript
 * match(predicateUpdater)(leftUpdater, rightUpdater)
 * ```
 *
 * **Description**
 *
 * Creates a proxy updater that:
 *
 * - calls **`leftUpdater`** if `predicateUpdater` returns true, or
 * - calls **`rightUpdater`** if `predicateUpdater` returns false and `rightUpdater` is defined, or
 * - returns the state unchanged if `predicateUpdater` returns false and `rightUpdater` is undefined.
 *
 * @example
 * match(p, t, f)
 * // Is equivalent to
 * action => state => p(action)(state) ? t(action)(state) : f(action)(state)
 *
 * @example
 * match(p, t)
 * // Is equivalent to
 * action => state => p(action)(state) ? t(action)(state) : state
 */
export const match = (predicateUpdater: (action: mixed) => (state: mixed) => boolean, leftUpdater: Updater, rightUpdater: ?Updater): Updater => {
  if (leftUpdater !== undefined) {
    return action => state => predicateUpdater(action)(state)
      ? leftUpdater(action)(state)
      : (rightUpdater !== undefined ? rightUpdater(action)(state) : state)
  }

  return (leftUpdater, rightUpdater) => match(predicateUpdater, leftUpdater, rightUpdater)
}

/**
 * **Syntax**
 * ```javascript
 * withDefaultState(defaultState, updater)
 * ```
 *
 * ```javascript
 * withDefaultState(defaultState)(updater)
 * ```
 *
 * **Description**
 *
 * Creates a proxy updater that:
 *
 * calls `updater` with `defaultState` if incoming state is undefined, or calls it with the incoming state.
 * @example
 * withDefaultState(0, add)
 * // Is equivalent to
 * action => (state = 0) => add(action)(state)
 */
export const withDefaultState = (defaultState: mixed, updater: Updater): Updater => {
  if (updater !== undefined) {
    return match(() => state => state === undefined)(
      action => () => updater(action)(defaultState),
      updater
    )
  }

  return updater => withDefaultState(defaultState, updater)
}

/**
 * **Syntax**
 * ```javascript
 * concat(...updaters)
 * ```
 *
 * **Description**
 *
 * Creates a proxy updater that:
 *
 * calls each updater with the preceding updater's outgoing state (left-to-right).
 * @param {...Updater} updaters
 * @example
 * concat(f, g, h)
 * // Is equivalent to
 * action => state => h(action)(g(action)(f(action)(state)))
 */
export const concat = (...updaters): Updater => action => state => {
  return updaters.reduce((s, updater) => updater(action)(s), state)
}

/**
 * **Syntax**
 * ```javascript
 * combine(pathFragmentUpdaterMap)
 * ```
 *
 * **Description**
 *
 * Like [`combineReducers`](http://redux.js.org/docs/api/combineReducers.html), but for updaters.
 *
 * @example
 * combine({
 *   foo: fooUpdater,
 *   bar: barUpdater
 * })
 * // Is equivalent to
 * concat(
 *   updateStateAt('foo', fooUpdater),
 *   updateStateAt('bar', barUpdater)
 * )
 *
 */
export const combine = (pathFragmentUpdaterMap: Object): Updater => withDefaultState({}, concat(
  ...Object.keys(pathFragmentUpdaterMap)
    .map(k => updateStateAt(k, pathFragmentUpdaterMap[k]))
))

/**
 * @private
 */
export const combineUpdaters = (...args) => {
  if (!warning.combineUpdaters) {
    warning.combineUpdaters = true
    // eslint-disable-next-line
    console.warn('Warning: combineUpdaters(pathMap) is deprecated. Use combine(pathFragmentUpdaterMap)')
  }
  return combine(...args)
}

/**
 * **Syntax**
 * ```javascript
 * handleAction(actionType, updater)
 * ```
 *
 * ```javascript
 * handleAction(actionType)(updater)
 * ```
 *
 * **Description**
 *
 * Creates a proxy updater that:
 *
 * calls `updater` if `actionType` matches incoming action's type, or returns the state unchanged.
 * @example
 * handleAction('SOME_ACTION', someUpdater)
 * // Is equivalent to
 * match(action => () => action.type === 'SOME_ACTION', someUpdater)
 */
export const handleAction = (actionType: string, updater: Updater): Updater => {
  if (updater !== undefined) {
    return match(
      action => () => typeof action === 'object' && action != null && action.type === actionType,
      updater
    )
  }

  return updater => handleAction(actionType, updater)
}

/**
 * **Syntax**
 * ```javascript
 * handleActions(actionTypeUpdaterMap)
 * ```
 *
 * **Description**
 *
 * Creates a proxy updater that:
 *
 * delegates to a matching updater from `actionTypeUpdaterMap` based on the incoming action's type, or returns the state unchanged.
 *
 *
 * @example
 * handleActions({
 *   ACTION_ONE: updaterOne,
 *   ACTION_TWO: updaterTwo
 * })
 * // Is equivalent to
 * concat(
 *   handleAction('ACTION_ONE', updaterOne),
 *   handleAction('ACTION_TWO', updaterTwo)
 * )
 */
export const handleActions = (actionTypeUpdaterMap: Object): Updater => concat(
  ...Object.keys(actionTypeUpdaterMap)
    .map(k => handleAction(k, actionTypeUpdaterMap[k]))
)

/**
 * **Syntax**
 * ```javascript
 * updateStateAt(path, updater)
 * ```
 *
 * ```javascript
 * updateStateAt(path)(updater)
 * ```
 *
 * **Description**
 *
 * Creates a proxy updater that:
 *
 * calls `updater` with incoming state focused at `path`, then merges the result into outgoing state.
 *
 *
 * @example
 * const updater = updateStateAt('a.b', () => state => state + 1)
 * const state = { a: { b: 1 }, c: 0 }
 *
 * updater()(state)
 * // Result: `{ a: { b: 2 }, c: 0 }`
 */
export const updateStateAt = (path: string, updater: Updater): Updater => {
  if (updater !== undefined) {
    return action => state => {
      return dotProp.set(state, path, v => {
        if (dotProp.get(state, path) !== undefined) {
          return updater(action)(v)
        }
        return updater(action)(undefined)
      })
    }
  }

  return updater => updateStateAt(path, updater)
}

/**
 * **Syntax**
 * ```javascript
 * mapState(updater)
 * ```
 *
 * **Description**
 *
 * Creates a proxy updater that:
 *
 * maps incoming state via `updater` as iteratee.
 *
 * @example
 * mapState(action => state => state + action)
 * // Is equivalent to
 * action => state => state.map(item => item + action)
 */
export const mapState = (updater: Updater): Updater => action => state => {
  return state.map(updater(action))
}

/**
 * **Syntax**
 * ```javascript
 * filterState(updater)
 * ```
 *
 * **Description**
 *
 * Creates a proxy updater that:
 *
 * filters incoming state via `updater` as predicate.
 * @example
 * filterState(action => state => action > state)
 * // Is equivalent to
 * action => state => state.filter(item => action > item)
 */
export const filterState = (updater: (action: mixed) => (state: mixed) => boolean): Updater => action => state => {
  return state.filter(updater(action))
}

/**
 * **Syntax**
 * ```javascript
 * constantState(value)
 * ```
 *
 * **Description**
 *
 * Creates an updater that always returns `value`.
 * @example
 * constantState('foo')
 * // Is equivalent to
 * () => () => 'foo'
*/
export const constantState = (value: mixed): Updater => () => () => value

/**
 * **Syntax**
 * ```javascript
 * decorate(...fns, value)
 * ```
 *
 * **Description**
 *
 * Applies to `value` a function created by composing `...fns`.
 *
 * @example
 * decorate(f, g, h, value)
 * // Is equivalent to
 * f(g(h(value)))
 * @example
 * decorate(
 *   withDefaultState(0),
 *   handleAction('ADD'),
 *   action => state => state + action.payload
 * )
 * // Is equivalent to
 * withDefaultState(0, handleAction('ADD', action => state => state + action.payload))
 * @param {...Function} fns
 * @param {any} value
 * @returns {any}
*/
export const decorate = (...fns) => {
  const value = fns.slice(-1)[0]
  fns = fns.slice(0, -1)

  if (fns.length === 0) {
    return value
  }

  return compose(...fns)(value)
}

/**
 * Action-first curried reducer.
 */
type Updater = (action: mixed) => (state: mixed) => mixed

redpajama_set_name: RedPajamaGithub


text:
US20090194483A1 - Microfluidic device having monolithic separation medium and method of use - Google Patents
Microfluidic device having monolithic separation medium and method of use Download PDF
mobile phase
microfluidic device
Karla M. Robotti
Hongfeng Yin
Agilent Technologies Inc
2008-01-31 Application filed by Agilent Technologies Inc filed Critical Agilent Technologies Inc
2008-05-15 Assigned to AGILENT TECHNOLOGIES, INC. reassignment AGILENT TECHNOLOGIES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ROBOTTI, KARLA M., YIN, HONGFENG
B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
B01D—SEPARATION
B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
B01D15/08—Selective adsorption, e.g. chromatography
B01D15/10—Selective adsorption, e.g. chromatography characterised by constructional or operational features
B01D15/16—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to the conditioning of the fluid carrier
B01D15/163—Pressure or speed conditioning
B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
B01J20/28042—Shaped bodies; Monolithic structures
B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
B01J20/282—Porous sorbents
B01J20/285—Porous sorbents based on polymers
B01J20/286—Phases chemically bonded to a substrate, e.g. to silica or to polymers
B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
B01L3/502738—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by integrated valves
G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
G01N30/02—Column chromatography
G01N30/26—Conditioning of the fluid carrier; Flow patterns
G01N30/28—Control of physical parameters of the fluid carrier
G01N30/32—Control of physical parameters of the fluid carrier of pressure or speed
B01J2220/00—Aspects relating to sorbent materials
B01J2220/50—Aspects relating to the use of sorbent or filter aid materials
B01J2220/54—Sorbents specially adapted for analytical or investigative chromatography
B01L2300/00—Additional constructional details
B01L2300/08—Geometry, shape and general structure
B01L2300/0809—Geometry, shape and general structure rectangular shaped
B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
B01L2300/0887—Laminated structure
B01L2300/14—Means for pressure control
B01L2400/00—Moving or stopping fluids
B01L2400/06—Valves, specific forms thereof
B01L2400/0622—Valves, specific forms thereof distribution valves, valves having multiple inlets and/or outlets, e.g. metering valves, multi-way valves
B01L2400/0633—Valves, specific forms thereof with moving parts
B01L2400/0644—Valves, specific forms thereof with moving parts rotary valves
B01L2400/08—Regulating or influencing the flow resistance
B01L2400/084—Passive control of flow resistance
G01N30/04—Preparation or injection of sample to be analysed
G01N30/16—Injection
G01N30/20—Injection using a sampling valve
G01N2030/202—Injection using a sampling valve rotary valves
G01N2030/328—Control of physical parameters of the fluid carrier of pressure or speed valves, e.g. check valves of pumps
G01N30/50—Conditioning of the sorbent material or stationary liquid
G01N30/52—Physical parameters
G01N2030/524—Physical parameters structural properties
G01N2030/528—Monolithic sorbent material
G01N30/60—Construction of the column
G01N30/6095—Micromachined or nanomachined, e.g. micro- or nanosize
A microfluidic device, a device including the microfluidic device and methods of operation are described.
Chemical and biological separations are routinely performed in various industrial and academic settings to determine the presence and/or quantity of individual species in complex sample mixtures. There exist various techniques for performing such separations.
One particularly useful analytical process is chromatography, which encompasses a number of methods that are used for separating ions or molecules for analysis. Liquid chromatography ('LC') is a physical method of separation wherein a liquid 'mobile phase' carries a sample containing multiple molecules or ions for analysis (analytes) through a separation medium or 'stationary phase.' Stationary phase material typically includes a liquid-permeable medium such as packed granules (particulate material) or a microporous matrix (e.g., porous monolith) disposed within a tube or similar boundary. The resulting structure including the packed material or matrix contained within the tube is commonly referred to as a 'separation column.' In the interest of obtaining greater separation efficiency, so-called 'high performance liquid chromatography' ('HPLC') methods often utilizing high operating pressures are commonly used.
In recent years, microdevice technologies, also referred to as microfluidic technologies and Lab-on-a-Chip technologies, have been used in LC and HPLC applications. These microdevices are useful in many applications, particularly in applications that involve rare or expensive analytes, such as proteomics and genomics. Furthermore, the small size of the microdevices allows for the analysis of minute quantities of sample.
Microdevices (or often referred to as microfluidic devices) may be adapted to carry out a number of different separation techniques. Capillary electrophoresis (CE), for example, separates molecules based on differences in the electrophoretic mobility of the molecules. Typically, microfluidic devices employ a controlled application of an electric field to induce fluid flow and or to provide flow switching. In order to effect reproducible and/or high-resolution separation, a fluid sample 'plug,' a predetermined volume of fluid sample, must be controllably injected into a capillary separation column or conduit. For fluid samples containing high molecular weight charged biomolecular analytes such as DNA fragments and proteins, microdevices containing a capillary electrophoresis separation conduit a few centimeters in length may be effectively used in carrying out sample separation of small volumes of fluid sample having a length on the order of micrometers. Once injected, high sensitivity detection such as laser-induced fluorescence (LIF) may be employed to resolve a separated fluorescently-labeled sample component.
For samples containing analyte molecules with low electrophoretic differences, such as those containing small drug molecules, the separation technology of choice is often based LC, and particularly HPLC. As described, in LC, separation occurs when the mobile phase carries sample molecules through the stationary phase where sample molecules interact with the stationary phase surface. The velocity at which a particular sample component travels through the stationary phase depends on the component's partition between mobile phase and stationary phase.
Among other desired results, it is useful to provide separated analytes to a detector. As will be appreciated, the better the resolution of the absorption peaks of the analytes that is obtained, the more accurate is the liquid chromatography in analyzing a sample. One way to improve the separation and thus the resolution of the absorption peaks is to improve the retention behavior of the stationary phase. Unfortunately, in many known microfluidic devices, improving the retention behavior has proven difficult mostly due to the limitations of known materials used for the stationary phase.
What is needed, therefore, is a microfluidic device that provides improved retention and emission and absorption data resolution in liquid chromatography applications.
The present teachings are best understood from the following detailed description when read with the accompanying drawing figures. The features are not necessarily drawn to scale. Wherever practical, like reference numerals refer to like features.
FIG. 1 is a perspective view of a microfluidic device in communication with a detector in accordance with a representative embodiment.
FIG. 2A is an exploded perspective view of a device comprising a microfluidic device and a rotary flow switch in accordance with a representative embodiment.
FIG. 2B is a top view of a portion of the microfluidic device in accordance with representative embodiment.
FIG. 2C is a top view of a rotary flow switch in accordance with representative embodiment.
FIG. 3 is a conceptual view showing the in-situ polymerization forming an organic polymer-based monolithic separation medium in accordance with representative embodiment.
FIG. 4 is a graphical representation of absorption versus time for a liquid chromatograph at different mobile phase pressures in accordance with a representative embodiment.
FIG. 7 is a flow-chart of a method of operating an LC device in accordance with a representative embodiment.
DEFINED TERMINOLOGY
It is to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting.
As used in the specification and appended claims, the terms 'a', 'an' and 'the' include both singular and plural referents, unless the context clearly dictates otherwise. Thus, for example, 'a device' includes one device and plural devices.
In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings:
The term 'LC' as used herein refers to a variety of liquid chromatography devices including, but not limited to HPLC devices;
The term 'fluid-transporting feature' as used herein refers to an arrangement of solid bodies or portions thereof that direct fluid flow. Fluid-transporting features include, but are not limited to, chambers, reservoirs, conduits, channels and ports.
The term 'controllably introduce' as used herein refers to the delivery of a predetermined volume of a fluid sample in a precise manner. A fluid sample may be 'controllably introduced' through controllable alignment of two components (i.e., fluid-transporting features) of a microfluidic device;
The term 'flow path' as used herein refers to the route along which a fluid travels or moves. Flow paths are formed from one or more fluid-transporting features of a microdevice;
The term 'conduit' as used herein refers to a three-dimensional enclosure formed by one or more walls and having an inlet opening and an outlet opening through which fluid may be transported;
The term 'channel' is used herein to refer to an open groove or a trench in a surface. A channel in combination with a solid piece over the channel forms a conduit; and
The term 'fluid-tight' is used herein to describe the spatial relationship between two solid surfaces in physical contact such that fluid is prevented from flowing into the interface between the surfaces.
In the following detailed description, for purposes of explanation and not limitation, representative embodiments disclosing specific details are set forth in order to provide a thorough understanding of the present teachings. Descriptions of known systems, devices, materials, methods of operation and methods of manufacture may be omitted so as to avoid obscuring the description of the example embodiments. Nonetheless, systems, devices, materials and methods that are within the purview of one of ordinary skill in the art may be used in accordance with the representative embodiments.
FIG. 1 is a perspective view of a microfluidic device 101 in communication with a detector 102 in accordance with a representative embodiment. As is known, a variety of detectors may be used in LC applications to provide a chromatogram for a sample. As such, it is contemplated that the detector 102 may be one of: a refractive index (RI) detector; an ultra-violet (UV) detector; a UV-Visible Light (UV-Vis) detector; a fluorescent detector (e.g., LIF detector); a radiochemical detector; an electrochemical detector; a near-infra red (Near-IR) detector; a mass spectroscopy (MS) detector; a nuclear magnetic resonance (NMR) detector; and a light scattering (LS) detector. It is emphasized that other types of detectors may be used. In the interest of ease of description, the detectors of the representative embodiments are absorption-type detectors that provide chromatograms of the radiation absorbed by the analytes of a sample.
A separation medium 103 is disposed in a substrate 104 of the device. The separation medium 103 illustratively comprises an organic polymer-based monolithic separation column provided in the substrate between conduits (not shown) where a sample for analysis and a mobile phase are introduced. As described more fully herein, the separation medium 103 comprises a conduit in a substrate having an organic-based (sometimes referred to herein as 'organic') separation material (not shown in FIG. 1) located in the conduit. The conduit with the organic separation material therein may be referred to herein as the 'separation column.'
As will become clearer as the present description continues, the substrate 104 may comprise more than one layer, with one or more channels provided in at least one of the layers. The mobile phase and the sample-containing analytes are controllably introduced at a selected flow rate into conduits in the substrate 104 via a rotary flow switch (not shown in FIG. 1). The mobile phase and sample traverse the separation medium 103 and are introduced into a conduit 105 within the detector 102 where their absorption of electromagnetic radiation is monitored by the detector 102. The sample and mobile phase flow through the separation medium 103 at a prescribed flow rate and are provided to a return conduit 106 for expulsion as waste. For ease of initial description, the microfluidic device 101 is shown having only a few conduits. This is merely illustrative, and it is noted that as described more fully herein, additional fluid-transporting features may be provided in the microfluidic device 101. For instance, as described more fully below, flow restrictors are provided to enable the selective modulation of the pressure of the mobile phase and thus the pressure of the sample through the separation medium.
In representative embodiments, the microfluidic 101 is provided in an LC and the detector 102 is a part of that LC. The type of detector 102 and the other components of the LC required for analysis of the sample are governed by a variety of factors. As such a comparatively wide variety of detectors may be used in the representative embodiments. For example, high sensitivity detection (such as by LIF) of the sample may be employed to resolve a separated fluorescently-labeled sample component. Details the sample emission and absorption detection are generally omitted to avoid obscuring the description of the representative embodiments.
The microfluidic device 101 shares many features, dimensions, materials, methods of fabrication and methods of operation described in commonly owned U.S. Pat. No. 7,128,876 entitled 'Microdevice and Method for Component Separation' to Hongfeng Yin, et al.; commonly owned U.S. Pat. No. 6,845,968 entitled 'Flow-Switching Microdevice' to Kileen, et al.; and commonly owned U.S. patent application Ser. No. 12/022,684 (Attorney Docket Number 10060671-02), entitled 'Microfluidic Device for Sample Analysis' to Yin, et al., and filed on Jan. 30, 2008. The disclosures of these patents and patent application are specifically incorporated herein by reference. Repetition of the features, dimensions, materials, methods of fabrication and methods of operation is generally avoided herein to avoid obscuring the description of representative embodiments.
FIG. 2A is a perspective view of a device 200 comprising a microfluidic device and a rotary flow switch element 203 in accordance with a representative embodiment. The microfluidic device comprises a first substrate 201 and a second substrate 202. The rotary flow switch 203 is disposed in contact with the surface of the second substrate 202 remote from first substrate 201. Alternatively, there may be one or more layers (not shown) disposed between the rotary flow switch 203 and the surface of the second substrate 202 remote from the first substrate 201. Notably, the substrates 201, 202 and switch 203 are shown in an uncoupled or partially exploded arrangement to facilitate description of certain features of each. As described more fully herein and in the incorporated patent application and patents, when coupled together, the substrates 201, 202, the rotary flow switch 203 and any intervening layers (not shown) form fluid-tight conduits from channels formed in each.
The first substrate 201 and the second substrate 202 can be laminated to provide conduits in a manner described in the incorporated application and patents. Alternatively, the microfluidic device may comprise a single substrate having conduits described in connection with the substrate 202. In particular, some channels formed in the substrate 202 are converted into conduits when the first substrate 201, or the fluid switch 203, or both, are brought in fluid-tight communication with the second substrate 202. Naturally, as needed inlet and outlet conduits may be formed in the second substrate 202 to provide a flow path to/from the channel. In this manner, the first substrate 201 can be foregone and the microfluidic device may comprise the second substrate alone. Still other embodiments are contemplated in which the microfluidic device comprises layers in addition to first and second substrates 201, 202.
The second substrate 202 comprises an organic polymer-based monolithic separation medium 204. In a representative embodiment, the organic polymer-based monolithic separation medium 204 comprises an organic polymer-based separation material 204A provided in a fluid-transporting feature 204B. The organic polymer-based separation medium 204 comprises an inlet at one end and an outlet at another end. As described more fully herein, the organic polymer-based monolithic separation medium 204 is illustratively formed in-situ by polymerizing monomers in the fluid-transporting feature 204B in the second substrate 202.
In addition to flow paths operative to provide a minimum fluid impedance or a baseline of fluid impedance, the second substrate 202 also includes a first flow restrictor 205 and a second flow restrictor 206 formed from fluid-transporting features in the substrate 202, with each flow restrictor 205, 206 having an inlet and an outlet. Like other fluid-transporting features of the representative embodiments, the flow restrictors 205, 206 can have a variety of configurations, such as a straight, serpentine, spiral, or any tortuous path. However, the flow restrictors 205, 206 are also designed to introduce different degrees of fluid impedance in the flow path of the mobile phase to provide a different pressure in the separation medium 204 for a given flow rate. In certain embodiments, fluid impedance can be effected by providing a fluid-transporting feature in the substrate 202 with smaller cross-sectional sectional area than other fluid-transporting features in the flow path. Moreover, and as described more fully herein, the rotary flow switch 203 allows for the selection of a particular flow restrictor between flow restrictors 205, 206 or a baseline or minimum flow impedance through another fluid-flow feature, and thus for the selection of a particular pressure in the separation column for the fluid flow of a particular LC test. In an embodiment, a fluid-transporting feature with a greater cross-sectional area than that of an illustrative flow restrictor can provide a baseline or a minimum flow impedance.
A sample loading channel 207 is provided in the second substrate 202 as shown and is in fluid tight communication with the conduit in first substrate 201, labeled 'Sample In'. The sample loading channel 207 may be packed with suitable material for sample enrichment prior to LC separation. A sample is controllably introduced into channel 207. After proper rotation of the rotary flow switch 203, the sample is introduced into the separation medium 204. After traversing the separation medium 204 and the selected flow restrictor 205, 206, the sample and mobile phase are introduced into an output conduit 208, which is coupled to an outlet in the second substrate 202. The outlet of the output conduit 208 is provided to a detector, such as described in connection with FIG. 1. Notably, the output can be sprayed into a detector (e.g., a mass spectrometry electrospray) or can be introduced into another fluid-transporting feature (e.g., conduit 105 (FIG. 1)).
The rotary flow switch 203 of the representative embodiment comprises an outer rotor 209 and an inner rotor 208. As described in the incorporated patent application to Yin, et al., the rotors 208, 209 have fluid-transporting features operative to controllably introduce the sample and the mobile phase into the conduits of the second substrate 202. In a representative embodiment, the outer rotor 209 is used to controllably introduce the mobile phase through a flow restrictor (e.g., 205 or 206) or other fluid-transporting feature in the microfluidic device; and the inner rotor 208 is used to controllably introduce the sample into separation medium 204. The conduits and channels shown in FIG. 2A and their respective functions are described more fully in connection with FIGS. 2B and 2C.
FIG. 2B is a top view of a portion of the microfluidic device in accordance with representative embodiment; and FIG. 2C is a top view of the rotary flow switch 203 in accordance with representative embodiment. Connections between fluid-transporting features (labeled 204 through 226) of the second substrate 202, and fluid-transporting features (labeled 311 through 328) of the rotary flow switch 203 may be made via a variety of configurations. An explanation of the fluid flow in illustrative configurations of the rotors 209, 210 is best understood by describing FIGS. 2B and 2C together.
As noted, the rotary flow switch 203 is disposed in contact with the second substrate 202 to effect the controllable introduction of the mobile phase and sample. The surface of the rotary flow switch 203 switch shown in FIG. 2C is in contact with the opposing surface of the surface of the second substrate 202 shown in FIG. 2B, with the fluid-transporting features thereof aligned in a manner described below. With the rotors 209, 210 arranged as shown, the mobile phase is controllably introduced via a conduit 'LC Pump In' (FIG. 2A) into a conduit 226 that is aligned with and in fluid tight communication with a port 336 of a channel 327 on the inner rotor 209. The mobile phase flows through the channel 327 on rotor 210 to a port 321. The port 321 is in fluid tight communication with conduit 221 that extends through the substrate 202. The conduit 221 provides the inlet to the organic polymer-based monolithic separation medium 204. The mobile phase flows from an outlet 216 of the organic polymer-based monolithic separation medium 204 and to a port 316 of the outer rotor 209. The mobile phase flows across a channel 323 to a port 317 and then to conduit 217 in communication with the second flow restrictor 206. After flowing through the flow restrictor 206, the mobile phase flows through a conduit 220 and to a port 320 on the outer rotor 209. From the port 320, the mobile phase flows to a conduit 211 in communication with the output conduit 208 and then to the detector as described previously. After passing through the detector, the sample and mobile phase are returned as waste through a conduit 224, which is in fluid tight communication with a conduit labeled 'Waste Out' in FIG. 2A.
The sample is controllably introduced into the sample channel 207 through a conduit 223, which is in fluid tight communication with the conduit labeled 'Sample In' in FIG. 2A. The sample is controllably introduced into the mobile phase by rotating the inner rotor 208 clockwise 60° so that a port 321 is aligned with the conduit 221 of the organic polymer-based monolithic separation medium 204.
By rotating the outer rotor 209 clockwise 36°, the first flow restrictor 205 can be engaged. Specifically, by rotating the outer rotor 209 clockwise in this manner, conduit 216 at an end of the organic polymer-based monolithic separation medium 204 is aligned with an inlet 217 of the outer rotor 209. The mobile phase traverses a channel 323 on the outer rotor 209, and passes through port 316, which is now in communication with an inlet 215 of the first flow restrictor 205. With port 312 in communication with conduit 211 by this arrangement, the mobile phase is provided to the output conduit 208.
In a representative embodiment, the second flow restrictor 206 provides a greater resistance to fluid flow than the first flow restrictor 205. For a given flow rate, this results in a greater pressure in the flow path of the mobile phase described above. By contrast, selection of the first flow restrictor 205 results in a comparatively lower pressure in the flow path of the mobile phase. Moreover, a flow path that does not include one of the flow restrictors 205, 206, may be selected to provide a lower pressure (e.g., a minimum pressure or a baseline pressure) for a selected flow rate. The selection of the pressure for the flow of the mobile phase and the ability to change the pressure by a comparatively simple adjustment of the outer rotor 209 provides benefits in LC applications. Some of these benefits are described more fully herein, while others will become apparent to those of ordinary skill in the art upon review of the present disclosure.
In order to simplify description of the present teachings, the embodiments described include only two fluid restrictors that can be selectively engaged. It is emphasized that use of two flow restrictors is intended to be merely illustrative and in no way limiting. The present teachings also contemplate the inclusion of more or fewer than two flow restrictors; and one or more fluid-transporting features that provides a baseline or a minimum fluid impedance, with the flow-restrictor(s) and fluid-transporting feature(s) selectively engaged through adjustment of the fluid switch 203. Notably, additional ports, channels and conduits, and arrangements thereof on the switch 203 will be required to effect the alignment of to the additional flow restrictors.
FIG. 3 is a conceptual view showing the in-situ polymerization used to form an organic polymer-based monolithic separation medium in accordance with representative embodiment. As noted, the organic polymer-based monolithic separation medium can be formed by in-situ polymerization of monomers, cross-linkers and inert porogenic solvents in a fluid-transporting feature (e.g., a conduit or a channel) formed in a substrate of the microfluidic device. For example, in-situ polymerization presently described in a conduit or channel in substrate 104 and second substrate 202 shown in FIGS. 1 and 2A can be used to fabricate organic monolithic separation media 108 and 204, respectively.
In representative embodiments, monomers 302 are provided in a fluid-transporting feature (e.g., a conduit or a channel) having a wall 301 and are polymerized in such a way as to incorporate the wall. As shown in FIG. 3, the wall 301 has been chemically modified prior to introduction of the monomers to have an extension that contains a double bond. During the polymerization process, the dangling bonds of the modified walls are incorporated into the resultant polymer network. Further details of the process for fabrication the organic-based monolithic separation media are provided in commonly-owned U.S. patent application Ser. No. 11/820,856, entitled "Microfluidic Devices Comprising Fluid Flow Paths Having A Monolithic Chromatographic Material" to Karla Robotti. This application, which was filed on Jun. 20, 2007, is specifically incorporated herein by reference.
In accordance with certain representative embodiments, polymers 303 comprise methylstyrene-vinylbenzene derivatives and form a network between the walls 301 of the fluid-transporting feature. It is emphasized that the use of methylstyrene-vinylbenzene derivatives for the organic polymer-based monolithic separation media is merely illustrative and that other materials are contemplated. Other materials contemplated include, but are not limited to styrene-vinylbenzenes, polymethacrylates and methacrylate copolymerizates. As described more fully herein, these formulations have allowed successful separations of both large and very small molecules.
Among other benefits, the organic polymers of the monolithic separation media of the representative embodiments provide a skeleton structure with macropores that serve as through-pores for all of the mobile phase. This allows the analytes to be transported to the meso/micro pores on the skeletal network for separation. This significantly enhances mass transfer rates and allows much higher flow rates while keeping a low back pressure. Moreover, and as is known, in some instances it is useful to reduce the flow rate of the mobile in LC testing, particularly when the sample volume, or the analyte size, or both are small. A comparatively low flow rate can foster a higher retention time and ultimately better resolution and selectivity. As described more fully below, the organic polymer-based monolithic separation medium of the representative embodiments provides greater surface area at higher pressure. Thus, retention can be improved even at comparatively low flow rates.
In addition, the separation medium of the representative embodiments has a greater porosity and permeability compared to traditional bead-packed columns. As such, in use in LC applications, the organic polymer-based monolithic separation medium provides for a convection flow system on a continuous bed as opposed to a diffusion flow system with beads (with slow mass transfer). Thus, a high speed separation may be realized without compromising the resolution. Moreover, the organic polymer-based medium of representative embodiments is flexible and therefore deforms under pressure with a pressure-dependent deformation. This allows the separation characteristics of the medium to be defined by the selected pressure. Among other benefits, Applicants have discovered improved retention, plate height, resolution and separation through the modulation of pressure of the mobile phase when using organic polymer monoliths.
FIGS. 4-6 are chromatograms showing absorption versus time at different operating pressures using a microfluidic device with an organic polymer-based monolithic separation medium in accordance with representative embodiments. Notably, in the representative embodiments described presently, the organic separation medium comprises polymethylstyrene-co-vinylbenzene.
Certain quantitative indicia are normally used to describe the chromatograms and, as a result, the performance characteristics of the microfluidic device in an LC application. These indicia are known to those in the art and as such are only briefly summarized herein. One such indicium is known as resolution. Resolution is the distance between peak centers divided by average base width of the peaks and provides a measure of how well the peaks are separated from one another. Another quantitative indicium used in liquid chromatography is number of 'plates' and is a term of art with roots in distillation theory. The number of plates is a measure of band broadening within the LC system and is equal to square quotient of the rate of retention volume and the peak width times a factor. In general, the number of plates is an indication of the efficiency of the separation column.
A quantity related to the number of plates and also having roots in distillation is the plate height. The plate height is equal to the quotient of the length of the separation medium (column) and the plate number. The plate height is a useful measure of the efficiency of the separation column. In general, the lower the plate height, the narrower the peaks; the more readily discerned are the peaks for individual analytes; and the greater the efficiency of the column.
Another measure of the performance of a separation column is the separation factor or selectivity. This is a measure of the net retention time ratio for two absorption peaks. In general, it is useful to increase the selectivity to the extent possible. Finally, the retention time (to) of a peak that has no retention is a useful quantitative measure. This term is also known as the retention time of the void volume or the void time, and provides a measure of the time through the separation column for an unretained sample. In general, it is useful to increase the retention time to the extent possible.
FIG. 4 is a graphical representation of absorption versus time of a liquid chromatograph at constant flow rate and different mobile phase pressures in accordance with a representative embodiment. It is noted that to properly discern the results, the chromatograms have been separated vertically, thus providing a qualitative comparison of the peaks rather than a true quantitative comparison.
Chromatogram 401 represents the absorption peaks of analytes provided at the set flow rate and at a first mobile phase pressure. The flow rate and pressure serve as a baseline for other absorption peaks. Notably, the retention time for an unretained peak is 0.409. The resolution between peaks 402 and 403 is 0.875 and between peaks 404 and 405 is 1.34. Moreover, the selectivity between peaks 402, 403 is 1.94 and between peaks 404, 405 are 2.07.
Chromatogram 406 represents the absorption peaks of analytes provided at the set flow rate and at a second mobile phase pressure. Notably, the analytes/mobile phase are the same as those providing the absorption data of chromatogram 401, but the pressure of the mobile phase is greater than the first mobile phase pressure that garnered the data of chromatogram 401. The pressure variation may be effected using the rotary flow switch 203 described above to select a different flow restrictor having a great resistance to fluid flow. For example, the change in mobile phase pressure may be realized by changing from no flow restrictor, which provides, for example, a minimum or a baseline pressure, to one of the flow restrictors 205, 206; or from one restrictor to another (e.g., from flow restrictor 205 to flow restrictor 206).
Qualitatively, from a review of chromatogram 406, one can recognize that the absorption peaks are separated more in time; and do not have as much overlap as the absorption peaks of chromatogram 401. Quantitatively, the retention time of an unretained peak is 0.425. The resolution between peaks 408 and 409 is 1.04 and between peaks 410 and 411 is 1.56. Moreover, the selectivity between peaks 408, 409 is 2.03 and between peaks 410, 411 is 2.16. As will be appreciated, the resolution and selectivity are improved for the same flow rate and increased mobile phase pressure. Furthermore, the increased pressure also results in a lower plate height and improved efficiency.
Applicants surmise that the increased retention time, separation and resolution results from the increased pressure's opening the elastic pores of the organic polymer network of the organic polymer-based monolithic separation medium. This increases the surface area, thereby providing more area for molecular separation of the analytes as they traverse the medium. The increased retention time with increasing pressure implies that the monolith has a lower linear velocity at higher pressure. This is a result of the actual interstitial and interstitial porosities within the organic polymer-based monolithic separation medium.
Chromatogram 412 represents the absorption versus time of the same analytes/mobile phase at the same set flow rate as chromatograms 401 and 406 and with the mobile phase pressure restored to that of chromatogram 401 after chromatogram 406 was taken. The pressure variation may be effected using the rotary flow switch 203 described above to switch back to no flow restrictor or to the previous flow restrictor. For example, the change in mobile phase pressure may be realized by changing from the selected flow restrictor (205 or 206) selected for higher pressure, back to no flow restrictor or to flow restrictor selected for lower pressure (i.e. following the previous example, from flow restrictor 206 back to flow restrictor 205).
As will be appreciated from a comparison of the absorption peaks of the chromatogram 412 to those of chromatogram 401, the retention time, the resolution and the selectivity of are substantially identical. Chromatogram 412 is provided to show that in spite of being expanded by the greater pressure in the test run resulting in the chromatogram 406, the separation medium's function is substantially the same as before the higher pressure test run captured in chromatogram 401. Applicants surmise that the polymer network relaxes/returns to its previous state after the pressure variation to the lower pressure.
The ability to select a greater mobile phase pressure and then select a lower mobile phase pressure (i.e., to modulate the pressure) for a set flow rate allows the operator to modulate the retention behavior of the organic polymer-based monolithic separation medium. This potentially affords a number of useful applications. One such application may be to release a sample and mobile phase from a system after running a test by selecting a lower pressure of operation. This reduction in pressure will cause the polymer network to relax and thereby reduce the retention time of the mobile phase, allowing its release in a more expeditious manner.
FIG. 5 is a graphical representation of absorption versus time for a liquid chromatograph at a set flow rate and different mobile phase pressures in accordance with a representative embodiment. The sample in each case was substantially identical and comprised an isocratic test mix of four parabens, with comparatively small molecular size. The test runs were made at the same flow rate but with different mobile phase pressures. A microfluidic device having at least two flow restrictors such as described in connection with representative embodiments could be used to run each test. The rotary flow switch 203 could be used to change the flow path to selectively engage flow restrictors and to bypass flow restrictors to realize desired pressures as described presently.
A first chromatogram 501 is of a first test run of the isocratic test mix with a selected flow rate at a nominal pressure, generated without engaging a flow restrictor. A second chromatogram 502 is of a second test run of the isocratic mix with the selected flow rate with the pressure of the mobile phase increased over that of the nominal pressure in the first run by changing the flow path so that the mobile phase traverses a first flow restrictor. A third chromatogram 503 is of a third test run of the isocratic mix with the selected flow rate with the pressure of the mobile phase increased compared to the nominal pressure and the pressure of the second run by changing the flow path so that the mobile phase traverses a second flow restrictor.
From a review of chromatograms 501, 502 and 503, it is apparent that the corresponding four absorption peaks of the analytes (in this case the four parabens) have different resolution and selectivity. Moreover, the retention time differs from one chromatogram to the next. Notably, the resolution, selectivity and retention time are increased with increasing pressure at the selected flow rate. This is consistent with the characteristics of organic polymer-based monolithic separation media described previously.
FIG. 6 is a graphical representation of absorption versus time for a liquid chromatograph at a set flow rate and different mobile phase pressures in accordance with a representative embodiment. Chromatogram 601 shows absorption versus time for a four component sample run at a selected flow rate and first pressure. Chromatogram 602 shows absorption versus time for a four component sample run at the same flow rate but at a greater pressure. The retention, resolution, selectivity and plate height of chromatogram 602 are significantly improved compared to those of chromatogram 601. Moreover, the higher pressure run was completed and shortly thereafter, the lower pressure run was completed. This is evidence of the resilience of the organic polymer-based monolithic separation medium, which can be stretched during a higher pressure run, but will relax to its original configuration when the pressure is reduced. The ability to change the pressure of the mobile phase from higher pressure to lower pressure comparatively easily, with no loss of function of the separation column, and multiple times using the microfluidic device of representative embodiment will allow users to determine the optimal flow rate.
As noted previously, in some instances it is useful to have a comparatively high flow rate, while in others a comparatively low flow rate is desired. The selection of an optimal flow rate to garner the greatest efficiency is determined from the so-called van Deemter plot. As is known, the van Deemter plot is a graph of the plate height versus linear velocity. The flow rate that affords the greatest efficiency may then be selected from the plot. However, if for some reason, it is difficult to operate an LC device at the optimal flow rate, the ability to select multiple pressures and flow rates in an efficient manner using a microfluidic device with a rotor of the representative embodiments affords significant advantages of functionality of the LC.
FIG. 7 is a flow-chart of a method of operating an LC device in accordance with a representative embodiment. Illustratively, the method may be implemented using the microfluidic device and rotary flow switch 203 described previously. Alternatively, the method may be implemented using other microfluidic devices and flow controllers. At step 701, a sample is controllably introduced in the microfluidic device. At step 702, a mobile phase is controllably introduced in the microfluidic device at a flow rate. At step 703, a flow path for the mobile phase through one of a plurality of flow paths having different flow impedances to obtain a first pressure for the mobile phase through an the organic polymer-based monolithic separation medium 204. The selected flow path may include one of the flow restrictors 205, 206, or may include another fluid-transporting feature that provides the desired first pressure. For example, rather than traversing one of the flow restrictors 205, 206, the flow path may include a fluid-transporting feature that provides a baseline pressure for the LC test undertaken. After the test is completed at the selected first pressure, the method may be repeated beginning at step 701. In a subsequent sequence of the method, the same analytes may be provided in the sample.
At step 703, however, another flow path may be selected to provide a second pressure for the mobile phase. This pressure may be greater than, or less than the first pressure. After completion of the second test, the method may be repeated beginning at step 701. In this manner, a plurality of chromatograms (e.g., the chromatograms shown in FIGS. 4-6) may be garnered for different pressures or different flow rates, or both.
In view of this disclosure it is noted that the methods and microfluidic devices can be implemented in keeping with the present teachings. Further, the various components, materials, structures and parameters are included by way of illustration and example only and not in any limiting sense. In view of this disclosure, those skilled in the art can implement the present teachings in determining their own applications and needed components, materials, structures and equipment to implement these applications, while remaining within the scope of the appended claims.
1. In a liquid chromatography (LC) device, a method comprising:
controllably introducing a sample in a microfluidic device;
controllably introducing a mobile phase in the microfluidic device at a flow rate; and
selecting a flow path for the mobile phase through one of a plurality of flow paths having different flow impedances to obtain a first pressure for the mobile phase before introducing the mobile phase into an organic polymer-based monolithic separation medium.
2. A method as claimed in claim 1, further comprising, after the selecting the flow path, and before introducing, selecting another flow path for the mobile phase to obtain a second pressure for the mobile phase through the organic polymer-based monolithic separation medium.
3. A method as claimed in claim 2, wherein the first pressure is greater than the second pressure, and the organic polymer-based monolithic separation medium provides a greater retention time at the first pressure than at the second pressure.
4. A method as claimed in claim 1, wherein one or more of the plurality of flow paths comprises a flow restrictor.
5. A method as claimed in claim 1, wherein the organic polymer-based monolithic separation medium comprises an organic polymer-based material comprising a network of interconnected macro-pores and meso-pores.
6. A method as claimed in claim 5, wherein the organic polymer-based material comprises one of: a styrene-vinylbenzene polymer; a methylstyrene-vinylbenzene polymer; a polymethacrylate polymer; and a methacrylate-co-polymerizate.
7. A method as claimed in claim 1, wherein the selecting the flow path further comprises providing a rotary flow switch; and selecting a first position of the rotary flow switch.
8. A method as claimed in claim 7, wherein the rotary flow switch comprises a first rotor and a second rotor and the controllably introducing the sample further comprises:
selecting a first position of a second rotor of the rotary flow switch;
injecting the sample into an opening of the second rotor of the rotary flow switch; and
rotating the second rotor to a second position to introduce the sample into the organic polymer-based monolithic separation medium.
9. A microfluidic device, comprising:
fluid-transporting features;
an organic polymer-based monolithic separation medium;
a first flow restrictor configured to provide a first fluid impedance; and
a second flow restrictor configured to provide a second fluid impedance, wherein each of the first and second flow restrictors are adapted to selectively engage at least one of the fluid-transporting features coupled to the organic polymer-based monolithic separation medium.
10. A microfluidic device as claimed in claim 9, wherein the first flow restrictor is adapted to provide a first pressure for the mobile phase at a flow-rate of fluid.
11. A microfluidic device as claimed in claim 10, wherein second flow restrictor is adapted to provide a second pressure for the mobile phase at the flow rate.
12. A microfluidic device as claimed in claim 9, wherein at least one of the fluid transporting features is adapted to receive the mobile phase.
13. A microfluidic device as claimed in claim 9, wherein at least one of the fluid transporting features is adapted to receive a sample.
14. A microfluidic device as claimed in claim 9, wherein the organic polymer-based monolithic separation medium comprises a network of interconnected macro-pores and meso-pores.
15. A microfluidic device as claimed in claim 13, wherein the organic polymer-based monolithic separation medium provides a greater retention at a higher pressure than at a lower pressure.
16. A microfluidic device as claimed in claim 13, wherein the organic polymer-based material comprises one of: a styrene-vinylbenzene polymer; a methylstyrene-vinylbenzene polymer; a polymethacrylate polymer; and a methacrylate-co-polymerizate.
17. A device for performing liquid chromatography, comprising:
a microfluidic device, comprising: fluid-transporting features; an organic polymer-based monolithic separation medium; a first flow restrictor configured to provide a first fluid impedance; and a second flow restrictor configured to provide a second fluid impedance, wherein each of the first and second flow restrictors are adapted to selectively engage at least one of the fluid-transporting features coupled to the organic polymer-based monolithic separation medium; and
a rotary flow switch operative to selectively engage the fluid-transporting features of the microfluidic device to introduce a mobile phase and a sample to the microfluidic device.
18. A device as claimed in claim 17, wherein the rotary flow switch comprises a first rotor and a second rotor, the first rotor being adapted to introduce the mobile phase to the microfluidic device and the second rotor being adapted to introduce the sample to the microfluidic device.
19. A device as claimed in claim 17, wherein the first flow restrictor is adapted to provide a first pressure for the mobile phase at a flow-rate of fluid.
20. A device as claimed in claim 19, wherein the second flow restrictor is adapted to provide a second pressure for the mobile phase at the flow rate.
21. A device as claimed in claim 17, wherein the organic polymer-based monolithic separation medium comprises a network of interconnected macro-pores and meso-pores.
22. A device as claimed in claim 17, wherein the organic polymer-based monolithic separation medium provides a greater retention at a greater pressure than at a lower pressure.
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The Racine Green Party will host 2016 presidential candidate Jill Stein to talk about decriminalizing cannabis and other issues facing Racine. Countless of people's lives are ruined everyday because of outdated cannabis laws, while our local leaders do little to nothing in helping to alleviate the problem. Come help the Racine Green Party put marijuana decriminalization on the ballot in 2018. All you can eat pizza and drinks for $10. Everyone is welcomed! Open to the public.


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Are Catholic Clergy more Likely to Be Paedophiles than the General Public?
The Tippling Philosopher
June 30, 2017 by Jonathan MS Pearce
This is a question that has been kicking around ever since the child sex abuse scandal involving the Catholic church came to the fore. In around 2010, loads of articles came out, citing some data, that the priesthood was broadly in line with national averages, some people claimed it was actually worse in Protestant churches/organisations, and many claiming (as a result) that this was not a Catholic problem per se, and that other denominations rate the same.
The reality could be, as Andrew Brown surmised, that the notoriety of the scandal and public perception might be skewed because of the institutional cover-up of the Catholic church. Let's have a brief look.
The Royal Commission, an investigation started by the then Australian PM Julia Gillard into historic sex abuse, has thrown this data wide open.
The research has shown that, in Australia, 7% of priests nationally have been accused of sex abuse. In the Diocese of Sale, it is twice as many, with 15.1%, and a whopping 40% of the St John of God order being accused. Here are some interesting Australian stats:
Catholic Data Project Results:
4,444 — number of people who alleged incidents of child sexual abuse,
1,000 — The number of separate institutions the claims related to,
78 percent male, 22 percent female — gender of the person making the claim,
97 percent male — people who made claims of child sexual abuse received by religious orders, with only religious brother members,
11.5 for boys, 10.5 for girls — the average age of people who made claims of child sexual abuse at the time of the alleged abuse,
33 years —the average time between the alleged abuse and the date the claim was made,
1880 — number alleged perpetrators were identified in claims,
597 or 32 percent were religious brothers,
572 or 30 percent were priests,
543 or 29 percent were lay people,
96 or 5 percent were religious sisters,
90 percent male, 10 percent female — age [??] of the allege perpetrators,
500+ — number of unknown people were identified as alleged perpetrators.#
The relevance of this is that this is now perhaps the biggest and most comprehensive review of Catholic sex abuse.


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Once in a While Lyrics
Lyrics to Once in a While
Once in a While Video:
Once in a while will you try to give
One little thought to me
Though someone else may be
Nearer your heart?
Once in a while will you dream
Of the moments I shared with you
Moments before we two
Drifted apart?
In love's smoldering ember
One spark may remain
If love still can remember
That spark may burn again
I know that I'll be contented
With yesterday's memory
Knowing you think of me
Once in a while
The spark may burn again
"Once in a While" as written by William Henry Butler
Lyrics © Universal Music Publishing Group, EMI Music Publishing, Sony/ATV Music Publishing LLC, Warner/Chappell Music, Inc.
Lyrics powerd by LyricFind
Songwriters: O'BRIEN, RICHARD
Publisher: Lyrics © Warner/Chappell Music, Inc., EMI Music Publishing, Sony/ATV Music Publishing LLC, Universal Music Publishing Group


I'd venture to guess that anyone who is passionate about cooking, and is also comfortable using technology, has at least once in their life browsed PINTEREST for new cooking ideas, suggestions, or recipes. And any of these cooks would have to admit that, on occasion, some attempts to recreate a Pinterest recipe at home have ended in epic failure. On the web you can find thousands of these laughable fails. The Huffingtonpost even dedicated a slideshow to the subject! Well, this tempting super cute recipe recently caught my attention; I thought it looked perfect for Easter! So last Saturday I tried it out, and while making it, I thought it was going down on the "Pinterest Failures" list. But instead, it turned out perfect- super cute, sweet and delicious! So, if you want to surprise your kids with a new Easter treat, or you'll have the time to make it a family project, I highly recommend trying this delicious cookie recipe! And just to clarify, I wasn't looking particularly for a vegan recipe; this one I tried just happens to use a lemon cream that's delicious AND vegan. As for the ingredients, you probably already have all of them in your pantry. But be sure you have at least three big juicy lemons, an egg shaped cookie cutter, and some yellow food coloring dye or some turmeric powder to die the cream.
Make sure to zest 2 of the 3 lemons before juicing them, keeping the zest in two separate piles, since you will need the zest of one lemon for the cookie dough, and the zest of one lemon for the cream.
Now, on to the cookie dough. In a bowl, mix the flour, the powdered sugar, the cool butter cut in cubes, the egg yolk, and the lemon zest and hand-knead for a few minutes until you get a smooth and homogeneous ball of dough. This was the FIRST moment I thought I messed up the recipe: the dough seemed to stay crumbly forever and I was tempted to add an egg. But I kept kneading, and at some point I got the smooth and homogeneous ball the recipe talked about. Cover the ball with plastic wrap and let it chill in the refrigerator for at least 30 minutes. (Sorry I forgot to take the pictures of these phases, but in case you are in doubt, you can take a look to my favorite butter cookie recipe to get an idea about what the ball should look like). While the dough rests, prepare the lemon cream. In a small pot, mix the sugar and the corn starch. In another container, mix the water, the lemon juice and the lemon zest.
Add the mix of water and lemon to the sugar/corn starch, quickly adding a drop of yellow food dye, and whisking quickly to avoid chunks forming. Cook at medium heat until it gets dense.
At first the cream may look watery, but once it cools off it will have the perfect consistency to fill the cookies.
Going back to the dough: take it out of the fridge and roll it out on a floured surface, and using the egg shaped cookie cutter make twenty "eggs." Set ten of them aside; these will be the "base" of the eggs. Then, by using a round shape cookie cutter, cut a circle in the other ten (I used the neck of a baby bottle). These will be the "cover." This was the SECOND TIME I thought the recipe would fail: even though I let the dough chill in the refrigerator for the appropriate time, it wasn't easy to roll out and kept breaking, so it took me a while before I was able to shape twenty cookies. (Honestly, if you want an easier butter cookie dough, use my favorite one by clicking this link).
Next, arrange the cookies in your oven sheet (better if covered with parchment) and even if the original recipe says to cook for 15 minutes at 360 F. (180 C.), I've noticed that my cookies where going to get burnt so I took them out after 11 minutes. This was the THIRD TIME I thought the recipe had failed: some of the cookies looked overcooked and too dark for my taste. Anyway, they ended up tasting good, and the powdered sugar helped me disguise any imperfections! (However, next time I will definitely use a slightly lower temperature for not more that 12 minutes.) Let the cookies cool off. Dust those with the hole with powdered sugar, spread the lemon cream on the bases, and close with the holed half.
YOU ARE DONE AND YOUR EGG-SHAPED EASTER EGGS ARE READY!
TIPS: – These butter cookies have a quite intense taste of lemon. I personally loved it, but they may not be a favorite for anyone who doesn't really love lemon.
– Usually butter cookies keep their crispy texture even a few days after they have been made, but in this case the "vegan lemon cream" is practically made with water, so after a day, the butter pastry tends to get kind of soggy. Anyway, even the day after they are delicious!
– If you prefer to use a "non vegan cream", feel free to fill the cookies with custard: you won't even need the yellow edible dye or the turmeric.
Oh these are gorgeous, and can only imagine how delightful they must taste.
Looks so cute. The lemon cream looks luscious.
Thanks! I personally prefer custard, but even this lemon cream isn't bad at all!


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Robert Kopstein
Bob Kopstein: Movie Review of Little Rose at the Rady JCC's Tarbut Festival
Robert Kopstein, posted Nov 29, 2012
Title: Little Rose
Filmed: Poland, 2010
Screenplay: Maciej Karpinski, Jan Kidawa-Blonski
Director: Jan Kidawa-Blonski
Screened at the Berney Theatre, November 21, 2012, as part of the Tarbut Festival of Jewish Culture at the Rady Centre, Little Rose is set in 1967 Communist Poland. It is based upon a true story written about a famous writer and historian, whose wife, a communist. Agent, betrayed him. "Little Rose" is the code name assigned to Kamila (Magdalena Boczarska), a beautiful young woman. She is is induced by her boorish boyfriend, Roman Rozek (Robert Wieckiewicz), who is a member of the secret police, to befriend and, indeed, to seduce, well known professor, and intellectual, Adam Warczewski (Andrzej Seweryn), for the purpose of procuring information from him, spying upon his activities, and reporting upon what she learned. Adam is many years her senior, and is a widower.
Adam is suspected by the police of being a Zionist, and of being a trouble maker, and, perhaps, of being connected with the adverse broadcasts on Radio Free Europe about the Polish regime. The only activity in which the professor appears to be engaged, in fact, is advocacy against state censorship.
Kamila, though not enthusiastic about the assignment, wants to please her boyfriend, and undertakes to carry out the seduction and surveillance for him. She is prevailed upon to sign an oath of loyalty regarding her mission. At first she does deliver reports about the professor and his activities, but as she spends more time with him she is drawn to him, and falls in love with him. He too, is in love. She eventually leaves her boyfriend to move in with Adam, and she stops reporting his activities. The role for which Kamila was recruited, however, is revealed to Adam. The result of that revelation leads to unfortunate consequences.
Quite central to the film are erotic scenes, that depict, and seem to characterize the difference in Kamila's relationships with the two men in her life..
The direction and acting are superb! The principals as well as the several supporting actors portray the roles of the characters they represent with credibility and sensitivity. Even Adam's young daughter, Dorota (Julia Kornacka), plays her role with quiet aplomb, as a little nuisance, inserting her presence into the growing relationship between Kamila and Adam. Presumably she was protecting the place her mother had held in their family prior to her passing.
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Home /Journey Through Trauma: A Trail Guide to the 5-Phase Cycle of Healing Repeated Trauma (Hardcover)
Journey Through Trauma: A Trail Guide to the 5-Phase Cycle of Healing Repeated Trauma (Hardcover)
By Gretchen L. Schmelzer
For survivors of PTSD and repeated, relational trauma -- and the people who love them.
Gretchen Schmelzer watched too many people quit during treatment for trauma recovery. They found it too difficult or too frightening or just decided that for them it was too late. But as a therapist and trauma survivor herself, Dr. Schmelzer wants us to know that it is never too late to heal from trauma, whether it is the suffering caused within an abusive relationship or PTSD resulting from combat. Sometimes what feels like a big setback is actually an unexpected difficult step forward. So she wrote Journey Through Trauma specifically for survivors--to help them understand the terrain of the healing process and stay on the path.
There are three basic principles that every trauma survivor should know: Healing is possible. It requires courage. And it cannot be done alone. Traumas that happen more than once--child abuse, sexual abuse, domestic violence, gang violence, even war--are all relational traumas. They happened inside a relationship and therefore must be healed inside a relationship, whether that relationship is with a therapist or within a group.
Journey Through Trauma gives us a map to help guide us through that healing process, see where the hard parts show up, and persevere in the process of getting well. We learn the five phases that every survivor must negotiate along the way and come to understand that since the cycle of healing is not linear, circling back around to a previous stage does not mean defeat - it actually means progress as well as facing new challenges.
Authoritative and accessible, Journey Through Trauma provides support for survivors and their loved ones through one of the most challenging but necessary processes of healing that anyone can face.
Gretchen Schmelzer, PhD, is a licensed psychologist, trained as a Harvard Medical School Fellow. She is a trauma survivor who has worked for twenty-five years with the complex issues of trauma, integration, and behavior change across every level, from individuals to groups to large systems and countries. She has worked with individuals and groups in large clinics and clinics in housing projects, in residential treatment facilities, in psychiatric units and medical hospital units, and in private practice. She has more than a decade of experience working with traumatized children and adolescents in residential treatment and psychiatric units. She is the founder and editor of The Trail Guide, a web-mag featured on www.gretchenschmelzer.com dedicated to healing repeated trauma.
"This Harvard-trained psychologist has some shrewd observations, including the reminder that "repeated trauma is about both what did happen and what didn't happen" (in other words, "the normal developmental growth that would have taken place during the years that the trauma was occurring.")"
"With vast personal and professional experience, Gretchen Schmeltzer provides a thoughtful, compassionate trail guide for trauma survivors in recovery. A keen scholar and talented clinician with broad individual and systems "know-how", she gives us a book unique in helping health workers, survivors and families to understand not only the different types of trauma, but, more importantly, the diversity in experiences and ways of coping. Must reading!"
—Barbara F. Okun, Ph.D., Professor Emeritus, Northeastern University
"This is a one of the most helpful and hopeful books I have read during my own journey of healing trauma. Gretchen Schmelzer gives us a clear road map and gentle encouragement to stay on path and do the hard, but necessary, work to integrate the past so we can embrace the future."
—Lea Waters, Ph.D., Psychologist and President of the International Positive Psychology Association and author of The Strength Switch
Publisher: Avery
Publication Date: February 6th, 2018
Self-help / Post-Traumatic Stress Disorder (PTSD)
Psychology / Psychopathology / Post-Traumatic Stress Disorder (PTSD)
Psychology / Mental Health


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Children's Health Insurance Program (CHIP)
Date Start Date End Date
Topics Coronavirus (COVID-19) (2) Health Costs (12) Health Reform (40) HIV/AIDS (2) Medicaid (222) Medicare (7) Private Insurance (7) Racial Equity and Health Policy (7) Uninsured (116) Women's Health Policy (4)
Content Type Event (15) Fact Sheet (34) Issue Brief (77) News Release (7) Poll Finding (7) Report (79) Slide (3) State Indicator (5)
Tags Access to Care (51) Administrative Costs (1) Adolescents (2) Affordability (1) Affordable Care Act (15) Alabama (2) Alliance for Health Reform Briefing (3) American Indian/Alaska Native (1) Asian (1) Benefits (2) Black (1) Build Back Better (1) California (1) Chart of the Week (1) Children (188) Colorado (1) Consumer Protection (1) Cost Sharing (14) Coverage (126) Delivery System (1) Disability (17) Dual Eligible (6) Economy (3) Eligibility (27) Employer Health (6) Enrollment (38) Federal Budget (3) Financing (3) Florida (1) Health I.T. (1) Hispanic (1) Home/Community Services (1) Illinois (1) Immigrants (2) Individual Market (3) Iowa (1) KFF/HSPH Surveys (1) Long-Term Care (3) Low income (89) Managed Care (9) Marketplaces (4) Massachusetts (1) Maternal and Child Health (2) Medicaid's Future (7) Medicare Advantage (1) Medicare Part D (2) Michigan (1) NPR/KFF Surveys (1) Oral Health (1) Oregon (1) Pennsylvania (1) Politics (6) Polling (11) Premiums (1) Prescription Drugs (4) Race/Ethnicity (1) Reproductive Health (3) Retiree Coverage (1) Seniors (2) South Carolina (1) State Budgets (12) State Level (12) STDs (2) Tracking Poll (2) Waivers (10) WaPo/KFF Surveys (1)
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Mitigating Childhood Lead Exposure and Disparities: Medicaid and Other Federal Initiatives May 20, 2022 Issue Brief
Exposure to lead can seriously harm a child's health, including damage to the brain and nervous system, slowed growth and development, learning and behavior problems, and hearing and speech problems. The effects of lead on the nervous system can cause lower IQ, decreased ability to pay attention, and under performance in school.
Unwinding the PHE: What We Can Learn From Pre-Pandemic Enrollment Patterns May 10, 2022 Issue Brief
This brief examines typical enrollment patterns for Medicaid and CHIP and uses 2018 Medicaid claims data to gain insight into the effects of the continuous enrollment requirements by eligibility group. Roughly 2% of Medicaid enrollees come on or leave the program in an average month, although there is variation across eligibility groups. A policy to require continuous enrollment would result in sharp reductions in monthly disenrollment rates and would also reduce monthly enrollment rates due to reductions in churn.
Potential Costs and Impact of Health Provisions in the Build Back Better Act November 23, 2021 Issue Brief
A summary of 10 of the major health coverage and financing provisions of the current Build Back Better Act, with discussion of the potential implications for people and the federal budget.
Analysis of Recent Declines in Medicaid and CHIP Enrollment November 25, 2019 Fact Sheet
This fact sheet provides analysis of this recent enrollment decrease and discusses potential implications for coverage rates. It is based on Kaiser Family Foundation analysis of the Centers for Medicare and Medicaid Services (CMS) Performance Indicator Project Data.
36 States Saw Declines in Monthly Medicaid, CHIP Enrollment Since 2017 November 26, 2019 Slide
Following enrollment gains since the Affordable Care Act, Medicaid and CHIP enrollment declined in 36 states, by 1.9 million nationwide, between December 2017 and July 2019.
Nearly 20 Million Children Live in Immigrant Families that Could Be Affected by Evolving Immigration Policies April 18, 2018 Issue Brief
President Trump has intensified national debate about immigration by implementing policies to enhance immigration enforcement and restrict legal immigration. Recent findings show that the climate surrounding these policies has significantly increased fear and uncertainty among immigrant families, broadly affecting families across different immigration statuses and locations. The effects extend to lawfully present immigrants, including lawful permanent residents or "green card" holders, and children in immigrant families, who are predominantly U.S.-born citizens. In particular, findings point to both short- and long-term negative consequences on the health and well-being of children in immigrant families.
Potential changes to public charge policies intended to reduce use of public programs by immigrant families, including their citizen children, could further increase strains on immigrant families and lead to losses in health coverage. To provide insight into the scope of potential impacts of continually evolving immigration policy on children, this data note provides nationwide and state-level estimates (Table 1) of citizen children living in immigrant families and the number currently covered by Medicaid/CHIP coverage.
Analyzing Recent Trends in Medicaid/CHIP Applications: What We Do and Do Not Know January 28, 2021 Issue Brief
This data note discusses changes in the number of applications for Medicaid/CHIP coverage during the coronavirus pandemic. Although enrollment in Medicaid/CHIP has increased steadily by more than 6 million individuals (9%) from February to September 2020, the total number of Medicaid/CHIP applications has decreased by more than 150,000 (-6%) in the same time period. The decline in applications might on the surface suggest that fewer people are applying for coverage even in the face of large job and income losses, but data limitations – in particular, the fact that application statistics do not distinguish between new signups and renewals – make it difficult to draw any clear conclusions.
State Plans for CHIP as Federal CHIP Funds Run Out December 6, 2017 Fact Sheet
Federal funding for the Children's Health Insurance Program (CHIP) expired on September 30, 2017. CHIP covers 8.9 million children in working families who earn too much to qualify for Medicaid but cannot afford or access private coverage. (See here for state Medicaid and CHIP eligibility limits for children.) This fact…
President Trump's 2018 Budget Proposal Reduces Federal Funding for Coverage of Children in Medicaid and CHIP May 23, 2017 Fact Sheet
This fact sheet reviews proposed changes in coverage for children in Medicaid and CHIP in President Trump's 2018 budget proposal.
Extending Federal Funding for CHIP: What is at Stake? November 2, 2017 Fact Sheet
This fact sheet provides an overview of the status of action to extend federal funding for the Children's Health Insurance Program (CHIP).


In midst of the apple orchards and vineyards that surround our neighboring home amidst came wild grapes that settled in our garden. Coincidentally, I also happen to LOVE dolmádes. And so with grapes, comes grape leaves…thus, I seized the opportunity!
Original compilation for grape leaves preservation were adapted from various sources.
Rinse the leaves in a sink full of water and drain them, then repeat. Make a stack of approximately 25 leaves.
Place leaves vein side up on a cutting board. Trim the stem from the leaf. I found kitchen shears to be the best tool for this job.
Roll the stack up and then tie it with string or sewing thread.
Bring 1 quart water and salt to a boil. Blanch the leaves for 30 seconds. Remove leaves from pot with tongs or a slotted spoon taking care not to rip them. Allow to cool in a bowl with ice water.
Bring water and lemon juice to a boil. Stack leaves in piles of 25 and roll up from side to side. Place rolls upright in a sterile wide-mouth pint mason jar. Fold over tops to allow 1/2 head space. Pour hot water/lemon juice mixture over the leaves leaving a 1/2 inch head space. Wipe rim of jar with a clean towel.
Top with a lid and screw down lid. Process for 15 minutes in a boiling water bath or keep in the refrigerator.
TIP: Save the bigger leaves, which may be too tough for stuffing, as the lining vessel for the pot/pan. Wash them out, pat them dry, and place them in a freezer bag for later use.
Posted in Jams/Preserves/Aigre-Doux, Menu and tagged agrarian, Grape leaves, Homesteading, recipes, rustic food, the cooking apprentice, vegetarian. Bookmark the permalink.


Despite the looming Panama verdict. We believe that there are just a few undervalued and suppressed stocks left in the markets which present a minimum downside risk and a maximum upside potential regardless of the verdict. Last time we had recommended BOP at Rs 11. It had gone up to Rs 19. Then came the rumours of a RIGHTS ISSUE and subsequent selling took place. The rights issue seems to have been settled and based on the market behaviour new buyers have entered with confidence that there is no rights issue coming up. BOP is one of the few banks left trading below its actual value. Results should be coming up for BOP and we expect the yearly earnings to clock in around Rs 3.45. Based on this and a PE ratio of just 7, which is still a very low calculated PE, the stock should be trading around 24 Rs. Which is an upside potential of 50% from today's price. We are issuing a BUY CALL with confidence that it should reach its TP fairly comfortably.
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